As front-line therapy, a chemotherapy-free regimen combining the tyrosine kinase inhibitor (TKI) ponatinib and the bispecific T-cell engager blinatumomab significantly outperformed standard treatment with imatinib plus chemotherapy in adults with newly diagnosed Philadelphia chromosome–positive (Ph-positive) acute lymphoblastic leukemia (ALL) in the phase III GIMEMA ALL2820 trial, researchers reported at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition.1
In this first formal comparison of the two treatment approaches, the chemotherapy-free strategy resulted in substantial improvements in event-free survival, remission rates, and measurable residual disease (MRD) response, said Sabina Chiaretti, MD, PhD, of Sapienza University of Rome, Italy.
“The first results of the GIMEMA ALL2820 trial show, in a randomized fashion, that a chemotherapy-free, targeted approach is superior to conventional chemotherapy plus TKI in basically every outcome… We conclude that this strategy should be considered now as the standard approach in treating patients with Ph-positive ALL,” Dr. Chiaretti said in a press briefing during the meeting.
Press briefing moderator Laura Michaelis, MD, Chief, Division of Hematology/Oncology at Froedtert & the Medical College of Wisconsin, commented on the findings, “The introduction of highly potent tyrosine kinase inhibitors and the use of bispecific T-cell engagers such as blinatumomab have absolutely changed how we think about Ph-positive ALL. Future risk stratification systems and decision making on transplant will have to take into account the results of this study.”
Speaking further to The ASCO Post, Dr. Michaelis added that among the advantages of the chemotherapy-free regimen would be a reduced risk of secondary malignancies, which is especially important to young patients who are frequently among the ALL subset. “This would be a giant step forward,” she said.
Study Details
GIMEMA ALL2820 enrolled 236 adults with Ph-positive ALL and randomly assigned them 2:1 to either ponatinib plus blinatumomab (n = 158) or imatinib plus chemotherapy (n = 78). Patients received steroids before treatment.
In the experimental arm, patients aged 18 to 65 years were given ponatinib at 45 mg/day for the first 22 days, then at 30 mg/day until day 70, followed by two cycles of blinatumomab plus ponatinib; patients older than 65 years were given 30 mg/day of ponatinib until day 70 followed by two cycles of blinatumomab and ponatinib. In the control arm, patients aged 18 to 65 years received chemotherapy plus imatinib for three cycles until day 70, with cycles four, five, and six of imatinib only; patients over 65 received mild chemotherapy plus imatinib for three cycles until day 7, followed by a fourth of imatinib. Patients who lacked a complete hematologic response or remained MRD-positive could cross over to the experimental regimen.
Key Findings
“The hematologic responses after induction were strongly in favor of the experimental arm,” Dr. Chiaretti announced. Complete hematologic responses were achieved by 94.3% receiving ponatinib/blinatumomab vs 79.4% receiving imatinib/chemotherapy (P = .004). MRD responses also favored the chemotherapy-free strategy. While at the end of induction, responses were similar between the arms, after treatment completion (following blinatumomab) 70.9% of patients achieved MRD-negative status, compared with 48.7% of control patients (after chemotherapy) (P < .001).
At a median follow-up of 23.4 months, event-free survival was 90% in the experimental arm vs 74% in the control arm (P = .0015). Overall survival was 94% vs 77% (P = .00071), respectively, and reached 97% for patients in the control arm who crossed over to receive the experimental therapy, “suggesting that this strategy is successful in rescuing MRD-positive patients,” she said.
Relapses occurred in 6% of the experimental arm and 8% of the control arm; interestingly, she noted, median white blood cell counts were three times higher among patients relapsing in the experimental arm, and the only relapses with ponatinib/blinatumomab were in the central nervous system.Rates of death were 4.7% and 8.0%, respectively.
Although the study population was limited to centers in Italy, the researchers maintained 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 tyrosine kinase inhibitors without increasing relapse risk, they said.
The safety profiles were consistent with the known toxicities of each agent, and most adverse events could be managed with dose modifications. Vascular toxicity was low and comparable between the arms.
DISCLOSURE: Dr. Chiaretti has received honoraria from Incyte, BeiGene, Pfizer, and Gilead; and has consulted for Amgen. Dr. Michaelis has received honoraria from Merck, Kura, Incyte, UpToDate, and Research to Practice.
REFERENCE
1. Chiaretti S, Di Trani M, Skert C, et al. First results of the Phase III GIMEMA ALL2820 trial. 2025 ASH Annual Meeting & Exposition. Abstract 439. Presented December 7, 2025.
EXPERT POINT OF VIEW
Ibrahim T. Aldoss, MD, Associate Professor in the Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, Duarte, California, commented on the GIMEMA study.
“The early results from the GIMEMA ALL2820 trial1 are highly impactful, demonstrating the superiority of a chemotherapy-free regimen over the traditional chemotherapy plus imatinib approach in adults with newly diagnosed Philadelphia chromosome–positive (Ph-positive) ALL. While previous single-arm studies have shown excellent outcomes with blinatumomab and tyrosine kinase inhibitors (TKIs) as front-line therapy, the strength of this trial lies in its randomized design, confirming benefits such as higher response rates, lower early mortality, and superior MRD [measurable residual disease] response, event-free survival, and overall survival. These findings strongly support chemotherapy-free regimens as the new standard of care for Ph+ ALL,” Dr. Aldoss maintained.
“This shift is particularly important because Ph-positive ALL occurs more frequently in older and frail patients, and the disease is often chemotherapy-refractory. Early integration of immunotherapy addresses these challenges by overcoming chemotherapy resistance and offering a safer alternative to traditional regimens,” he explained.
Aside from this key message from the findings, Dr. Aldoss did acknowledge a challenge in interpreting the data from this study: the imbalance in TKI potency between the two arms since the experimental arm included a more potent third-generation TKI while the chemotherapy arm used imatinib. “The PhALLCON phase III trial2 has already demonstrated ponatinib’s superiority over imatinib in achieving complete molecular remission at 3 months when combined with low-intensity chemotherapy,” he pointed out. “Upcoming results from EA9181, comparing second- or third-generation TKIs with either chemotherapy or blinatumomab, will help validate these findings as the TKI use is balanced in this study.”
Dr. Aldoss also noted another issue for further exploration: high white blood cell count, which is emerging as a risk factor for relapse even with chemotherapy-free regimens. “It is unclear whether adding chemotherapy cycles can overcome this high-risk feature,” he said. “Extramedullary relapses, particularly CNS [central nervous system] involvement, appear disproportionately high with chemotherapy-free regimens. Although overall relapse rates are lower, CNS relapse is the main manifestation of treatment failure. Experts have proposed strategies to mitigate CNS relapse including increasing intrathecal chemotherapy doses, introducing systemic chemotherapy with good CNS penetration between blinatumomab cycles, and designing future studies with immunotherapies that have CNS activity, such as CAR [chimeric antigen receptor] T-cell therapy.”
These concerns aside, the overall take-home message, Dr. Aldoss concluded, is very positive: “The GIMEMA ALL2820 trial adds compelling evidence that chemotherapy-free regimens should be considered the front-line standard of care for newly diagnosed adult patients with Ph-positive ALL, improving early safety and efficacy and translating into better long-term survival outcomes.”
DISCLOSURE: Dr. Aldoss has served as a consultant or advisor for Autolus, Amgen, Pfizer, AstraZeneca, Kite, Jazz, Syndax, AbbVie, Takeda, Servier, Acentage, Adaptive, and Sumitomo, and has received research support from AbbVie, Jazz, Novartis, and MacroGenics.
REFERENCES
1. Chiaretti S, Di Trani M, Skert C, et al. First results of the Phase III GIMEMA ALL2820 trial. 2025 ASH Annual Meeting & Exposition. Abstract 439. Presented December 7, 2025.
2. Aldoss I, Ribera J-M, Kantarjian H, et al. Ponatinib Versus Imatinib in Patients with Newly Diagnosed Ph+ ALL: Subgroup Analysis of the Phase 3 PhALLCON Study. Blood 142 (Supplement 1): 2871, 2023..
