Background

Patients with Philadelphia chromosome (Ph)-positive B-cell acute lymphoblastic leukemia (ALL) treated with Hyper-CVAD and ponatinib achieve deep responses and long-term overall survival (OS). We aim to investigate if a reduced intensity regimen of mini-Hyper-CVD (mini-HCVD) with sequential blinatumomab (blina) in combination with ponatinib may further improve outcomes while mitigating the toxicity of intensive chemotherapy and the need for hematopoietic stem cell transplantation (HSCT).

Methods

Patients age ≥18 years with newly diagnosed (ND) or relapsed/refractory (R/R) Ph-positive ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Other inclusion criteria included adequate liver, renal and cardiac function, and ECOG performance status ≤2. Patients with baseline central nervous system (CNS) involvement were not excluded. All patients had BCR::ABL1 transcripts and fluorescence in situ hybridization (FISH) for t(9;22) done at baseline. Morphological analysis of FISH patterns was performed in ND patients to identify if the BCR::ABL1 signal was observed in myeloid cells (e.g., segmented neutrophils). Four cycles (C) of mini-HCVD alternating with methotrexate (MTX) + cytarabine were followed by blina 28µg/d given for four weeks every six weeks during C5-8. Patients received ponatinib 30mg daily initially, with a dose reduction to 15mg daily once in complete molecular remission (CMR). CMR was defined as undetectable BCR::ABL1 with an assay sensitivity of 0.01%. Rituximab was given for CD20-positive disease. Maintenance ponatinib, vincristine and prednisone for 15 cycles with blina + ponatinib every three cycles was given, followed by ponatinib for at least five years. All patients without CNS disease received 12 intrathecal injections of MTX or cytarabine.

Results

20 patients (12 ND, 4 R/R, 4 CML-LBP) were treated between November 2019 and May 2023. Baseline characteristics are shown in Table 1. One patient with CML-LBP had received prior dasatinib while in chronic phase. The predominant BCR::ABL1 transcript was p190 in 7 (58%) ND patients. All patients achieved a complete remission (CR). Among patients in the ND, R/R, and CML-LBP cohorts, CMR was achieved in 10/12 (83%), 3/4 (75%), and 4/4 (100%) patients, respectively. In the ND cohort, six (50%) patients achieved CMR after C1 and eight (67%) after C3. Five (42%) ND patients had documented BCR::ABL1 signal in myeloid cells by FISH. Four of them achieved CMR, after C1, C3, C4 and C3 maintenance respectively.

With a median follow-up of 25 months (range, 2-42), the 2-year continuous remission duration (CRD) and OS rates were 93% and 83% for the entire cohort (Figure 1), and 90% and 82% in the ND cohort, respectively. In the ND cohort, one (8%) patient had isolated CNS relapse (during C4 of maintenance with blina and ponatinib), three (25%) patients died (two in CR due to COVID-19 and one of HSCT complications), and eight (67%) patients are in remission without HSCT. No patients relapsed in the R/R cohort; one patient underwent HSCT, one patient died in CR from MTX-associated disseminated necrotizing leukoencephalopathy, and two patients are in remission without HSCT. None of the CML-LBP relapsed; one patient underwent HSCT in CR.

Ponatinib dose was reduced in two patients prior to obtaining CMR (one had pancreatitis, one had cardiomyopathy). One patient switched from ponatinib to dasatinib due to a pulmonary embolism in C2. No patients required dose modification of blina. The 60-day mortality rate was 0%.

Conclusion

In patients with Ph-positive ALL, the combination of mini-HCVD and ponatinib followed by sequential blina and ponatinib yielded excellent outcomes with durable remissions. The toxicity profile was favorable and HSCT was avoided in most patients with ND disease. Longer follow-up is needed to confirm the durability of responses.

Jabbour:Abbvie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding. Short:Stemline therapeutics: Research Funding; Amgen: Honoraria; Takeda: Consultancy, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Issa:Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax: Research Funding; Merck: Research Funding; NuProbe: Consultancy; Celgene: Research Funding. Yilmaz:Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Daver:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Jazz: Consultancy; Celgene: Consultancy; FATE: Research Funding; AROG: Consultancy; Amgen: Consultancy, Research Funding; Shattuck Labs: Consultancy; Syndax: Consultancy; Glycomimetics: Research Funding; Novimmune: Research Funding; AbbVie: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Hanmi: Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Research Funding; Agios: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Kronos Bio: Research Funding. Pemmaraju:ASH Committee on Communications: Other: Leadership; Protagonist Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pacylex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intellisphere: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Physician Education Resource (PER): Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cimeio Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aplastic Anemia & MDS International Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Harborside Press: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ClearView Healthcare Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Neopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Imedex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; OncLive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Patient Power: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PeerView Institute for Medical Education: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; Curio Science: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CareDx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASCO Cancer.Net Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; United States Department of Defense (DOD): Research Funding; Medscape: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magdalen Medical Publishing: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CancerNet: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aptitude Health: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; HemOnc Times/Oncology Times: Other: Uncompensated; Bristol Myers Squibb Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Masarova:MorphoSys US: Membership on an entity's Board of Directors or advisory committees. Ravandi:Syros: Consultancy, Honoraria, Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomea fusion: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Xencor: Research Funding; Amgen: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding. Jain:Fate Therapeutics: Research Funding; Loxo Oncology: Research Funding; Incyte: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Medisix: Research Funding; Ipsen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Beigene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; CareDX: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Precision Biosciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TransThera Sciences: Research Funding; Dialectic Therapeutics: Research Funding; Newave: Research Funding; ADC Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Mingsight: Research Funding; Takeda: Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pfizer: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; BMS: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; MEI Pharma: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Servier: Research Funding; Novalgen: Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Kantarjian:Abbvie (Inst): Research Funding; Taiho Pharmaceutical: Honoraria; Shenzhen Target Rx: Honoraria; Precision Biosciences: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; KAHR Medical: Honoraria; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; Ipsen: Honoraria; Immunogen (Inst): Honoraria, Research Funding; Daiichih-Sankyo (Inst): Honoraria, Research Funding; AstraZeneca/MedImmune: Honoraria; Astellas Pharma: Honoraria; Ascentage Pharma Group: Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria; Novartis (Inst): Research Funding; Bristol-Myers Squibb (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Amgen (Inst): Research Funding.

Figure 1
Figure 1
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2023
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