Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations

Abstract

Dasatinib is a BCR-ABL inhibitor with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Imatinib failure is commonly caused by BCR-ABL mutations. Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR-ABL mutations after prior imatinib. Among 1043 patients, 39% had a preexisting BCR-ABL mutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-threedifferent BCR-ABL mutations affecting 49 amino acids were detected at baseline, with G250, M351, M244, and F359 most frequently affected. After 2 years of follow-up, dasatinib treatment of imatinib-resistant patients with or without a mutation resulted in notable response rates (complete cytogenetic response: 43% vs 47%) and durable progression-free survival (70% vs 80%). High response rates were achieved with different mutations except T315I, including highly imatinib-resistant mutations in the P-loop region. Impaired responses were observed with some mutations with a dasatinib median inhibitory concentration (IC(50)) greater than 3nM; among patients with mutations with lower or unknown IC(50), efficacy was comparable with those with no mutation. Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844.

Figure 1.

Cumulative response rates in patients with or without a BCR-ABL mutation who received dasatinib treatment at any dose or 100 mg once daily (QD) after resistance or suboptimal response to imatinib. CHR indicates complete hematologic response; MCyR, major cytogenetic response; CCyR, complete cytogenetic response; and MMR, major molecular response.

Figure 2.

Time to first major cytogenetic response (MCyR). (A) Patients with or without a BCR-ABL mutation who received dasatinib treatment at any dose or 100 mg once daily (QD) after resistance or suboptimal response to imatinib. (B) Patients within the total analysis population with commonly mutated amino acids (n ≥ 20).

Figure 3.

Kaplan-Meier analyses of patients with or without a BCR-ABL mutation who received dasatinib treatment at any dose or 100 mg once daily (QD) after resistance or suboptimal response to imatinib. (A) Duration of complete cytogenetic response (CCyR). (B) Progression-free survival (PFS). (C) Overall survival (OS).

Figure 4

Best response achieved in each patient and overall rates of hematologic or cytogenetic response after dasatinib treatment of patients with different BCR-ABL mutations. Individual mutations occurring in ≥ 5 patients are listed with dasatinib IC₅₀ values (in nanomolar), as reported by O'Hare et al and Redaelli et al. Other indicates total of all patients with other mutations that are not listed.

Figure 5.

Analysis of responses and outcomes according to dasatinib IC₅₀, based on cellular IC₅₀ values reported by O'Hare et al and Redaelli et al.. (A) Time to major cytogenetic response (MCyR). (B) Progression-free survival (PFS). (C) Transformation-free survival (TFS).

Figure 6.

New BCR-ABL mutations detected at the time of progression or dasatinib discontinuation (n = 174). Other progression event indicates loss of complete hematologic response, loss of major cytogenetic response, or increasing white cell count. The progression event was not specified by the investigator for 3 patients who developed M244V, T315I, or V299L. AP indicates accelerated phase; BP, blast phase.