Updated results of the chemotherapy-free regimen of blinatumomab and ponatinib in patients with newly diagnosed Philadelphia-positive B-cell acute lymphoblastic leukemia.

6514 Background: Chemotherapy-free regimens incorporating blinatumomab (blina) and ponatinib have demonstrated promising activity in frontline Philadelphia-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL). We report the long-term outcomes from an ongoing, phase II study of blina with ponatinib in adults with newly diagnosed (ND) Ph+ B-ALL. Methods: Patients (pts) ≥18 yrs with Ph+ B-ALL received up to 5 simultaneous cycles of blina with ponatinib 30 mg daily, reduced to 15 mg daily upon complete molecular response (CMR). Pts continued ponatinib for at least 5 yrs. IT chemo was increased from 12 to 15 with pt #64 to reduce the risk of central nervous system (CNS) relapse. Protocol was amended to add 2 cycles of high-dose methotrexate (MTX) and cytarabine for pts with WBC >70x10 9 /L. Results: As of January 2025, 88 pts were enrolled (median age of 50 yrs [range, 18-83]; 19%>70 yrs). Median baseline WBC was 15.2 x10 9 /L (0.6-322). 78% of pts had BCR::ABL1 p190 transcripts, 20% had p210. 25 out of 48 pts (52%) with SNP array testing had IKZF1+ genotype. The objective response rate was 96%, with a complete remission (CR) rate of 95%. Measurable residual disease (MRD)-negativity by next-generation sequencing (NGS) was achieved in 95% of evaluable pts; 43% after 1 cycle. CMR rates by RT-PCR was 83%, 67% after 1 cycle. Median follow-up was 3 yrs. 70 pts (79%) remain in molecular remission without allogeneic stem cell transplant (SCT). Of these, 1 received inotuzumab for MRD-positivity and 1 received CAR T-cell therapy. 2 pts (2%) went to SCT in CR1 due to persistent positive p190 transcripts; neither pt had NGS-MRD available. 11 pts (12%) relapsed (10 with p190 transcripts) after a median of 20 months (8-33) from CR: 5 were bone marrow only, 5 CNS only, and 1 extramedullary only; 7/11 relapsed pts (64%) had baseline WBC>70x10 9 /L. Three of the 11 relapsed pts died. There were 2 early deaths, and 3 pts died in CR. Since increasing IT chemo to 15, there has been 1 CNS relapse. 3 pts received 2 cycles of high-dose MTX and cytarabine for WBC>70x10 9 /L; none have relapsed. Median event-free survival (EFS) and overall (OS) have not yet been reached; 3-yr EFS and OS rates are 79% and 89%, respectively. Outcomes did not differ significantly by transcript type nor by NGS MRD clearance after C1. For pts with WBC≥70x10 9 /L vs. WBC<70x10 9 /L, the 3-yr cumulative incidence of relapse (CIR) was 31% vs. 6.7% (p=0.005). The CIR for IKZF1+ vs non- IKZF1+ was 16% vs. 21% (p=0.6). Conclusions: Frontline blina with ponatinib induced deep, durable remission in Ph+ B-ALL, allowing most patients to avoid SCT. Relapses are seen with high presenting WBC, supporting the use of baseline-risk intensified strategies, including increased IT chemo, incorporation of high-dose chemo into consolidation, as well as CAR T-cell therapy. Clinical trial information: NCT03263572 .