Dasatinib or high‐dose imatinib for chronic‐phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily

Abstract

BACKGROUND In patients with chronic-phase chronic myeloid leukemia (CP-CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325-fold more potent inhibition than imatinib against unmutated Bcr-Abl in vitro. Data with a minimum of 2 years of follow-up were available for the current study of dasatinib and high-dose imatinib in CP-CML resistant to imatinib at daily doses from 400 mg to 600 mg. METHODS A phase 2, open-label study was initiated of 150 patients with imatinib-resistant CP-CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n = 101) or high-dose imatinib 800 mg (400 mg twice daily; n = 49). RESULTS At a minimum follow-up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P = .034), major cytogenetic response (MCyR) (53% vs 33%; P = .017), and complete cytogenetic response (44% vs 18%; P = .0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high-dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high-dose imatinib (29% vs 12%; P = .028). The estimated progression-free survival also favored dasatinib (unstratified log-rank test; P = .0012). CONCLUSIONS After 2 years of follow-up, dasatinib demonstrated durable responses and improved response and progression-free survival rates relative to high-dose imatinib.

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

“…As previously described, the START-R trial evaluated dasatinib 70 mg twice daily compared with imatinib dosed at 400 mg twice daily in resistant CP-CML patients, and demonstrated that dasatinib gave superior rates of CHR, MCyR, CCyR, MMR and PFS beyond 12 weeks. 36 The START-C trial also evaluated dasatinib in 288 imatinib-resistant patients, and demonstrated that 85% of patients had achieved a new CHR, 51% obtained a new MCyR and 40% had achieved a new CCyR, corroborating the results from the START-R trial. 105 Nilotinib has also been evaluated in several trials for patients with imatinib-resistant CP-CML.…”

“…35 When subset data from the international, open-label, randomized Phase II study SRC/ABL Tyrosine kinase inhibition Activity Research Trials of dasatinibFResistant (START-R) trial was analyzed according to the presence of one of the protocol-specified mutations (L248V, G250E, Q252H/R, Y253H/F, E255K/V, T315I/D, F317L and H369P/R), there were more responses to dasatinib than high-dose imatinib, although only two patients with these mutations were treated with imatinib. 36 In patients with imatinib-resistant or -intolerant accelerated phase disease were treated with dasatinib, similar rates of hematological and cytogenetic responses were also seen in those with or without a mutation. 37 For imatinib-resistant or -intolerant patients with either lymphoid or myeloid blast phase-CML (BP-CML), hematological and cytogenetic response rates to dasatinib were independent of the presence or absence of a baseline Bcr-Abl mutation.…”

“…112 When grouped together, the presence or absence of an Abl kinase mutation did not appear to influence the rates of CHR or MCyR in imatinib-resistant patients receiving dasatinib in the previously published START trials. 36,105 However, specific mutations appear to be differentially resistant to dasatinib both in vitro, as well as in vivo. Jabbour and colleagues also recently demonstrated equivalent response rates to second-generation TKIs when imatinib-resistant patients were grouped according to the presence or absence of a mutation.…”

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

“…Second, dose escalation of imatinib can improve response rates in patients with inadequate response to standard-dose imatinib, but switching to second-line nilotinib or dasatinib can be more effective [55]. Several studies that evaluated second-line nilotinib [56,57] or dasatinib [56,58] and high-dose imatinib (400 mg BID) have demonstrated significantly higher rates of CHR, CCyR, and MMR with the newer TKIs than with high-dose imatinib. Moreover, PFS in these studies was better with the newer TKIs than with high-dose imatinib.…”

Principles and Current Topics Concerning Management of Tyrosine Kinase Inhibitor Therapy for Chronic Myelogenous Leukemia

“…According to the results of START-C trial, after 2 months of treatment with dasatinib, CCyR and MMR had been achieved in, respectively, 45% and 37% of IM-resistant, and 78% and 78% of IM-intolerant patients with CML-CP [42]. These effects were much inferior to those obtained for treatment-naïve CML-CP, and, as was to be expected, the effects of dasatinib were rather limited for advanced phase CML [52][53][54]. Similarly, the effect of nilotinib as second-line treatment is also much inferior to that observed in treatment-naïve patients.…”