Ponatinib and Blinatumomab for Patients with Relapsed/Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Chronic Myeloid Leukemia in Lymphoid Blast Phase: A Subgroup Analysis from a Phase II Study

Background: Ponatinib and blinatumomab are both highly effective in relapsed or refractory Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The combination of these two agents may lead to deep and durable responses without the need for chemotherapy.

Methods: In this phase II study, adults with relapsed/refractory (R/R) Ph+ ALL or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Results from patients (pts) with newly diagnosed Ph+ ALL are being reported separately. Pts were required to have a performance status of ≤2, total bilirubin ≤2x the upper limit of normal (ULN), and alanine aminotransferase and aspartate aminotransferase ≤3x the ULN. 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 as a continuous infusion at standard doses. Ponatinib 30mg daily was given during cycle 1. Ponatinib was decreased to 15mg daily once a complete molecular response (CMR) was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years in responding pts. Twelve doses of prophylactic intrathecal chemotherapy with alternating cytarabine and methotrexate were administered. The primary endpoint was the overall response rate (defined as the composite of CR/CRi). Secondary endpoints included safety measures, complete molecular response (CMR) rate, event-free survival (EFS) and overall survival (OS).

Results: Between February 2018 and June 2022, 20 patients were treated (14 R/R and 6 CML-LBP). Baseline characteristics are shown in Table 1. The median age of the R/R Ph+ ALL and CML-LBP cohorts were 38 years (range, 24-61) and 69 years (range, 29-82), respectively. BCR::ABL1 transcripts were p190 in 93% in the R/R cohort. 43% of pts in the R/R Ph+ ALL cohort were in salvage 2 or beyond. Among the CML-LBP pts, 3 were de novo and 3 were transformed from previously treated CML (1 of whom had received prior therapy for LBP).

Among the 14 pts with R/R Ph+ ALL, 1 was in CR but still with detectable BCR::ABL1 at enrollment. 12 of the 13 evaluable pts (92%) achieved CR/CRi, with CR in 11 pts (85%). The one non-responding pt had received prior ponatinib-based therapy in an earlier salvage regimen. After one cycle, 11/14 (79%) achieved MMR and 10/14 pts (71%) achieved CMR. 12/14 (86%) achieved MMR and 11/14 pts (79%) achieved CMR at any time over the course of therapy.

Among the 6 pts with CML-LBP, 5 (83%) achieved CR/CRi, and 1 achieved PR as best response. After one cycle, 1/6 pts (17%) achieved MMR and CMR. 3/6 (50%) achieved MMR and 2/6 (33%) achieved CMR at any time over the course of therapy.

The median follow-up is 22 months (range, 6-51+ months) in the R/R cohort, and 25 months (range, 11-38+ months) in the CML-LBP cohort. Among the 14 pts in the R/R cohort, 1 did not respond, 6 proceeded to allogeneic stem cell transplant (ASCT) (1 of whom relapsed post-ASCT and died and 5 of whom are still alive without relapse), 4 did not undergo ASCT and subsequently relapsed after a median of 6.4 months (range, 2.7-8.1), 1 died in CR, and 2 are in ongoing response without ASCT. Of the 5 relapses, 2 were hematologic only, 2 were in the CNS with MRD positivity in the bone marrow, and 1 was CNS only. The estimated 2-year EFS and OS for the R/R cohort are 46% and 59%, respectively (Figure 1). Among the 5 pts in the CML-LBP cohort who achieved CR/CRi, 3 relapsed (1 of whom had an immunophenotypic switch to a myeloid blast phase CML with loss of CD19 expression) and 2 are in ongoing response without ASCT. The estimated 2-year EFS and OS for the CML-LBP cohort are 33% and 60%, respectively (Figure 1).

Grade 3 adverse events observed on study were: febrile neutropenia, cytokine release syndrome, lipase increase, and alkaline phosphatase increase in 1 pt each. There were no grade 4-5 events. One pt discontinued ponatinib due to treatment-related adverse event (due to grade 3 portal vein thrombosis). One pt discontinued blinatumomab due to toxicity (due to persistent grade 2 tremor). No early deaths were observed.

Conclusion: The chemotherapy-free combination of ponatinib and blinatumomab is a safe and effective regimen in both R/R Ph+ ALL and CML-LBP. High rates of deep molecular response were observed in R/R Ph+ ALL. However, CMR rates were relatively low in pts with CML-LBP, suggesting that alternative approaches should be considered in these pts.

Kantarjian:Pfizer: Honoraria, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; ImmunoGen: Research Funding; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Amgen: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; AbbVie: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria. Short:Novartis: Consultancy; Amgen: Consultancy, Honoraria; Takeda Oncology: Consultancy, Research Funding; Pfizer: Consultancy; Astellas: Research Funding; Stemline Therapeutics: Research Funding; AstraZeneca: Consultancy. Jain:Cellectis: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; Beigene: Honoraria; ADC Therapeutics: Research Funding; Cellectis: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Loxo Oncology: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Servier Pharmaceuticals LLC: Research Funding; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Dialectic Therapeutics: Research Funding; Incyte Corporation: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Newave: Research Funding; Pfizer: Research Funding; Mingsight: Research Funding; Medisix: Research Funding; Takeda: Research Funding; TransThera Sciences: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novalgen: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; TG Therapeutics: Honoraria; MEI Pharma: Honoraria; Ipsen: Honoraria; CareDx: Honoraria. Kadia:Pfizer: Research Funding; Glycomimetics: Research Funding; Astex: Honoraria; Regeneron: Research Funding; PinotBio: Consultancy; cyclacel: Research Funding; Astellas: Research Funding; AstraZeneca: Research Funding; Agios: Consultancy; JAZZ: Consultancy, Research Funding; Novartis: Consultancy; Genentech: Consultancy, Research Funding; Genfleet: Research Funding; BMS: Consultancy, Research Funding; Servier: Consultancy; Delta-Fly: Research Funding; cellenkos: Research Funding; Ascentage: Research Funding; Amgen: Research Funding; Iterion: Research Funding; Abbvie: Consultancy, Research Funding. Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; Daiichi-Sankyo/Lilly: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding. Garcia-Manero:Astex: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Aprea: Honoraria; Acceleron Pharma: Consultancy; Curis: Honoraria, Research Funding; Gilead Sciences: Research Funding. Issa:Celgene, Kura Oncology, Syndax, Merck, Novartis: Research Funding; Novartis, Kura Oncology: Consultancy. Konopleva:Stemline Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Patents & Royalties, Research Funding; Sanofi: Other: grant support, Research Funding; Rafael Pharmaceutical: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: Grant support, Research Funding; Calithera: Other: Grant Support, Research Funding; Cellectis: Consultancy, Other: Grant support, Research Funding; Eli Lilly: Consultancy, Patents & Royalties, Research Funding; Reata Pharmaceuticals: Current equity holder in private company, Patents & Royalties; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kisoji: Consultancy, Honoraria; Amgen: Consultancy; Forty-Seven: Consultancy, Honoraria, Other: Grant support; F. Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grant support, Research Funding; Genentech: Consultancy, Other: grant support, Research Funding; AbbVie: Consultancy, Other: grant support, Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Syos: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding; Amgen: Honoraria, Research Funding; Xencor: Research Funding; Prelude: Research Funding; Novartis: Consultancy. Jabbour:Spectrum: Research Funding; Takeda: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding.