Blinatumomab and ponatinib demonstrates ongoing efficacy as frontline therapy in Philadelphia positive B-cell acute lymphoblastic leukemia: Long-term follow-up from a phase 2 Study Free

Background The chemotherapy-free combination of blinatumomab (blina) and the potent pan-BCR-ABL tyrosine kinase inhibitor (TKI) ponatinib has demonstrated high efficacy for the treatment of Philadelphia-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). Here, we report updated results with 3 years of follow-up from a phase 2 study of blina and ponatinib in adults with Ph+ B-ALL.

Methods This phase 2 study included pts>18 yrs of age with Ph+ B-ALL. Pts could receive up to 5 cycles of blina with ponatinib 30 mg daily starting cycle 1 day 1, with reduction to 15 mg daily upon complete molecular response (CMR). After completion of blina, pts continued ponatinib for at least 5 yrs. IT chemotherapy was increased from 12 to 15 with pt #64 to reduce the risk of central nervous system (CNS) relapse. The protocol was amended to add 2 cycles of high-dose methotrexate and cytarabine for pts with white blood cell (WBC)>70x10⁹/L.

Results As of July 2025, 85 pts were enrolled with a median age of 50 yrs (range, 18-83); 20%>70 yrs. Median baseline WBC was 15.2 x10⁹/L (0.6-322.1). Most pts (79%) had BCR::ABL1 p190 transcripts, 21% had p210. Twenty-five out of 48 pts (52%) with single nucleotide polymorphism array testing had IKZF1+ genotype.

The objective response rate was 97% with a complete remission (CR) rate of 95%. Measurable residual disease (MRD)-negativity by next-generation sequencing (NGS) was achieved in 64 pts (97%) at any time; 44% achieved after 1 cycle; median time to NGS-negativity was 2.8 months (0.79-50.9). Seventy-two pts (99%) achieved major molecular response (MMR) and 63 pts (83%) achieved complete molecular response (CMR) with 57% achieving after 1 cycle. Discordance between NGS-MRD and PCR was observed with 16% NGS-negative/transcript positive and 4% NGS-positive/transcript negative.

Median follow-up was 31 months (3-81). Of the 85 pts, 67 (79%) remain in remission without allogeneic stem cell transplant (ASCT). Of these pts, 1 received inotuzumab for MRD-positivity and 1 received CAR T-cell therapy. Two pts (2%) were offered ASCT in CR1 due to persistent positive p190 transcripts; neither pt had NGS-MRD available. Eleven pts (12%) relapsed (10/11 with p190 transcripts) after a median of 20 months (8-33) from CR. Five relapses were bone marrow only (median of 17 months to relapse), 5 were CNS only (median of 21 months to relapse), and 1 was extramedullary only (lymph nodes/peritoneum); 7/11 relapsed pts (64%) had baseline WBC>70x10⁹/L. Three of the 11 relapsed pts died (median age 47 yrs). There were 2 early deaths (1 intracranial hemorrhage from prior chemotherapy; 1 toxic megacolon). Three pts died in CR (1 post-procedural bleeding, 1 cerebral aneurysm, 1 respiratory failure). Since increasing IT chemo to 15, there has been 1 CNS relapse in these pts. Three pts received 2 cycles of high-dose methotrexate and cytarabine for WBC>70; none have relapsed.

The median EFS and OS have not yet been reached. Three-yr EFS and OS rates are 78% and 89%, respectively. There was no significant difference in OS (p=0.86) or EFS (p=0.49) in p190 vs. p210 transcripts; there was no significant difference in OS (p=0.5) or EFS (p=0.24) by NGS MRD clearance after 1 cycle. With death as a competing risk, the 3-yr cumulative incidence of relapse (CIR) was 17%, and cumulative incidence of death without relapse was 3%. For pts with WBC>70x10⁹/L vs. WBC<70x10⁹/L, the 3-yr CIR was 22% vs. 9% (p=0.0002), and cumulative incidence of death without relapse was 3% vs. 0% (p=0.237), respectively. The CIR and death without relapse for IKZF1+ vs non-IKZF1+ was 16% vs. 20% (p=0.6) and 0% vs. 4% (p=0.6).

The most common grade >3 AE were increased ALT (n=13), increased lipase (n=14), febrile neutropenia (n=11), pneumonia (n=10), HTN (n=9). Neurotoxicity included memory impairment (n=2), tremor (n=2), paresthesia/neuropathy (n=8), dizziness (n=2); all events were grade 1-2 and resolved with dose-reduction in blina or discontinuation of blina in 3 pts. Ponatinib was discontinued in 9 pts and dose-reduced in 1 pt.

ConclusionContinued follow-up of pts with Ph-positive B-ALL on frontline blina and ponatinib demonstrates ongoing deep, durable remissions without the need for ASCT in the majority of pts. The survival data continues to mature and patterns of relapse are being analyzed since the addition of CNS-disease directed amendments. No new safety signals have been identified.