Blinatumomab/Ponatinib Provides Chemo-Free Option in Ph+ ALL

A head-to-head comparison of ponatinib (Iclusig) plus blinatumomab (Blincyto) vs imatinib (Gleevec) and chemotherapy supports the use of a chemotherapy-free approach for adult patients with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL), according to results from the phase 3 GIMEMA ALL2820 trial (NCT04722848) presented at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.

A complete hematologic response (CHR) was observed in 94.3% of patients in the ponatinib plus blinatumomab arm vs 79.4% in the control arm of imatinib plus chemotherapy; 2.5% vs 10.2% of patients died, 0% vs 1.3% had refractory disease, and 2.8% vs 8.9% of patients were off treatment (P = .004). These data were considered to be statistically significant.

In the ponatinib-plus-blinatumomab arm, there were no molecular responses in 53.2% of patients at the end of induction vs 29.1% after 2 cycles of blinatumomab, a complete molecular response (CMR) in 30.4% vs 51.9%, positive non-quantifiable (PNQ) in 16.5% vs 19.0%, and the overall molecular response was 46.8% vs 70.9%.

In the imatinib-plus-chemotherapy arm, there was no molecular response in 56.4% of patients at the end of induction vs 51.3% after 4 to 6 cycles of chemotherapy, depending on age; 35.9% vs 37.2% had a CMR, 7.7% vs 11.5% had a PNQ, and 43.6% vs 48.7% had overall molecular responses.

Results were compared with previous findings from the D-ALBA trial (n = 63) and showed that in the experimental arm, the overall molecular response was 26.9% at the end of induction vs 52.4% after 2 cycles of blinatumomab therapy.

At a median follow-up of 23.4 months, the event-free survival (EFS) rate in the ponatinib plus blinatumomab arm was 90% (range, 86%-95%) vs 74% (range, 65%-85%) in the control arm (P = .0015). The overall survival (OS) was 94% (range, 91%-98%) in the ponatinib plus blinatumomab arm vs 77% (range, 66%-91%) in the control arm, and 97% (range, 90%-100%) crossed over.

“A chemotherapy-free approach should be the new standard for Ph ALL,” Sabina Chiaretti, MD, PhD, from the Sapienza University of Rome in Italy, said during the presentation. “The first results of the phase 3 GIMEMA ALL2820 trial show for the first time, in head-to-head comparison, a significant advantage of a chemotherapy-free, targeted immunotherapeutic-based approach over a tyrosine kinase inhibitor and chemotherapy strategy, with a higher CHR and minimal residual disease response, fewer deaths, and improved EFS and OS.”

Patients were randomly assigned 2:1 to either the experimental arm (n = 158) or the control arm (n = 78). In the experimental arm, if patients were between 18 and 65 years old they were given ponatinib at 45 mg/day for the first 22 days, followed by 30 mg per day until day 70, and followed by 2 cycles of blinatumomab plus ponatinib; if patients were 65 years or older, they were given 30 mg of ponatinib per day until day 70 followed by 2 cycles of blinatumomab and ponatinib therapy.

In the control arm, if patients were between 18 and 65 years old they were given chemotherapy plus imatinib for 3 cycles until day 70, followed by cycles 4 to 6 of imatinib; if patients were 65 years old or older they were given mild chemotherapy plus imatinib for 3 cycles until day 7, followed by cycle 4 of imatinib if there was no CHR or minimal residual disease (MRD) response patients could cross over to the experimental arm.

Chiaretti noted there are additional ongoing studies to be presented at further meetings of this treatment regimen, including:

1. BCR::ABL1 and IG/TR MRD monitoring by RQ-PCR and droplet digital PCR (ddPCR)
2. ABL1 mutations monitored by ddPCR in patients who are MRD positive
3. Host immune modulation
4. Quality of life

Disclosures: Chiaretti cited honoraria from Incyte, BeiGene, Pfizer, and Gilead; and consultancy from Amgen.

Reference

Chiaretti S, Di Trani M, Skert C, et al. First results of the Phase III GIMEMA ALL2820 trial comparing ponatinib plus blinatumomab to imatinib and chemotherapy for newly diagnosed adult Ph+ acute lymphoblastic leukemia patients. Blood. 2025;146(suppl 1):439. doi.10.1182/blood-2025-439