(ORLANDO, Dec. 7, 2025) A chemotherapy-free combination treatment outperformed a combination of targeted therapy and chemotherapy among patients with Ph+ acute lymphoblastic leukemia (ALL) in a new study . The phase III trial, which included adult patients with no upper age limit, is the first formal comparison of the efficacy and safety of these two approaches in newly diagnosed patients with Ph+ ALL.
Researchers say the findings offer reassurance that chemotherapy can be omitted without detrimental effects and suggest that a chemo-free targeted agent and immunotherapy combination could become the new standard of care for this patient group.
"The chemo-free approach significantly reduced the rate of death in addition to increasing the rate of complete remission," said lead study author Sabina Chiaretti, MD, associate professor at Sapienza University of Rome in Italy. "The significance was very impressive, a more than 20% difference in terms of molecular response achievement [a sensitive test for residual cancer cells following treatment], so this approach truly is better."
ALL is a fast-growing type of leukemia affecting white blood cells, while Ph+ ALL is a genetic subtype characterized by the causal genetic abnormality in the Philadelphia chromosome. Patients with Ph+ ALL have historically faced a poor prognosis and increased resistance to chemotherapy, pointing to a need for improved treatments. In recent years, targeted tyrosine kinase inhibitors (TKIs) and immunotherapies have brought promising results, with good efficacy and fewer side effects than chemotherapy. Researchers have sought to identify the optimal combination of therapies among TKIs, immunotherapies, and chemotherapy.
For the trial, researchers enrolled 236 adult patients with Ph+ ALL, ranging in age from 19 to 84 years. Two-thirds of participants were randomly assigned to the experimental arm and received a TKI plus immunotherapy; one-third were assigned to the control arm and received a TKI plus chemotherapy. Patients in the experimental group received an initial course of steroids, a 70-day induction with the TKI ponatinib, and two to five cycles of the immunotherapy blinatumomab. Patients in the control group received the TKI imatinib along with either four or six cycles of chemotherapy for patients older or younger than age 65, respectively.
Patients in the chemo-free experimental arm had a significantly higher rate of event-free survival and a better response to treatment. At a median follow-up of 23 months, event-free survival was 87% in the experimental arm and 71% in the control arm, while the rate of death was 3.5% in the experimental arm and 10% in the control arm. The relapse rate was similar among arms (6% in the experimental group and 8% in the control group), although about half of the relapses in the experimental group occurred in patients who had discontinued their treatment.
Complete remission was achieved in 94% of those in the experimental arm and 79% of those in the control group. The chemo-free treatment regimen also resulted in a higher rate of negative measurable residual disease (MRD) status, an indicator that all or nearly all cancer cells have been eradicated. While only 49% of those in the control group achieved MRD-negative status, 71% of those in the experimental group achieved MRD-negative status after two cycles of blinatumomab, and 80% reached this status after five cycles.
"The more cycles with blinatumomab, the more the molecular remission rate increased," said Dr. Chiaretti. "This suggests that patients really should receive the planned five cycles. This is important because we have been working with blinatumomab for years, but we did not yet know how many cycles should be recommended."
Participants randomized to the control group were offered the option to cross over to the experimental arm if their disease was MRD-positive. About 37% of patients in the control arm eventually received the experimental treatment regimen, and 62% of these patients subsequently achieved MRD-negative status.
Most of the deaths occurred in older patients, and infections were a primary cause of death among those that occurred in the experimental arm. The safety profiles were consistent with those expected for each therapy involved in the study, and researchers said that most adverse events were successfully addressed by reducing dosage.
While the study was conducted exclusively in Italy, Dr. Chiaretti noted that the results should be applicable in any country. She added that a chemo-free treatment approach can bring economic benefits by reducing the need for hospitalization and allowing patients to continue working while undergoing cancer treatment.
A separate study is now underway to determine whether patients with sustained MRD-negative status can discontinue TKI treatment without raising the risk of a relapse.
Sabina Chiaretti, MD, of Sapienza University of Rome, will present this study on Sunday, December 7, 2025, at 9:30 a.m. Eastern time in W224A-F of the Orange County Convention Center.
