Blazing a Trail in Ph-ALL: Chemotherapy-Free Options Gain Ground

The pillars of recent success in the treatment of acute lymphoblastic leukemia (ALL) include a better breakdown of high-risk subgroups and the introduction of novel therapies, according to Nick J. Short, MD, associate professor, Department of Leukemia at The University of Texas MD Anderson Cancer Center.

During The HemOnc Pulse Live! held on May 2 and 3, 2025, in Austin, TX, Dr. Short gave a presentation, in which he homed in on paradigm shifts. One of the biggest paradigm shifts, according to Dr. Short, has been in the Philadelphia chromosome-positive (Ph) ALL, a rather aggressive subtype of the disease.¹

“PH-positive ALL was historically one of the most aggressive subtypes of leukemia that needed chemotherapy, allogeneic transplant, and still had relatively poor outcomes. And now we’re talking about chemotherapy-free regimens where many of these patients were not transplanted,” said Dr. Short.

Evolving the Treatment Landscape

In the phase 3 PhaLLCON study (NCT03589326), ponatinib plus reduced-intensity chemotherapy achieved better MRD-negative complete remission (CR) at the end of induction therapy compared with imatinib in adult patients with newly diagnosed disease.²

Of the 245 patients enrolled in the study, the MRD-negative CR with ponatinib was 34.4% versus 16.7% with imatinib, showing a risk difference of 0.18 (95% CI, 0.06-0.29; P=0.002). Among patients treated with ponatinib, the median event-free survival (EFS) was not reached vs 29 months in the imatinib-treated patients.

Safety results showed that the two agents had similar adverse event profiles. Occurrences of arterial occlusion were observed in 2.5% of the ponatinib arm compared with 1.25% of the imatinib arm.

Another clinical trial causing a shift in the way hematologic oncologists treat Ph-ALL is the GIMEMA LAL2116 (D-ALBA) trial, which offered the chemotherapy-free option of dasatinib and blinatumomab as induction and consolidation therapy for adults with newly diagnosed Ph-ALL. According to the long-term findings published in the Journal of Clinical Oncology,² as of data cutoff, 96.5% of responders remain in complete hematologic response (CHR) at a median follow up of 48 months (range 22-64 months).

Finally, new research presented at the American Society of Hematology Annual Meeting & Exposition showed that ponatinib in combination with blinatumomab achieved high rates of MRD negativity along with durable remissions.³ As another chemotherapy-free combination, ponatinib/blinatumomab may further shift the paradigm, according to Dr. Short.¹

“We’re now achieving a four-year survival rate of around 80% with chemotherapy-free regimens. That’s an incredible shift in the treatment landscape,” he said.

Future Treatment Considerations

Each year, more possibilities are being introduced at medical meetings, explained Dr. Short. However, unanswered questions remain around the power and implications of MRD, the utility of transplant in the front-line setting, and how chimeric antigen receptor (CAR) T-cell therapy factors in.¹

Short said, “a really big factor that dictates outcomes is MRD response, and we now have better MRD tools and understanding of the dynamics during frontline therapy.” At MD Anderson, research is reportedly ongoing to generate more information around the correlation between MRD and efficacy outcomes.

In terms of transplant, there is no definitive evidence to support excluding it from care, but Short noted that “in the E1910 study, there was no clear benefit of transplant — even among patients with unfavorable risk ALL. In fact, non-transplanted patients did better numerically,” he said.

As experts continue to consider the future of treatment, there is no doubt that CAR T cells have a role. However, Short explained that their role is for a specific subgroup of patients.

“We’re very interested in CAR T cells as consolidation for high-risk frontline patients. Early data show strong expansion and very low relapse, but more investigation is needed,” Short stated.

Reference:

1. Short, Nick, Acute Lymphoblastic Leukemia. Presented at: The HemOnc Pulse Live; May 2-3, 2025; Austin, TX.
2. Jabbour E, et al. JAMA. 2024;331(21):1814-1823. doi:1001/jama.2024.4783
3. Foa R, et al. J Clin Oncol. 2024: 10;42(8):881-885. doi:1200/JCO.23.01075