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Dasatinib/Blinatumomab Produces High Rates of Molecular Response and Survival in Philadelphia Chromosome–Positive ALL


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In an Italian phase II trial (GIMEMA LAL2116) reported in The New England Journal of Medicine, Robin Foà, MD, of Sapienza University of Rome, and colleagues, found that first-line induction and consolidation treatment with dasatinib and blinatumomab produced a high rates of molecular response as well as disease-free and overall survival in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL).1

Study Details

In the multicenter trial, 63 patients were enrolled between May 2017 and January 2019. Patients received glucocorticoid treatment for 7 days prior to the start of dasatinib induction and for an additional 24 days. Dasatinib at 140 mg once daily was given as induction therapy for 84 days. Patients completing the induction phase received consolidation treatment with blinatumomab at 28 μg/d via continuous intravenous infusion in 28-day cycles with a 2-week washout interval, with dexamethasone at 20 mg given prior to each blinatumomab cycle. A minimum of two blinatumomab cycles was mandatory, with a maximum of five permitted. Dasatinib was continued during and after blinatumomab treatment. Patients received levetiracetam at 500 mg twice daily during blinatumomab treatment to prevent central nervous system adverse events. The primary endpoint was the rate of sustained molecular response in the bone marrow after two cycles of blinatumomab consolidation.

Robin Foà, MD

Robin Foà, MD

Median patient age was 54 years (range = 24–82 years); 34 (54%) were female; median white blood cell count was 13,000/mm3; and fusion protein type was p190 in 41 (65%), p210 in 17 (27%), and both in 5 (8%); the latter two groups were combined in analyses. In addition to the presence of the Philadelphia chromosome, copy-number analysis in 46 patients with available genomic material showed that the IKZF1 deletion was present in 25 patients (54%), with aberrations in CDKN2A or CDKN2B in 13 (28%), PAX5 in 10 (22%), RB1 in 6 (13%), and EBF1 in 5 (11%). A total of 11 patients (24%) were classified as having IKZF1plus, defined as IKZF1 deletions accompanied by PAX5 deletions, CDKN2A or CDKN2B deletions, or both.

Responses and Survival

At the end of the induction phase (day +85), a complete hematologic remission was observed in 98% of the patients (62/63), with 17 (29%) of 59 evaluable patients having a molecular response.

After induction, there was no significant difference in molecular response among patients with p190 vs p210 fusion proteins (32% vs 24%); molecular clearance was more rapid among those with p190. Molecular response was less common in patients with IKZF1plus (1 of 11 patients, 9%) than among those with IKZF1 deletion alone or no IKZF1 deletion (9 of 33 patients, 27%).

Of 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. The median time from the end of induction therapy to the start of blinatumomab was 10 days (range = 7–41 days). After two cycles of consolidation (primary endpoint of the study), a molecular response was observed in 33 of 55 (60%) evaluable patients, with the rate being 52% in the intent-to-treat population. Molecular response was observed in 70% of patients (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

After two cycles of blinatumomab, there was no significant difference in molecular response rate between patients with p190 vs p210 fusion proteins and no significant difference between patients with IKZF1plus vs those with IKZF1 deletion alone or no IKZF1 deletions.

KEY POINTS

  • Complete remission was achieved in 98% of patients after dasatinib induction therapy.
  • Molecular response was achieved in 60% of evaluable patients completing two cycles of blinatumomab consolidation.

At a median follow-up of 18 months (range = 1–25 months), overall survival was 95% and disease-free survival was 88%. The probability of disease-free survival among patients with molecular response at the end of induction therapy was 100%, compared with 85% among those without a molecular response. No significant difference in disease-free survival was observed between patients with p190 vs p210 fusion proteins (85% vs 95%). Disease-free survival was poorer among patients with IKZF1plus, with rates of 100% among patients with no IKZF1 deletions, 92% among patients with IKZF1 deletions alone, and 64% among those with IKZF1plus (overall P = .03). Overall survival was also poorer among patients with IKZF1plus, with rates of 100% among patients with no IKZF1 deletions, 93% among those with IKZF1 deletions alone, and 82% among those with IKZF1plus (overall P = .15).

A total of six relapses were observed, with a cumulative incidence of 8%. Among patients who relapsed, three had IKZF1plus, and one had IKZF1 deletion alone. ABL1 T315I mutations were found in five of six patients who relapsed.

In an ABL1 mutational analysis in 15 patients with evidence of increased minimal residual disease during induction, 8 had wild-type disease and 7 harbored ABL1 mutations (T315I in 6 and E255K in 1). All mutations were cleared during blinatumomab treatment.

Adverse Events

The most common adverse events of any grade were pyrexia in 12 patients (19%), cytomegalovirus infection/reactivation in 6 (10%), and neutropenia in 4 (6%). A total of 21 grade 3 or 4 adverse events were observed, including cytomegalovirus  infection/reactivation in 6 (10%); neutropenia in 4 (6%); persistent fever in 2 (3%); and pleural effusion, pulmonary hypertension, infection, alanine aminotransferase increase, gamma-glutamyltransferase increase, diarrhea, hypoxia, maculovesicular rash, and neurologic disorder in 1 patient each (1.5%).

The investigators concluded: “A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with [Philadelphia chromosome]–positive ALL.” 

DISCLOSURE: The study was funded by the Associazione Italiana per la Ricerca sul Cancro and others. Dr. Foà has served on a speakers bureau or as a consultant/advisor for AbbVie, Amgen, Incyte, Johnson & Johnson Health Care Systems, Novartis, and Pfizer.

REFERENCE

1. Foà R, Bassan R, Vitale A, et al: Dasatinib–blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med 383:1613-1623, 2020.

 


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