Sorafenib Monotherapy Is Effective In Relapsed and RefractoryFlt3-ITD Positive Acute Myeloid Leukemia, Particularly After Allogenic Stem Cell Transplantation

Abstract

AbstractAbstract 3314 Introduction:The FLT3-internal tandem duplication is the most frequent genetic aberration in normal karyotype acute myeloid leukemia (NK-AML) and associated with a poor prognosis. Patients with FLT3-ITD positive AML relapsing after allogenic stem cell transplantation (allo-SCT) have very limited therapeutic options. Sorafenib is a multikinase inhibitor, which is approved in Europe for the treatment of metastatic renal cell and hepatocellular carcinoma. It inhibits the FLT3 receptor tyrosine kinase, and, at low nanomolar concentrations also the mutated variant of FLT3, FLT3-ITD. Sorafenib also inhibits Raf, the platelet derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR). We have previously reported that sorafenib monotherapy is effective in relapsed FLT3-ITD positive AML (Metzelder et al., Blood 2009; Metzelder et al., ASH 2009, poster #2060). Here we significantly extend these compassionate use experiences by reporting on clinical response details from 39 relapsed or refractory FLT3-ITD positive AML patients treated with sorafenib monotherapy. Methods:A questionnaire was developed and sent to 60 centers in Germany, Singapore and the United States, where FLT3-ITD-positive patients had been treated with sorafenib monotherapy. 26 centers returned information on therapy details of 55 patients. These included data on age, FAB-classification, karyotype, FLT3-ITD molecular testing, type and duration of response to prior therapy and to sorafenib, sorafenib dosing and tolerability. 16 patients were excluded from further analysis because of FLT3-ITD negativity or application of chemotherapy concomitant to sorafenib. Results:There were 39 evaluable patients (20 male, 19 female), grouped into i) primary refractory patients (PR-P) (n=11), receiving one (n=5) or two cycles (n=6) of chemotherapy before commencing sorafenib, ii) relapsing patients (REL-P) (n=12) with hematological recurrence after between one and four cycles of prior chemotherapy, syngenic, or autologous SCT, and iii) patients relapsing after allogenic SCT (SCT-P) (n=16). One patient was treated first line with sorafenib. One patient was treated before and after allo-SCT. Patients received between 200mg and 800mg sorafenib p.o. daily. The median treatment duration was 71 days (range, 13 to 270) for PR-P, 76 days (range, 9 to 160 days) for REL-P, and 76 days (range, 20 to 489 days) for SCT-P. All reported patients in this cohort responded to sorafenib. In the PR-P group, there were 6 hematological remissions (HR), characterized by complete (n=4) or near complete peripheral blast clearance (n=2), 4 complete remissions (bone marrow blasts < 5% with (CR) or without (CRp) normalization of peripheral blood counts) and one complete molecular remission (CMR, molecular negativity for FLT3-ITD). Six of these 11 PR-P underwent allo-SCT after responding to sorafenib induction. In the REL-P group there was one patient with a partial blast clearance (PR), 8 HR, 2 bone marrow responses (which includes a HR) and 1 CRp. In the SCT-P group there were 3PR, 2HR, 7 BMR and 4 CMR. Notably, the median time to treatment failure due to frank clinical sorafenib resistance was 119 days for PR-P and REL-P, but was not reached in the SCT-P group. This difference was statistically significant (p-value 0.0217). Sorafenib was generally well tolerated. Pancytopenia or thrombocytopenia grade III and IV were the most significant but manageable side effects. Other reported side effects such as diarrhea, exanthema were documented from the centers as being minor. Conclusion:This analysis on a large cohort of 39 FLT3-ITD positive patients confirms our previous reports on the remarkable clinical activity of sorafenib monotherapy in FLT3-ITD positive AML. Evidence is accumulating that sorafenib may be particularly effective in the context of allo-SCT, where long-term responses were seen. Disclosures:No relevant conflicts of interest to declare.