Ponatinib/Blinatumomab Regimen Improves EFS in Ph-Positive ALL

A frontline chemotherapy-free regimen of ponatinib (Iclusig) plus blinatumomab (Blincyto) significantly improved event-free survival (EFS) compared with imatinib (Gleevec) plus chemotherapy in adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL), according to results from the phase 3 GIMEMA ALL2820 trial (NCT04722848) published in The New England Journal of Medicine.

What were the key efficacy outcomes?

A total of 236 adult patients were randomly assigned in a 2:1 ratio to receive ponatinib plus blinatumomab (n = 158) or imatinib plus chemotherapy (n = 78), with a crossover to the intervention regimen permitted for control-group patients with persistent or reappearing measurable residual disease (MRD). The median patient age was 55 years (range, 24-82).

At a median follow-up of 23.7 months, the estimated 24-month EFS was 86% (95% CI, 80%-92%) in the intervention group vs 67% (95% CI, 56%-79%) in the control group (P <.001). Beyond the primary EFS end point, survival with no MRD—molecular EFS—was 68% (95% CI, 61%-76%) in the intervention group vs 42% (95% CI, 32%-55%) in the control group, and the overall survival (OS) rates were 90% (95% CI, 85%-95%) vs 85% (95% CI, 78%-94%), respectively.

At the end of induction, a complete hematologic response was observed in 94% of the intervention group vs 79% of the control group, and after blinatumomab consolidation, a molecular response was observed in 71% vs 49%. The cumulative incidence of relapse was 5% vs 13%.

According to Peter Abdelmessieh, DO, MSc, an assistant professor in the Department of Bone Marrow Transplant and Cellular Therapies at Fox Chase Cancer Center, the toxicity difference between the arms was a central driver of the EFS separation. “The main driver and the most important part of this study is not only is [ponatinib/blinatumomab] superior in terms of its efficacy measured by MRD and disease response, it’s less toxic because one arm had nothing but chemotherapy and one arm had no chemotherapy,” he told CancerNetwork® in an interview.

Can transplantation be avoided in some patients?

As of the report, only 19% of patients in the intervention group had undergone allogeneic hematopoietic stem-cell transplantation (HSCT) after a first complete hematologic response, compared with 26% in the control group; overall, 45 of 211 patients (21%) who had a first complete hematologic response underwent the procedure, which was assigned by a biologically driven algorithm based on MRD status and the IKZF1 plus genetic signature. Among the 31 patients in the control group who crossed over to the intervention regimen, all of whom had MRD positivity, MRD negativity was achieved in 20 (65%).

Abdelmessieh said the findings support forgoing transplantation in a meaningful subset of patients. “I think this therapy can be enough, and patients do not need a stem cell transplant in [first complete remission] with Ph-positive disease,” he said. “A lot of single-institution studies from the US, namely at MD Anderson, show that there’s no benefit to [allogeneic] transplant in [first complete remission] in this subtype of patient…Blinatumomab is excellent at eradicating MRD in a [patient with] MRD-positive [disease], regardless of which ALL it is, Ph-positive or Ph-negative.”

What explains the low rate of CNS relapse?

Only a single central nervous system (CNS) relapse was recorded in the intervention group. The investigators noted that they could not definitively attribute the low CNS relapse incidence to ponatinib itself or to the trial’s augmented CNS prophylaxis strategy, which used 15 chemotherapy-delivering lumbar punctures (18 in patients with CNS positivity at diagnosis). Abdelmessieh attributed the result primarily to the intensified prophylaxis.

“I do think [it reflects] better disease control at ponatinib, but…the intensified prophylaxis [was] driving that—15 [intrathecal] therapies as opposed to a standard of 2,” he said. He identified CNS and extramedullary relapse as the outcomes he would most want to track with longer follow-up, given the chemotherapy-free design.

What was the safety profile, and what does it mean for practice?

Serious adverse events of grade 3 or higher occurred in 34% of patients in the intervention group vs 47% in the control group, and early deaths during induction were less frequent in the intervention group (3% vs 9%). Cardiovascular events, a potential concern with ponatinib, were rare in both groups and occurred only among patients who received the 45-mg dose, more frequently in older patients.

Abdelmessieh said the regimen’s tolerability could broaden access across age groups, with drug delivery, a continuous 28-day blinatumomab infusion typically requiring a home infusion center, being the main practical hurdle rather than toxicity. “This is far less toxic, and if I were a community oncologist, I would jump at this kind of study because it’d allow me to give therapy to patients up to age 90,” he said. He framed the results as a milestone for a disease that “used to be the worst ALL…Now anybody can tolerate the therapy, and it can be delivered with [little] toxicity.”

In the intervention group, induction consisted of ponatinib at 45 mg daily in patients 65 years or younger and 30 mg daily in those older than 65 years followed by 2 to 5 cycles of intravenous blinatumomab administered concurrently with ponatinib. Patients in the control group received imatinib plus age-adjusted chemotherapy. The study authors concluded that the frontline chemotherapy-free targeted and immunotherapeutic approach was superior to imatinib and chemotherapy.

Reference

Chiaretti S, Piciocchi A, Skert C, et al. Ponatinib–blinatumomab or imatinib–chemotherapy for adult Ph-positive ALL. N Engl J Med. 2026;395(15):1483-1494. doi:10.1056/NEJMoa2606208