Dasatinib Plus Low-Intensity Chemotherapy Results in Long-Term Survival for Older Patients with Ph+ ALL

A long-term study focusing on older patients with Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia (ALL) found that 96 percent of patients treated with a combination of low-intensity chemotherapy and dasatinib (a second-generation multi-targeted tyrosine kinase inhibitor of the BCR-ABL1 and SRC family kinases) achieved complete remission (CR). In addition, 58 percent of patients remained relapse-free at 12 months.

“Elderly patients can be successfully treated with the combination of dasatinib and low-intensity chemotherapy without excessive toxicity, with the expectation of a 41 percent overall survival at three years outside allogeneic hematopoietic cell transplantation (alloHCT),” Philippe Rousselot, MD, PhD, lead author of the study, told ASH Clinical News. Dr. Rousselot, from the Hemato-Oncology Unit at the Hôpital André Mignot in Le Chesnay, France, and colleagues conducted the prospective, phase II study of 71 patients (median age = 69 years; range = 59-83 years) who were treated between August 2007 and July 2010 in Belgium, Germany, Italy, and France.

Patients had newly diagnosed Ph+ and/or BCR-ABL1-positive ALL, with or without documented central nervous system involvement, and had not received prior treatment (except for corticosteroids or single-dose vincristine).

After pre-treatment with dexamethasone (10 mg/day on days 3-7) and one intrathecal dose of methotrexate (15 mg), the study protocol consisted of:

  • Induction: dasatinib 140 mg, once daily during induction, plus weekly vincristine 2 mg administered intravenously (IV) and dexamethasone 40 mg for 2 days (20 mg for patients >70 years) for 4 weeks
  • Consolidation: dasatinib 100 mg/day sequentially with methotrexate 1,000 mg/m2 on day 1 and asparaginase 10,000 UI/m2 on day 2 of cycles 1, 3, and 5; and cytarabine 1,000 mg/m2 every 12 hours on days 1, 3, and 5 of cycles 2, 4, and 6
  • Maintenance: dasatinib 100 mg/day sequentially with 6-mercaptopurine 60 mg/m2/day and methotrexate 25 mg/m2/week administered orally once every other month and dexamethasone/vincristine every 2-3 months for up to 24 months

Dasatinib at a dose of 100 mg was administered daily after maintenance therapy until relapse or death.

Patients were permitted to undergo alloHCT or autologous HCT (AHCT) with reduced-intensity conditioning or myeloablative conditioning.

At the beginning of the study, the researchers noticed an excess rate of treatment discontinuation in the first 11 patients >70 years who were receiving dasatinib 140 mg per day, so after 15 months the protocol was amended to reduce dasatinib and chemotherapy doses for older patients to dasatinib 100 mg per day during induction, methotrexate 500 mg/m2, asparaginase 5,000 Ul/m2, and cytarabine 500 mg/m2 during consolidation.

Researchers monitored BCR-ABL1 activity by RTQ-PCR, and minimal residual disease (MRD) was assessed after induction, during consolidation, and throughout maintenance therapy.

The median follow-up was 32 months (range = 2-88 months) for the entire study population and 66 months (range = 21-88 months) for the 22 surviving patients (31% of total population). Eight of these patients (36%) were still receiving dasatinib.

The median time on dasatinib therapy was 7.8 months (range = 0.6-72.4). Patients discontinued treatment due to death (n=38), adverse events (AEs) or investigator decision (n=14), or alloHCT (n=7).

Serious AEs included:

  • Pleural effusion (n=7)
  • Renal failure (n=6)
  • Transaminase elevation (n=5)
  • Atrial fibrillation (n=4)
  • Subdural hemorrhage (n=3)
  • Digestive hemorrhage (n=3)
  • Pulmonary embolism (n=3)
  • Cardiac failure (n=2)
  • Tumor lysis syndrome (n=2)

Among the 67 patients who achieved a CR after induction, 36 relapsed (54%). Ten of these patients achieved a second CR (28%), six of whom relapsed a second time.

Forty-nine patients died (69% of total population), with 32 deaths related to relapsed or refractory disease; and 14 deaths occurred in CR. Treatment-related mortality was reported in 12 percent of patients (n=6).

Of the 55 patients who reached first CR and were evaluable for MRD, 33 (66%) achieved a major molecular response (MMR; defined as a BCR-ABL1/ABL1 ratio ≤0.1%), and 11 (20%) achieved a deep molecular response (MR5; defined as a 5 log reduction in BCR-ABL1 transcript level). After maintenance therapy, 36 patients reached MMR (65%), and 13 reached MR5 (24%).

Rates of relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) at three and five years are shown in TABLE.

Seven patients underwent alloHCT, and three patients relapsed following transplant. In the total population, 36 relapses occurred (14 during consolidation, 19 during maintenance, and 3 after alloHCT), for a cumulative incidence of relapse of 54 percent at five years (95% CI 42-66).

Dr. Rousselot and colleagues performed a mutation analysis in 24 patients to determine which, if any, mutations were associated with relapse. Three patients who relapsed did not have detectable mutations, and among the remaining patients:

  • 18 relapses were associated with the T315I mutation
  • 1 relapse was associated with the F317L mutation
  • 1 relapse was associated with the V299L mutation
  • 1 relapse was associated with a compound mutation without T315I

“Relapses were associated with clones harboring mutations known to confer a high degree of resistance to dasatinib,” the authors noted. Ten of 43 patients were found to have the T315I mutation at diagnosis: eight of these patients eventually relapsed, one patient died in CR during maintenance, and one died during alloHCT.

The small patient sample size and single-arm design of the study are limitations, as was variable drug compliance. The investigators suggested that future trials include “a tailored choice based on patient status and adverse disease-related risk factors, such as the monitoring of mutation” in an effort to balance risk and efficacy.


Reference

Rousselot P, Coudé MM, Gokbuget N, et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood. 2016 April 27. [Epub ahead of print]

TABLE. Rates of Relapse-Free, Event-Free, and Overall Survival
3 Years 5 Years Median
Relapse-free survival 33% (95% CI 22-44) 28% (95% CI 18-39) 19.1 months
Event-free survival 31% (95% CI 21-42) 27% (95% CI 17-37) 18.9 months
Overall survival 41% (95% CI 29-52) 36% (95% CI 25-47) 25.8 months

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