A chemotherapy-free-based regimen of the TKI ponatinib combined with targeted immunotherapy showed significant benefits in the treatment of newly diagnosed adult Philadelphia (PH)-positive acute lymphoblastic leukemia (ALL) compared with a TKI plus chemotherapy.

“The first results of the phase 3 GIMEMA ALL2820 trial show, for the first time in a head-to-head comparison, a significant advantage of a chemo-free targeted/immunotherapeutic strategy over a TKI/chemotherapy approach [in PH-positive ALL],” said first author Sabina Chiaretti, MD, PhD, assistant professor in the Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, in Rome, Italy, while presenting the findings at American Society of Hematology (ASH) 2025 Annual Meeting.

The study showed “higher complete hematological and minimal residual disease [MRD] responses, fewer deaths, and improved event-free and overall survival.”

Based on the results, “the chemo-free approach should be considered as the new standard of care for treating adult patients with PH-positive ALL,” said Chiaretti.

PH-positive ALL has long been associated with poor outcomes, however, the advent of TKIs has significantly improved prognoses, and the more recent addition of immunotherapy such as blinatumomab has further improved outcomes, suggesting the chance to avoid the toxicities of chemotherapy without compromising but improving the efficacy, she said.

Methods and Results

To compare chemo-free with a regimen of a TKI plus chemotherapy, Chiaretti and colleagues conducted the phase 3 GIMEMA ALL2820 trial, enrolling 236 patients with newly diagnosed PH-positive ALL.

The patients were randomized 2:1 to treatment either with a chemotherapy-free regimen of ponatinib 45 mg or 30 mg, based on age below or above 65 years, along with at least two cycles (maximum five) of intravenous blinatumomab, or to a regimen of imatinib 800 mg or 600 mg daily, also depending on age below or above 65 years, plus chemotherapy, in six or four cycles for patients, based on the 65-year age cutoff.

Patient characteristics were similar in the chemo-free (n = 158) and control (n = 78) arms, with a median age of 57 and 55 years, with 44% and 21% over the age of 65; and 50% and 59% male participants, respectively.

For the endpoint of responses at the end of induction, evaluated after day 70 in the chemo-free arm and after three chemotherapy courses in the control arm, complete hematologic remission was significantly higher in the chemo-free arm, at 94.3% vs 79.4% (P =.001).

After induction, deaths had occurred in four patients (2.5%) in the chemo-free arm and eight patients (10.2%) in the control arm.

No patients in the chemo-free arm were refractory to treatment at the end of induction compared to one patient in the control group, and five patients (2.8%) in the chemo-free group were off treatment compared to seven patients (8.9%) in the control arm, for a combined, P value of .004 in favor of the chemo-free group for all four of the end-of-induction outcomes.

MRD responses after induction were similar between the groups, with rates of 46.8% in the chemo-free arm and 43.6% in the control arm.

Overall MRD responses at day 133 (after two blinatumomab cycles or four or six chemotherapy cycles) were also notably higher in the chemo-free arm, at 112 (70.9%) compared with 38 (48.7%) in the control arm.

Crossover to Chemo-Free Arm

Under the study protocol, patients in the control arm were permitted to crossover to the chemo-free arm if they were MRD-positive after cycle 4/6, or earlier if they became refractory or developed mutations, and 31 patients (37.2%) did so, with four patients (13.8%) at very early timepoints, including one patient having become refractory, and three developing mutations.

Of the 31 crossover patients, 20 achieved MRD negativity. Of those patients, 14 subsequently underwent allogeneic stem cell transplantation.

In patients, overall, at the time of the analysis, 14 relapses had occurred, including nine (6%) in the chemo-free arm and five (8%) in the control arm. The median time to relapse was 5.6 months in the chemo-free arm and 11.3 months in the control arm.

Among patients who relapsed, the median white blood cell count was more than three times higher in the chemo-free arm, at 36 × 10⁹/L, compared with 12 × 10⁹/L in the control arm.

Four relapses occurred in the chemo-free arm among patients who discontinued treatment vs none in the control arm.

Overall, there were seven deaths (4.7%) in the chemo-free arm and five (8%) in the control arm, including four after allogeneic stem cell transplant in the chemo-free arm vs none in the control arm.

In the chemo-free arm, two deaths were related to pneumonia and one to cardiac arrest; and in the control arm, three deaths were related to septic shock, one due to a pulmonary hemorrhage, and one to multi-organ failure.

The event-free survival rate, with a median follow-up at 23.4 months, was 90% in the chemo-free group vs 74% in the control arm (P = .0015).

Overall survival rates were highest in the crossover arm (97%), and the rate was 94% in the chemo-free group vs 77% in the control group (P = .00071).

Serious adverse events (SAEs) occurred in 49 patients (27.5%) in the chemo-free arm and 34 patients (50%) in the control arm, with infections and hematologic toxicity among the most common causes of SAEs in both groups.

Importantly, in addition to the benefits to patients starting with the chemo-free regimen, the results show that “a crossover is capable of rescuing MRD-positive patients in the control arm,” Chiaretti said.

Commenting on the study, session moderator Laura Michaelis, MD, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, agreed that the findings suggest important improvements in the treatment of PH-positive ALL.

“I think that the introduction of highly potent TKIs and the use of bispecifics like blinatumomab have absolutely changed how we think about PH-positive ALL,” she said at a press briefing at the meeting.

Future risk stratification systems and decision-making on transplant will need to take these results into account, she added.

Chiaretti declared having relationships with Incyte, BeiGene, Pfizer, Amgen, and Gilead. Michaelis declared having relationships with Incyte Corporation, Kura, and Merck.