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First-line dasatinib prolongs DFS in adults with Ph-positive ALL
The incorporation of dasatinib into first-line chemotherapy yielded molecular responses and durable DFS in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, according to phase 2 study results.
Treatment with chemotherapy and imatinib (Gleevec, Novartis) has improved outcomes among adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).
However, a majority of patients die due to disease progression.
Seok Lee, MD, PhD, of the Catholic Blood and Marrow Transplant Center at The Catholic University of Korea, and colleagues evaluated whether adding dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) to first-line chemotherapy would improve outcomes for patients with Ph+ALL by increasing the major molecular response rate, thus allowing more patients to undergo allogeneic hematopoietic stem cell transplantation (HSCT).
The analysis included data from 51 patients (median age, 46 years; range, 19-64) with newly diagnosed Ph+ALL who received a cycle of chemotherapy followed by 100 mg daily dasatinib for 4 weeks. Patients received up to four cycles depending on donor availability (for patients undergoing HSCT) or tolerability (for patients not undergoing HSCT).
Patients unable to undergo allogeneic HSCT received dasatinib for 2 years if they maintained stable disease.
The major molecular response rate by the end of the second dasatinib cycle served as the primary endpoint. Researchers defined complete molecular response as undetectable minimal residual disease (MRD), or the absence of detectable BCR-ABL1 transcripts.
Fifty patients (98%) achieved complete remission after the first dasatinib cycle. By the end of the second cycle, 93.9% (n = 46) of evaluable patients had a persistent complete remission.
Further, 38 patients (77.6%) had a major molecular response (n = 16) or undetectable MRD (n = 22).
The researchers classified 23 patients (46.9%) as early-stable molecular responders, 15 patients (30.7%) as late molecular responders and 11 patients (22.4%) as poor molecular responders.
Thirty-nine patients (76.5%) received allogeneic HSCT in first complete remission, with a median time to transplantation of 156 days (range, 112-248) from the start of treatment. The remaining patients did not undergo HSCT due to early death (n = 2), relapse at the end of the second cycle (n = 2), persistent lack of complete remission (n = 1) or lack of a suitable donor (n = 7).
Twenty-six patients remain alive after a median follow-up of 54 months (range, 40-63).
The 4-year cumulative incidence of relapse was 30% among all patients and 20.5% among those who underwent HSCT in first complete remission. Four-year DFS was 52% among all patients and 64.1% among those who underwent HSCT.
Poor responders had a higher cumulative incidence of relapse (60% vs. 21.7%; P = .0018) and a lower DFS rate than early-stable molecular responders (30% vs. 69.6%; P = .0015).
No patient withdrew from the study due to treatment-related adverse events; however, six patients temporarily discontinued therapy (median length, 7 days; range, 3-14), two of whom resumed dasatinib at a reduced 70 mg dose.
Study limitations included the lack of randomization and the researchers’ inability to address the role of dasatinib treatment after HSCT.
“Further efforts are required to determine the role of MRD kinetics with standardization of MRD quantification, the best tyrosine kinase inhibitors with refinement of chemotherapy intensity, and the necessity of allogeneic HSCT in the era of wider range TKIs in adults with Ph+ALL," Lee and colleagues wrote. – by Cameron Kelsall
Disclosure: Bristol-Myers Squibb provided funding for this study. Lee reports research funding from Bristol-Myers Squibb. One other study researcher reports research funding from Bristol-Myers Squibb, Novartis and Pfizer.