Blinatumomab and Ponatinib for Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Updated Results and Predictors of Relapse
Authors: Short Nicholas J. , Kantarjian Hagop , Jain Nitin , Takahashi Koichi , Furudate Ken , Senapati Jayastu , Haddad Fadi G. , Karrar Omer , Kadia Tapan M. , Chien Kelly S. , Sasaki Koji , Kugler Eitan , Garris Rebecca , Ravandi Farhad , Jabbour Elias 
Published: December 2024

Background: The combination of blinatumomab and ponatinib may offer an effective chemotherapy-free strategy for patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and reduce the need for allogeneic stem cell transplantation (SCT) in first remission. Long-term durability of these responses and predictors or relapse remain largely unknown.

Methods: In this phase II study, pts ≥18 years of age with newly diagnosed Ph+ ALL were eligible. Pts with uncontrolled cardiovascular disease or clinically significant central nervous system (CNS) comorbidities (except for CNS leukemia) were excluded. Pts received up to 5 cycles of blinatumomab at standard doses. Ponatinib 30mg was given continuous daily starting on cycle 1 day 1 and was decreased to 15mg daily once a complete molecular response (CMR; absence of detectable BCR::ABL1 by PCR) was achieved. After 5 cycles of blinatumomab, ponatinib was continued for at least 5 years. Initially, 12 doses of prophylactic IT chemotherapy (alternating cytarabine and methotrexate) were administered; this was later increased to 15 doses to further prevent CNS relapses (beginning with pt #64).

Results: Between June 2018 to May 2024, 76 pts with newly diagnosed Ph+ ALL were enrolled. The median age was 50 years (range, 18-83). BCR::ABL1 transcripts were p190 in 80% and p210 and 20%. 23 pts were in CR at start due to receiving minimal prior therapy before enrollment.

Among the 53 pts evaluable for hematologic response, 52 (98%) achieved CR/CRi (CR rate: 96%). There was 1 early death (intracranial hemorrhage on day 18). All hematologic responses occurred after 1 cycle. Among 69 pts evaluable for CMR, 41 (59%) achieved CMR after cycle 1, and 55 (80%) achieved CMR at any time. There was a trend towards higher rates of CMR after cycle 1 in pts with p190 (35/55; 64%) than for p210 (6/14; 43%) (P=0.16). Next-generation sequencing (NGS) MRD negativity (sensitivity: 1x10-6) was achieved in 17/37 (46%) after cycle 1 and 56/61 (92%) at any time. Of note, all 7 pts who did not achieve CMR and who were also assessed with NGS MRD were NGS MRD negative.

Among the 76 pts, 2 (3%) died in CR, 1 (1%) had early death, 7 (9%) relapsed, 2 (3%) underwent SCT in first remission (both due to lack of CMR), and the other 64 (84%) are in ongoing remission without SCT (56 of whom remain on ponatinib). Among the 7 relapses, the median time to relapse was 19.9 months (range, 7.6-24.5 months); 4 were CNS-only, 1 extramedullary (lymph nodes and peritoneal cavity)-only and 2 bone marrow-only. 4 of these relapsed pts are alive and in remission after receiving CD19 CAR T-cell therapy.

The median follow-up is 24 months (range, 1-71 months). The estimated 3-year CIR is 15%, 3-year EFS is 80% and 3-year OS is 89%. The most predictive factor for relapse risk was WBC ≥70K, which accounted for 22% of the study cohort (3-year CIR 47% vs. 5% for WBC &lt;70K; P&lt;0.001). No relapses occurred in the 15 pts with p210 transcripts (4 of whom also had WBC ≥70K), and the 3-year CIR for p190 vs. p210 transcripts was 19% vs. 0%, respectively; P=0.15. NGS MRD negativity after 1 cycle was not predictive for CIR (P=0.71), suggesting the rapid clearance of MRD was not protective for relapse.

Conclusion: The chemotherapy-free combination of ponatinib and blinatumomab results in high rates of deep MRD negativity (10-6 sensitivity) and durable remissions without need for SCT in most pts. Elevated WBC (≥70K) is associated with a higher risk of relapse, which is predominantly extramedullary. The study has now been amended to increase the number of doses of IT chemotherapy from 12 to 15 and also institutes 2 cycles of high-dose methotrexate and cytarabine for patients with high WBC. The association of genomic alterations (including IKZF1plus genotype) with MRD responses and relapse risk is being analyzed and will be presented at the meeting.