Clinical Characteristics and Outcome of Patients (pts) with V299L BCRABL Kinase Domain (KD) Mutation after Therapy with Tyrosine Kinase Inhibitors (TKIs).

Background. Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding.

Aims. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML and Ph+ ALL at our institution, and the response following change of therapy.

Results. V299L mutation was detected in 14 pts (12 CML, 2 Ph+ ALL): 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 47 pts (19%) who developed mutations on dasatinib therapy, and 4 among 18 pts (22%) who developed mutations on bosutinib therapy (p<0.001); none of the 49 pts who developed mutations on nilotinib therapy acquired V299L. Median age was 55 years (range, 26–82 years). Seven pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). Nine pts developed V299L after being on dasatinib for a median of 14 mos (range, 1–30 mos); 7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib. In 4 pts V299L appeared after receiving bosutinib as 3^rd TKI after imatinib and dasatinib failure, for a median of 5 mos (range, 2–8 mos). None of the 11 evaluable pts treated with 2^nd generation TKIs had V299L at start of therapy. The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 4 bosutinib) was complete hematologic response only in 5 (36%, 4 dasatinib, 1 bosutinib), minor cytogenetic response in 2 (14%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (29%; 3 dasatinib, 1 bosutinib); no response in 3 pts (1 dasatinib, 2 bosutinib). The median duration of response was 14 mos. V299L was associated with primary resistance in 3 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 4 pts were in chronic (CP), 7 in accelerated (AP), 1 in blast phase (BP), and 2 with Ph+ ALL. 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 responded (major molecular response sustained for 16+ mos). One pt received INNO406 and did not respond. One pt with Ph+ ALL was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 8 mos (range, 3–29 mos), from the time V299L was detected, 4 died (1 CP, 1 BP, 2 ALL). The estimated 2-year survival from mutation detection was 74%.

Conclusion. V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation.