Dasatinib Plus Blinatumomab Increases Response and MRD Negativity in Ph-Positive Acute Lymphocytic Leukemia

Combining the second-generation tyrosine kinase inhibitor (TKI) dasatinib with the bispecific monoclonal antibody blinatumomab induced high response rates in adult patients with Philadelphia chromosome (Ph)–positive acute lymphocytic leukemia (ALL), according to preliminary findings from the phase II GIMEMA LAL2116 D-ALBA trial. A high proportion of patients treated with the combination also achieved measurable residual disease (MRD) negativity, according to lead author Sabina Chiaretti, MD, PhD, from Sapienza University of Rome, who presented the findings of this interim analysis at the 24th Congress of the European Hematology Association.

The introduction of TKIs “has led to overall survival (OS) rates approaching 50% in adults with Ph-positive ALL,” the investigators explained, but “a significantly better survival is observed in patients who become MRD negative, [suggesting] MRD negativity should be considered the primary endpoint of treatment.”

In this trial, researchers enrolled 63 adult patients (median age = 54.5 years; range = 24.1-81.7 years) with newly diagnosed adult B-precursor Ph-positive ALL from multiple centers throughout Italy.

Prior to receiving dasatinib, patients were treated with a seven-day course of steroids; steroids were continued for 24 days and stopped at day 31. Induction consisted of dasatinib 140 mg/day, administered for 85 days. Patients who experienced a complete hematologic response (CHR) at this timepoint received post-induction consolidation with blinatumomab for at least two cycles. Participants received a minimum of two cycles, but patients could receive up to three additional cycles, depending on response to blinatumomab or medical decision. Dasatinib and blinatumomab were administered simultaneously throughout the study.

Patients received central nervous system prophylaxis during the entire treatment period.

After a median follow-up of 8.75 months (range = 0-19.5 months), a total of 50 patients had completed induction; 43 completed the first cycle of blinatumomab and 15 completed a fifth cycle. Two patients discontinued study treatment (for medical decisions and for toxicity), and one patient died during induction treatment.

At the end of induction, 13 of 50 patients (26%) achieved a molecular response: four with a complete molecular remission (CMR) and nine with positive nonquantifiable (PNQ) disease.

At the end of the second blinatumomab treatment cycle, more than half of participants (54%; n=19) experienced a molecular response (the study’s primary endpoint). Ten patients were in CMR and nine had PNQ disease status.

The rates of molecular responses further increased after subsequent cycles of blinatumomab (68% after the third cycle and 80% after the fourth cycle), the authors added. However, response duration was not reported.

Eleven patients were evaluable for MRD status and underwent ABL1 mutational analysis. Of these, six patients had wild-type ABL1 and five had mutations for T315I (n=4) and E255K (n=1). Only one of the mutations occurred after the start of blinatumomab, yet in all cases, mutations were cleared with the therapy. This finding, according to the investigators, attested to blinatumomab’s “efficacy also in ABL1-mutated cases.”

Following the completion of treatment, one patient (who was in CHR as of data presentation) redeveloped T315I, Y253H, and E255K mutations. Another two patients experienced relapsed disease, including one with hematologic relapse and one with isolated central nervous system involvement.

In addition, eight patients have received an allogeneic transplant, with no instances of transplant-related mortality observed. The 12-month OS and disease-free survival rates were 96.2% and 91.6%, respectively.

“This is the first chemotherapy-free induction/consolidation protocol for [this patient population], based on a combination of a targeted and immunotherapeutic strategy,” Dr. Chiaretti concluded. “Although preliminary, the rates of molecular responses and survival are highly promising.” Other limitations of this analysis include the lack of a comparator arm and the small patient population.

The authors report no relevant conflicts of interest.

Reference

Chiaretti S, Bassan R, Vitale A, et al. A dasatinib-blinatumomab combination for the front-line treatment of adult PH+ ALL patients. Preliminary results of the GIMEMA LAL2116 D-ALBA trial; on behalf of GIMEMA acute leukemia working party. Abstract #S1617. Presented at the 24th European Hematology Association Annual Congress, June 16, 2019; Amsterdam, The Netherlands.

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