Case report: rapid and durable response to PDGFR targeted therapy in a child with refractory multiple infantile myofibromatosis and a heterozygous germline mutation of the PDGFRB gene
Despite the finding that the patient exhibited a partial response to systemic VAC treatment, the disease continued to progress; moreover, the patient experienced severe, life threatening dose-limiting toxicities.
Inflammatory myofibroblastic tumors that harbor an ALK/ROS1 or PDGFR? kinase fusion are potentially targetable with TKIs due to the presence of a constitutively active kinase domain that drives cellular proliferation [6, 16]. A response to the ALK inhibitor crizotinib is reported in tumors that harbor any of the ALK kinase fusions. Patients with IMT and ALK negative rearrangements are unlikely to respond to such targeted treatment.
PDGFRB mutations are reported to be involved in the pathogenesis of infantile myofibromatosis in a proposed autosomal dominant pattern with incomplete penetrance and variable expressivity [7]. The missense PDGFRB c.1681CT (R681C) mutation is located in exon 12 and is predicted to decrease the autoinhibition of the JM domain (an autoinhibitory domain that masks the catalytic cleft when the receptor is not bound by its ligand) at baseline, which leads to increased kinase firing and promotes the formation of myofibromas in tissues with high PDGFR? signaling activity. More recently, it was demonstrated in a cell culture model that the R561C mutation activates signaling pathways that are normally activated by the stimulated wild-type PDGFR? receptor in the absence of PDGF [14]. PDGFR is the immediate NOTCH3 target gene [17]. If these two signaling pathways are linked and the IM disease-causing mutations in either PDGFRB or NOTCH3 are demonstrated to be activating, theoretically, the inhibition of PDGFRB or NOTCH3 would result in a targeted therapeutic strategy [7]. Our case report shows the clinical efficacy of such an approach. Targeted therapy against altered PDGFR? with a TKIs inhibitor can overcome tumor growth and can lead to tumor shrinkage. Compared to the toxicity of conventional chemotherapy, treatment with sunitinib was tolerated well except for the occurrence of asymptomatic granulocytopenia and one episode of symptomatic hypoglycemia. However, the cessation of the drug lead to increased tumor activity and a decreased drug dose of the single agent sunitinib led to a stable disease only.
The analysis of tumor tissue or a patient’s samples and the use of a subsequent results driven treatment provide a new opportunity for personalized medicine as opposed to a population based study. Such treatments are supported by new insights into the molecular pathology of rare diseases, such as IM. A similar strategy would at least justify the off-label use of new drugs when the individual tumor biology and data about the safety of such drugs is well defined. TKIs could be an example, as these drugs are not available to orphan disease patients because of the absence of appropriate clinical trials. The careful management and regular observation of the patient is mandatory, however, in situations where standard approaches are either exploited or ineffective or absent, the prudent use of targeted agents based on the mechanism of action might lead to impressive results.
The rapid tumor re-growth that occurred when the patient was off of the sunitinib during the induction treatment indicates that metronomic dosing should be maintained at a lower dose with limited toxicity rather than being interrupted. The successful use of low dose vinblastine that is described here, together with the use of sunitinib at a dose of approximately 1/3 of the usually recommended dose per kg or m2 in adults, could be at least in part explained by the fact that targeted agents could act as biology response modifiers and lower doses of biological agents and chemotherapy could be nontoxic and advantageous [18, 19]. This theory is supported by our observation of the clear disease progression when sunitinib therapy was interrupted. Regular observations of the patient and preemptive measures such as the after-feeding dosing of sunitinib should be considered during treatment.
The finding of the Slavic mutation of the NBS was noted as accidental during NGS sequencing and the relevance for the disease course is unknown. The toxicity of chemotherapy might be at least in part conditioned by the NBS mutation As known, the intensity of chemotherapy in NBS patients must be adapted to individual risk factors and tolerance. The use of radiomimetics, alkylating agents, and epipodophyllotoxins should be avoided, and the dose of methotrexate should be limited [20].
However, the overall duration of such clinically effective treatment remains speculative, especially in patients with germline mutations. Different approaches that consider cancer to be a chronic disease, such as diabetes, should be considered in instances in which pathogenic germline mutations are in place. Should such targeted agents be maintained for a very long time, e.g., maintenance therapies in childhood acute leukemia, where other mechanisms of action, not only the cytostatic effect are in place? [21]. Should some pulses of targeted agents be considered?
These are only a few of the new questions that arose by the increased availability of diagnostic methods, such as NGS and functional proteomics.
The patients with an orphan disease like IM could benefit from detailed insights into the biology of their tumor and genome. Such approach is necessary to better understand the molecular pattern of disease and mechanisms of action of less toxic and effective drugs except for up to date population-based chemotherapy regimens. Morover, an unexpected finding of germline mutation can be important for treatment decisions. Progressive and resistant incurable infantile myofibromatosis can be successfully treated with the new approach described herein.