A Chemotherapy-Free Regimen Beat Standard Treatment for Adults With Ph-Positive Leukemia in a 236-Patient Trial
Adults with Philadelphia-positive acute lymphoblastic leukemia (Ph-positive ALL) who received two targeted drugs and no chemotherapy did better than adults who received the standard chemotherapy regimen, according to a randomized trial of 236 patients. The estimated rate of event-free survival, the trial's primary end point, was 86% at 24 months with ponatinib plus blinatumomab and 67% with imatinib plus chemotherapy (P<0.001). The New England Journal of Medicine published the results in October 2026.
Dr. Sabina Chiaretti of Sapienza University of Rome and the GIMEMA Investigators, an Italian group of hematology researchers, ran the trial. The Associazione Italiana per la Ricerca sul Cancro and others funded it.
From fewer than 5% cured to a chemotherapy-free trial arm
Ph-positive means the leukemia cells carry the Philadelphia chromosome, a genetic abnormality that produces an abnormal protein called BCR::ABL1. The subtype is common in older adults. A 2016 GIMEMA paper in Haematologica puts it at about 22% of ALL in patients aged 21 to 50 and more than 50% in patients older than 50.
Before targeted drugs existed, standard chemotherapy cured virtually no adult patients (fewer than 5%). Median survival was 8 to 10 months unless a patient could receive an allogeneic stem-cell transplant, a transplant of donor cells that the same paper calls the only potentially curative strategy. Tyrosine kinase inhibitors (TKIs), drugs that block the BCR::ABL1 protein, changed that. In GIMEMA's earlier LAL 0904 study, which paired imatinib, the first TKI used for this disease, with chemotherapy and transplant where possible, 48.8% of patients were alive at 60 months.
What the trial compared
Researchers assigned 158 patients to ponatinib plus blinatumomab and 78 to imatinib plus chemotherapy, a 2-to-1 split. Ponatinib is a third-generation TKI. Blinatumomab is an immunotherapy known as a bispecific T-cell engager. The first group took ponatinib, then two cycles of blinatumomab alongside it. The control group received three cycles of chemotherapy with imatinib, then imatinib alone for cycles four through six.
At the end of induction, the first treatment phase, 94% of the chemotherapy-free group had a complete hematologic response (a standard measure of remission), against 79% of the control group. After blinatumomab consolidation, 71% had a molecular response, against 49% in the control group. Survival with no measurable residual disease (MRD), meaning no leukemia cells detectable by sensitive tests, was 68% versus 42%. The cumulative incidence of relapse was 5% versus 13%.
Control patients whose MRD persisted or returned could cross over to the ponatinib-blinatumomab regimen. Of 31 patients who did, 20 (64%) had a molecular response afterward. As of the report, 19% of the chemotherapy-free group had gone on to a stem-cell transplant after a first complete hematologic response.
Where the numbers get more complicated
Overall survival was 90% in the chemotherapy-free group and 85% in the control group. Event-free survival differs by 19 percentage points and overall survival by 5 (our arithmetic). The abstract, as indexed by Europe PMC, lists no P value for overall survival, and the crossover option moved 31 patients from the control group onto the new regimen.
The first results from this trial appeared at the American Society of Hematology (ASH) annual meeting in December 2025 with different figures. The ASCO Post reported event-free survival of 90% versus 74% at a median follow-up of 23.4 months, and overall survival of 94% versus 77%. The journal analysis uses a median follow-up of 23.7 months and reports 86% versus 67% and 90% versus 85%. The abstract does not explain the change, and the full paper sits behind a subscription, so this article uses the journal figures.
📍 Multiple Perspectives on the Story
Researchers say it should be the standard
At a press briefing during the 2025 ASH meeting, Chiaretti said this strategy "should be considered now as the standard approach" for Ph-positive ALL, as the ASCO Post reported. The journal paper's conclusion is shorter: a frontline chemotherapy-free targeted and immunotherapeutic approach was superior to imatinib and chemotherapy. Dr. Ibrahim Aldoss of City of Hope, who gave the expert commentary in the same ASCO Post report, also said chemotherapy-free regimens should be considered the front-line standard of care for newly diagnosed adults with Ph-positive ALL.
Relapses in the brain and spinal fluid are the failure to watch
In the December 2025 interim data, every relapse in the ponatinib-blinatumomab arm was a central nervous system (CNS) relapse, according to the ASCO Post. Dr. Aldoss described CNS relapse as disproportionately high with chemotherapy-free regimens and said an elevated white blood cell count is emerging as a relapse risk factor. Proposed countermeasures include higher doses of chemotherapy given into the spinal fluid, systemic chemotherapy between blinatumomab cycles, and CAR T-cell therapy.
The trial compares whole regimens, not single drugs
The arms used different TKIs: ponatinib, a third-generation drug, against imatinib. The result therefore cannot show how much of the gain comes from blinatumomab, how much from the stronger TKI, and how much from dropping chemotherapy. Dr. Aldoss pointed to the EA9181 trial, which balances TKI use, as a way to validate the findings. Every center in GIMEMA ALL2820 was in Italy, though the investigators argue the results should generalize across health systems.
Open questions the investigators still list
Ongoing work includes molecular monitoring, ABL1 mutation monitoring in patients with MRD, and quality of life, according to CURE. Whether patients with deep, sustained MRD negativity can safely stop TKIs remains under study, per the ASCO Post. Chiaretti disclosed honoraria from Incyte, BeiGene, Pfizer and Gilead and consultancy for Amgen, as OncLive reported.
What the trial shows and what it leaves open
The paper establishes a head-to-head result on event-free survival at about two years, in a randomized trial with a named primary end point. It does not yet show how patients fare at five or ten years, or how the overall survival gap behaves with longer follow-up. Treatment decisions belong to patients and their oncology teams. Readers who want the full results tables can check the NEJM paper itself (DOI 10.1056/NEJMoa2606208).
Frequently Asked Questions
What did the 2026 NEJM trial find about chemotherapy-free treatment for Ph-positive ALL?
In a randomized phase 3 trial of 236 adults, ponatinib plus blinatumomab with no chemotherapy gave an estimated 24-month event-free survival of 86%, against 67% for imatinib plus chemotherapy (P<0.001). Overall survival was 90% versus 85%.
What is Ph-positive acute lymphoblastic leukemia?
It is a form of acute lymphoblastic leukemia (ALL) whose cells carry the Philadelphia chromosome, a genetic abnormality that produces the BCR::ABL1 protein. A 2016 GIMEMA paper puts it at about 22% of ALL in patients aged 21 to 50 and more than 50% in patients older than 50.
Are ponatinib and blinatumomab now the standard treatment?
The trial authors say the approach should be considered the standard. We found no guideline update in the sources we reviewed, and the trial's median follow-up is about two years. Patients should talk with their oncology team about their own treatment.
Does this mean chemotherapy-free treatment works for all leukemia?
No. The trial covered adults with Ph-positive ALL, with a median age of 55 (range 24 to 82). It did not test other leukemia types.