The role of mutation testing in patients with chronic myeloid leukemia in chronic phase after imatinib failure and their outcomes after treatment modification: Single-institutional experience over 13 years

Abstract

Introduction:BCR-ABL1 kinase domain mutations represent the most frequent mechanism of resistance to tyrosine kinase inhibitor (TKI) therapy, being detected in 40%–50% of imatinib-resistant patients with chronic myeloid leukemia in chronic phase (CML-CP). Over 100 BCR-ABL1 single-point mutations have been reported in patients with imatinib-resistant CML. There were few studies reported from India on BCR-ABL kinase mutations in imatinib failure patients. We present our data on imatinib resistance mutation analysis (IRMA) and use of imatinib dose hike and 2nd-generation TKI at our institute.Materials and Methods:All patients with a diagnosis of CML in a university hospital from June 2003 to July 2016 and who were tested for IRMA in view of imatinib failure, those in CP, and age <18 years were included in the study.Results:A total of 2110 cases of CML reviewed and 269 cases of CML with imatinib failure were analyzed. The male to female ratio was 1.7:1. The median age at presentation was 36 years (range: 18–66 years). Among these, 26% were primary failures and 74% were secondary failures. The treatment was modified either as imatinib dose hike or nilotinib/dasatinib. Molecular response at 12 months was achieved in 25.7% in imatinib dose hike, 46.6% in nilotinib, and 53.8% in dasatinib arms. The 4-year overall survival in mutation detected group was 37.5% and in nonmutated group was 87.7%.Conclusion:Imatinib-resistant mutations were more common in the cases with secondary failure though not statistically significant. T315I mutation was the common mutation found in the study. Imatinib dose hike to the failure cases resulted in optimal hematological response rates.

A Retrospective Analysis of BCR-ABL1 Kinase Domain Mutations in the Frontline Drug Intolerant or Resistant Chronic Myeloid Leukemia Patients: An Indian Experience from a High-End Referral Laboratory

“…This is in corroboration with previous Indian patient reports by Chaitanya et al 16 and Rajappa et al 15 describing TKD mutations in 33 and 29% CML patients, respectively. Overall, the incidence of TKD mutation has been reported in 30 to 50% imatinib-intolerant patients worldwide.…”

“…Overall, the incidence of TKD mutation has been reported in 30 to 50% imatinib-intolerant patients worldwide. 27 28 29 30 Gender distribution of the present cohort is comparable to Chandrasekhar et al, 2 Tripathi et al, 7 and Chaitanya et al 16 but is significantly different from Patkar et al 19 and Rajappa et al 15 We also observe a slightly higher median age in comparison to other studies ( Table 2 and 4 ). In addition, treatment resistant cases that harbored a mutation ( n = 236) in the BCR-ABL1 KD show that the female gender has a markedly lower presentation of resistant mutations suggesting alternative mechanisms that may possibly be contributing to their suboptimal response to therapy.…”

“…Although there have been a few studies describing the BCR-ABL1 KD mutation patterns from India; however, these studies are restricted to specific geographic locations. 7 14 15 16 17 18 19 Herein, we sought to identify and characterize the patterns of KD mutation in one of the largest cohorts of Indian CML patients across the country, especially those who presented with resistance or intolerance to frontline therapy.…”

Overcoming Secondary Mutations of Type II Kinase Inhibitors

“…Numerous studies have reported on the frequency of secondary mutations following treatment with type II inhibitors. Although the rankings of mutation frequencies may vary slightly, the gatekeeper mutation T315I consistently emerges as the most frequent mutation after imatinib treatment. − For quizartinib, mutations associated with the D835 residue in the A-loop are prevalent. , Notably, mutations at these two locations pose significant challenges for type II inhibitors to overcome and require specific efforts from medicinal chemists. ,, …”