Clinical Characteristics and Outcome of Patients (pts) with F317L BCR-ABL Kinase Domain (KD) Mutation after Therapy with Tyrosine Kinase Inhibitors (TKIs).
Authors: Jabbour Elias , Kantarjian Hagop , Jones Dan , O’Brien Susan , Garcia-Manero Guillermo , Burger Jan , Cortes Jorge 
Published: April 2020

Background. Point mutations of the Bcr-Abl KD are the most frequently identified mechanism of resistance in pts with CML who failed TKI. The setting for outgrowth of different mutations and their subsequent response to different TKIs varies significantly. For example, mutations in codon 317, which would be predicted to impair dasatinib binding, have been generated during in vitro mutagenesis with dasatinib but not nilotinib, and the F317L, in particular, has been reported following treatment with dasatinib.

Aims. We assessed the incidence and pattern of development F317L mutations in pts with TKI-resistant CML at our institution and responses following change in therapy.

Results. F317L mutation was detected in 20 patients: 12 occurred among 99 pts (12%) after imatinib failure who had KD mutation assessment, and 8 among 16 pts (50%) who developed new mutations on dasatinib therapy (among 77 treated) (p=0.001). Median age for all pts with F317L was 49 years (range, 34–66 years). Pts had received imatinib for a median of 23 months (mo) (range, 2–69). Best response to imatinib was complete hematologic response in 11 and cytogenetic response in 8 (5 complete, 2 partial, 1 minor). One pt did not respond. At the time the mutation was detected, 8 pts were in chronic (CP), 6 in accelerated (AP) and 6 in blast phase (BP). Patients with F317L-mutated tumors developing on imatinib or dasatinib had similar characteristics as those who had KD mutations at other sites or no mutation detected. Among pts with F317L at start of 2nd TKI, 3 received dasatinib and all 3 had transient hematologic responses (best response) (1 partial -PHR-, 2 complete -CHR-) lasting 4, 12 and 19 mo;.4 were treated with nilotinib and 3 responded (1 CHR, 1 major molecular response-MMR-,1 complete molecular response -CMR-); 2 had imatinib dose escalation after appearance of F317L and both had a sustained complete cytogenetic response (CCyR) for 24+ and 26+ months; one pt received stem cell transplant and is in CMR 20 months after transplant; one pt did not respond to a combination of imatinib and farnesyl transferase inhibitor; and one pt was lost of follow-up with no further therapy. Among pts who developed F317L while on dasatinib (n=8), 4 never responded and 4 had an initial response to dasatinib (1 CHR, 3 CCyR) lost after a median of 15 months (range, 3 to 26); one pf these was then treated with nilotinib and achieved an ongoing CCyR for 3+ months and 2 received bosutinib after failing both nilotinib and dasatinib, achieving a transient CHR lasting 6 and 9 months, respectively. After a median follow-up of 29 months from treatment failure and 25 months from the detection of F317L, 10 pts (50%) are alive (7 CP, 2 AP, 1 BP at F317L). Median survival of pts with F317L from mutation detection was 19 mo. Survival of pts with F317L was similar to those with other mutations or without mutation when survival was dated from the time of treatment failure (p=0.51) or from mutation detection (p=0.92).

Conclusion. F317L occurs more frequently after dasatinib therapy paralleling the findings of in vitro studies. TKIs showing differential in vitro activity against this mutation (e.g. nilotinib or INNO-406) may represent good candidates for treatment failure associated with F317L-mutated tumors.