Dasatinib, low-intensity chemotherapy effective for older patients with ALL
Treatment with dasatinib and low-intensity chemotherapy improved the 5-year OS rate of older patients with Philadelphia chromosome–positive acute lymphoblastic leukemia, according to the results of a phase 2 study.
Further, prospective monitoring of the BCR-ABL1T315I mutation may help identify patients at an increased risk for early relapse, results showed.
Nearly 50% of patients aged 60 years or older with ALL harbor the Philadelphia chromosome. Treatment with the tyrosine kinase inhibitor imatinib and age-adapted chemotherapy has improved outcomes in this patient population.
Philippe Rousselot, MD, PhD, of Hôpital de Versailles in Le Chesnay, France, and colleagues prospectively studied combination treatment with dasatinib (Sprycel, Bristol-Myers Squibb) — another potent TKI that can bind to active and inactive conformations of the ABL kinase — and a backbone of low-intensity chemotherapy, in patients aged 55 years or older with Ph+ALL.
The study included data from 71 patients (median age, 69 years; range, 59-83) enrolled between August 2007 and July 2010 in four countries. The researchers assigned patients to daily dasatinib (140 mg; 100 mg for patients older than 70 years), with intrathecal chemotherapy, vincristine and dexamethasone during induction.
Patients who achieved complete remission continued on dasatinib as consolidation therapy, with reduced doses of sequential cytarabine and methotrexate for 6 months.
Maintenance therapy consisted of dasatinib with vincristine and dexamethasone reinduction for 18 months, followed by dasatinib until death or relapse.
RFS at 12 months served as the primary endpoint.
Median follow up was 32 months (range, 2-88).
Sixty-seven patients (96%) achieved complete remission. Of the four patients who did not, three died during induction. The remaining patient was refractory but achieved complete remission after salvage therapy.
Fifty-four percent (n = 36) of patients who achieved complete remission relapsed. Subsequently, 28% (n = 10) achieved a second complete remission, six of whom relapsed again.
The cumulative incidence of relapse at 5 years was 54% (95% CI, 42-66).
Seven patients underwent hematopoietic stem cell transplantation. No patient received an autograft.
Forty-nine patients (69%) died, largely from relapse or refractory disease (n = 32). Fourteen patients died in complete remission. Six patients (12%) experienced treatment-related mortality.
The researchers evaluated 55 patients (82%) for minimal residual disease. Thirty-three patients (60%) experienced a major molecular response.
Thirty-six percent of living patients (n = 8 of 22) remained on dasatinib at the time of analysis.
The researchers tested for BCR-ABL1T315I mutations in 43 patients and observed an association with short-term relapses in carriers. Ten patients tested positive for this mutation before therapy, eight of whom relapsed.
“Despite a relatively small number of patients studied, we report high efficacy of dasatinib combined with low-intensity chemotherapy in elderly Ph+ALL patients, with a 36% long-term survival without intensive chemotherapy or allogeneic HSCT,” Rousselot and colleagues wrote. “We report the first evidence supporting a prospective monitoring of the T315I mutation in patients not eligible for intensive therapies in order to personalize therapy before hematologic relapse.” – by Cameron Kelsall
Disclosure: Rousselot reports a research grant from Bristol-Myers Squibb. The other researchers report no relevant financial disclosures.