Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Childhood Acute Lymphoblastic Leukemia Treatment

General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] Because treatment of children with acute lymphoblastic leukemia (ALL) entails many potential complications and requires intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), this treatment is best coordinated by pediatric oncologists and performed in cancer centers or hospitals with all of the necessary pediatric supportive care facilities. It is important that the clinical centers and the specialists directing the patient's care maintain contact with the referring physician in the community. Strong lines of communication optimize any urgent or interim care required when the child is at home.

Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For ALL, the 5-year survival rate has increased over the same time from 60% to 89% for children younger than 15 years and from 28% to 50% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Incidence and Epidemiology

ALL is the most common cancer diagnosed in children and represents 23% of cancer diagnoses among children younger than 15 years. ALL occurs at an annual rate of approximately 30 to 40 per million.[3,4] There are approximately 2,900 children and adolescents younger than 20 years diagnosed with ALL each year in the United States,[4] and there has been a gradual increase in the incidence of ALL in the past 25 years.[5] A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>80 per million per year), with rates decreasing to 20 per million for ages 8 to 10 years. The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is nearly tenfold greater than that for adolescents aged 16 to 21 years.

For unexplained reasons, the incidence of ALL is substantially higher in white children than in black children, with a nearly threefold higher incidence from age 2 to 3 years in white children compared with black children.[3,4] The incidence of ALL appears to be highest in Hispanic children (43 per million).[3,4]

Risk Factors for Developing ALL

Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL include the following:

  • Prenatal exposure to x-rays.
  • Postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).
  • Down syndrome and other genetic conditions.
  • Inherited genetic polymorphisms.

Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia (AML),[6,7] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[6,7] Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL. Patients with ALL and Down syndrome have a lower incidence of both favorable (t[12;21] and hyperdiploidy) and unfavorable (t[9;22], t[4;11], and hypodiploidy) cytogenetic findings and a lower incidence of T-cell phenotype.[8,9,10,11] Approximately 50% of children with Down syndrome and ALL have a recurring interstitial deletion of the pseudoautosomal region (PAR) of chromosomes X and Y that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. The resulting P2RY8-CRLF2 fusion gene is observed at a much lower frequency (<10%) in non-Down children with B-precursor ALL.[12,13] Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[14,15,16] a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk B-precursor ALL.[17] Almost all Down syndrome ALL cases with JAK2 mutations also have the PAR deletion and express the P2RY8-CRLF2 fusion gene.[12] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL.[15]

While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year),[8] ALL in children with Down syndrome has an age distribution similar to that of ALL in non–Down syndrome children, with a median age of 3 to 4 years.[9,10] Increased occurrence of ALL is also associated with other genetic conditions, including neurofibromatosis,[18] Shwachman syndrome,[19,20] Bloom syndrome,[21] and ataxia telangiectasia.[22]

Genome-wide association studies show that germline (inherited) genetic polymorphisms are associated with the development of childhood ALL.[23] For example, the risk alleles of ARID5B, a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation, are strongly associated with the development of hyperdiploid B-precursor ALL.[24,25]

Some cases of ALL have a prenatal origin. Evidence in support of this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient's leukemia cells can be detected in blood samples obtained at birth.[26,27] Similarly, in ALL characterized by specific chromosomal abnormalities, data exist to support that patients had blood cells carrying the abnormalities at the time of birth with additional cooperative genetic changes acquired postnatally.[26,27,28] Genetic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[29]

Overall Outcome for ALL

Among children with ALL, more than 95% attain remission and 75% to 85% survive free of leukemia recurrence at least 5 years from diagnosis with current treatments that incorporate systemic therapy (e.g., combination chemotherapy) and specific central nervous system preventive therapy (e.g., intrathecal chemotherapy with or without cranial radiation).[30,31,32,33,34]

Despite the treatment advances noted in childhood ALL, numerous important biologic and therapeutic questions remain to be answered to achieve the goal of curing every child with ALL with the least associated toxicity. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with ALL are generally designed to compare therapy that is currently accepted as standard with investigational regimens that seek to improve cure rates and/or decrease toxicity. In certain trials, in which the cure rate for the patient group is very high, therapy reduction questions may be asked. Much of the progress made in identifying curative therapies for childhood ALL and other childhood cancers has been achieved through investigator-driven discovery, and tested in carefully randomized, controlled clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.
3. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute, 1999. Also available online. Last accessed June 9, 2011 .
4. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 17-34. Also available online. Last accessed June 9, 2011.
5. Shah A, Coleman MP: Increasing incidence of childhood leukaemia: a controversy re-examined. Br J Cancer 97 (7): 1009-12, 2007.
6. Hasle H: Pattern of malignant disorders in individuals with Down's syndrome. Lancet Oncol 2 (7): 429-36, 2001.
7. Whitlock JA: Down syndrome and acute lymphoblastic leukaemia. Br J Haematol 135 (5): 595-602, 2006.
8. Chessells JM, Harrison G, Richards SM, et al.: Down's syndrome and acute lymphoblastic leukaemia: clinical features and response to treatment. Arch Dis Child 85 (4): 321-5, 2001.
9. Zeller B, Gustafsson G, Forestier E, et al.: Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 128 (6): 797-804, 2005.
10. Arico M, Ziino O, Valsecchi MG, et al.: Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Cancer 113 (3): 515-21, 2008.
11. Maloney KW, Carroll WL, Carroll AJ, et al.: Down syndrome childhood acute lymphoblastic leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome: a report from the Children's Oncology Group. Blood 116 (7): 1045-50, 2010.
12. Mullighan CG, Collins-Underwood JR, Phillips LA, et al.: Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 41 (11): 1243-6, 2009.
13. Harvey RC, Mullighan CG, Chen IM, et al.: Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 115 (26): 5312-21, 2010.
14. Bercovich D, Ganmore I, Scott LM, et al.: Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 372 (9648): 1484-92, 2008.
15. Gaikwad A, Rye CL, Devidas M, et al.: Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol 144 (6): 930-2, 2009.
16. Kearney L, Gonzalez De Castro D, Yeung J, et al.: Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood 113 (3): 646-8, 2009.
17. Mullighan CG, Zhang J, Harvey RC, et al.: JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 106 (23): 9414-8, 2009.
18. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994.
19. Strevens MJ, Lilleyman JS, Williams RB: Shwachman's syndrome and acute lymphoblastic leukaemia. Br Med J 2 (6129): 18, 1978.
20. Woods WG, Roloff JS, Lukens JN, et al.: The occurrence of leukemia in patients with the Shwachman syndrome. J Pediatr 99 (3): 425-8, 1981.
21. Passarge E: Bloom's syndrome: the German experience. Ann Genet 34 (3-4): 179-97, 1991.
22. Taylor AM, Metcalfe JA, Thick J, et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87 (2): 423-38, 1996.
23. de Jonge R, Tissing WJ, Hooijberg JH, et al.: Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood 113 (10): 2284-9, 2009.
24. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al.: Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 41 (9): 1006-10, 2009.
25. Treviño LR, Yang W, French D, et al.: Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet 41 (9): 1001-5, 2009.
26. Greaves MF, Wiemels J: Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3 (9): 639-49, 2003.
27. Taub JW, Konrad MA, Ge Y, et al.: High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia. Blood 99 (8): 2992-6, 2002.
28. Bateman CM, Colman SM, Chaplin T, et al.: Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood 115 (17): 3553-8, 2010.
29. Greaves MF, Maia AT, Wiemels JL, et al.: Leukemia in twins: lessons in natural history. Blood 102 (7): 2321-33, 2003.
30. Möricke A, Reiter A, Zimmermann M, et al.: Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111 (9): 4477-89, 2008.
31. Mitchell CD, Richards SM, Kinsey SE, et al.: Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 129 (6): 734-45, 2005.
32. Moghrabi A, Levy DE, Asselin B, et al.: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109 (3): 896-904, 2007.
33. Pui CH, Campana D, Pei D, et al.: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360 (26): 2730-41, 2009.
34. Veerman AJ, Kamps WA, van den Berg H, et al.: Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet Oncol 10 (10): 957-66, 2009.

Cellular Classification and Prognostic Variables

Children with acute lymphoblastic leukemia (ALL) are usually treated according to risk groups defined by both clinical and laboratory features. The intensity of treatment required for favorable outcome varies substantially among subsets of children with ALL. Risk-based treatment assignment is utilized in children with ALL so that patients with favorable clinical and biological features who are likely to have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, and potentially more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival.[1,2,3] Certain ALL study groups use a more or less intensive induction regimen based on a subset of pretreatment factors, while other groups give a similar induction regimen to all patients. All groups modify the intensity of postinduction therapy based on a variety of prognostic factors.

Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. For children with ALL, a number of clinical and laboratory features have demonstrated prognostic value, some of which are described below.[4] The factors described are grouped into the following categories:

  • Patient characteristics at diagnosis.
  • Leukemic cell characteristics at diagnosis.
  • Response to initial treatment.

As in any discussion of prognostic factors, the relative order of significance and the interrelationship of the variables are often treatment dependent and require multivariate analysis to determine which factors operate independently as prognostic variables.[5,6] Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors.

A subset of the prognostic and clinical factors discussed below is used for the initial stratification of children with ALL for treatment assignment. At the end of this section are brief descriptions of the prognostic groupings currently applied in ongoing clinical trials in the United States.

Patient Characteristics at Diagnosis

1. Age at diagnosis

Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.[7] Young children (aged 1–9 years) have a better disease-free survival (DFS) than older children, adolescents, or infants.[1,7,8] The improved prognosis in younger children is at least partly explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts including hyperdiploidy with 51 or more chromosomes and/or favorable chromosome trisomies, or the ETV6-RUNX1 (t[12;21], also known as the TEL-AML1 translocation).[7,9] The outcome for adolescents has improved significantly over time.[10,11,12] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[13,14,15] (For more information about adolescents with ALL, see the Postinduction Treatment for Childhood Acute Lymphoblastic Leukemia Subgroups section of this summary.)

Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in infants younger than 6 months and in those with extremely high presenting leukocyte counts and/or a poor response to a prednisone prophase.[16,17,18,19] Infants with ALL can be divided into two subgroups on the basis of the presence or absence of translocations that involve the MLL gene located at chromosome 11q23.[18,19,20] Approximately 80% of infants with ALL have an MLL gene rearrangement.[18,20,21] The rate of MLL gene translocations is extremely high in infants younger than 6 months; from 6 months to 1 year the incidence of MLL translocations decreases but remains higher than that observed in older children.[18] Infants with leukemia and MLL translocations have very high white blood cell (WBC) counts, increased incidence of central nervous system (CNS) involvement, and a poor outcome.[18,19] Blasts from infants with MLL translocations are typically CD10 negative and express high levels of FLT3.[18,19,20,22] Conversely, infants whose leukemic cells show a germline MLL gene configuration frequently present with CD10-positive precursor-B immunophenotype. These infants have a significantly better outcome than infants with ALL characterized by MLL translocations.[18,19,20] Infants diagnosed within the first month of life have higher WBC counts, higher incidence of MLL translocations, significantly higher relapse rate, and poorer overall survival compared with infants older than 1 month at diagnosis.[23]

2. WBC count at diagnosis

Patients with B-precursor ALL and high WBC counts at diagnosis have an increased risk of treatment failure compared with patients with low initial WBC counts. A WBC count of 50,000/µL is generally used as an operational cut point between better and poorer prognosis,[1] although the relationship between WBC count and prognosis is a continuous rather than a step function. There are conflicting data regarding the prognostic significance of presenting leukocyte counts in T-cell ALL.[6,24,25,26,27,28,29]

3. CNS involvement at diagnosis

The presence or absence of CNS leukemia at diagnosis has prognostic significance. Patients who have a nontraumatic diagnostic lumbar puncture may be placed into one of three categories according to the number of WBC/µL and the presence or absence of blasts on cytospin as follows:

  • CNS1: Cerebrospinal fluid (CSF) that is cytospin negative for blasts regardless of WBC count.
  • CNS2: CSF with fewer than five WBC/µL and cytospin positive for blasts.
  • CNS3 (CNS disease): CSF with five or more WBC/µL and cytospin positive for blasts.

Compared with patients classified as CNS1 or CNS2, children with ALL who present with CNS disease (i.e., CNS3) at diagnosis are at a higher risk of treatment failure (both within the CNS and systemically).[30] The adverse prognostic significance associated with CNS2 status, if any, may be overcome by the application of more intensive intrathecal therapy, especially during the induction phase.[30,31] A traumatic lumbar puncture (=10 erythrocytes/µL) that includes blasts at diagnosis appears to be associated with increased risk of CNS relapse and indicates an overall poorer outcome.[30,32] To determine whether a patient with a traumatic lumbar puncture (with blasts) should be treated as CNS3, the Children's Oncology Group (COG) uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the peripheral blood.[33]

4. Testicular involvement at diagnosis

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males, most commonly in T-cell ALL. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, it does not appear that testicular involvement at diagnosis has prognostic significance.[34,35] For example, the European Organization for Research and Treatment of Cancer (EORTC, [EORTC-58881]) reported no adverse prognostic significance for overt testicular involvement at diagnosis.[35] The role of radiation therapy for testicular involvement is unclear. A study from St. Jude Children's Research Hospital (SJCRH) suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[34] The COG has also adopted this strategy for boys with testicular leukemia that resolves completely by the end of induction therapy. COG considers patients with testicular involvement to be high risk regardless of other presenting features, but most other large clinical trial groups in the United States and Europe do not consider testicular disease to be a high-risk feature.

5. Down syndrome (trisomy 21)

Outcome in Down syndrome children with ALL has generally been reported as somewhat inferior to outcomes observed in non-Down syndrome children.[36,37,38,39] The lower event-free survival (EFS) and overall survival (OS) of children with Down syndrome appear to be related to higher rates of treatment-related mortality and the absence of favorable biological features.[36,37,38,39,40] Patients with Down syndrome and ALL have a significantly lower incidence of favorable cytogenetic abnormalities such as ETV6-RUNX1 or trisomies of chromosomes 4 and 10.[40] In a report from the COG, among B-precursor ALL patients who lacked MLL translocations, BCR-ABL1, ETV6-RUNX1, or trisomies of chromosomes 4 and 10, the EFS and OS were similar in children with and without Down syndrome.[40]

6. Gender

In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[41,42,43] One reason for the better prognosis for girls is the occurrence of testicular relapses among boys, but boys also appear to be at increased risk of bone marrow and CNS relapse for reasons that are not well understood.[41,42,43] However, in clinical trials with high 5-year EFS rates (>80%), outcomes for boys are closely approaching those of girls.[31,44]

7. Race

Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[45,46] This difference may be therapy-dependent; a report from SJCRH found no difference in outcome by racial groups.[47] Asian children with ALL fare slightly better than white children.[46] The reason for better outcome in white and Asian children compared with black and Hispanic children is at least partially explained by the different spectrum of ALL subtypes. For example, blacks have a higher incidence of T-cell ALL and lower rates of favorable genetic subtypes of ALL. However, these differences do not completely explain the observed racial differences in outcome.[46]

Leukemic Cell Characteristics at Diagnosis

1. Morphology

In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.[48] However, because of the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used. Most cases of ALL that show L3 morphology express surface immunoglobulin (Ig) and have a C-MYC gene translocation identical to that seen in Burkitt lymphoma (i.e., t[8;14]). Patients with this specific rare form of leukemia (mature B cell or Burkitt leukemia) should be treated according to protocols for Burkitt lymphoma. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information on the treatment of B-cell ALL and Burkitt lymphoma.)

2. Immunophenotype

The World Health Organization (WHO) classifies ALL as either B lymphoblastic leukemia or T lymphoblastic leukemia. B lymphoblastic leukemia is subdivided by the presence or absence of specific recurrent genetic abnormalities (t[9;22]), MLL rearrangement, t(12;21), hyperdiploidy, hypodiploidy, t(5;14), and t(1;19).[49]

Prior to 2008, the WHO classified B lymphoblastic leukemia as precursor-B lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL, now termed Burkitt leukemia, which requires different treatment than has been given for precursor B-cell ALL. The older terminology will continue to be used throughout this summary.

  • Precursor B-cell ALL (WHO B lymphoblastic leukemia): Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR, and other B cell-associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of precursor B-cell ALL cases express the CD10 (formerly known as common ALL antigen [cALLa]) surface antigen. Absence of CD10 is associated with MLL translocations, particularly t(4;11), and a poor outcome.[18,50] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.[51]

    There are three major subtypes of precursor B-cell ALL as follows:

    • Pro-B ALL-CD10 negative and no surface or cytoplasmic Ig.

      Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in infants and is often associated with a t(4;11) translocation.

    • Common precursor B-cell ALL-CD10 positive and no surface or cytoplasmic Ig.

      Approximately three-quarters of patients with precursor B-cell ALL have the common precursor B-cell immunophenotype and have the best prognosis. Patients with favorable cytogenetics almost always show a common precursor B-cell immunophenotype.

    • Pre-B ALL presence of cytoplasmic Ig.

      The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients with pre-B ALL have the t(1;19) translocation with TCF3-PBX1 (also known as E2A-PBX1) fusion (see below).[52,53]

    Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain without expression of light chain, C-MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for precursor B-cell ALL.[54]

    Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with FAB L3 morphology and a translocation involving the C-MYC gene), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from that for precursor B-cell ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with C-MYC gene translocations should also be treated as mature B-cell leukemia.[54] (Refer to the PDQ summary on Childhood Non-Hodgkin's Lymphoma Treatment for more information on the treatment of children with B-cell ALL and Burkitt lymphoma.)

  • T-cell ALL: T-cell ALL is defined by expression of the T cell-associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts and is frequently associated with a constellation of clinical features, including male gender, older age, leukocytosis, and mediastinal mass.[8,24,44] With appropriately intensive therapy, children with T-cell ALL have an outcome similar to that of children with B-lineage ALL.[8,24,44]

    There are few commonly accepted prognostic factors for patients with T-cell ALL. There are conflicting data regarding the prognostic significance of presenting leukocyte counts in T-cell ALL.[6] The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.[55]

    A distinct subset of childhood T-cell ALL, termed early precursor T-cell ALL, was identified by gene expression profiling, flow cytometry, and single nucleotide polymorphism array analyses.[56] This subset, identified in 13% of T-cell ALL cases, is characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of stem cell or myeloid markers and weak expression of CD5). It has the same gene expression profile of normal early thymic precursor cells, a population of recent immigrants from bone marrow to the thymus, which retains multilineage differentiation potential.[56] A retrospective analysis suggested that this subset may have a poorer prognosis than other cases of T-cell ALL.[56] Another retrospective study found that the absence of biallelic deletion of the TCRgamma locus (a finding characteristic of early thymic-precursor cells), as detected by comparative genomic hybridization (CGH) and quantitative DNA polymerase chain reaction (DNA-PCR), was associated with early treatment failure in patients with T-cell ALL.[57]

    Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL.[58,59] Multiple chromosomal translocations have been identified in T-cell ALL, with many genes encoding for transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2) fusing to one of the T-cell receptor (TCR) loci and resulting in aberrant expression of these transcription factors in leukemia cells.[58,60,61,62,63,64] These translocations are often not apparent by examining a standard karyotype, but are identified using more sensitive screening techniques, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).[58] High expression of TLX1/HOX11 resulting from translocations involving this gene occurs in 5% to 10% of pediatric T-cell ALL cases and is associated with more favorable outcome in both adults and children with T-cell ALL.[60,61,62,64] Overexpression of TLX3/HOX11L2 resulting from the t(5;14)(q35;q32) translocation occurs in approximately 20% of pediatric T-cell ALL cases and appears to be associated with increased risk of treatment failure,[62] though not in all studies.

    NOTCH1 gene mutations occur in approximately 50% of T-cell ALL cases, but their prognostic significance has not been established.[65,66,67,68,69,70]

    A NUP214–ABL1 fusion has been noted in 4% to 6% of adults with T-cell ALL. The fusion is usually not detectable by standard cytogenetics. Tyrosine kinase inhibitors may have therapeutic benefit in this type of T-cell ALL.[71,72,73]

  • Myeloid antigen expression: Up to one-third of childhood ALL cases have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with MLL translocations and those with the ETV6-RUNX1 gene rearrangement.[74,75] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[74,75]
  • Ambiguous lineage: Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[76,77,78] These cases are distinct from ALL with myeloid coexpression in that the predominant lineage cannot be determined by immunophenotypic and histochemical studies. The definition of leukemia of ambiguous lineage varies among studies, although most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria.[79,80,81] In the WHO classification, the presence of myeloperoxidase (MPO) is required to establish myeloid lineage. This is not the case for the EGIL classification. Leukemias of mixed phenotype comprise two groups of patients: (1) bilineal leukemias in which there are two distinct population of cells, usually one lymphoid and one myeloid, and (2) biphenotypic leukemias where individual blast cells display features of both lymphoid and myeloid lineage. Biphenotypic cases represent the majority of mixed phenotype leukemias.[76] B-myeloid biphenotypic leukemias lacking the ETV6-RUNX1 fusion have a lower rate of complete remission and a significantly worse EFS compared with patients with B-precursor ALL.[76] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen,[77,78] although the optimal treatment for patients remains unclear.
3. Cytogenetics

A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities, such as high hyperdiploidy (51–65 chromosomes) and the ETV6-RUNX1 fusion, are associated with more favorable outcomes, while others, including the Philadelphia chromosome (t[9;22]), rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21), are associated with a poorer prognosis.[82]

Prognostically significant chromosomal abnormalities in childhood ALL include the following:

  • Chromosome number
    • High Hyperdiploidy: High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in 20% to 25% of cases of precursor B-cell ALL but very rarely in cases of T-cell ALL.[83] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. Interphase FISH may detect hidden hyperdiploidy in cases either with a normal karyotype or in which standard cytogenetic analysis was unsuccessful. High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1–9 years with a low WBC count) and is itself an independent favorable prognostic factor.[83,84] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[85] which may explain the favorable outcome commonly observed for these cases.

      While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, gender, WBC count, and specific trisomies have been shown to modify its prognostic significance.[86] For instance, patients with trisomies of chromosomes 4, 10 , and 17 (triple trisomies) have been shown to have a particularly favorable outcome as demonstrated by both Pediatric Oncology Group (POG) and Children's Cancer Group (CCG) analyses of National Cancer Institute (NCI) standard-risk ALL.[87] POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[88]

      Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified based on the prognostic significance of the translocation. For instance, in one study, 8% of patients with the Philadelphia chromosome (t[9;22]) also had high hyperdiploidy,[89] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-Philadelphia chromosome–positive high hyperdiploid patients.

      Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[90] These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome, similar to those with hypodiploidy.[90]

      Near triploidy (68 to 80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[91] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbors a cryptic ETV6-RUNX1 fusion.[91,92,93] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.[91,93]

    • Hypodiploidy (<44 chromosomes): A significant trend is observed for a progressively worse outcome with a decreasing chromosome number. Cases with 24 to 28 chromosomes (near haploidy) have the worst outcome.[90] Patients with fewer than 44 chromosomes have a worse outcome than patients with 44 or 45 chromosomes in their leukemic cells.[90]
  • Chromosomal translocations
    • ETV6-RUNX1 (t[12;21] cryptic translocation, formerly known as TEL-AML1): Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 can be detected in 20% to 25% of cases of B-precursor ALL but is rarely observed in T-cell ALL.[90] The t(12;21) occurs most commonly in children aged 2 to 9 years.[94,95] Hispanic children with ALL have a lower incidence of t(12;21) compared with white children.[96] Reports generally indicate favorable EFS and OS in children with the ETV6-RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by factors such as early response to treatment, NCI risk category, and treatment regimen.[97,98,99] In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6-RUNX1, to be independent prognostic factors.[97] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other B-precursor ALL.[97,100] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients.[101] Some relapses in patients with t(12;21) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6-RUNX1 translocation).[102]
    • Philadelphia chromosome (t[9;22] translocation): The Philadelphia chromosome t(9;22) is present in approximately 3% of children with ALL, and leads to production of a BCR-ABL1 fusion protein with tyrosine kinase activity. This subtype of ALL is more common in older patients with precursor B-cell ALL and high WBC count. Historically, it was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic stem cell transplantation in patients in first remission.[89,103,104,105] Inhibitors of the BCR-ABL tyrosine kinase, such as imatinib, are effective in patients with Philadelphia chromosome-positive ALL. A study by the COG, which used intensive chemotherapy and concurrent imatinib given daily, demonstrated a 3-year EFS rate of 80.5%, which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib) era.[106] Longer follow-up is necessary to determine whether this treatment improves the cure rate or merely prolongs DFS.
    • MLL translocations: Translocations involving the MLL (11q23) gene occur in up to 5% of childhood ALL cases and are generally associated with an increased risk of treatment failure.[50,107,108,109] The t(4;11) is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 2% of cases.[107] Patients with t(4;11) are usually infants with high WBC counts; they are more likely than other children with ALL to have CNS disease and to have a poor response to initial therapy.[18] While both infants and adults with the t(4;11) are at high risk of treatment failure, children with the t(4;11) appear to have a better outcome than either infants or adults.[50,107] Irrespective of the type of 11q23 abnormality, infants with leukemia cells that have 11q23 abnormalities have a worse treatment outcome than older patients whose leukemia cells have an 11q23 abnormality.[50,107] Of interest, the t(11;19) occurs in approximately 1% of cases and occurs in both early B-lineage and T-cell ALL.[110] Outcome for infants with t(11;19) is poor, but outcome appears relatively favorable in older children with T-cell ALL and the t(11;19) translocation.[110]
    • TCF3-PBX1 (E2A-PBX1; t[1;19] translocation): The t(1;19) translocation occurs in approximately 5% of childhood ALL cases and involves fusion of the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1.[52,53] The t(1;19) may occur as either a balanced translocation or as an unbalanced translocation and is primarily associated with pre-B ALL immunophenotype (cytoplasmic Ig positive). Black children are more likely than white children to have pre-B ALL with the t(1;19).[47] The t(1;19) translocation had been associated with inferior outcome in the context of antimetabolite-based therapy,[111] but the adverse prognostic significance was largely negated by more aggressive multi-agent therapies.[53] However, in a trial conducted by SJCRH on which all patients were treated without cranial radiation, the t(1;19) was associated with a higher risk of CNS relapse.[31]
  • Intrachromosomal amplification of chromosome 21 (iAMP21)

    iAMP21 with multiple extra copies of the RUNX1 (AML1) gene occurs in 1% to 2% of precursor B-cell ALL cases and may be associated with an inferior outcome.[112,113]

  • Other molecular genetic abnormalities

    Recent application of microarray-based genome-wide analysis of gene expression and DNA copy number, complemented by transcriptional profiling, resequencing, and epigenetic approaches, has identified a specific subset of patients with high-risk B-precursor ALL with a very poor prognosis. These patients have a gene-expression signature similar to patients with BCR-ABL-positive ALL, but lack that translocation. IKZF1 deletions were identified in about 30% of high-risk B-precursor ALL and were significantly associated with a very poor outcome.[114,115] A subset of patients with IKZF1 deletions were found to have JAK kinase mutations (about 10% of all high-risk cases), suggesting a possible future therapeutic target.[116]

    Overexpression of CRLF2, a cytokine receptor gene located on the pseudoautosomal regions (PAR) of the sex chromosomes, has been identified in 5% to 10% of cases of B-precursor ALL.[117,118] Chromosomal abnormalities described in cases with CRLF2 overexpression include translocations of the IgH locus (chromosome 14) to CRLF2 and interstitial PAR1 deletions resulting in a PDRY8-CRLF2 fusion.[117,118,119]CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions and JAK mutations;[118,119] they are also more common in children with Down syndrome.[118] The results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance, although none have established it as an independent predictor of outcome.[117,118,119]

    In another retrospective study of gene expression classification in ALL, children could be classified as low, intermediate, and high risk based on a combination of gene expression and flow cytometric measures of minimal residual disease (MRD). These prognostic groups have yet to be tested in a prospective study.[120][Level of evidence: 3iiiA]

  • Gene polymorphisms in drug metabolic pathways

    A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[121,122,123] For example, patients with mutant phenotypes of thiopurine methyltransferase (a gene involved in the metabolism of thiopurines, such as 6-mercaptopurine), appear to have more favorable outcomes,[124] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[125,126]

    Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse. Polymorphisms of IL-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols.[127] Polymorphic variants involving the reduced folate carrier have been linked to methotrexate metabolism, toxicity, and outcome.[128] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations; whether individualized dose modification based upon these findings will improve outcome is unknown.

Response to Initial Treatment

The rapidity with which leukemia cells are eliminated following onset of treatment is associated with long-term outcome, as is level of residual disease at the end of induction. Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics,[129] early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:

1. Day 7 and day 14 bone marrow responses:

Patients who have a rapid reduction in leukemia cells to less than 5% in their bone marrow within 7 or 14 days following initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow.[130]

2. Peripheral blood response to steroid prophase:

Patients with a reduction in peripheral blast count to less than 1,000/µL after a 7-day induction prophase with prednisone and one dose of intrathecal methotrexate (a good prednisone response) have a more favorable prognosis than do patients whose peripheral blast counts remain above 1,000/µL (a poor prednisone response).[8] Poor prednisone response is observed in fewer than 10% of patients.[8,131] Treatment stratification for protocols of the German Berlin-Frankfurt-Muenster (BFM) clinical trials group is partially based on early response to the 7-day prednisone prophase (administered immediately prior to the initiation of multiagent remission induction). Patients with no circulating blasts on day 7 have a better outcome than those patients whose circulating blast level is between 1 and 999/µL.[132,133]

3. Peripheral blood response to multiagent induction therapy:

Patients with persistent circulating leukemia cells at 7 to 10 days after the initiation of multiagent chemotherapy are at increased risk of relapse compared with patients who have clearance of peripheral blasts within 1 week of therapy initiation.[134] Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.[134]

4. Induction failure:

The vast majority of children with ALL achieve complete morphologic remission by the end of the first month of treatment. The presence of greater than 5% lymphoblasts at the end of the induction phase is observed in up to 5% of children with ALL. Patients at highest risk of induction failure include those with T-cell phenotype (especially without a mediastinal mass) and patients with B-precursor ALL with very high presenting leukocyte counts and/or the Philadelphia chromosome.[135,136] Induction failure portends a very poor outcome.[135] In the French FRALLE 93 study, the 5-year OS rate for patients with initial induction failure was 30%.[136]

5. MRD determination:

Morphologic assessment of residual leukemia in blood or bone marrow is often difficult and is relatively insensitive. Traditionally, a cutoff of 5% blasts in the bone marrow (detected by light microscopy) has been used to determine remission status. This corresponds to a level of 1 in 20 malignant cells. If one wishes to detect lower levels of leukemic cells in either blood or marrow, specialized techniques such as PCR assays, which determine unique Ig/TCR gene rearrangements, fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes, are required. With these techniques, detection of as few as 1 leukemia cell in 100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells can be detected routinely.[137]

Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with ALL.[98,138,139,140] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities.[141] Patients with higher levels of end-induction MRD have a poorer prognosis than those with lower or undetectable levels.[98,137,138,139,142] End-induction MRD is used by almost all groups as a factor determining the intensity of postinduction treatment, with patients found to have higher levels allocated to more intensive therapies. MRD levels at earlier (e.g., day 8 and day 15 of induction) and later time points (e.g., week 12 of therapy) also predict outcome.[98,137,139,141,142,143,144,145]

MRD measurements, in conjunction with other presenting features, have also been used to identify subsets of patients with an extremely low risk of relapse. The COG reported a very favorable prognosis (5-year EFS of 97% ± 1%) for patients with B-precursor phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the ETV6-RUNX1 fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and end-induction (from bone marrow).[98]

Although MRD is the most important prognostic factor in determining outcome, there are no data to conclusively show that modifying therapy based on MRD determination significantly improves outcome in newly diagnosed ALL.[141]

Prognostic Groups

This subsection does not discuss infants as a prognostic group. For information about infants with acute lymphoblastic leukemia, refer to the Postinduction Treatment for Specific ALL Subgroups section of this summary.

Former CCG studies made an initial risk assignment of patients older than 1 year as standard risk or high risk based on the NCI consensus age and WBC criteria, regardless of phenotype.[1] The standard-risk category included patients aged 1 to 9 years who had a WBC count at diagnosis less than 50,000/µL. The remaining patients were classified as high risk. Final treatment assignment for CCG protocols was based on early response to therapy with slow early responders being treated as high-risk patients.

Former POG studies defined the low-risk group based on the NCI consensus age and WBC criteria and required the absence of adverse translocations, absence of CNS disease and testicular disease, and the presence of either the ETV6-RUNX1 translocation or trisomy of chromosomes 4 and 10. The high-risk group required the absence of favorable translocations and the presence of CNS or testicular leukemia, or the presence of MLL gene rearrangement, or unfavorable age and WBC count.[98] The standard-risk category included patients not meeting the criteria for inclusion in any of the other risk group categories. In POG studies, patients with T-cell ALL were treated on different protocols than patients with precursor B-cell ALL.

The very high-risk category for CCG and POG was defined by one of the following factors taking precedence over all other considerations: presence of the t(9;22), M3 marrow on day 29 or M2 or M3 marrow on day 43, or hypodiploidy (DNA index <0.95).[90]

Since 2000, risk stratification on BFM protocols has been based almost solely on treatment response criteria. In addition to prednisone prophase response, treatment response is assessed via MRD measurements at two time points, end induction (week 5) and end consolidation (week 12). Patients who are MRD negative at both time points are classified as standard risk, those who have positive MRD at week 5 and low MRD (<10-3) at week 12 are considered intermediate risk, and those with high MRD (=10-3) at week 12 are high risk. Patients with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD. Phenotype, leukemic cell mass estimate, also known as BFM risk factor, and CNS status at diagnosis do not factor into the current risk classification schema. However, patients with either the t(9;22) or the t(4;11) are considered high risk, regardless of early response measures.

Prognostic groups under clinical evaluation

A large, retrospective analysis of CCG and POG data led to the development of a new classification system for the COG.[3] Based on this analysis, patients with precursor B-cell ALL are initially assigned to a standard-risk or high-risk group based on age and initial WBC count. Patients aged 1 to 9.99 years with less than 50,000 WBC/µL are considered standard risk. All children with T-cell phenotype are considered high risk regardless of age and initial WBC count and are treated on a T-cell specific clinical trial. The COG has recently developed a new classification system for precursor-B ALL.

For NCI standard-risk patients (COG-AALL0932), patients will be stratified as low risk, standard (average) risk, or very high risk for end-induction treatment based on cytogenetics, day 8 peripheral blood MRD, and day 28 bone marrow MRD:

  • Standard Risk – Low: Patients will be considered low risk if they have: (1) day 8 peripheral blood MRD less than 0.01%; (2) day 28 marrow MRD less than 0.01%; and (3) either ETV6-RUNX1 or hyperdiploidy with extra copies of chromosomes 4 and 10 (favorable genetics). No morphologic assessment of early response will be performed and extra copies of chromosome 17 will no longer be required for assignment to favorable cytogenetics.
  • Standard Risk – Average: NCI standard-risk patients with: (1) favorable cytogenetics; (2) less than 0.01% peripheral blood MRD on day 8; and (3) less than 0.01% marrow MRD on day 28 will be assigned to an average risk subgroup. Patients with: (1) neither favorable nor unfavorable cytogenetics who have less than 1% MRD in peripheral blood on day 8; and (2) less than 0.01% marrow MRD on day 28 are also assigned to an average-risk subgroup.
  • Standard Risk – Very High: All patients with marrow MRD greater than 0.01% on day 28, with the exception of patients with favorable cytogenetics, will be assigned to a very high-risk group. Favorable cytogenetic patients with day 28 marrow MRD greater than 0.01% and patients with neither favorable nor unfavorable cytogenetics with day 8 peripheral blood MRD greater than 1% and day 28 marrow MRD less than 0.01% also will be assigned to a high-risk subgroup.

The following cytogenetic findings will classify a patient as very high risk regardless of other findings:

  • BCR-ABL1 fusion and/or t(9;22).
  • Hypodiploidy (fewer than 44 chromosomes).

The Dana-Farber Cancer Institute ALL Consortium is also testing a new risk classification system for patients with precursor B-cell ALL. All patients are initially classified as either standard risk or high risk based on age, presenting leukocyte count, and the presence or absence of CNS disease. At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined. Patients with high MRD (=0.01) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.01) continue to receive treatment based on their initial risk-group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<44 chromosomes) are classified as very high risk, regardless of MRD status or phenotype. Patients with the Philadelphia chromosome are treated as high risk, but receive a tyrosine kinase inhibitor (imatinib) beginning mid-induction and are eligible for an allogeneic stem cell transplant in first remission.

At SJCRH, risk classification is based mainly on MRD level (assessed by flow cytometry) after 6 weeks of remission induction therapy as follows: low risk (<0.01%), standard risk (0.01% – <1%), and high risk (=1%). Patients with early T-cell precursor ALL are also considered to be high risk.[56]

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85. Synold TW, Relling MV, Boyett JM, et al.: Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest 94 (5): 1996-2001, 1994.
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87. Sutcliffe MJ, Shuster JJ, Sather HN, et al.: High concordance from independent studies by the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI Standard-Risk B-precursor Acute Lymphoblastic Leukemia: a Children's Oncology Group (COG) initiative. Leukemia 19 (5): 734-40, 2005.
88. Harris MB, Shuster JJ, Carroll A, et al.: Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study. Blood 79 (12): 3316-24, 1992.
89. Heerema NA, Harbott J, Galimberti S, et al.: Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome. Leukemia 18 (4): 693-702, 2004.
90. Nachman JB, Heerema NA, Sather H, et al.: Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood 110 (4): 1112-5, 2007.
91. Raimondi SC, Zhou Y, Shurtleff SA, et al.: Near-triploidy and near-tetraploidy in childhood acute lymphoblastic leukemia: association with B-lineage blast cells carrying the ETV6-RUNX1 fusion, T-lineage immunophenotype, and favorable outcome. Cancer Genet Cytogenet 169 (1): 50-7, 2006.
92. Attarbaschi A, Mann G, König M, et al.: Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis. Leukemia 18 (10): 1611-6, 2004.
93. Lemez P, Attarbaschi A, Béné MC, et al.: Childhood near-tetraploid acute lymphoblastic leukemia: an EGIL study on 36 cases. Eur J Haematol 85 (4): 300-8, 2010.
94. Rubnitz JE, Wichlan D, Devidas M, et al.: Prospective analysis of TEL gene rearrangements in childhood acute lymphoblastic leukemia: a Children's Oncology Group study. J Clin Oncol 26 (13): 2186-91, 2008.
95. Kanerva J, Saarinen-Pihkala UM, Niini T, et al.: Favorable outcome in 20-year follow-up of children with very-low-risk ALL and minimal standard therapy, with special reference to TEL-AML1 fusion. Pediatr Blood Cancer 42 (1): 30-5, 2004.
96. Aldrich MC, Zhang L, Wiemels JL, et al.: Cytogenetics of Hispanic and White children with acute lymphoblastic leukemia in California. Cancer Epidemiol Biomarkers Prev 15 (3): 578-81, 2006.
97. Loh ML, Goldwasser MA, Silverman LB, et al.: Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. Blood 107 (11): 4508-13, 2006.
98. Borowitz MJ, Devidas M, Hunger SP, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood 111 (12): 5477-85, 2008.
99. Madzo J, Zuna J, Muzíková K, et al.: Slower molecular response to treatment predicts poor outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia: prospective real-time quantitative reverse transcriptase-polymerase chain reaction study. Cancer 97 (1): 105-13, 2003.
100. Forestier E, Heyman M, Andersen MK, et al.: Outcome of ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia in the NOPHO-ALL-1992 protocol: frequent late relapses but good overall survival. Br J Haematol 140 (6): 665-72, 2008.
101. Seeger K, Stackelberg AV, Taube T, et al.: Relapse of TEL-AML1--positive acute lymphoblastic leukemia in childhood: a matched-pair analysis. J Clin Oncol 19 (13): 3188-93, 2001.
102. Zuna J, Ford AM, Peham M, et al.: TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia. Clin Cancer Res 10 (16): 5355-60, 2004.
103. Aricò M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342 (14): 998-1006, 2000.
104. Schrappe M, Aricò M, Harbott J, et al.: Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 92 (8): 2730-41, 1998.
105. Ribeiro RC, Broniscer A, Rivera GK, et al.: Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts. Leukemia 11 (9): 1493-6, 1997.
106. Schultz KR, Bowman WP, Aledo A, et al.: Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol 27 (31): 5175-81, 2009.
107. Johansson B, Moorman AV, Haas OA, et al.: Hematologic malignancies with t(4;11)(q21;q23)--a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases. European 11q23 Workshop participants. Leukemia 12 (5): 779-87, 1998.
108. Raimondi SC, Peiper SC, Kitchingman GR, et al.: Childhood acute lymphoblastic leukemia with chromosomal breakpoints at 11q23. Blood 73 (6): 1627-34, 1989.
109. Harrison CJ, Moorman AV, Barber KE, et al.: Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study. Br J Haematol 129 (4): 520-30, 2005.
110. Rubnitz JE, Camitta BM, Mahmoud H, et al.: Childhood acute lymphoblastic leukemia with the MLL-ENL fusion and t(11;19)(q23;p13.3) translocation. J Clin Oncol 17 (1): 191-6, 1999.
111. Crist WM, Carroll AJ, Shuster JJ, et al.: Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study. Blood 76 (1): 117-22, 1990.
112. Moorman AV, Richards SM, Robinson HM, et al.: Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood 109 (6): 2327-30, 2007.
113. Attarbaschi A, Mann G, Panzer-Grümayer R, et al.: Minimal residual disease values discriminate between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and an intrachromosomal amplification of chromosome 21: the Austrian and German acute lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. J Clin Oncol 26 (18): 3046-50, 2008.
114. Mullighan CG, Su X, Zhang J, et al.: Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 360 (5): 470-80, 2009.
115. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al.: A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 10 (2): 125-34, 2009.
116. Mullighan CG, Zhang J, Harvey RC, et al.: JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 106 (23): 9414-8, 2009.
117. Cario G, Zimmermann M, Romey R, et al.: Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol. Blood 115 (26): 5393-7, 2010.
118. Ensor HM, Schwab C, Russell LJ, et al.: Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial. Blood 117 (7): 2129-36, 2011.
119. Harvey RC, Mullighan CG, Chen IM, et al.: Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 115 (26): 5312-21, 2010.
120. Kang H, Chen IM, Wilson CS, et al.: Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia. Blood 115 (7): 1394-405, 2010.
121. Davies SM, Bhatia S, Ross JA, et al.: Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia. Blood 100 (1): 67-71, 2002.
122. Krajinovic M, Costea I, Chiasson S: Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet 359 (9311): 1033-4, 2002.
123. Krajinovic M, Lemieux-Blanchard E, Chiasson S, et al.: Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 4 (1): 66-72, 2004.
124. Schmiegelow K, Forestier E, Kristinsson J, et al.: Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia 23 (3): 557-64, 2009.
125. Relling MV, Hancock ML, Boyett JM, et al.: Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 93 (9): 2817-23, 1999.
126. Stanulla M, Schaeffeler E, Flohr T, et al.: Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA 293 (12): 1485-9, 2005.
127. Yang JJ, Cheng C, Yang W, et al.: Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301 (4): 393-403, 2009.
128. Gregers J, Christensen IJ, Dalhoff K, et al.: The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood 115 (23): 4671-7, 2010.
129. Relling MV, Dervieux T: Pharmacogenetics and cancer therapy. Nat Rev Cancer 1 (2): 99-108, 2001.
130. Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer 80 (9): 1717-26, 1997.
131. Möricke A, Reiter A, Zimmermann M, et al.: Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111 (9): 4477-89, 2008.
132. Lauten M, Stanulla M, Zimmermann M, et al.: Clinical outcome of patients with childhood acute lymphoblastic leukaemia and an initial leukaemic blood blast count of less than 1000 per microliter. Klin Padiatr 213 (4): 169-74, 2001 Jul-Aug.
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136. Oudot C, Auclerc MF, Levy V, et al.: Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study. J Clin Oncol 26 (9): 1496-503, 2008.
137. van Dongen JJ, Seriu T, Panzer-Grümayer ER, et al.: Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352 (9142): 1731-8, 1998.
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144. Panzer-Grümayer ER, Schneider M, Panzer S, et al.: Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia. Blood 95 (3): 790-4, 2000.
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Treatment Option Overview

Treatment of childhood acute lymphoblastic leukemia (ALL) typically involves chemotherapy given for 2 to 3 years. Since myelosuppression and generalized immunosuppression are anticipated consequences of both leukemia and chemotherapy treatment, patients must be closely monitored at diagnosis and during treatment. Adequate facilities must be immediately available both for hematologic support and for the treatment of infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients die during induction therapy and another 1% to 3% die during the initial remission from treatment-related complications.[1,2] Children with ALL should be cared for at a center with specialized expertise in pediatric cancer.[3]

Nationwide clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (low) risk of treatment failure and for children at higher risk of treatment failure. Clinical trials for children with ALL are generally designed to compare therapy that is currently accepted as standard for a particular risk group with a potentially better treatment approach that may improve survival outcome and/or diminish toxicities associated with the standard treatment regimen. Many of the therapeutic innovations that produced increased survival rates in children with ALL have been established through nationwide clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial. Treatment planning by a multidisciplinary team of pediatric cancer specialists with experience and expertise in treating leukemias of childhood is required to determine and implement optimum treatment.

Treatment for children with ALL is typically divided as follows:

  • Remission induction (at the time of diagnosis).
  • Postinduction therapy (after achieving complete remission).
    • Consolidation/intensification therapy.
    • Maintenance or continuation therapy.

Risk-Based Treatment Assignment

Risk-based treatment assignment is an important therapeutic strategy utilized for children with ALL. This approach allows children who historically have a very good outcome to be treated with modest therapy and to be spared more intensive and toxic treatment, while allowing children with a historically lower probability of long-term survival to receive more intensive therapy that may increase their chance of cure. As discussed in the Cellular Classification and Prognostic Variables section of this summary, a number of clinical and laboratory features have demonstrated prognostic value. The intensity of induction (some, but not all groups) is determined by National Cancer Institute (NCI) risk group and immunophenotype and postinduction therapy (all groups) is determined by prognostic factors such as early response determinations and cytogenetics.[4] With this treatment approach, approximately 80% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors.[5,6,7,8,9,10]

In COG protocols, a subset of the known prognostic factors (e.g., age, white blood cell [WBC] count at diagnosis, immunophenotype, and presence of extramedullary disease) are used for the initial stratification of children with ALL into treatment groups with varying degrees of risk of treatment failure. Event-free survival (EFS) rates exceed 85% in children meeting good-risk criteria (aged 1–9 years, WBC count <50,000/µL, and precursor B-cell immunophenotype); in children meeting high-risk criteria, EFS rates are approximately 70%.[5,6,7,8,11] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., day 7 and/or day 14 marrow blast percentage and minimal residual disease [MRD] levels at the end of induction), considered in conjunction with presenting age, WBC count, and immunophenotype, can identify patient groups with expected EFS rates ranging from less than 40% to greater than 95%.[11,12]

Subgroups of patients who have a poor prognosis with current risk-adapted, multiagent chemotherapy regimens may require different therapeutic approaches. For example, infants with ALL are at much higher risk for treatment failure than older children.[13,14] Infants with ALL are generally treated on separate protocols using more intensified regimens, although the likelihood of long-term EFS appears to be no better than 50% for infants with MLL translocations even with a more intensive therapeutic approach.[13,14,15,16] Infants with MLL translocations and other subsets of patients who have a less than 50% chance of long-term remission with current therapies (such as patients with hypodiploidy or with initial induction failure) are sometimes considered candidates for allogeneic stem cell transplantation in first remission.[15,17,18,19] However, because of small numbers, possible patient selection bias, and center preference, studies to definitively show whether CR1 transplantation is superior to intensive chemotherapy for these very high-risk patients have not been feasible.

Allogeneic bone marrow transplantation was once considered to be the treatment of choice for children with t(9;22) Philadelphia chromosome–positive (Ph+) ALL, especially those with high-risk clinical features (age >10 years or high initial leukocyte count) or poor early treatment response.[20,21] However, a COG study demonstrated a 3-year EFS rate of 80.5% in Ph+ patients treated with concurrent intensive chemotherapy and a tyrosine kinase inhibitor (imatinib) given daily during premaintenance therapy.[22] While longer follow-up is necessary to determine if this treatment regimen indeed improves cure rates or merely prolongs the duration of disease-free survival, these results suggest that the presence of the Philadelphia chromosome should no longer be considered an absolute indication for transplantation in first remission.

Treatment of Sanctuary Sites (Central Nervous System, Testes)

Successful treatment of children with ALL requires the control of systemic disease (e.g., marrow, liver and spleen, lymph nodes), as well as the prevention or treatment of extramedullary disease, particularly in the central nervous system (CNS). Approximately 3% of patients have detectable CNS involvement by conventional criteria at diagnosis (cerebrospinal fluid specimen with =5 WBC/µL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, the majority of children will eventually develop overt CNS leukemia. Therefore, all children with ALL should receive systemic combination chemotherapy together with some form of CNS prophylaxis. Therapies that may be used for CNS prophylaxis include intrathecal chemotherapy and cranial radiation. CNS-penetrant systemic chemotherapy (such as intravenous methotrexate and high-dose cytarabine) and other drugs, including dexamethasone and asparaginase, may contribute to CNS prophylaxis as well. At present, most newly diagnosed children with ALL are treated without cranial radiation; many groups administer cranial radiation only to those patients considered to be at highest risk for subsequent CNS relapse, such as those with documented CNS leukemia at diagnosis (as defined above) (>5 WBC/µL with blasts; CNS3) and/or T-cell phenotype with high presenting WBC count.[23] Ongoing trials seek to determine if radiation can be eliminated from the treatment of all children with ALL without compromising survival or leading to increased rate of toxicities from upfront and salvage therapies.[7,8]

CNS-directed therapy is provided during premaintenance chemotherapy by all groups. Some protocols provide ongoing intrathecal chemotherapy during maintenance (COG, St. Jude Children's Research Hospital [SJCRH], and Dana-Farber Cancer Institute), while others do not (Berlin-Frankfurt-Muenster).

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.[24,25] The role of radiation therapy for testicular involvement is also unclear. A study from SJCRH suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[24] The COG has also adopted this strategy for boys with testicular leukemia that resolves completely during induction chemotherapy.

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9. Salzer WL, Devidas M, Carroll WL, et al.: Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children's oncology group. Leukemia 24 (2): 355-70, 2010.
10. Gaynon PS, Angiolillo AL, Carroll WL, et al.: Long-term results of the children's cancer group studies for childhood acute lymphoblastic leukemia 1983-2002: a Children's Oncology Group Report. Leukemia 24 (2): 285-97, 2010.
11. Schultz KR, Pullen DJ, Sather HN, et al.: Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG). Blood 109 (3): 926-35, 2007.
12. Borowitz MJ, Devidas M, Hunger SP, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood 111 (12): 5477-85, 2008.
13. Pui CH, Gaynon PS, Boyett JM, et al.: Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 359 (9321): 1909-15, 2002.
14. Pieters R, Schrappe M, De Lorenzo P, et al.: A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370 (9583): 240-50, 2007.
15. Kosaka Y, Koh K, Kinukawa N, et al.: Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 104 (12): 3527-34, 2004.
16. Hilden JM, Dinndorf PA, Meerbaum SO, et al.: Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 108 (2): 441-51, 2006.
17. Balduzzi A, Valsecchi MG, Uderzo C, et al.: Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 366 (9486): 635-42, 2005 Aug 20-26.
18. Schrauder A, Reiter A, Gadner H, et al.: Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol 24 (36): 5742-9, 2006.
19. Ribera JM, Ortega JJ, Oriol A, et al.: Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol 25 (1): 16-24, 2007.
20. Aricò M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342 (14): 998-1006, 2000.
21. Mori T, Manabe A, Tsuchida M, et al.: Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13. Med Pediatr Oncol 37 (5): 426-31, 2001.
22. Schultz KR, Bowman WP, Aledo A, et al.: Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol 27 (31): 5175-81, 2009.
23. Pui CH, Howard SC: Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol 9 (3): 257-68, 2008.
24. Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403, 2005.
25. Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study 58881. Pediatr Blood Cancer 49 (3): 344-8, 2007.

Remission Induction for Newly Diagnosed ALL

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric Treatment Editorial Board uses a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Induction Chemotherapy

Three-drug induction therapy using vincristine, corticosteroid (prednisone or dexamethasone), and L-asparaginase in conjunction with intrathecal (IT) therapy, results in complete remission (CR) rates of greater than 95%.[1] For patients presenting with high-risk features, a more intensive induction regimen (four or five agents) may result in improved event-free survival (EFS).[2,3] Such patients generally receive induction therapy that includes an anthracycline (e.g., daunorubicin) in addition to vincristine, prednisone/dexamethasone, plus L-asparaginase. For patients who are at standard risk or low risk of treatment failure, four or more drug induction therapy does not appear necessary for favorable outcome provided that adequate postremission intensification therapy is administered.[2,4,5] The Children's Oncology Group (COG) protocols risk stratify at diagnosis and do not administer anthracycline during induction to patients with National Cancer Institute (NCI) standard-risk precursor B-cell acute lymphoblastic leukemia (ALL). While other groups, such as the Berlin-Frankfurt-Muenster (BFM) Group in Europe, St. Jude Children's Research Hospital (SJCRH), and the Dana-Farber Cancer Institute (DFCI) ALL Consortium, utilize either a four- or five-drug induction for all patients, regardless of presenting features.[6,7,8]

Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy. The Children's Cancer Group (CCG) conducted a randomized trial comparing dexamethasone and prednisone in standard-risk ALL patients, and reported that dexamethasone was associated with a superior EFS.[9] Results from another randomized trial conducted by the United Kingdom Medical Research Council (MRC) demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.[10] In the MRC trial, patients who received dexamethasone had a significantly lower incidence of both central nervous system (CNS) and non-CNS relapses than patients who received prednisolone.[10] However, other randomized trials did not confirm an EFS advantage with dexamethasone.[11] It appears that the ratio of dexamethasone to prednisone dose used may influence outcome. Studies in which the dexamethasone to prednisone ratio is 1:5 to 1:7 have shown a better result for dexamethasone, while studies using a 1:10 ratio have shown similar outcomes.[12]

While dexamethasone may be more effective than prednisone, data also suggest that dexamethasone may also be more toxic, especially in the context of more intensive induction regimens and in adolescents. Several reports indicate that dexamethasone may increase the frequency and severity of infections and/or other complications in patients receiving anthracycline-containing induction regimens.[13,14] The increased risk of infection with dexamethasone during the induction phase has not been noted with three-drug induction regimens (vincristine, dexamethasone, and L-asparaginase).[10] Dexamethasone appears to have a greater suppressive effect on short-term linear growth than prednisone,[15] and has been associated with a higher risk of osteonecrosis, especially in adolescent patients.[16]

Several forms of L-asparaginase are available for use in the treatment of children with ALL in the United States. PEG-L-asparaginase, a form of L-asparaginase in which the Escherichia coli-derived enzyme is modified by the covalent attachment of polyethylene glycol, is the most common preparation used during both induction and postinduction phases of treatment in newly diagnosed patients. PEG-L-asparaginase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion following a single injection.[17] A single intramuscular (IM) dose of PEG-L-asparaginase given in conjunction with vincristine and prednisone during induction therapy appeared to have similar activity and toxicity as nine doses of IM E. coli L-asparaginase (3 times a week for 3 weeks).[18] Studies have shown that a single dose of PEG-L-asparaginase given either IM or intravenously (IV) as part of multiagent induction results in serum enzyme activity (>100 IU/mL) in nearly all patients for at least 2 to 3 weeks.[18,19,20] The toxicity of PEG-L-asparaginase seems to be similar to that observed with native E. coli asparaginase. In a randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase in which each agent was to be given for a 30-week period following achievement of remission, similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients.[21] In another randomized trial in which patients with standard-risk ALL were randomly assigned to receive PEG-L-asparaginase versus native E. coli asparaginase in induction and each of two delayed intensification courses, the use of PEG-L-asparaginase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies.[18] It is safe to give IV PEG-L-asparaginase in pediatric patients.[19,20] Pharmacokinetics and toxicity profiles are similar for IV and IM PEG-L-asparaginase administration.[20]

Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase. The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or PEG-L-asparaginase (5.7 days).[17] If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration and a higher dose to achieve adequate asparagine depletion. In two studies, newly diagnosed patients randomly assigned to receive Erwinia L-asparaginase on the same schedule and dosage as E. coli L-asparaginase had a significantly worse EFS.[22,23] However, when administered more frequently (twice weekly), the use of Erwinia asparaginase did not adversely impact EFS in patients experiencing an allergic reaction to E. coli L-asparaginase.[24]

More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of the 2% to 4% of patients who fail to achieve CR within the first 4 weeks, approximately half will experience a toxic death during the induction phase (usually due to infection) and the other half will have resistant disease (persistent morphologic leukemia).[23,25,26]; [27][Level of evidence: 3iA] Patients with persistent leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic stem cell transplant once CR is achieved.[28,29,30]

For patients who achieve CR, measures of the rapidity of blast clearance and minimal residual disease (MRD) determinations have important prognostic significance, as discussed in the Cellular Classification and Prognostic Variables section of this summary. Morphologic persistence of marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with higher relapse risk,[31] and has been used by the COG to risk-stratify patients. Similarly, end-induction levels of submicroscopic MRD, assessed either by multiparameter flow cytometry or polymerase chain reaction, strongly correlates with long-term outcome.[32,33,34,35] Intensification of postinduction therapy for patients with high levels of end-induction MRD is under investigation by many groups. MRD levels earlier in induction (e.g., days 8 and 15) and at later postinduction time points (e.g., week 12 after starting therapy) have also been shown to have prognostic significance.[34,36,37]

Central Nervous System (CNS) Therapy

Historically, survival rates for children with ALL did not improve until CNS-directed therapy was instituted. The early institution of adequate CNS therapy is critical for eliminating clinically evident CNS disease at diagnosis and for preventing CNS relapse in all patients. Options for CNS-directed therapy include IT chemotherapy, CNS-penetrant systemic chemotherapy, and cranial radiation. The type of CNS-therapy that is used is based on a patient's risk of CNS-relapse, with higher-risk patients receiving more intensive treatments. A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurotoxicity and other late effects. The proportion of patients receiving cranial radiation has decreased significantly over time. In patients still receiving cranial radiation, the dose has been significantly reduced.

All therapeutic regimens for childhood ALL include IT chemotherapy. IT chemotherapy is usually started at the beginning of induction, intensified during consolidation (four to eight doses of IT given every 2–3 weeks), and, in certain protocols, continued throughout the maintenance phase. IT chemotherapy typically consists of either methotrexate alone or methotrexate with cytarabine and hydrocortisone.[38] Unlike IT cytarabine, IT methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.[39]

In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis. Systemically administered drugs, such as dexamethasone, L-asparaginase, and high-dose methotrexate with leucovorin rescue, provide some degree of CNS prophylaxis. For example, in a randomized CCG study of standard-risk patients who all received the same dose and schedule of IT methotrexate without cranial irradiation, oral dexamethasone was associated with a 50% decrease in the rate of CNS relapse compared with oral prednisone.[9] In a recent standard-risk ALL trial (COG-1991), lower-dose IV methotrexate without rescue significantly reduced the CNS relapse rate compared to oral methotrexate given during each of two interim maintenance phases.[abstract]

CNS therapy for standard-risk patients

Intrathecal chemotherapy without cranial radiation, given in the context of appropriate systemic chemotherapy, results in CNS relapse rates of less than 5% for children with standard-risk ALL.[4,25,40,41,42,43] The use of cranial radiation does not appear to be a necessary component of CNS-directed therapy for these patients.[23,44]

The CCG-1952 study for NCI standard-risk patients compared the relative efficacy and toxicity of triple IT chemotherapy (methotrexate, prednisone, and cytarabine) with methotrexate as the sole IT agent in nonirradiated patients.[45] There was no significant difference in either CNS or non-CNS toxicities. Triple IT chemotherapy was associated with a lower rate of isolated CNS relapse (3.4% ± 1.0% compared with 5.9% ± 1.2% for IT methotrexate; P = .004). This effect was especially notable in patients with CNS2 status at diagnosis (lymphoblasts seen in cerebrospinal fluid [CSF] cytospin, but with <5 WBC/hpf on CSF cell count); the isolated CNS relapse rate was 7.7% ± 5.3% for CNS2 patients who received triple IT chemotherapy compared with 23.0% ± 9.5% for those who received IT methotrexate alone (P = .04). There were, however, more bone marrow relapses in the group that received the triple IT therapy, leading to a worse overall survival (OS) (90.3% ± 1.5%) compared with the IT methotrexate group (94.4% ± 1.1%; P = .01). When the analysis was restricted to patients with precursor B-cell ALL and rapid early response (M1 marrow on day 14), there was no difference between triple and single IT therapy in terms of rates of CNS relapse rate, OS, or EFS.[45] In a follow-up study of neurocognitive functioning in the two groups, there were no clinically significant differences.[46][Level of evidence: 1iiC]

Patients with blasts in the CSF but fewer than 5 WBC/µL (CNS2) are at increased risk of CNS relapse,[47] although this risk appears to be nearly fully abrogated if they receive more intensive IT chemotherapy, especially during the induction phase.[48] Data also suggest that patients who have a traumatic lumbar puncture showing blasts at the time of diagnosis have an increased risk of CNS relapse, and these patients receive more intensive CNS-directed therapy on some treatment protocols.[48,49]

CNS therapy for high-risk patients

Controversy exists as to which, if any, high-risk patients should be treated with cranial radiation. Depending on the protocol, up to 20% of children with ALL receive cranial radiation as part of their CNS-directed therapy, even if they present without CNS involvement at diagnosis. Patients receiving cranial radiation on many treatment regimens include those with T-cell phenotype and high initial WBC count and certain patients with high-risk precursor B-cell ALL (e.g., those with extremely high presenting leukocyte counts and/or adverse cytogenetic abnormalities).[50]

Both the proportion of patients receiving radiation and the dose of radiation administered has decreased over the last 2 decades. For example, in a trial conducted between 1990 and1995, the BFM group demonstrated that a reduced dose of prophylactic radiation (12 Gy instead of 18 Gy) provided effective CNS prophylaxis in high-risk patients.[26] In the follow-up trial conducted by that group between 1995 and 2000 (BFM-95), cranial radiation was administered to approximately 20% of patients (compared with 70% on the previous trial), including patients with T-cell phenotype, a slow early response (as measured by peripheral blood blast count after a 1-week steroid prophase), and/or adverse cytogenetic abnormalities.[42] While the rate of isolated CNS relapses was higher in the nonirradiated higher-risk patients compared with historic (irradiated) cohorts, their overall EFS rate was not significantly different.[42]

Two studies, one conducted by the SJCRH and the other by the Dutch Childhood Oncology Group (DCOG), omitted cranial radiation for all patients.[4,43] Each of these studies included four doses of high-dose methotrexate administered every 2 weeks during postinduction consolidation, as well as an increased frequency of IT triple chemotherapy (cytarabine, methotrexate, and hydrocortisone) and frequent vincristine/dexamethasone pulses during the first 1 to 2 years of therapy. The 5-year cumulative incidence of isolated CNS relapse on each trial was between 2% and 3%, although some patient subsets had a significantly higher rate of CNS relapse. On the SJCRH study, clinical features associated with a significantly higher risk of isolated CNS relapse included T-cell phenotype, the t(1;19) translocation, or the presence of blasts in the CSF at diagnosis.[43] The overall EFS for these studies was 85.6% (SJCRH) and 81% (DCOG), in line with outcomes achieved by contemporaneously conducted clinical trials on which some patients received prophylactic radiation. Of note, on the SJCRH study 33 of 498 (6.6%) patients in first remission with high-risk features (including 26 with high MRD, six with Philadelphia chromosome-positive ALL, and one with near haploidy) received an allogeneic stem cell transplant, which included total-body irradiation.[43]

Therapy for ALL patients with clinically evident CNS disease (>5 WBC/hpf with blasts on cytospin; CNS3) at diagnosis typically includes IT chemotherapy and cranial radiation (usual dose is 18 Gy).[23,42] Spinal radiation is no longer used. On the SJCRH Total XV (TOTXV) study, patients with CNS3 status (N = 9) were treated without cranial radiation (observed 5-year EFS, 43% ± 23%).[43] On that study, CNS-leukemia at diagnosis (defined as CNS3 status or traumatic LP with blasts) was an independent predictor of inferior EFS. The 5-year EFS of CNS3 patients (N = 21) treated without cranial radiation on the DCOG-9 trial was 67% ± 10%.[4] Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.

Toxicity of CNS-directed therapy

Toxic effects of CNS-directed therapy for childhood ALL can be divided into the following two broad groups:

  • Acute/subacute toxicities include seizures, stroke, somnolence syndrome, and ascending paralysis.
  • Late developing toxicities include meningiomas and other second neoplasms, leukoencephalopathy and a range of neurocognitive, behavioral, and neuroendocrine disturbances.[51,52,53]

The most common acute side effect associated with IT chemotherapy alone is seizures. Up to 5% of nonirradiated patients with ALL treated with frequent doses of IT chemotherapy will have at least one seizure during therapy.[43] Higher rates of seizure were observed with consolidation regimens that included multiple doses of high-dose methotrexate in addition to IT chemotherapy.[54] Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome.[55] Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities.[55]

Long-term deleterious effects of cranial radiation, particularly at doses higher than 18 Gy, have been recognized for years. Children receiving these higher doses of cranial radiation are at significant risk of neurocognitive and neuroendocrine sequelae.[56,57,58,59,60] Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae following cranial radiation.[61,62,63] Girls may be at a higher risk of radiation-induced neuropsychologic and neuroendocrine sequelae than boys.[62,63,64] Long-term survivors treated with 18 Gy radiation appear to have less severe neurocognitive sequelae than those who had received higher doses of radiation (24 Gy–28 Gy) on clinical trials conducted in the 1970s and 1980s.[65] In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation; in fact, cognitive function for both groups was not significantly impaired.[66]; [67][Level of evidence: 1iiC] On current clinical trials, many patients who receive prophylactic or presymptomatic cranial radiation are treated with an even lower dose (12 Gy). Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of neurologic sequelae.

In general, patients who receive IT chemotherapy without cranial radiation appear to have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.[67,68,69,70] This modest decline is primarily seen in young children and girls.[71] A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple IT therapy showed no clinically meaningful difference.[46][Level of evidence: 3iiiC] Controversy exists about whether patients who receive dexamethasone are at higher risk for neurocognitive disturbances,[72] although long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization.[73]

Cranial radiation has also been associated with an increased risk of second neoplasms, many of which are benign or of low malignant potential, such as meningiomas.[53,74,75] Leukoencephalopathy has been observed after cranial radiation in children with ALL, but appears to be more common with higher doses than are currently administered.[76] In general, systemic methotrexate doses greater than 1 g/m2 should not be given following cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy.

Presymptomatic CNS therapy options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • COG-AALL0434: In the COG-AALL0434 protocol for patients with T-cell ALL, low-risk T-cell patients (those with NCI standard-risk features and a rapid response to induction therapy) are treated without cranial radiation, and intermediate-risk T-cell patients receive 12 Gy (instead of 18 Gy) cranial radiation. High-risk T-cell patients continue to receive 18 Gy cranial radiation. All patients are randomly assigned to receive either high-dose methotrexate (5 g/m2 over 24 hours) with leucovorin rescue or escalating-dose methotrexate without leucovorin rescue during the initial interim maintenance phase of therapy.
  • SJCRH Total XVI (TOTXVI): Patients receive both intrathecal chemotherapy and high-dose methotrexate without radiation therapy. Certain patients with high-risk features, including those with a t(1;19) translocation, receive intensified intrathecal therapy.
  • DFCI-05001: A DFCI ALL Consortium Protocol is testing whether IT chemotherapy alone can replace cranial radiation in some high-risk patients. Approximately 20% of patients will receive cranial radiation, including B-lineage patients with high presenting leukocyte counts (=100,000 /µL), CNS3 disease at diagnosis, or high MRD levels at the end of remission induction, and all T-cell ALL patients. The remaining 80% of patients will receive triple IT chemotherapy, but no radiation. The goal of this treatment schema is to reduce neurotoxicity and other CNS late effects without compromising efficacy by limiting the number of patients exposed to radiation and by lowering the radiation dose (12 Gy instead of 18 Gy) given to those still receiving radiation.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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34. Borowitz MJ, Devidas M, Hunger SP, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood 111 (12): 5477-85, 2008.
35. Conter V, Bartram CR, Valsecchi MG, et al.: Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 115 (16): 3206-14, 2010.
36. Coustan-Smith E, Sancho J, Behm FG, et al.: Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 100 (1): 52-8, 2002.
37. Basso G, Veltroni M, Valsecchi MG, et al.: Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 27 (31): 5168-74, 2009.
38. Pullen J, Boyett J, Shuster J, et al.: Extended triple intrathecal chemotherapy trial for prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 11 (5): 839-49, 1993.
39. Thyss A, Suciu S, Bertrand Y, et al.: Systemic effect of intrathecal methotrexate during the initial phase of treatment of childhood acute lymphoblastic leukemia. The European Organization for Research and Treatment of Cancer Children's Leukemia Cooperative Group. J Clin Oncol 15 (5): 1824-30, 1997.
40. Tubergen DG, Gilchrist GS, O'Brien RT, et al.: Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report. J Clin Oncol 11 (3): 520-6, 1993.
41. Conter V, Aricò M, Valsecchi MG, et al.: Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Münster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia Pediatrica. J Clin Oncol 13 (10): 2497-502, 1995.
42. Möricke A, Reiter A, Zimmermann M, et al.: Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111 (9): 4477-89, 2008.
43. Pui CH, Campana D, Pei D, et al.: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360 (26): 2730-41, 2009.
44. Clarke M, Gaynon P, Hann I, et al.: CNS-directed therapy for childhood acute lymphoblastic leukemia: Childhood ALL Collaborative Group overview of 43 randomized trials. J Clin Oncol 21 (9): 1798-809, 2003.
45. Matloub Y, Lindemulder S, Gaynon PS, et al.: Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group. Blood 108 (4): 1165-73, 2006.
46. Kadan-Lottick NS, Brouwers P, Breiger D, et al.: Comparison of neurocognitive functioning in children previously randomly assigned to intrathecal methotrexate compared with triple intrathecal therapy for the treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 27 (35): 5986-92, 2009.
47. Mahmoud HH, Rivera GK, Hancock ML, et al.: Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 329 (5): 314-9, 1993.
48. Bürger B, Zimmermann M, Mann G, et al.: Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol 21 (2): 184-8, 2003.
49. Gajjar A, Harrison PL, Sandlund JT, et al.: Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 96 (10): 3381-4, 2000.
50. Pui CH, Howard SC: Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol 9 (3): 257-68, 2008.
51. Moore IM, Espy KA, Kaufmann P, et al.: Cognitive consequences and central nervous system injury following treatment for childhood leukemia. Semin Oncol Nurs 16 (4): 279-90; discussion 291-9, 2000.
52. Goshen Y, Stark B, Kornreich L, et al.: High incidence of meningioma in cranial irradiated survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 49 (3): 294-7, 2007.
53. Hijiya N, Hudson MM, Lensing S, et al.: Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 297 (11): 1207-15, 2007.
54. Mahoney DH Jr, Shuster JJ, Nitschke R, et al.: Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy--a Pediatric Oncology Group study. J Clin Oncol 16 (5): 1712-22, 1998.
55. Relling MV, Pui CH, Sandlund JT, et al.: Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia. Lancet 356 (9226): 285-90, 2000.
56. Stubberfield TG, Byrne GC, Jones TW: Growth and growth hormone secretion after treatment for acute lymphoblastic leukemia in childhood. 18-Gy versus 24-Gy cranial irradiation. J Pediatr Hematol Oncol 17 (2): 167-71, 1995.
57. Rowland JH, Glidewell OJ, Sibley RF, et al.: Effects of different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia. J Clin Oncol 2 (12): 1327-35, 1984.
58. Halberg FE, Kramer JH, Moore IM, et al.: Prophylactic cranial irradiation dose effects on late cognitive function in children treated for acute lymphoblastic leukemia. Int J Radiat Oncol Biol Phys 22 (1): 13-6, 1992.
59. Hill JM, Kornblith AB, Jones D, et al.: A comparative study of the long term psychosocial functioning of childhood acute lymphoblastic leukemia survivors treated by intrathecal methotrexate with or without cranial radiation. Cancer 82 (1): 208-18, 1998.
60. Pui CH, Cheng C, Leung W, et al.: Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 349 (7): 640-9, 2003.
61. Jankovic M, Brouwers P, Valsecchi MG, et al.: Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. ISPACC. International Study Group on Psychosocial Aspects of Childhood Cancer. Lancet 344 (8917): 224-7, 1994.
62. Sklar C, Mertens A, Walter A, et al.: Final height after treatment for childhood acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial irradiation. J Pediatr 123 (1): 59-64, 1993.
63. Christie D, Leiper AD, Chessells JM, et al.: Intellectual performance after presymptomatic cranial radiotherapy for leukaemia: effects of age and sex. Arch Dis Child 73 (2): 136-40, 1995.
64. Waber DP, Tarbell NJ, Kahn CM, et al.: The relationship of sex and treatment modality to neuropsychologic outcome in childhood acute lymphoblastic leukemia. J Clin Oncol 10 (5): 810-7, 1992.
65. Waber DP, Shapiro BL, Carpentieri SC, et al.: Excellent therapeutic efficacy and minimal late neurotoxicity in children treated with 18 grays of cranial radiation therapy for high-risk acute lymphoblastic leukemia: a 7-year follow-up study of the Dana-Farber Cancer Institute Consortium Protocol 87-01. Cancer 92 (1): 15-22, 2001.
66. Waber DP, Silverman LB, Catania L, et al.: Outcomes of a randomized trial of hyperfractionated cranial radiation therapy for treatment of high-risk acute lymphoblastic leukemia: therapeutic efficacy and neurotoxicity. J Clin Oncol 22 (13): 2701-7, 2004.
67. Waber DP, Turek J, Catania L, et al.: Neuropsychological outcomes from a randomized trial of triple intrathecal chemotherapy compared with 18 Gy cranial radiation as CNS treatment in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. J Clin Oncol 25 (31): 4914-21, 2007.
68. Jansen NC, Kingma A, Schuitema A, et al.: Neuropsychological outcome in chemotherapy-only-treated children with acute lymphoblastic leukemia. J Clin Oncol 26 (18): 3025-30, 2008.
69. Espy KA, Moore IM, Kaufmann PM, et al.: Chemotherapeutic CNS prophylaxis and neuropsychologic change in children with acute lymphoblastic leukemia: a prospective study. J Pediatr Psychol 26 (1): 1-9, 2001 Jan-Feb.
70. Copeland DR, Moore BD 3rd, Francis DJ, et al.: Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study. J Clin Oncol 14 (10): 2826-35, 1996.
71. von der Weid N, Mosimann I, Hirt A, et al.: Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences. Eur J Cancer 39 (3): 359-65, 2003.
72. Waber DP, Carpentieri SC, Klar N, et al.: Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol 22 (3): 206-13, 2000 May-Jun.
73. Kadan-Lottick NS, Brouwers P, Breiger D, et al.: A comparison of neurocognitive functioning in children previously randomized to dexamethasone or prednisone in the treatment of childhood acute lymphoblastic leukemia. Blood 114 (9): 1746-52, 2009.
74. Löning L, Zimmermann M, Reiter A, et al.: Secondary neoplasms subsequent to Berlin-Frankfurt-Münster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial radiotherapy. Blood 95 (9): 2770-5, 2000.
75. Bhatia S, Sather HN, Pabustan OB, et al.: Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood 99 (12): 4257-64, 2002.
76. Filley CM, Kleinschmidt-DeMasters BK: Toxic leukoencephalopathy. N Engl J Med 345 (6): 425-32, 2001.

Postinduction Treatment of ALL

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric Treatment Editorial Board uses a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Consolidation/Intensification Therapy

Once remission has been achieved, systemic treatment in conjunction with central nervous system (CNS) sanctuary therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification following achievement of remission and before beginning maintenance therapy. Intensification may involve use of the following:

  • Intermediate-dose or high-dose methotrexate (1–5 g/m2) with leucovorin rescue or escalating-dose methotrexate without rescue.[1,2,3,4]
  • Drugs similar to those used to achieve remission (reinduction or delayed intensification).[1,5]
  • Different drug combinations with little known cross-resistance to the induction therapy drug combination including cyclophosphamide, cytarabine, and a thiopurine.[6]
  • L-asparaginase for an extended period of time.[4,7]
  • Combinations of the above.[1,8,9]

Standard-risk ALL

In children with standard-risk acute lymphoblastic leukemia (ALL), there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.[10,11,12] For example, regimens utilizing a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase) have been used with good results for children with standard-risk ALL.[2,3,11] Similarly favorable results for standard-risk patients have been achieved with regimens utilizing multiple doses of L-asparaginase (20–30 weeks) as consolidation, without any postinduction exposure to alkylating agents or anthracyclines.[7,13]

Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of delayed intensification improved outcome for children with standard-risk ALL treated with regimens using a German Berlin-Frankfurt-Muenster (BFM) backbone.[14,15,16] The delayed intensification phase on such regimens, including those of the Children's Oncology Group, consists of a 3-week reinduction (including anthracycline) and reconsolidation containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 3 months after remission is achieved.[1,14,17] In a Children's Cancer Group (CCG) study for standard-risk ALL, which utilized dexamethasone for induction, a second delayed intensification phase provided no benefit in patients who were rapid early responders.[18]COG-1991 for NCI standard-risk patients compared escalating intravenous (IV) methotrexate in conjunction with vincristine versus a standard maintenance combination including oral methotrexate given during two interim maintenance phases. IV methotrexate produced a significant improvement in event-free survival (EFS), which was primarily a result of a decreased incidence of CNS relapse.[abstract]

High-risk ALL

In high-risk patients, a number of different approaches have been used with comparable efficacy.[7,19,20]; [17][Level of evidence: 2Di] Treatment for high-risk patients generally is more intensive than that for standard-risk patients, and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short- and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens. In a Dana-Farber Cancer Institute (DFCI) ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2 /dose to a cumulative dose of 300 mg/m2) or the same dose of doxorubicin with dexrazoxane during the induction and intensification phases of multiagent chemotherapy. Study results demonstrated that the use of the cardioprotectant dexrazoxane prior to doxorubicin resulted in better left ventricular fractional shortening and improved end-systolic dimension Z-scores without any adverse effect on EFS or increase in second malignancy risk compared with the use of doxorubicin alone 5 years posttreatment. In addition, a greater long-term protective effect was noted in girls compared to boys.[21,22]

The former CCG developed an augmented BFM treatment regimen featuring repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and L-asparaginase during interim maintenance and additional vincristine/L-asparaginase pulses during initial consolidation and delayed intensification. Augmented therapy also included a second interim maintenance and delayed intensification phase. In the CCG-1882 trial, National Cancer Institute (NCI) high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy. The augmented therapy regimen produced a significantly better EFS compared with standard CCG modified BFM therapy.[23] In an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to a prednisone prophase.[24]

The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies as well as therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among rapid early responders. Augmented therapy was associated with an improvement in EFS; there was no benefit associated with the administration of the second interim maintenance and delayed intensification phases.[25][Level of evidence: 1iiA] Of note, there was a significant incidence of osteonecrosis of bone in teenaged patients who received the augmented-BFM regimen.[26]

Very high-risk ALL

Approximately 10% to 20% of patients with ALL are classified as very high risk, including infants, those with adverse cytogenetic abnormalities (e.g., t[9;22], t[4;11], or low hypodiploidy [<44 chromosomes]) and poor response to initial therapy (e.g., high end-induction minimal residual disease [MRD] or high absolute blast count after a 7-day steroid prophase).[17,27] Patients who fail induction therapy are also at very high risk of subsequent relapse even if they achieve complete remission. Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase, often including agents not typically used in frontline ALL regimens for standard- and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide.[17] However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset.[17,28]

On some clinical trials, very high-risk patients have also been considered candidates for allogeneic stem cell transplantation (SCT) in first remission, [28,29,30] although it is not clear if outcomes are better with transplantation. In a European cooperative group study, very high-risk patients (defined as one of the following: morphologically persistent disease after a four-drug induction, t[9;22], t[4;11], or poor response to prednisone prophase in patients with either T-cell phenotype or presenting WBC >100,000/µL) were assigned to receive either an allogeneic SCT in first remission (based on the availability of a human lymphocyte antigen [HLA]-matched related donor) or intensive chemotherapy.[28] Using an intent-to-treat analysis, patients assigned to allogeneic SCT (on the basis of donor availability) had a superior 5-year disease-free survival (DFS) compared with those assigned to intensive chemotherapy (57% ± 7% for transplant versus 41% ± 3% for chemotherapy, P = .02); however, there was no significant difference in overall survival (OS) (56% ± 6% for transplant versus 50% ± 3% for chemotherapy, P = .12) . For patients with T- cell ALL and a poor response to prednisone prophase, both DFS and OS rates were significantly better with allogeneic SCT.[29] In another study of very high-risk patients, which included children with extremely high presenting leukocyte counts in addition to those with adverse cytogenetic abnormalities and/or initial induction failure (M2 marrow), allogeneic SCT in first remission was not associated with either a DFS or OS advantage.[30]

Maintenance Therapy

Backbone of maintenance therapy

The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. Clinical trials generally call for giving oral mercaptopurine in the evening, which is supported by evidence that this practice may improve EFS.[31] On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy.[32]

Treating physicians must also recognize that some patients may develop severe hematopoietic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[33,34] These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.[33,34] Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematopoietic toxicity than patients who are homozygous for the normal allele.[33]

The use of continuous 6-thioguanine (6-TG) instead of 6-mercaptopurine (6-MP) during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension.[35,36,37,38,39] Because of the risk of hepatic complications, 6-TG is no longer utilized in maintenance therapy in current protocols.

The Brazilian Childhood Cooperative group reported a variation in approach to maintenance therapy.[40][Level of evidence: 1A] In a cohort that was comprised of mostly lower-risk children, standard oral versus intermittent IV dosing of methotrexate (weekly vs. every three weeks) and 6-mercaptopurine (daily vs. 10 days on and 11 days off) was compared. Intermittently dosed medications were given at higher doses overall compared with standard dosing. In addition, boys on the protocol received only 2 years of therapy. A significant survival advantage was noted in boys receiving intermittent dosing, while the outcome with girls was equivalent. Because of differences in risk classification and OS rates slightly lower than reported by other groups, it is difficult to know whether the benefits this approach offered to boys would apply in other settings.

Vincristine/corticosteroid pulses

Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of intensive, multiagent regimens remains controversial.

A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients receiving monthly vincristine/prednisone pulses,[41] and a meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.[42,43] However, a systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials raised the question of whether such pulses are of value in current ALL treatment, which includes more intensive early therapy.[43]

In a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.[44] However, a small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving vincristine plus corticosteroid pulses. In that study, there was no difference in outcome based on type of steroid (prednisone vs. dexamethasone).[45][Level of evidence: 1iiA]

When steroid pulses are used during the maintenance phase, dexamethasone is preferred over prednisone for younger patients based on data from a CCG study, in which dexamethasone was compared with prednisone for children aged 1 to 9 years with lower-risk ALL.[14,46] On that trial, patients randomized to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.[14,46] In a Medical Research Council trial comparing dexamethasone versus prednisolone during induction and maintenance therapies in both standard-risk and high-risk patients, the EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.[47] The benefit of using dexamethasone in children aged 10 to 18 years requires further investigation because of the increased risk of steroid-induced osteonecrosis in this age group.[26,48]

Duration of maintenance therapy

Maintenance chemotherapy generally continues until 2 to 3 years of continuous complete remission. On some studies, boys are treated longer than girls;[14] on others, there is no difference in the duration of treatment based on gender.[7,17] It is not clear that longer duration of maintenance therapy reduces relapse in boys, especially in the context of current therapies.[17][Level of evidence: 2Di] Extending the duration of maintenance therapy beyond 3 years does not improve outcome.[42]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and protocols are designed for specific patient populations that have varying degrees of risk for treatment failure. The Cellular Classification and Prognostic Variables section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.

COG studies for standard-risk ALL

The COG recently opened a new trial for NCI standard-risk patients (COG-AALL0932). Patients receive a three-drug induction with dexamethasone, vincristine, and IV PEG-L-asparaginase. Patients are assigned to various postinduction treatments based on assessment of day 8 peripheral blood MRD, end-induction marrow MRD, and cytogenetics. No assessment of morphologic early response is performed.

  • Standard Risk – Low: Patients are included if they have day 8 peripheral blood MRD less than 0.01%, day 28 marrow MRD less than 0.01% and either t(12;21) or hyperdiploidy with additional copies of chromosomes 4 and 10 (favorable cytogenetics). Patients are randomly assigned to receive one of two postinduction treatments. The first treatment is POG-9404 therapy which includes a consolidation phase of six courses of IV methotrexate with leucovorin, oral 6-mercaptopurine, and intermittent dexamethasone and vincristine pulses. Patients do not receive a delayed intensification phase but proceed directly to maintenance, in which vincristine/dexamethasone pulses are given every 16 weeks. The second treatment is the standard arm of the COG-1991 study, which includes IV methotrexate without rescue in each of two interim maintenance phases, a standard reinduction, reconsolidation including doxorubicin, cyclophosphamide, and cytarabine, and maintenance with vincristine/dexamethasone pulses given every 12 weeks. Both regimens are expected to produce an EFS of approximately 95%.
  • Standard Risk – Average: All patients will have end-induction MRD less than 0.01%. This stratum will include patients with favorable cytogenetics and day 8 peripheral blood MRD greater than 0.01% and patients with non favorable and non unfavorable cytogenetics with less than 1% MRD in peripheral blood on day 8. Patients will be randomly assigned to receive either 20 mg/m2 or 40 mg/m2 of oral methotrexate during maintenance and every 4-week versus every 12-week pulses of vincristine and dexamethasone. Backbone therapy will consist of the IV methotrexate arm of COG-1991.
  • Standard Risk – with Down syndrome: NCI standard-risk patients with Down syndrome who show less than 0.01% MRD on day 28, regardless of day 8 peripheral blood MRD and cytogenetics, will receive post induction treatment on a separate arm of the trial.

All other patients who do not meet the above criteria will go off study at the end of induction and receive treatment at the discretion of the individual investigator. When the new COG high-risk study opens, such patients will be treated on that protocol.

Other studies

  • Total XVI study (TOTXVI): A study at St. Jude Children's Research Hospital is randomly assigning patients to receive either standard-dose (2,500 u/m2) or high-dose (3,500 u/m2) PEG-L-asparaginase during postremission therapy.
  • DFCI-05001: A DFCI Consortium protocol is comparing the relative efficacy and toxicity of IV PEG-L-asparaginase with intramuscular E. coli asparaginase during postinduction consolidation for patients in all risk groups. This protocol is also testing whether an intensified consolidation including high-dose cytarabine and etoposide improves the outcome for very high-risk patients (patients with high MRD at the end of remission induction, MLL translocations, or hypodiploidy [<44 chromosomes]).

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000.
2. Veerman AJ, Kamps WA, van den Berg H, et al.: Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet Oncol 10 (10): 957-66, 2009.
3. Mahoney DH Jr, Shuster JJ, Nitschke R, et al.: Intensification with intermediate-dose intravenous methotrexate is effective therapy for children with lower-risk B-precursor acute lymphoblastic leukemia: A Pediatric Oncology Group study. J Clin Oncol 18 (6): 1285-94, 2000.
4. Pui CH, Campana D, Pei D, et al.: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360 (26): 2730-41, 2009.
5. Tubergen DG, Gilchrist GS, O'Brien RT, et al.: Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial. J Clin Oncol 11 (3): 527-37, 1993.
6. Pui CH, Pei D, Sandlund JT, et al.: Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 24 (2): 371-82, 2010.
7. Silverman LB, Gelber RD, Dalton VK, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 97 (5): 1211-8, 2001.
8. Hann I, Vora A, Richards S, et al.: Benefit of intensified treatment for all children with acute lymphoblastic leukaemia: results from MRC UKALL XI and MRC ALL97 randomised trials. UK Medical Research Council's Working Party on Childhood Leukaemia. Leukemia 14 (3): 356-63, 2000.
9. Rizzari C, Valsecchi MG, Aricò M, et al.: Effect of protracted high-dose L-asparaginase given as a second exposure in a Berlin-Frankfurt-Münster-based treatment: results of the randomized 9102 intermediate-risk childhood acute lymphoblastic leukemia study--a report from the Associazione Italiana Ematologia Oncologia Pediatrica. J Clin Oncol 19 (5): 1297-303, 2001.
10. Veerman AJ, Hählen K, Kamps WA, et al.: High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia. Results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. J Clin Oncol 14 (3): 911-8, 1996.
11. Chauvenet AR, Martin PL, Devidas M, et al.: Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201. Blood 110 (4): 1105-11, 2007.
12. Gustafsson G, Kreuger A, Clausen N, et al.: Intensified treatment of acute childhood lymphoblastic leukaemia has improved prognosis, especially in non-high-risk patients: the Nordic experience of 2648 patients diagnosed between 1981 and 1996. Nordic Society of Paediatric Haematology and Oncology (NOPHO) Acta Paediatr 87 (11): 1151-61, 1998.
13. Pession A, Valsecchi MG, Masera G, et al.: Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol 23 (28): 7161-7, 2005.
14. Gaynon PS, Angiolillo AL, Carroll WL, et al.: Long-term results of the children's cancer group studies for childhood acute lymphoblastic leukemia 1983-2002: a Children's Oncology Group Report. Leukemia 24 (2): 285-97, 2010.
15. Riehm H, Gadner H, Henze G, et al.: Results and significance of six randomized trials in four consecutive ALL-BFM studies. Hamatol Bluttransfus 33: 439-50, 1990.
16. Hutchinson RJ, Gaynon PS, Sather H, et al.: Intensification of therapy for children with lower-risk acute lymphoblastic leukemia: long-term follow-up of patients treated on Children's Cancer Group Trial 1881. J Clin Oncol 21 (9): 1790-7, 2003.
17. Möricke A, Reiter A, Zimmermann M, et al.: Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111 (9): 4477-89, 2008.
18. Matloub Y, Angiolillo A, Bostrom B, et al.: Double delayed intensification (DDI) is equivalent to single DI (SDI) in children with National Cancer Institute (NCI) standard-risk acute lymphoblastic leukemia (SR-ALL) treated on Children's Cancer Group (CCG) clinical trial 1991 (CCG-1991). [Abstract] Blood 108 (11): A-146, 2006.
19. Gaynon PS, Steinherz PG, Bleyer WA, et al.: Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106. J Clin Oncol 11 (11): 2234-42, 1993.
20. Pui CH, Mahmoud HH, Rivera GK, et al.: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92 (2): 411-5, 1998.
21. Lipshultz SE, Scully RE, Lipsitz SR, et al.: Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 11 (10): 950-61, 2010.
22. Barry EV, Vrooman LM, Dahlberg SE, et al.: Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J Clin Oncol 26 (7): 1106-11, 2008.
23. Nachman JB, Sather HN, Sensel MG, et al.: Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 338 (23): 1663-71, 1998.
24. Aricò M, Valsecchi MG, Conter V, et al.: Improved outcome in high-risk childhood acute lymphoblastic leukemia defined by prednisone-poor response treated with double Berlin-Frankfurt-Muenster protocol II. Blood 100 (2): 420-6, 2002.
25. Seibel NL, Steinherz PG, Sather HN, et al.: Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 111 (5): 2548-55, 2008.
26. Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000.
27. Schultz KR, Pullen DJ, Sather HN, et al.: Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG). Blood 109 (3): 926-35, 2007.
28. Balduzzi A, Valsecchi MG, Uderzo C, et al.: Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 366 (9486): 635-42, 2005 Aug 20-26.
29. Schrauder A, Reiter A, Gadner H, et al.: Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol 24 (36): 5742-9, 2006.
30. Ribera JM, Ortega JJ, Oriol A, et al.: Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol 25 (1): 16-24, 2007.
31. Schmiegelow K, Glomstein A, Kristinsson J, et al.: Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol Oncol 19 (2): 102-9, 1997 Mar-Apr.
32. Davies HA, Lilleyman JS: Compliance with oral chemotherapy in childhood lymphoblastic leukaemia. Cancer Treat Rev 21 (2): 93-103, 1995.
33. Relling MV, Hancock ML, Rivera GK, et al.: Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91 (23): 2001-8, 1999.
34. Andersen JB, Szumlanski C, Weinshilboum RM, et al.: Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 87 (1): 108-11, 1998.
35. Broxson EH, Dole M, Wong R, et al.: Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy. Pediatr Blood Cancer 44 (3): 226-31, 2005.
36. De Bruyne R, Portmann B, Samyn M, et al.: Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia. J Hepatol 44 (2): 407-10, 2006.
37. Vora A, Mitchell CD, Lennard L, et al.: Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet 368 (9544): 1339-48, 2006.
38. Jacobs SS, Stork LC, Bostrom BC, et al.: Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative Children's Oncology Group/National Cancer Institute pilot trial (CCG-1942). Pediatr Blood Cancer 49 (3): 250-5, 2007.
39. Stork LC, Matloub Y, Broxson E, et al.: Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial. Blood 115 (14): 2740-8, 2010.
40. Brandalise SR, Pinheiro VR, Aguiar SS, et al.: Benefits of the intermittent use of 6-mercaptopurine and methotrexate in maintenance treatment for low-risk acute lymphoblastic leukemia in children: randomized trial from the Brazilian Childhood Cooperative Group--protocol ALL-99. J Clin Oncol 28 (11): 1911-8, 2010.
41. Bleyer WA, Sather HN, Nickerson HJ, et al.: Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group. J Clin Oncol 9 (6): 1012-21, 1991.
42. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Childhood ALL Collaborative Group. Lancet 347 (9018): 1783-8, 1996.
43. Eden TO, Pieters R, Richards S, et al.: Systematic review of the addition of vincristine plus steroid pulses in maintenance treatment for childhood acute lymphoblastic leukaemia - an individual patient data meta-analysis involving 5,659 children. Br J Haematol 149 (5): 722-33, 2010.
44. Conter V, Valsecchi MG, Silvestri D, et al.: Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet 369 (9556): 123-31, 2007.
45. De Moerloose B, Suciu S, Bertrand Y, et al.: Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood 116 (1): 36-44, 2010.
46. Bostrom BC, Sensel MR, Sather HN, et al.: Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 101 (10): 3809-17, 2003.
47. Mitchell CD, Richards SM, Kinsey SE, et al.: Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 129 (6): 734-45, 2005.
48. Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 19 (12): 3066-72, 2001.

Postinduction Treatment for Specific ALL Subgroups

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric Treatment Editorial Board uses a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

T-cell ALL

Historically, patients with T-cell ALL have had a worse prognosis than children with precursor B-cell ALL. With current treatment regimens, outcomes for children with T-cell ALL are now approaching those achieved for children with precursor B-cell ALL. For example, the 5-year event-free survival (EFS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI) Consortium ALL protocols was 75% compared with 84% for children with precursor B-cell ALL.[1]

Treatment options

Protocols of the former Pediatric Oncology Group (POG) treated children with T-cell ALL differently from children with B-lineage ALL. The POG-9404 protocol for patients with T-cell ALL was designed to evaluate the role of high-dose methotrexate. The multiagent chemotherapy regimen for this protocol was based on the DFCI-87001 regimen.[2] Results of an interim analysis of the POG protocol led investigators to conclude that the addition of high-dose methotrexate to the DFCI-based chemotherapy regimen resulted in significantly improved EFS, due in large measure to a decrease in the rate of central nervous system (CNS) relapse (estimated 3-year EFS 80%).[3] This POG study was the first clinical trial to provide evidence that high-dose methotrexate can improve outcome for children with T-cell ALL. High-dose asparaginase and doxorubicin were also important components of this regimen.[1,3]

Protocols of the former Children's Cancer Group (CCG) treated children with T-cell ALL on the same treatment regimens as children with precursor B-cell ALL, basing protocol and treatment assignment on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and the disease response to initial therapy. Most children with T-cell ALL meet National Cancer Institute (NCI) high-risk criteria. Results from CCG-1961 showed that an augmented Berlin-Frankfurt-Muenster (BFM) regimen with a single delayed intensification course produced the best results for patients with morphologic rapid response to initial induction therapy (estimated 5-year EFS 83%).[4] Almost 60% of events in this group, however, were isolated CNS relapses. Overall results from POG-9404 and CCG-1961 were similar, though POG-9404 used cranial radiation for every patient while CCG-1961 used cranial radiation only for patients with slow morphologic response.[5,3] Among children with NCI standard-risk T-cell ALL, the EFS for children treated on CCG-1952 and COG-1991 studies was inferior to the EFS for children treated on the POG-9404 study.[6]

In the Children's Oncology Group (COG), children with T-cell ALL are no longer treated on the same protocols as children with precursor B-cell ALL. Pilot studies from the COG have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) [7,8] in the context of a BFM regimen for patients with newly diagnosed T-cell ALL; efficacy is being evaluated in the current trial.[9]

The role of prophylactic cranial radiation in the treatment of T-cell ALL is controversial. Some groups, such as St. Jude Children's Research Hospital (SJCRH) and the Dutch Childhood Oncology Group (DCOG), do not use cranial radiation in first-line treatment of ALL, while other groups, such as DFCI, COG, and BFM, use radiation for the majority of patients with T-cell ALL.

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • COG-AALL0434: COG-AALL0434 is a phase III trial for patients aged 1 to 30 years with T-cell ALL utilizing a modified augmented BFM regimen. Patients are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and minimal residual disease (MRD) level at day 29. The objectives of the trial are (1) to determine the safety and efficacy of adding nelarabine to the modified augmented BFM regimen in high- and intermediate-risk patients, (2) to determine the relative safety and efficacy of high-dose (5 g/m2) versus Capizzi escalating lower dose methotrexate without rescue during interim maintenance, and (3) to test the efficacy of treating NCI standard-risk T-cell ALL patients who are rapid responders (about 15% of patients) without cranial radiation.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with T-cell childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Infants With ALL

Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL.[10] Because of their distinctive biological characteristics and their high risk for leukemia recurrence, infants with ALL are treated on protocols specifically designed for this patient population. Common therapeutic themes of the intensive chemotherapy regimens used to treat infants with ALL are the inclusion of postinduction intensification courses with high doses of cytarabine and methotrexate.[11,12,13] Despite intensification of therapy, long-term EFS rates remain below 50%, and for those infants with MLL gene rearrangement, the EFS rates continue to be in the 17% to 40% range.[11,12,14,15,16][Level of evidence: 2A] Factors predicting poor outcome for infants with MLL translocations include a very young age (<6 months), extremely high presenting leukocyte count (=200,000–300,000/µL), and high levels of MRD at the end of induction and consolidation phases of treatment.[12]; [17][Level of evidence: 3iDii] Infants with congenital leukemia (diagnosed within 1 month of birth) have a particularly poor outcome (17% overall survival).[16][Level of evidence: 2A]

Treatment options

Infants with MLL gene translocations are generally treated on intensified chemotherapy regimens using agents not typically incorporated into frontline therapy for older children with ALL. However, despite these intensified approaches, EFS rates remain poor for these patients. The international Interfant clinical trials consortium utilized a cytarabine-intensive chemotherapy regimen, with increased exposure to both low- and high-dose cytarabine during the first few months of therapy, resulting in a 5-year EFS of 37% for infants with MLL translocations.[12] The COG tested intensification of therapy with a regimen including multiple doses of high-dose methotrexate, cyclophosphamide, and etoposide, with a 5-year EFS of 34%.[11]

The role of allogeneic stem cell transplant during first remission in infants with MLL gene translocations remains controversial. Case series have suggested that allogeneic transplants in first remission may be effective.[18,19,20]; [21][Level of evidence: 3iA] In a COG report that included 189 infants treated on CCG or POG infant ALL protocols between 1996 and 2000, there was no difference in EFS between patients who received stem cell transplant (SCT) in first complete remission (CR) and those who received chemotherapy alone.[22] The Interfant clinical trials group, after adjusting for waiting time to transplantation, also did not observe any difference in disease-free survival (DFS) in high-risk infants (defined by prednisone response) with MLL translocations treated on the Interfant-99 trial with either allogeneic SCT in first CR or chemotherapy alone.[12] However, in a subset analysis from the same trial, allogeneic SCT in first remission was associated with a significantly better DFS for infants with MLL translocations who were younger than 6 months at diagnosis and had either a poor response to steroids at day 8 or leukocytes =300 g/L.[23] In this subset, SCT in first remission was associated with a 64% reduction in the risk of failure resulting from relapse or death compared with chemotherapy alone.

The optimal treatment for infants without MLL translocations also remains unclear. On the Interfant-99 trial, such patients achieved a relatively favorable outcome with the cytarabine-intensive treatment regimen (4-year EFS was 74%).[12] A favorable outcome for this subset of patients was obtained in a Japanese study using therapy comparable to that used to treat older children with ALL;[14] however, that study was limited by small numbers.

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • Interfant-06 Study Group trial: The Interfant-06 Study Group is conducting an international collaborative randomized trial (including sites in the United States) to test whether an ALL/acute myeloid leukemia hybrid regimen might improve outcomes for infants with MLL-rearranged ALL. The role of allogeneic transplantation in first remission is also being assessed in high-risk patients (defined as infants with MLL-rearranged ALL, younger than 6 months, and WBC >300,000 /µL) or poor peripheral blood response to steroid prophase. Infants with MLL-rearranged ALL with high MRD at end of consolidation phase are also eligible for allogeneic SCT in first remission regardless of other presenting features).
  • COG-AALL0631: In this COG study of infant ALL, an FLT3 inhibitor, lestaurtinib, is being studied in infants with MLL rearrangement. Infants with MLL rearrangement are known to have a high level of FLT3 mRNA expression and lestaurtinib has been shown to selectively kill MLL-rearranged ALL cells in vitro and in vivo.[24] This study combines lestaurtinib with intensive chemotherapy previously utilized in POG-P9407. There is an initial safety/activity phase followed by an efficacy phase in which children will be randomly assigned to chemotherapy with or without lestaurtinib. Infants with germline MLL will be nonrandomly assigned to less-intensive chemotherapy without lestaurtinib.

Adolescent Patients with ALL

Treatment options

Older children and adolescents (>10 years) with ALL more frequently present with adverse prognostic factors at diagnosis, including T-cell immunophenotype and Philadelphia chromosome–positivity, and have a lower incidence of favorable cytogenetic abnormalities.[25,26] These patients have a less favorable outcome than children aged 1 to 9 years at diagnosis, and more aggressive treatments are generally employed.[27] A study from France of patients aged 15 to 20 years and diagnosed between 1993 and 1999, demonstrated superior outcome for patients treated on a pediatric trial (67%; 5-year EFS) compared with patients treated on an adult trial (41%; 5-year EFS).[28]

Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens.[26,29,30,31]; [32][Level of evidence: 2A] For instance, the DFCI ALL Consortium reported a 5-year EFS of 78% in adolescents aged 15 to 18 years in a pediatric trial.[26] In the COG high-risk study (CCG-1961), the 5-year EFS rate for patients aged 16 to 21 years was 71.5%.[33][Level of evidence: 1iiDi] For rapid responders randomized to early intensive postinduction therapy on the augmented intensity arms of this study, the 5-year EFS rate was 82%. In a SJCRH study, 44 adolescents aged 15 to 18 years had an EFS of approximately 85% ± 5%.[34] Also, in a Spanish study, adolescents (aged 15–18 years) and young adults (aged 19–30 years) with standard risk ALL were treated with a pediatric-based regimen.[32][Level of evidence: 2A] The complete remission rate was 98%, EFS rate was 61%, and overall survival rate was 69%, with no differences in outcome between adolescents and young adults. Given the relatively favorable outcome that can be obtained in these patients with chemotherapy regimens used for pediatric ALL, there is no role for the routine use of allogeneic SCT in first remission for adolescents and young adults with ALL.[33]

The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not known, although possible explanations include treatment setting (i.e., site experience in treating ALL), adherence to protocol therapy, and the components of protocol therapy.[29] Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[26,35,36,37] High body mass index is also a risk factor for osteonecrosis,[38] and may be associated with a higher relapse rate in older patients.[39]

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • COG-AALL0434: This is a phase III trial for patients aged 1 to 30 years with T-cell ALL utilizing a modified augmented BFM regimen. Patients are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and MRD level at day 29. The objectives of the trial are (1) to determine the safety and efficacy of adding nelarabine to the modified augmented BFM regimen in high- and intermediate-risk patients, (2) to determine the relative safety and efficacy of high-dose versus Capizzi methotrexate during interim maintenance, and (3) to test the efficacy of treating low-risk T-cell ALL patients without cranial radiation.
  • CALGB-10403: This is a phase II trial for adolescent and young adults aged 15 to 40 years with newly diagnosed ALL (B-cell or T-cell) treated with a regimen that is nearly identical to the Capizzi methotrexate arm of the COG-AALL0232 trial and treated by adult hematologists/oncologists at multiple sites.
  • OSU-08066: DFCI protocol 06-254 (OSU-08066) is a phase II trial conducted by the DFCI ALL Consortium for patients aged 18 to 50 years with newly diagnosed ALL. The treatment regimen is identical to the very high-risk arm on the pediatric DFCI protocol, DFCI-05001, and includes 30 weeks of postinduction consolidation with intravenous PEG-asparaginase (given every 2 weeks). Older adolescents (aged 15–18 years) are treated on pediatric protocol DFCI-05001 as high-risk patients.

Philadelphia Chromosome–Positive ALL

Treatment options

Prior to use of imatinib mesylate (see below), hematopoietic stem cell transplantation (HSCT) from a matched sibling donor was the treatment of choice for patients with Philadelphia chromosome–positive (Ph+) ALL.[40,41,42] Data to support this include a retrospective multigroup analysis of children and young adults with Ph+ ALL, in which HSCT from a matched sibling donor was associated with a better outcome compared with standard (pre-imatinib) chemotherapy.[43] In this retrospective analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome. However, in a follow-up study by the same group evaluating outcomes in the subsequent decade (pre-imatinib era), transplantation with matched-related or matched-unrelated donors were equivalent. Disease-free survival at the 5-year time point showed an advantage for transplantation in first remission compared with chemotherapy that was borderline significant (P = .049), and overall survival was also higher for transplantation compared with chemotherapy, although the advantage at 5 years was not significant.[44]

Factors significantly associated with favorable prognosis in the pre-imatinib era included younger age and lower leukocyte count at diagnosis.[44] Early response measures were also shown to be prognostically significant in patients with Ph+ ALL in the pre-imatinib era.[44,45,46] Patients with Ph+ ALL who showed a rapid morphologic response or peripheral blood response to induction therapy had an improved outcome compared with patients who showed a slow response.[44,45] Following MRD by reverse transcription polymerase chain reaction for the BCR-ABL fusion transcript may also be useful to help predict outcome for Ph+ patients.[47,48,49]

Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and II studies of single-agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively high response rates, although these responses tended to be of short duration.[50,51] Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[52,53,54] Preliminary outcome for results for adults with Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[55,56,57]

The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with Ph+ ALL. Patients received imatinib mesylate in conjunction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic SCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases. The 3-year EFS for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib was 87.7% ± 10.9%. These patients fared better than historic controls treated with chemotherapy alone (without imatinib), and at least as well as the other patients on the trial who underwent allogeneic transplantation.[54] Longer follow-up is necessary to determine if this novel treatment improves cure rate or merely prolongs DFS.

As opposed to imatinib, dasatinib, a second-generation inhibitor of tyrosine kinases, is currently being studied in the initial treatment of Ph+ ALL. Of note, dasatinib has shown significant activity in the CNS, both in a mouse model and a series of patients with CNS-positive leukemia.[58]

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • COG-AALL0622: In this COG study, patients receive a second-generation tyrosine kinase inhibitor, dasatinib, with increased affinity for BCR/ABL1, in conjunction with the same chemotherapy regimen used in the COG-AALL0031 trial. The goals of this study are to determine the safety and feasibility of substituting dasatinib for imatinib and to measure the 3-year EFS.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with Philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Goldberg JM, Silverman LB, Levy DE, et al.: Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol 21 (19): 3616-22, 2003.
2. LeClerc JM, Billett AL, Gelber RD, et al.: Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber ALL Consortium Protocol 87-01. J Clin Oncol 20 (1): 237-46, 2002.
3. Asselin B, Shuster J, Amylon M, et al.: Improved event-free survival (EFS) with high dose methotrexate (HDM) in T-cell lymphoblastic leukemia (T-ALL) and advanced lymphoblastic lymphoma (T-NHL): a Pediatric Oncology Group (POG) study. [Abstract] Proceedings of the American Society of Clinical Oncology A-1464, 2001.
4. Seibel NL, Asselin BL, Nachman JB, et al.: Treatment of high risk T-cell acute lymphoblastic leukemia (T-ALL): comparison of recent experience of the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG). [Abstract] Blood 104 (11): A-681, 2004.
5. Seibel NL, Steinherz PG, Sather HN, et al.: Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 111 (5): 2548-55, 2008.
6. Matloub Y, Asselin BL, Stork LC, et al.: Outcome of children with T-Cell acute lymphoblastic leukemia (T-ALL) and standard risk (SR) features: results of CCG-1952, CCG-1991 and POG 9404. [Abstract] Blood 104 (11): A-680, 195a, 2004.
7. Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005.
8. Kurtzberg J, Ernst TJ, Keating MJ, et al.: Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol 23 (15): 3396-403, 2005.
9. Dunsmore K, Devidas M, Borowitz MJ, et al.: Nelarabine can be safely incorporated into an intensive, multiagent chemotherapy regimen for the treatment of T-cell acute lymphocytic leukemia (ALL) in children: a report of the Children's Oncology Group (COG) AALL00P2 protocol for T-cell leukemia. [Abstract] Blood 108 (11): A-1864, 2006.
10. Silverman LB: Acute lymphoblastic leukemia in infancy. Pediatr Blood Cancer 49 (7 Suppl): 1070-3, 2007.
11. Hilden JM, Dinndorf PA, Meerbaum SO, et al.: Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 108 (2): 441-51, 2006.
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15. Biondi A, Rizzari C, Valsecchi MG, et al.: Role of treatment intensification in infants with acute lymphoblastic leukemia: results of two consecutive AIEOP studies. Haematologica 91 (4): 534-7, 2006.
16. van der Linden MH, Valsecchi MG, De Lorenzo P, et al.: Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol. Blood 114 (18): 3764-8, 2009.
17. Van der Velden VH, Corral L, Valsecchi MG, et al.: Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 23 (6): 1073-9, 2009.
18. Sanders JE, Im HJ, Hoffmeister PA, et al.: Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia. Blood 105 (9): 3749-56, 2005.
19. Eapen M, Rubinstein P, Zhang MJ, et al.: Comparable long-term survival after unrelated and HLA-matched sibling donor hematopoietic stem cell transplantations for acute leukemia in children younger than 18 months. J Clin Oncol 24 (1): 145-51, 2006.
20. Jacobsohn DA, Hewlett B, Morgan E, et al.: Favorable outcome for infant acute lymphoblastic leukemia after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11 (12): 999-1005, 2005.
21. Kosaka Y, Koh K, Kinukawa N, et al.: Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 104 (12): 3527-34, 2004.
22. Dreyer ZE, Dinndorf PA, Camitta B, et al.: Analysis of the role of hematopoietic stem-cell transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene rearrangements: a report from the Children's Oncology Group. J Clin Oncol 29 (2): 214-22, 2011.
23. Mann G, Attarbaschi A, Schrappe M, et al.: Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study. Blood 116 (15): 2644-50, 2010.
24. Brown P, Levis M, McIntyre E, et al.: Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner. Leukemia 20 (8): 1368-76, 2006.
25. Möricke A, Zimmermann M, Reiter A, et al.: Prognostic impact of age in children and adolescents with acute lymphoblastic leukemia: data from the trials ALL-BFM 86, 90, and 95. Klin Padiatr 217 (6): 310-20, 2005 Nov-Dec.
26. Barry E, DeAngelo DJ, Neuberg D, et al.: Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols. J Clin Oncol 25 (7): 813-9, 2007.
27. Nachman J: Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia. Br J Haematol 130 (2): 166-73, 2005.
28. Boissel N, Auclerc MF, Lhéritier V, et al.: Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 21 (5): 774-80, 2003.
29. Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia: emerging from the shadow of paediatric and adult treatment protocols. Pediatr Blood Cancer 47 (6): 748-56, 2006.
30. Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 48 (3): 254-61, 2007.
31. Stock W, La M, Sanford B, et al.: What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 112 (5): 1646-54, 2008.
32. Ribera JM, Oriol A, Sanz MA, et al.: Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Español de Tratamiento en Hematología pediatric-based protocol ALL-96. J Clin Oncol 26 (11): 1843-9, 2008.
33. Nachman JB, La MK, Hunger SP, et al.: Young adults with acute lymphoblastic leukemia have an excellent outcome with chemotherapy alone and benefit from intensive postinduction treatment: a report from the children's oncology group. J Clin Oncol 27 (31): 5189-94, 2009.
34. Pui CH, Pei D, Campana D, et al.: Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol 29 (4): 386-91, 2011.
35. Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000.
36. Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 19 (12): 3066-72, 2001.
37. Bürger B, Beier R, Zimmermann M, et al.: Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)--experiences from trial ALL-BFM 95. Pediatr Blood Cancer 44 (3): 220-5, 2005.
38. Niinimäki RA, Harila-Saari AH, Jartti AE, et al.: High body mass index increases the risk for osteonecrosis in children with acute lymphoblastic leukemia. J Clin Oncol 25 (12): 1498-504, 2007.
39. Butturini AM, Dorey FJ, Lange BJ, et al.: Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol 25 (15): 2063-9, 2007.
40. Mori T, Manabe A, Tsuchida M, et al.: Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13. Med Pediatr Oncol 37 (5): 426-31, 2001.
41. Dombret H, Gabert J, Boiron JM, et al.: Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia--results of the prospective multicenter LALA-94 trial. Blood 100 (7): 2357-66, 2002.
42. Hahn T, Wall D, Camitta B, et al.: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 11 (11): 823-61, 2005.
43. Aricò M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342 (14): 998-1006, 2000.
44. Aricò M, Schrappe M, Hunger SP, et al.: Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol 28 (31): 4755-61, 2010.
45. Roy A, Bradburn M, Moorman AV, et al.: Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial. Br J Haematol 129 (1): 35-44, 2005.
46. Schrappe M, Aricò M, Harbott J, et al.: Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 92 (8): 2730-41, 1998.
47. Cazzaniga G, Lanciotti M, Rossi V, et al.: Prospective molecular monitoring of BCR/ABL transcript in children with Ph+ acute lymphoblastic leukaemia unravels differences in treatment response. Br J Haematol 119 (2): 445-53, 2002.
48. Jones LK, Saha V: Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol 130 (4): 489-500, 2005.
49. Lee S, Kim YJ, Chung NG, et al.: The extent of minimal residual disease reduction after the first 4-week imatinib therapy determines outcome of allogeneic stem cell transplantation in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer 115 (3): 561-70, 2009.
50. Champagne MA, Capdeville R, Krailo M, et al.: Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study. Blood 104 (9): 2655-60, 2004.
51. Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100 (6): 1965-71, 2002.
52. Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004.
53. Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24 (3): 460-6, 2006.
54. Schultz KR, Bowman WP, Aledo A, et al.: Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol 27 (31): 5175-81, 2009.
55. Burke MJ, Trotz B, Luo X, et al.: Allo-hematopoietic cell transplantation for Ph chromosome-positive ALL: impact of imatinib on relapse and survival. Bone Marrow Transplant 43 (2): 107-13, 2009.
56. Lee S, Kim YJ, Min CK, et al.: The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 105 (9): 3449-57, 2005.
57. de Labarthe A, Rousselot P, Huguet-Rigal F, et al.: Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood 109 (4): 1408-13, 2007.
58. Porkka K, Koskenvesa P, Lundán T, et al.: Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 112 (4): 1005-12, 2008.

Treatment of Recurrent ALL

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric Treatment Editorial Board uses a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Prognostic Factors in Recurrent ALL

The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on the time from diagnosis to relapse and site of relapse, as well as cytogenetics and immunophenotype.[1,2,3,4,5,6,7,8,9,10,11,12,13]; [14][Level of evidence: 3iiDi] For patients with relapsed B-precursor ALL, early relapses fare worse than later relapses, and marrow relapses fare worse than isolated extramedullary relapses. For instance, survival rates after marrow relapse range from less than 20% for patients with marrow relapses occurring within 18 months from diagnosis to 40% to 50% for those whose relapses occur more than 36 months from diagnosis.[5,13] For patients with isolated central nervous system (CNS) relapses, the overall survival (OS) rates for early relapse (<18 months from diagnosis) are 40% to 50% and are 75% to 80% for those with late relapses (>18 months from diagnosis).[13,15] No evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.[16]

Patients who have combined marrow/extramedullary relapses fare better than those with isolated marrow relapses.[5,13] The Berlin-Frankfurt-Muenster (BFM) group has also reported that high peripheral blast counts at the time of relapse (>10,000/µL) were associated with inferior outcomes in patients with late marrow relapses.[10] The Children's Oncology Group (COG) reported that risk group classification at the time of initial diagnosis was prognostically significant after relapse; patients who met National Cancer Institute (NCI) standard-risk criteria at initial diagnosis fared better after relapse than did NCI high-risk patients.[13] Age older than 10 years has also been reported as an independent predictor of poor outcome.[13]

Immunophenotype is an important prognostic factor at relapse. Patients with T-cell ALL who experience a marrow relapse (isolated or combined) at any point during treatment or posttreatment have a very poor prognosis.[5]

Patients with marrow relapses who have persistent morphologic disease at the end of the first month of reinduction therapy have an extremely poor prognosis, even if they subsequently achieve a second remission (CR2).[17][Level of evidence: 2Di] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of CR2 are of prognostic significance in relapsed ALL.[17,18,19,20]; [21][Level of evidence: 3iiiDi] High levels of MRD at the end of reinduction and at later time points have been correlated with an extremely high risk of subsequent relapse.

Treatment of Bone Marrow Relapse

Reinduction chemotherapy

Initial treatment of relapse consists of induction therapy to achieve a CR2. Using either a four-drug reinduction regimen (similar to that administered to newly diagnosed high-risk patients) or an alternative regimen including high-dose methotrexate and high-dose cytarabine, approximately 85% of patients with a marrow relapse achieve a CR2 at the end of the first month of treatment.[5];[22][Level of evidence: 2A]; [17][Level of evidence: 2Di] A United Kingdom-based randomized trial of patients with relapsed ALL compared reinduction with a four-drug combination using idarubicin versus mitoxantrone. A significant improvement in OS in the mitoxantrone arm (69% vs. 45%, P = .007) due to decreased relapse was reported.[23][Level of evidence: 1iiA] The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation. Patients with early marrow relapses have a lower rate of achieving a morphologic CR2 (approximately 70%) compared with those with late marrow relapses (approximately 95%).[17,22] Compared with patients with B-precursor phenotype, patients with relapsed T-cell ALL have much lower rates of achieving CR2 with standard reinduction regimens.[17] Treatment of children with first relapse of T-cell ALL in the bone marrow with single-agent therapy using the T-cell selective agent, nelarabine, has resulted in response rates of approximately 50%.[24] The combination of nelarabine, cyclophosphamide, and etoposide has produced remissions in patients with relapsed/refractory T-cell ALL.[25]

Other combinations of agents have been reported to induce remissions in patients with multiple-relapsed or refractory ALL. The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 56% of patients with refractory or relapsed disease.[26]

Postreinduction therapy (second complete remission)

Post-CR2 therapy for patients who experience a bone marrow relapse (either isolated or combined) while on therapy or within 6 months of discontinuing therapy generally includes hematopoietic stem cell transplantation (HSCT).[27,28] For B-precursor patients with an early marrow relapse, allogeneic transplant from a human leukocyte antigen (HLA)-identical sibling or matched unrelated donor that is performed in second remission has been reported in most studies to result in longer leukemia-free survival when compared with a chemotherapy approach.[7,21,29,30,31,32,33,34,35] However, even with transplantation, the survival rate for patients with early marrow relapse is less than 50%.

For patients with a late marrow relapse of B-precursor ALL, a primary chemotherapy approach after achievement of CR2 has resulted in survival rates of approximately 50%, and it is not clear whether allogeneic transplantation is associated with superior cure rate.[9,36,37] End-reinduction MRD levels may help to identify patients with a high risk of subsequent relapse if treated with chemotherapy alone (no SCT) in CR2. In a St. Jude Children's Research Hospital study, which included 23 patients with late relapses treated with chemotherapy in CR2, the 2-year cumulative incidence of relapse was 49% for the 12 patients who were MRD-positive at the end of reinduction and 0% for the 11 patients who were MRD-negative.[19] Whether transplantation benefits patients with late marrow relapse but a high level of MRD after reinduction treatment requires further study.

For patients with T-cell ALL and marrow relapse, outcomes with chemotherapy alone have generally been poor,[5] and these patients are usually treated with allogeneic SCT in CR2, regardless of time to relapse.

For patients proceeding to allogeneic SCT, total-body irradiation (TBI) appears to be an important component of the conditioning regimen. Two retrospective studies and a randomized trial suggest that transplant conditioning regimens that include TBI produce higher cure rates than chemotherapy-only preparative regimens.[29,38,39] TBI is often combined with either cyclophosphamide or etoposide. Results with either drug are generally equivalent,[40] although one study suggested that if cyclophosphamide is used, higher-dose TBI may be necessary.[41] The potential neurotoxic effects of TBI should be considered, particularly for very young patients.

In addition to the conditioning regimen, disease status at the time of transplantation also appears to be an important predictor of outcome. Several studies have demonstrated that the level of MRD at the time of transplant is an important predictor of survival in patients in CR2.[20,42,43]

Outcomes following matched unrelated donor and umbilical cord blood transplants have improved significantly over the past decade and may offer outcome similar to that obtained with matched sibling donor transplants.[33,44,45,46,47]; [48][Level of evidence: 2A]; [49][Level of evidence: 3iiiA] Rates of clinically extensive graft-versus-host disease (GVHD) and treatment-related mortality (TRM) remain higher with unrelated than with matched sibling transplants.[34,44,50] However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate, and National Marrow Donor Program and Center for International Blood and Marrow Transplant Research (CIBMTR) analyses have demonstrated that rates of GVHD, TRM, and OS have improved over time.[51]; [52,53][Level of evidence: 3iiA] Another CIBMTR study suggests that outcome after one or two antigen mismatched cord blood transplants may be equivalent to that for a matched family donor or a matched unrelated donor.[54] In certain cases in which no suitable donor is found or an immediate transplant is considered crucial, a haploidentical transplant utilizing large doses of stem cells may be considered.[55] For T cell-depleted CD34-selected haploidentical transplants in which a parent is the donor, patients receiving maternal stem cells may have a better outcome than those who receive paternal stem cells.[56][Level of evidence: 3iiA] There are a number of new options under study for preventing subsequent relapse after transplantation, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and natural killer cell therapy.[57]

For patients relapsing after an allogeneic HSCT for relapsed ALL, a second ablative allogeneic HSCT may be feasible. However, many patients will be unable to undergo a second HSCT procedure due to failure to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy.[58] Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT, approximately 10% to 30% may achieve long-term event-free survival (EFS).[58,59,60] Prognosis is more favorable in patients with longer duration of remission after the first HSCT and in patients with complete remission at the time of the second HSCT.[59,60] Reduced intensity approaches can also cure a percentage of patients when used as a second allogeneic transplant approach, but only if patients achieve a complete remission confirmed by flow cytometry.[61][Level of evidence: 2A] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.[62]; [63][Level of evidence: 3iiiA] Whether a second allogeneic transplant is necessary to treat isolated CNS and testicular relapse is unknown, and a small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.[64][Level of evidence: 3iA]

Treatment of Extramedullary Relapse

With the improved success of treatment of children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of isolated CNS relapse is less than 5% and testicular relapse is less than 1% to 2%.[65,66,67] Age older than 6 years at diagnosis is an adverse prognostic factor for patients with an isolated extramedullary relapse.[68] In the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques,[69] and successful treatment strategies must effectively control both local and systemic disease. Patients with an isolated CNS relapse who show greater than 0.01% MRD in a morphologically normal marrow have a worse prognosis compared with patients with either no MRD or MRD less than 0.01%.[69]

CNS relapse

While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by cranial or craniospinal radiation has improved the outlook, particularly for patients who did not receive cranial radiation during their first remission.[15,70,71,72] In a Pediatric Oncology Group (POG) study using this strategy, children who had not previously received radiation therapy and whose initial remission was 18 months or greater had a 4-year EFS rate of approximately 80% compared with EFS rates of approximately 45% for children with CNS relapse within 18 months of diagnosis.[72] In a follow-up POG study, children who had not previously received radiation therapy and with initial remission of 18 months or more were treated with intensive systemic and intrathecal chemotherapy for 1 year followed by 18 Gy of cranial radiation only.[15] The 4-year EFS was 78%. Children with an initial remission of less than 18 months also received the same chemotherapy but had craniospinal radiation (24 Gy cranial/15 Gy spinal) as in the first POG study and achieved a 4-year EFS of 52%.

A number of case series describing SCT in the treatment of isolated CNS relapse have been published.[73,74] In a study comparing outcome of patients treated with either HLA-matched sibling transplants or chemoradiotherapy as in the POG studies above, 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar (58% and 66%, respectively).[75][Level of evidence: 3iiiDii] This retrospective, registry-based study included transplantation of both early (<18 months from diagnosis) and late relapses. Because of the relatively good outcome of patients with isolated CNS relapse more than 18 months from diagnosis treated with chemoradiation therapy alone (>75%), transplantation is generally not recommended for this group. However, use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study. The use of post-HSCT intrathecal chemotherapy has been controversial, although the most current data would suggest no benefit.[76]

Testicular relapse

The results of treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year EFS of boys with overt testicular relapse during therapy is approximately 40%; it is approximately 85% for boys with late testicular relapse.[77] The standard approach for treating isolated testicular relapse in North America is to administer chemotherapy plus radiation therapy. In some European clinical trial groups, orchiectomy of the involved testicle is performed instead of radiation. Biopsy of the other testicle is performed at the time of relapse to determine if additional local control (surgical removal or radiation) is to be performed. While there are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy, the use of chemotherapy (e.g., high-dose methotrexate) that may be able to achieve antileukemic levels in the testes is being tested in clinical trials. Dutch investigators treated five boys with a late testicular relapse with high-dose methotrexate during induction (12 g/m2) and at regular intervals during the remainder of therapy (6 g/m2) without testicular radiation. All five boys were long-term survivors.[78] A study that looked at testicular biopsy at the end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult disease.[79] In a small series of boys who had an isolated testicular relapse after a SCT for a prior systemic relapse of ALL, five of seven boys had extended EFS without a second SCT.[64][Level of evidence: 3iA]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

Children's Oncology Group (COG)

The COG has divided patients with relapse into three risk categories as outlined in Table 1. Clinical trials in some risk categories are available.

Table 1. COG B-Cell ALL Relapse Risk Stratificationa and Clinical Trials

ALL = acute lymphoblastic leukemia; CNS = central nervous system; COG = Children's Oncology Group.
a All relapsed T-cell ALL is considered high risk—COG-AALL07P1.
b All intermediate-risk patients with matched siblings choosing allogeneic transplant, and all high-risk patients undergoing related or unrelated transplantation are encouraged to enroll in ASCT0431 (see below) after completion of the three induction blocks associated with these protocols.
  Isolated CNS or Testicular Relapse [Clinical Trial] Bone Marrow or Combined Relapse [Clinical Trial]
<18 months from diagnosis Intermediate risk [COG-AALL0433]b High risk [COG-ADVL04P2]b
18–36 months from diagnosis   High risk [COG-ADVL04P2]b
>36 months from diagnosis   Intermediate risk [COG-AALL0433]b
  • COG-ADVL04P2: Patients with high-risk relapse are eligible for this study. Epratuzumab (an anti-CD22 monoclonal antibody) is given in conjunction with a four-drug reinduction (Block 1). Two additional blocks of therapy are given after Block 1. MRD is determined by flow cytometry after each course once a remission is achieved.
    • Block 1: vincristine, prednisone, PEG-L-asparaginase, doxorubicin; cytarabine (by lumbar puncture) and methotrexate (by lumbar puncture) with epratuzumab.
    • Block 2: etoposide, cyclophosphamide, methotrexate (intravenously and by lumbar puncture).
    • Block 3: high-dose cytarabine, L-asparaginase.
  • COG-AALL0433: Patients with intermediate-risk relapse are eligible for this study. Patients in this study will receive a chemotherapy regimen similar to POG studies, POG-9061 and POG-9412, which have been shown to be efficacious in the isolated relapse setting and well tolerated. Intensification of vincristine is being studied in a randomized fashion. For patients with a matched sibling, the choice of bone marrow transplant or chemotherapy is left to the discretion of the treating physician and/or family. The vincristine randomization has been closed for patients younger than 10 years at diagnosis due to increased toxicity in the higher-dose vincristine arm.
  • COG-AALL07P1: Patients with relapse of T-cell ALL are eligible for this study. This is a phase II pilot study to determine the feasibility and safety of adding bortezomib to intensive reinduction chemotherapy. Bortezomib is a proteasome inhibitor that has been shown to sensitize leukemic cells to apoptosis induced by chemotherapy.
  • COG-ASCT0431: Patients with very high-risk CR1 (primary induction failure, hypodiploid [<44 chromosomes], Ph+ with high MRD) ALL or CR2 (B cell relapse <36 months, T-cell or Ph+ bone marrow relapse and any donor or bone marrow relapse =36 months, isolated extramedullary relapse <18 months and matched sibling donors only) ALL are eligible. This phase III transplant trial randomizes a standard tacrolimus/methotrexate graft-versus-host disease prophylaxis approach with tacrolimus/methotrexate/sirolimus. The hypothesis is that the anti-leukemic effects of the mTOR inhibitor, sirolimus, will decrease relapse and improve survival.

Other clinical trials investigating new agents and new combinations of agents are available for children with recurrent ALL and should be considered.[80,81,82] Targeted therapies specific for ALL are being developed, including monoclonal antibody-based therapies and using drugs that inhibit signal transduction pathways required for leukemia cell growth and survival.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

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2. Uderzo C, Conter V, Dini G, et al.: Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies. Haematologica 86 (1): 1-7, 2001.
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58. Mehta J, Powles R, Treleaven J, et al.: Outcome of acute leukemia relapsing after bone marrow transplantation: utility of second transplants and adoptive immunotherapy. Bone Marrow Transplant 19 (7): 709-19, 1997.
59. Eapen M, Giralt SA, Horowitz MM, et al.: Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant 34 (8): 721-7, 2004.
60. Bosi A, Laszlo D, Labopin M, et al.: Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol 19 (16): 3675-84, 2001.
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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board. Board members review recently published articles each month to determine whether an article should:

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  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Acute Lymphoblastic Leukemia Treatment are:

  • Robert J. Arceci, MD, PhD (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
  • Michael A. Pulsipher, MD (Primary Children's Medical Center)
  • Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
  • Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Malcolm Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2011-07-15

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