Multiparameter analysis of homogeneously R-CHOP-treated diffuse large B cell lymphomas identifies CD5 and FOXP1 as relevant prognostic biomarkers: report of the prospective SAKK 38/07 study

Research

Alexandar Tzankov^1*, Nora Leu¹, Simone Muenst¹, Darius Juskevicius¹, Dirk Klingbiel², Christoph Mamot³ and Stephan Dirnhofer¹

• *
  Corresponding author: Alexandar Tzankov [email protected]

Author Affiliations

¹ Institute of Pathology, University Hospital Basel, Schoenbeinstrasse 40, Basel, CH-4031, Switzerland

² Swiss Group for Clinical Cancer Research (SAKK), Effingerstrasse 40, Bern, CD-3008, Switzerland

³ Division of Hematology and Oncology, Cantonal Hospital Aarau, Tellstrasse house Nr. 40, Aarau, CH-5001, Switzerland

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Journal of Hematology Oncology 2015, 8:70 
doi:10.1186/s13045-015-0168-7

Published: 14 June 2015

Abstract (provisional)

Background The prognostic role of tumor-related parameters in diffuse large B cell
lymphoma (DLBCL) is a matter of controversy. Methods We investigated the prognostic
value of phenotypic and genotypic profiles in DLBCL in clinical trial (NCT00544219)
patients homogenously treated with six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin,
vincristine, prednisone (R-CHOP), followed by two cycles of R (R-CHOP-14). The primary
endpoint was event-free survival at 2 years (EFS). Secondary endpoints were progression-free
(PFS) and overall survival (OS). Immunohistochemical (bcl2, bcl6, CD5, CD10, CD20,
CD95, CD168, cyclin E, FOXP1, GCET, Ki-67, LMO2, MUM1p, pSTAT3) and in situ hybridization
analyses (BCL2 break apart probe, C-MYC break apart probe and C-MYC/IGH double-fusion
probe, and Epstein–Barr virus probe) were performed and correlated with the endpoints.
Results One hundred twenty-three patients (median age 58 years) were evaluable. Immunohistochemical
assessment succeeded in all cases. Fluorescence in situ hybridization was successful
in 82 instances. According to the Tally algorithm, 81 cases (66 %) were classified
as non-germinal center (GC) DLBCL, while 42 cases (34 %) were GC DLBCL. BCL2 gene
breaks were observed in 7/82 cases (9 %) and C-MYC breaks in 6/82 cases (8 %). “Double-hit”
cases with BCL2 and C-MYC rearrangements were not observed. Within the median follow-up
of 53 months, there were 51 events, including 16 lethal events and 12 relapses. Factors
able to predict worse EFS in univariable models were failure to achieve response according
to international criteria, failure to achieve positron emission tomography response
(p?lt;?0.005), expression of CD5 (p?=?0.02), and higher stage (p?=?0.021). Factors
predicting inferior PFS were failure to achieve response according to international
criteria (p?lt;?0.005), higher stage (p?=?0.005), higher International Prognostic
Index (IPI; p?=?0.006), and presence of either C-MYC or BCL2 gene rearrangements (p?=?0.033).
Factors predicting inferior OS were failure to achieve response according to international
criteria and expression of FOXP1 (p?lt;?0.005), cyclin E, CD5, bcl2, CD95, and pSTAT3
(p?=?0.005, 0.007, 0.016, and 0.025, respectively). Multivariable analyses revealed
that expression of CD5 (p?=?0.044) and FOXP1 (p?=?0.004) are independent prognostic
factors for EFS and OS, respectively. Conclusion Phenotypic studies with carefully
selected biomarkers like CD5 and FOXP1 are able to prognosticate DLBCL course at diagnosis,
independent of stage and IPI and independent of response to R-CHOP.