Background Hyper-CVAD plus ponatinib is highly effective in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The sequential combination of low-intensity chemotherapy and ponatinib followed by blinatumomab and ponatinib may lead to deeper and more durable responses, while minimizing toxicity of intensive chemotherapy and sparing the need for allogenic stem cell transplantation (ASCT).

Methods In this phase II study, adults with either newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Patients (pts) in the ND cohort could have received up to two cycles of therapy prior to enrollment. Pts received mini-hyper-CVD alternating with methotrexate and cytarabine on cycles 1-4, followed by blinatumomab and ponatinib on cycles 5-8. Ponatinib 30mg daily was given in cycle 1, and the dose was reduced to 15mg daily once a complete molecular response (CMR) was achieved. Pts with CD20+ disease received rituximab on cycles 1-4. Pts received 12 total administrations of prophylactic intrathecal chemotherapy with alternating cytarabine and methotrexate. Following consolidation, pts received maintenance therapy with 15 cycles of ponatinib plus vincristine/prednisone (maintenance cycles 1-3, 5-7, 9-11, and 13-15) alternating with ponatinib plus blinatumomab (maintenance cycles 4, 8, and 12) followed by ponatinib monotherapy daily for at least 5 years. The primary endpoint for pts with ND Ph+ ALL was the CMR rate. The primary endpoint for pts with R/R Ph+ ALL or CML-LBP was the CR/CRi rate. Secondary endpoints included complete remission duration (CRD), overall survival (OS), and safety.

Results Between November 2019 and December 2021, 16 pts were treated (11 ND, 3 R/R, 2 CML-LBP). Baseline characteristics are shown in Table 1. The median age of the ND cohort was 35 (range, 25-59). BCR::ABL1 transcripts were p190 in 7 (64%) pts in the ND cohort. All pts in the R/R and CML-LBP cohorts were p210. Five pts (31%) in the ND cohort had evidence of a myeloid component to their disease (BCR::ABL1 in the myeloid compartment by FISH analysis in 4 pts and a small population of myeloid blasts in 1 pt). One of the R/R pts was in salvage 1, and 2 pts were in salvage 2; none of the R/R pts had previously received ponatinib. Neither of the 2 pts with CML-LBP had received any prior therapy, including a TKI. Nine pts (6 ND, 2 R/R and 1 CML-LBP) were in CR at the time of enrollment, and 4 pts (3 ND and 1 R/R) were in CMR.

All pts who were evaluable for morphological response achieved CR. Among 8 evaluable ND pts, 6 achieved CMR. Two of 3 evaluable R/R pts and 1 of 2 evaluable CML-LBP pts achieved CMR. Among the 9 pts who achieved CMR, all but one achieved CMR during the chemotherapy plus ponatinib cycles. Out of the 5 ND pts who had evidence of myeloid involvement at presentation, 2 did not achieve CMR (both p190). All 6 pts who underwent Clonoseq MRD assessment achieved MRD negativity at 10-6 by this assay.

With a median follow-up of 23 months (range, 6-31), the 2-year CRD and OS rates are 90% and 78%, respectively, across all cohorts (Figure 1), and are 89% and 82%, respectively in the ND cohort. Among the 11 ND pts, 1 pt (9%) relapsed, 2 pts (18%) died in CR (both due to COVID-19), and 8 pts (73%) are in continuous remission without ASCT. The 1 ND pt who relapsed developed CNS-only relapse during maintenance in the setting of non-compliance with ponatinib. Among the 3 R/R pts, no pts relapsed, 1 pt underwent ASCT, 1 pt died in CR from methotrexate-associated disseminated necrotizing leukoencephalopathy (autopsy-proven), and 1 pt is alive in continuous remission without ASCT. Among the 2 CML-LBP pts, neither relapsed, 1 pt underwent ASCT in first remission, and both are alive.

Treatment was overall well-tolerated. The ponatinib dose was reduced in 2 pts prior to obtaining CMR due to toxicity (1 pancreatitis, 1 cardiomyopathy). One pt discontinued ponatinib and switched to dasatinib due to pulmonary embolism that occurred in cycle 2. No pts required dose-reduction or discontinuation of blinatumomab. The 30- and 60-day mortality rates were 0%.

Conclusion Sequential combination of low-intensity chemotherapy and ponatinib followed by blinatumomab and ponatinib is highly effective and well tolerated in Ph+ ALL.

Jabbour:Amgen: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Genentech: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding; Takeda: Other: Advisory Role, Research Funding. Short:Pfizer: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Honoraria; Novartis: Consultancy; Stemline Therapeutics: Research Funding; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding. Issa:Novartis, Kura Oncology, Nuprobe: Consultancy; Celgene, Kura Oncology, Syndax, Merck, Cullinan and Novartis: Research Funding. Yilmaz:Pfizer: Research Funding; Daiichi-Sankyo: 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. Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Ravandi:Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Syos: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding; Xencor: Research Funding; Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Prelude: Research Funding. Jain:TG Therapeutics: Honoraria; ADC Therapeutics: Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Medisix: Research Funding; CareDx: Honoraria; Servier Pharmaceuticals LLC: Research Funding; Fate Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novalgen: Research Funding; Beigene: Honoraria; Takeda: Research Funding; Newave: Research Funding; MEI Pharma: Honoraria; Ipsen: Honoraria; Mingsight: Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; Dialectic Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Incyte Corporation: Research Funding; TransThera Sciences: Research Funding; Cellectis: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Loxo Oncology: Research Funding; Cellectis: Honoraria, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding. Kantarjian:Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Takeda: Honoraria.

Author notes

This icon denotes a clinically relevant abstract

*

Asterisk with author names denotes non-ASH members.

Sign in via your Institution