Characteristics and Outcome of Patients (pts) with V299L BCR-ABL Kinase Domain (KD) Mutation After Therapy with Tyrosine Kinase Inhibitors (TKIs).

Abstract 3428

Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML 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.

We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML at our institution, and the response following change of therapy. V299L mutation was detected in 15 pts with CML: 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 69 of the 170 evaluable (i.e., had abl sequencing) pts (13%) who developed mutations on dasatinib, and 5 among 19 of the 72 evaluable pts (26%) who developed mutations on bosutinib (p<0.001); none of the 51 pts who developed mutations on nilotinib (among 125 tested) acquired V299L. Median age for pts with V299L was 56 years (range, 26–82 years). Eight pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). The median time to development of V299L was 14 mos (range, 1–30 mos) for those treated with dasatinib (7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib), and 13 mos (range, 2–48 mos) for those treated with bosutinib (after imatinib failure in 1, and as 3rd TKI after imatinib and dasatinib failure).

The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 5 bosutinib) was complete hematologic response only in 6 (40%, 4 dasatinib, 2 bosutinib), minor cytogenetic response in 2 (13%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (27%; 3 dasatinib, 1 bosutinib); no response in 3 pts (20%; 1 dasatinib, 2 bosutinib). The median duration of response was 17 mos.

V299L was associated with primary resistance in 4 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, 5 pts were in chronic (CP), 7 in accelerated (AP), and 3 in blast phase (BP). 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 in CPresponded (major molecular response sustained for 40+ mos). One pt received INNO406 and did not respond. One pt in BP 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 23 mos (range, 3–48 mos), from the time V299L was detected, 8 died (4 CP and 4 BP).

In 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 if treated in chronic phase, but more data is need to evaluate the long-term benefit of this approach.