Conference Coverage

Chemo-free induction-consolidation protocol for Ph+ ALL improved survival



– A front-line chemotherapy-free induction-consolidation protocol that combines dasatinib and blinatumomab for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resulted in high survival and molecular response rates in the phase 2 D-ALBA trial.

Dr. Sabina Chiaretti, Sapienza University, Rome Sharon Worcester/MDedge News

Dr. Sabina Chiaretti

At a median follow-up of 14.3 months, 61 of 63 patients enrolled in the multicenter trial had completed induction with the second-generation tyrosine kinase inhibitor (TKI) dasatinib, 60 had received the first cycle of treatment with the bispecific monoclonal antibody blinatumomab, and 56, 45, 36, and 25 had received second, third, fourth, and fifth cycles of blinatumomab, respectively, Sabina Chiaretti, MD, PhD, reported at the annual meeting of the American Society of Hematology.

The molecular response rate at the end of induction on day 85 was 29%, said Dr. Chiaretti of the department of translational and precision medicine, Sapienza University, Rome.

“Even more importantly, at the primary endpoint [the end of the second cycle of blinatumomab], 60% of patients were molecular responders,” she said.

Of note, the molecular response rate continued to increase with additional blinatumomab cycles; the rate was 79% after cycle 4, she said.

The overall survival (OS) and disease-free survival (DFS) rates also were “very exciting and promising” at 92.5% and 89.7%, respectively, she added.

DFS did not differ significantly based on molecular response at day 85 (100% vs. 87.4% in those with vs. without a molecular response; P = .154), but patients with p190 fusion protein had slightly worse DFS, compared with those who had p210 or both p190 and p210 fusion protein (83.5% vs. 100%; P = .48).

Study participants included adult Ph+ ALL patients with a median age of 54.5 years (range of 24.1-81.7 years) who were enrolled between May 2017 and January 2019; 54% were women and the median white blood cell count was 42 x109/L.

The percentage of study subjects with the p190, p210, and both p190/p210 fusion proteins was 65.1%, 27%, and 7.9% respectively, Dr. Chiaretti said.

Treatment included dasatinib at a dose of 140 mg/day as induction for 85 days along with steroids, which were started 7 days prior to induction and continued for a total of 31 days. Those who had a complete hematologic response (CHR) after induction received postinduction consolidation treatment with blinatumomab at a flat dose of 28 mcg/day for at least 2 cycles, and up to 3 additional cycles were allowed at physician discretion based on molecular response.

During the course of the study, 156 adverse events occurred, including 50 serious adverse events. The latter most often involved infections, including 6 cytomegalovirus infections and 6 cases of prolonged fever; one of those cases was likely related to blinatumomab.

Two patients died, including an 80-year-old woman who died during induction, and a patient who was in CHR. Six relapses occurred, including one that involved a major protocol violation; three were extramedullary.

Additional analyses in this study showed that the most frequent copy number aberration was, as expected based on the available literature, IKZF1 deletion, which was present in 25 of 46 available samples (54%). Of those, 11 (23.9%) were found to have the IKZF1-plus signature, defined as IKZF1 and/or PAX5 and/or CDKN2A/B deletions, she said.

Further, ABL1 mutational analysis conducted in 15 patients with evidence of MRD increase showed that 8 were wild type and 7 were mutated – with 6 of the 7 represented by the gatekeeper mutation T315I, and one by an E255K mutation. All but 1 mutation occurred in p190 cases prior to the start of blinatumomab.

Of note, and in line with prior findings, blinatumomab was effective for reducing or eradicating the MRD levels in these difficult-to-treat patients, Dr. Chiaretti said.

An analysis of the immunologic compartment carried out in 12 patients who completed all 5 cycles of blinatumomab showed a significant increase in the rate of CD8+ T cells (29% vs. 19.8% before the start of blinatumomab; P = .04) and a significant reduction in the rate of Tregs (3.7% vs. 11% before blinatumomab; P = .02), she added.

The findings of this study to date – with some patients having more than 2 years of follow-up – are notable given the high rates of molecular response and survival, Dr. Chiaretti said.

Outcomes in patients with Ph+ ALL were generally poor before the introduction of TKIs, but “the scenario completely changed,” she explained.

“In general, all TKI-based treatments – with or without chemotherapy – have led to overall survival rates in the range of 50% ... which means that we still need to improve our clinical management,” she said. “Another finding that became clear is the fact that patients who achieve MRD-negative status have a significantly better outcome than those who do not.”

The D-ALBA trial was designed with the aim of increasing the rate of MRD negativity in newly diagnosed patients using dasatinib and blinatumomab, and the results demonstrate that this chemotherapy-free induction/consolidation approach is feasible in the front-line setting for adult Ph+ ALL patients, she said, adding that “it is strongly effective in inducing high rates of MRD negativity, and it results in much better survival rates.”

The findings with respect to IKZF1-plus cases and ABL1 mutations underscore the need for further work, she said.

“We still have to face some challenging cases,” she explained. “This study, as others before, really proves that IKZF1-plus cases are very difficult to treat; they require intensification and probably alternative strategies.”

Dr. Chiaretti reported membership on a board of directors or advisory committee for Pfizer, Incyte, Amgen, and Shire.

SOURCE: Chiaretti S et al. ASH 2019, Abstract 740.

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