Combination Therapy with Nelarabine, Peg-Asparaginase and Venetoclax for Adults Patients with Relapsed/Refractory T-Cell ALL

Introduction

Nelarabine, an antimetabolite drug is approved for treatment for relapsed/refractory (R/R) T-ALL/LBL. When used as a single agent in this setting, the response rates (CR/CRi) range from 31 to 36% with median overall survival (OS) ranging from 4.6 to 8 months (DeAngelo,2007; Gokbuget, 2011; Candoni 2020). We report our experience of nelarabine combined with peg-asparaginase and venetoclax for adult patients (pts) with R/R T-ALL/LBL.

Methods & Results

We retrospectively identified a total of 12 pts with R/R T-ALL/LBL who were treated with at least 1 cycle of combination therapy with nelarabine, peg-asparaginase and venetoclax (NEL-PEG-VEN) from August 2018 to December 2021 at MD Anderson Cancer Center, Houston.

The median age of the population was 47 years (range, 21-64 years) and 8 (67%) were male. The pathological diagnosis at baseline was T-ALL/LBL in 10 pts and T/Myeloid MPAL in 2 pts. 3 (25%) pts had ETP and 1 (8.3%) pt had near-ETP immunophenotype. 3 (25%) pts had complex cytogenetics and NGS revealed NOTCH1/FBXW7 mutations in 7 (58%) and TP53 in 3 (25%) pts. Majority of the pts (n=9) received hyper-CVAD based therapy as initial line of treatment. Time from first therapy to use of NEL-PEG-VEN was a median of 3 months (range, 1.2 to 104 months). Median number of prior lines of therapy was 1.5 (1 prior Rx, n=6; 2 prior Rx, n=5; 3+ prior line Rx, n=1). The number of pts with prior exposure to nelarabine, peg-asparaginase and venetoclax were 2 (16%), 2 (16%) and 4 (32%), respectively. Two pts had received prior allogeneic stem cell transplant (allo-SCT).

The most common dosing regimen used was nelarabine at 650 mg/m2 for 5 days with peg-asparaginase as a single dose of 1000-1500 IU/m2 (cap 3750 IU) on the fifth day. Venetoclax was most commonly dosed at 400 mg daily for 7-14 days. Median number of cycles of NEL-PEG-VEN administered was 1 (range, 1-2). A total of 6/12 (50%) pts had a response (2 CR, 3 CRh, 1 CRi) while 1 pt had aplastic marrow, 1 pt had MLFS, and 4 had refractory disease. Among the responders, 4/6 achieved MRD negative remission by flow cytometry (10^-4 sensitivity) after 1 cycle of NEL-PEG-VEN. Notably, 5 of the 6 pts who responded to the therapy proceeded to an allo-SCT with median interval of 3.6 months from NEL-PEG-VEN initiation. The median OS of the whole cohort was 9.1 months. Among the responders (n=6), median RFS was 23 months. Among the 5 pts who underwent allo-SCT, 2/5 had a post-transplant relapse while the other three are alive and in remission at 33-, 34- and 62-months post NEL-PEG-VEN regimen. One pt had grade 4 neurotoxicity in the form of ascending sensorimotor polyradiculopathy causing paraparesis, and 1 pt had grade 3 neurotoxicity in the form of transient ischemic attacks.

Conclusions

The novel combination of nelarabine, peg-asparaginase and venetoclax is an effective nelarabine-based therapy for adults with R/R T-ALL/LBL. In our cohort of 12 pts, we observed an ORR of 6/12 (50%) of whom 5/6 (83%) could go on to receive allo-SCT. The median OS of the whole cohort was 9.1 months and the median RFS of the responders was 23 months. NEL-PEG-VEN regimen is an effective therapy in getting this difficult to treat population into a remission, allowing them to proceed with a potentially curative allo-SCT.

Jabbour:Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Astellas Pharma: Consultancy; Genentech: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Research Funding; Ascentage Pharma Group: Research Funding; AbbVie: Consultancy, Research Funding. Kadia:Amgen: Research Funding; Genentech: Consultancy, Research Funding; Sellas: Consultancy, Research Funding; Novartis: Honoraria; JAZZ: Research Funding; BMS: Consultancy, Research Funding; DrenBio: Consultancy, Research Funding; Servier: Consultancy; Rigel: Honoraria; Regeneron: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Ascentage: Research Funding; ASTEX: Research Funding; AstraZeneca: Research Funding; Abbvie: Consultancy, Research Funding; Cellenkos: Research Funding. Short:Autolus: Honoraria; BeiGene: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Stemline Therapeutics: Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding; NextCure: Research Funding; Xencor: Research Funding; Novartis: Honoraria; Adaptive Biotechnologies: Honoraria; Takeda Oncology: Honoraria, Research Funding; GSK: Consultancy, Research Funding; Pfizer Inc.: Honoraria. Borthakur:Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Pemmaraju:Blueprint Medicines: Consultancy, Honoraria; Daiichi Sankyo: Research Funding; DAVA Oncology: Honoraria, Other: Travel Expenses; Aptitude Health: Honoraria; Novartis: Honoraria, Research Funding; Affymetrix/Thermo Fisher Scientific: Research Funding; Triptych Health Partners: Consultancy; Pacylex: Consultancy; Protagonist Therapeutics: Consultancy; Cellectis: Research Funding; Immunogen: Consultancy; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; ClearView Healthcare Partners: Consultancy; Incyte: Honoraria; CareDx: Honoraria; Celgene: Honoraria, Other: Travel Expenses; Neopharm: Honoraria; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Springer Science + Business Media: Honoraria; LFB Biotechnologies: Honoraria; Roche Molecular Diagnostics: Honoraria; Bristol-Myers Squibb: Consultancy; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; CTI BioPharma: Consultancy; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Daver:FATE Therapeutics: Other: Consulting Fees, Research Funding; Trovagene: Research Funding; Menarini Group: Consultancy; Genentech: Consultancy, Research Funding; Novimmune: Research Funding; Trillium: Consultancy, Research Funding; Hanmi: Research Funding; Shattuck Labs: Consultancy; Pfizer: Consultancy, Research Funding; Glycomimetics: Research Funding; Agios: Consultancy; Servier: Consultancy, Research Funding; KITE: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Celgene: Consultancy; Jazz: Consultancy; Syndax: Consultancy; Novartis: Consultancy; Arog: Consultancy. Kebriaei:Jazz Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Sasaki:Chugai: Other: Lecture fees; Enliven: Research Funding; Daiichi-Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Otsuka: Other: Lecture fees. Ravandi:Amgen: Research Funding; Xencor: Research Funding; Prelude: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Astyex/Taiho: Research Funding; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Jain:Loxo Oncology: Research Funding; NovalGen: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Incyte: Research Funding; MingSight: Honoraria, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; ADC Therapeutics: Research Funding; Newave: Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Medisix: Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; CareDx: Consultancy, Honoraria, Other: Travel Support; Aprea Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; Takeda: Research Funding; Pfizer: Research Funding; Servier: Research Funding; Dialectic Therapeutics: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; TransThera Sciences: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding.