Kinase Domain Mutations and Responses to Dose Escalation in Chronic Myeloid Leukemia Resistant to Standard Dose Imatinib Mesylate.

There is no published data on imatinib mesylate (IM) resistance mutations and responses to dose escalation in Indian patients. This study analysed kinase domain (KD) mutations, response to dose escalation, event free survival (EFS) and overall survival (OS) of chronic phase CML (CP CML) patients resistant to IM 400mg. Patients and Methods: Patients with CP-CML resistant to IM 400 mg by European Leukemia Net (ELN) guidelines were screened for known KD mutations using nested PCR and gene sequencing. The IM dose was escalated to 800mg daily. Patients in accelerated (AP) or blast phases (BC) were excluded. Only patients with at least one cytogenetic evaluation after 6 months of dose escalation were analysed. EFS was defined as time from dose escalation to loss of complete hematologic (CHR) or major cytogenetic response (MCR), progression to AP/BC, no complete hematologic response at 3 months, no cytogenetic response at 6 months, less than MCR at 12 months and no complete cytogenetic response (CCR) at 18 months or death from any cause. OS was defined as time from dose escalation to death. Results: There were 90 patients with a median age of 36 years (range, 18-65) and M: F of 2.4:1. None had been on previous therapies other than IM 400mg. Median duration on IM 400 at resistance detection was 18 months (range, 3-48).Trigger for resistance testing was primary hematologic resistance (HR) in 10 (11.1%), primary cytogenetic resistance (CR) in 20 (22.2%), secondary HR in 55 (61.1%) and secondary CR in 5 (5.5%). Twenty nine (32.2%) patients had KD mutations. Of the 29, the most common were T315I in 9 patients (31.2%), G250E in 8 (27.6%), followed by F359V in 4 (13.8%) and M244V in 2 (6.8%). Y253F, Y253H, N374Y, L248V, H396R, and E355G were detected in 1(3.4%) patient each. Age, gender (male vs female, p=1), Sokal score at diagnosis (low + intermediate vs high, p=0.82), duration of IM prior to resistance (< vs ≥ 2 years, p=0.46) and trigger for testing (hematologic vs cytogenetic failure, p=0.14) did not predict for mutation detection. Of 90 patients, 11 (12.2%) with mutations that conferred absolute resistance to IM (T315I, Y253F, Y253H) were excluded from response, EFS and OS analysis.The median time to cytogenetic evaluation for the remaining 79 patients was 9 months (range, 6-13). The response to dose escalation is in Table 1. The type of resistance (primary vs secondary, p=0.1) and the mutation status (presence or absence, p=1.0) did not influence achievement of MCR. Patients with hematologic failure were less likely to achieve MCR compared to cytogenetic failure, 29 vs 76% (p=0.0002). At a median follow up of 18 months (range, 6-40), 35 (45%) patients are event free and 76 (93%) are alive. There were 44 events: failure to achieve CHR in 29 (66%), loss of CHR in 2 (4%), failure to achieve cytogenetic response in 7 (16%), progression to AP/BC in 3 (7%) and 3 (7%) deaths. Out of 44 patients with an event, 9 (19%) went on a clinical trial, 3 (7%) on dasatinib and 29 (66%) on hydroxyurea or no therapy. The following factors predicted for longer EFS: cytogenetic vs hematologic failure (not reached vs 18 months, p=0.0001), MCR vs others (41 vs 14 months, p=<0.0001) and primary vs secondary resistance (41 vs 20 months, p=0.03). The adverse events are in Table 2. Dose decreases were necessary in 16 (20%) and dose interruptions in 31 (39%).Three patients (7%) permanently discontinued IM due to adverse events. Conclusions: KD mutations were detected in a third of patients with resistance to IM 400 mg.T315I was the most common mutation. A quarter of patients achieved CCR after dose escalation. Majority of patients were hematologic failures resulting in inferior cytogenetic responses and EFS. IM dose escalation induced sustained responses in patients with cytogenetic failures. IM 800mg was well tolerated.

No relevant conflicts of interest to declare.