In an Italian phase II trial (GIMEMA LAL2116) reported in The New England Journal of Medicine, Foà et al found that first-line induction and consolidation treatment with dasatinib plus blinatumomab produced a high rate of molecular response in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL).
Study Details
Sixty-three patients were enrolled in the multicenter trial between May 2017 and January 2019. Patients received glucocorticoid treatment for 7 days prior to the start of dasatinib induction, and then for an additional 24 days. Dasatinib at 140 mg once daily was given as induction therapy for 85 days. Patients completing the induction phase received consolidation treatment with blinatumomab at 28 μg per day, 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 sustained molecular response in the bone marrow.
Responses
A total of 61 patients completed the dasatinib induction phase. At the end of the induction phase at day 85, complete remission was observed in 62 (98%) of 63 patients, with 17 (29%) of 59 evaluable patients having a molecular response. Molecular response was less common after induction in patients with IKZF1 deletion associated with PAX5 deletions or CDKN2A or CDKN2B deletions (IKZF1plus; 1 of 11 patients) than among those with IKZF1 deletion alone and among those with no IKZF1 deletion (9 of 33 patients).
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.
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. After two cycles, molecular response was observed in 33 (60%) of 55 evaluable patients, with the rate being 52% in the intent-to-treat population. Molecular response was observed in 70% of patients (28 of 40) after the third cycle, 81% (29 of 36) after the fourth cycle, and 72% (21 of 29) after the fifth cycle. After two cycles of blinatumomab, there was no significant difference in molecular response rate between patients with IKZF1plus and those with IKZF1 alone or with no IKZF1 deletion.
At 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 molecular response. Disease-free survival was 92% among patients with IKZF1 deletion alone and 64% among those with IKZF1plus. A total of 24 patients subsequently received a stem-cell allograft, with one death being related to transplantation.
ABL1 mutations were detected in six patients who had increased minimal residual disease during induction therapy, with all of the mutations being 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 six patients (10%); neutropenia in four (6%); persistent fever in two (3%); and pleural effusion, pulmonary hypertension, infection, alanine aminotransferase increase, gamma-glutamyltransferase increase, diarrhea, hypoxia, maculovesicular rash, and neurologic disorder in one 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. For full disclosures of the study authors, visit nejm.org.
