Dasatinib in imatinib‐resistant or ‐intolerant chronic‐phase, chronic myeloid leukemia patients: 7‐year follow‐up of study CA180‐034

Abstract

Dasatinib was approved at 100 mg once daily for imatinib‐resistant or ‐intolerant patients with chronic myeloid leukemia (CML) in chronic phase, based on results of the phase 3 CA180‐034 (NCT00123474) study. Here we present the final 7‐year analysis of this pivotal study, the longest follow‐up to date of any second‐generation BCR–ABL1 tyrosine kinase inhibitor (TKI). Patients (n = 670) with imatinib‐resistant or ‐intolerant CML in chronic phase received dasatinib. Nineteen percent of patients continued on study treatment, with a greater proportion in the 100 mg once daily arm remaining on therapy. Seven‐year rates for major molecular response (MMR), progression‐free survival (PFS), and overall survival (OS) were similar across doses; MMR, PFS, and OS results were 46, 42, and 65% at 100 mg once daily, respectively. Improved PFS and OS rates were reported in patients who achieved BCR–ABL1 ≤10% at 3 and 6 months. No new safety signals were identified. The incidence of drug‐related pleural effusion was 28% at 100 mg once daily and 35% at the other three dose groups. Incidence of drug‐related pulmonary hypertension and pulmonary arterial hypertension remained low (≤3% across all doses). Arterial ischemic events occurred in ≤4% of patients across all doses. These data support the long‐term efficacy and well‐established safety profile of dasatinib for patients with imatinib‐resistant or ‐intolerant CML in chronic phase. Am. J. Hematol. 91:869–874, 2016. © 2016 Wiley Periodicals, Inc.

Outcomes of switching to dasatinib after imatinib-related low-grade adverse events in patients with chronic myeloid leukemia in chronic phase: the DASPERSE study

“…AEs that did emerge once patients switched to dasatinib were consistent with those previously reported in dasatinib clinical trials [13, 23]. Although no new safety signals were reported, one limitation of this study is the small patient number, which could lead to differences in the incidence of AEs compared with previous reports.…”

“…Muscle spasms, eye/periorbital edema, and rash each had a ≥ 70% chance of resolution or improvement within 3 months of switching to dasatinib. Most patients (34 of 39 [87%]) experienced improvement of an imatinib-related AE, without a worsening of other imatinib-related toxicities, while on dasatinib, thus supporting the established tolerable safety profile and no cross-intolerance of dasatinib [13, 23]. …”

“…One case of PAH was confirmed in DASPERSE, which led to discontinuation; however, as echocardiograms were not regularly performed beyond assessments at baseline and study closure, it is unknown if this patient had elevated pulmonary artery pressure earlier in the study, prior to the PAH diagnosis. Important to note, the definition of intolerance in DASPERSE differed from that used in the second-line dasatinib after imatinib intolerance/resistance clinical trial (CA180-034) [13, 23]. In DASPERSE, intolerance included grade ≥ 2 nonhematologic toxicities, whereas in CA180-034 intolerance required grade ≥ 3 toxicities that led to discontinuation.…”

“…The level and sustainability of molecular response is becoming a critical efficacy marker in clinical trials enrolling patients on long-term treatment who wish to attempt TKI discontinuation [27–29]. Previous findings in the CA180-034 study, where 41% of patients received imatinib for at least 3 years, demonstrated improved efficacy and tolerability with second-line dasatinib after imatinib intolerance/resistance [23, 30]. Importantly, patients enrolled in DASPERSE were either able to maintain or improve their baseline molecular response level, regardless of whether patients completed the study.…”

Deterioration of pulmonary hypertension and pleural effusion with bosutinib following dasatinib lung toxicity

“…Until now, pulmonary side-effects, including pleural effusions and PAH, have been more frequently reported with dasatinib than with other TKIs. Indeed, dasatinib-induced exudative pleural effusion is a frequent adverse event ranging from 15% to 35% [2,3,[5][6][7]. Although the known incidence of bosutinib-induced pleural effusion is considered to be rare [8,9], we report two cases of exudative lymphocytic pleural effusions that rapidly regressed after bosutinib withdrawal.…”