Characteristics and Outcome of Patients with Chronic Myeloid Leukemia (CML) and T315I Mutation Following Failure of Imatinib Mesylate Therapy.
Authors: Jabbour Elias , Kantarjian Hagop , Jones Dan , Verstovsek Srdan , Ferrajoli Alessandra , Ravandi Farhad , O’Brien Susan , Cortes Jorge 
Published: April 2020

Background. T315I is an imatinib pocket binding mutation within the Bcr-Abl kinase domain that is highly resistant, both in vitro and in vivo, to imatinib and to 2nd generation tyrosine kinase inhibitors (TKIs). Several studies have suggested that patients with T315I have a poor outcome.

Study Aims. The objectives of this study were to define the clinical characteristics of patients harboring the T315I mutation, and to assess their outcome after imatinib failure.

Results. T315I was detected in 27 pts: 20 among a series of 186 pts assayed after imatinib failure (11% of all pts; 21% of all mutations detected) after a median of 37 months (mos) from start of imatinib, and 7 among 23 pts who developed new mutations after a median of 10 mos on therapy with a 2nd generation TKI. Median age was 52 years. Median time from diagnosis to T315I was 41 mos, and the median follow-up from the detection of mutation is 18 mos. At the time of T315I detection, 10 pts were in CP, 9 in AP, and 8 in BP. Fifteen pts (56%) had transformed to accelerated or blast phase at the time of T315I detection. Best response to TKI immediately preceding development of T315I (20 imatinib, 2 nilotinib, 2 dasatinib, 2 bosutinib, 1 INNO-406) was CHR in 13 (48%) and CyR in 9 (33%; complete in 6, partial in 1, minor in 2). The median duration of response was 44 mos. Except for the lack of response to a second TKI (p=0.001), there was no difference in pt characteristics between pts with or without T315I, other mutations, or no mutations. Among the 20 pts with T315I present prior to start of 2nd TKI, 5 responded, all hematologic (3 complete hematologic response -CHR-, 2 partial hematologic response -PHR-, 1 return to chronic phase); in contrast all 5 pts without T315I prior to 2nd TKI, responded (1 major molecular response -MMR-, 2 Minor cytogenetic response -CyR-, 1 CHR, 1 PHR); and among the 2 pts with unknown T315I status at start of 2nd TKI 1 had PHR and 1 complete cytogenetic response -CCyR-. Responses were usually transient but 3 pts had sustained responses for some time despite presence of T315I: 1 pt in AP harboring simultaneously F317L and G250E acquired a T315I mutation 5 mos after the start of nilotinib and achieved MMR that was sustained for 21 mos eventually lost to major CyR. A 2nd pt in AP treated with bosutinib acquired a T315I mutation 6 months after the start of bosutinib, but nonetheless achieved a minor CyR that has been sustained for more than 8 mos. A third patient with Y253H mutation developed T315I 1 mo after therapy with INNO-406 for CML AP; at the last follow-up, 4 months into therapy, he maintained a PHR. 4/14 pts (38%) treated with T315I-directed agents (aurora kinase inhibitors, homoharringtonine) responded. 4 pts received allogeneic stem cell transplant (ASCT) and 2 are alive: 1 in CMR 24+ months after ASCT and 1 in CCyR 9 months after ASCT, wit molecular relapse and recurrence of T315I. 11/27 pts with T315I (40%) died. Patients in CP had better outcome with 87% 2-year survival, compared to 45% in AP and 20% in BP. Survival of patients with T315I was similar to those with other mutations or without mutations (p=0.64).

Conclusion. Altough T315I is a mutation highly resistant to conventional BCR-ABL TKI, occasional responses can be observed. Overall survival of patients with T315I mutations is mostly dependent on the stage of the disease.