A chemotherapy-free front-line regimen of ponatinib plus blinatumomab significantly improved event-free survival compared with imatinib plus chemotherapy in adults with newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Chiaretti et al reported results from the phase III GIMEMA ALL2820 trial in The New England Journal of Medicine.
The study tested whether a chemotherapy-free targeted and immunotherapy strategy could outperform imatinib plus chemotherapy as frontline treatment.
Study Details
The open-label phase III trial enrolled 236 adults with newly diagnosed Ph-positive ALL. Patients were randomly assigned in a 2:1 ratio to ponatinib plus blinatumomab or imatinib plus chemotherapy, with 158 patients assigned to the intervention group and 78 to the control group.
Patients in the intervention group received ponatinib during induction followed by at least two cycles of blinatumomab, with ponatinib continued during consolidation and afterward. Patients in the control group received imatinib plus four to six cycles of age-adjusted chemotherapy.
Crossover to ponatinib plus blinatumomab was permitted for patients in the control group with persistent or recurrent measurable residual disease (MRD).
The primary endpoint was event-free survival, with events including failure to achieve complete molecular response, toxic effects, treatment resistance, and death.
Key Findings
At a median follow-up of 23.7 months, estimated 24-month event-free survival was 86% with ponatinib plus blinatumomab and 67% with imatinib plus chemotherapy (P < .001).
Molecular event-free survival, reflecting survival without measurable residual disease, was 68% with the chemotherapy-free regimen and 42% with imatinib plus chemotherapy.
By the end of induction, complete hematologic response had been achieved in 94% of patients receiving ponatinib plus blinatumomab and 79% of those receiving imatinib plus chemotherapy.
Molecular response rates were similar at the end of induction, at 47% with ponatinib plus blinatumomab and 44% with imatinib plus chemotherapy. After consolidation, however, response rates were 71% and 49%, respectively.
The cumulative incidence of relapse was 5% with ponatinib plus blinatumomab and 13% with imatinib plus chemotherapy. Overall survival at 24 months was 90% and 85%, respectively.
The trial also allowed patients with persistent MRD in the control group to cross over to ponatinib plus blinatumomab. Among 31 patients who crossed over, 20 subsequently achieved MRD negativity.
Use of allogeneic hematopoietic stem-cell transplantation was relatively limited. Among patients who achieved a first complete hematologic response, 19% in the ponatinib plus blinatumomab group underwent transplantation compared with 26% in the control group.
Safety
Severe adverse events of grade 3 or higher occurred in 34% of patients receiving ponatinib plus blinatumomab and 47% of those receiving imatinib plus chemotherapy.
Infections were the most common severe adverse events in both groups. Cardiovascular and vascular events, a known safety concern with ponatinib, were uncommon and occurred only among patients who had received the 45-mg dose. Patients who experienced these events were older, with a median age of 72 years.
Deaths during induction occurred in four patients (3%) in the ponatinib plus blinatumomab group and seven (9%) in the control group.
“In this phase III trial, we documented the superiority of a front-line chemotherapy-free targeted and immunotherapeutic approach over conventional treatment in adult patients with Ph-positive ALL,” the investigators wrote.
The authors noted that follow-up remains relatively short and that the open-label design could introduce bias.
Robin Foà, MD, of Sapienza University in Rome, is the corresponding author.
DISCLOSURE: The trial was supported by grants from Associazione Italiana per la Ricerca sul Cancro and other Italian research programs. For full disclosures of the study authors, visit nejm.org.
