Initial results from the phase III GIMEMA ALL2820 trial demonstrated that a front-line, chemotherapy-free regimen combining the tyrosine kinase inhibitor (TKI) ponatinib and the bispecific T-cell engager blinatumomab significantly outperformed a standard treatment strategy of imatinib plus chemotherapy in adults with newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). The study, which represents the first formal comparison of these two therapeutic approaches, demonstrated substantial improvements in event-free survival, remission rates, and measurable residual disease (MRD) responses with the chemotherapy-free strategy. Lead author Sabina Chiaretti, MD, of Sapienza University in Rome, Italy, presented the results of the study at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 439).
Study Details
For the trial, researchers enrolled 236 adults (aged 19–84 years) with Ph-positive ALL and randomly assigned them to either the experimental arm (TKI plus immunotherapy; n = 158) or the control arm (TKI plus chemotherapy; n = 78). Patients in the experimental group received steroid prephase therapy, a 70-day induction with ponatinib, and two to five cycles of blinatumomab. Those in the control received imatinib plus age-adjusted cycles of chemotherapy. Although relapse rates were similar between groups (6% vs 8%), roughly half of the relapses in the experimental group occurred in patients who had discontinued therapy early. In addition, 37% of patients in the control arm crossed over to receive the chemotherapy-free regimen if their disease remained MRD-positive, and 62% subsequently achieved MRD-negative status, reinforcing the efficacy of the combination even when used later in the treatment sequence.
Key Results
At a median follow-up of 23 months, event-free survival was 87% in the experimental arm vs 71% in the control. Death occurred in 3.5% of patients receiving the chemotherapy-free regimen vs 10% of those in the control arm, while complete remission was achieved in 94% and 79%, respectively. MRD responses also favored the chemotherapy-free strategy: 71% of patients achieved MRD-negative status after two cycles of blinatumomab, rising to 80% after five cycles, compared with 49% in the control arm.
Safety profiles were consistent with the known effects of each agent, and most adverse events were manageable with dose modification. Infections accounted for several deaths, primarily among older adults. The investigators noted that omitting chemotherapy may reduce hospitalization and allow more patients to maintain daily activities, offering both clinical and economic advantages.
According to Dr. Chiaretti, these results are highly compelling. She stated, “The [chemotherapy-free] approach significantly reduced the rate of death in addition to increasing the rate of complete remission. The significance was very impressive, a more than 20% difference in terms of molecular response achievement, so this approach truly is better.” She emphasized that the findings suggest targeted therapy combined with immunotherapy may replace chemotherapy as the preferred front-line strategy for adults with Ph-positive ALL.
Although the study population was limited to centers in Italy, the researchers emphasized that the results should be generalizable across health systems. Ongoing work will be aimed at evaluating whether patients who achieve deep, sustained MRD negativity can safely discontinue TKIs without increasing relapse risk—a question that may further refine long-term management of Ph-positive ALL.
Disclosure: For full disclosures of all study authors, visit hematology.org.
