Frontline HCVAD with Nelarabine and Peg-Asparaginase in T-Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL): Updated Results of a Phase II Trial
Authors: Maiti Abhishek , Jabbour Elias , Jain Nitin , Borthakur Gautam , Kadia Tapan M. , Burger Jan A. , Wierda William G. , Konopleva Marina , Alvarado Yesid , Short Nicholas J. , Faderl Stefan , O'Brien Susan M. , Ferrajoli Alessandra , Kornblau Steven M. , Daver Naval , Pemmaraju Naveen , Bose Prithviraj , Thompson Philip A. , Khoury Joseph D. , Balkin Hayley , Kelly Mary , Azzawi Hind , Garris Rebecca , Garcia-Manero Guillermo , Kantarjian Hagop M. , Ravandi Farhad 
Published: November 2020

Background: Intensive chemotherapy has improved complete remission (CR) rates in T-ALL/LBL. However, long-term overall survival (OS) continues to be suboptimal at about 50%. Nelarabine (NEL) is active in relapsed/refractory T-ALL. PEG-asparaginase (PEG) containing regimens have demonstrated significant activity in the pediatric population (Dunsmore et al. COG AALL0434. J Clin Oncol. 2018 Abstr #10500). We hypothesized that incorporating NEL and PEG in the frontline setting may further improve outcomes in adult T-ALL/LBL (NCT00501826). We had previously reported on the addition of nelarabine to the hyper-CVAD regimen (Abaza Y, Am J Hematol. 2018). Here, we report outcomes with the addition of PEG and longer follow-up.

Methods Pts with T-ALL/LBL, either newly diagnosed or minimally treated (no CR with 1 cycle or CR after ≤2 cycles of induction) were eligible. Pts needed to have ECOG performance status (PS) ≤3, creatinine ≤2 mg/dL, bilirubin ≤2 mg/dL and ALT/AST ≤4 x ULN. The objectives were to determine safety, CR rate, progression-free survival (PFS), and OS with this combination. Pts received 8 cycles of with HCVAD (odd cycles 1,3,5,7) alternating with methotrexate (MTX) and cytarabine (ara-C; even cycles 2,4,6,8) at approximately 3-week intervals. Initially pts received NEL 650 mg/m2 IV daily for 5 days after 8 cycles as above. After enrollment of 30 pts, protocol was amended to deliver the 2 courses of NEL after cycle 4 and 5 of therapy in an attempt to reduce risk of early relapse. After enrollment of 79 pts, PEG (1500 IU/m2 IV capped at 3750 IU for pts ≤60 yrs and at 2000 IU for pts &gt;60 yrs) was added to NEL courses on day 5. After completion of intensive phase, pts received 30 months of POMP maintenance (6-MP, vincristine, MTX, prednisone) with NEL/PEG replacing cycle 6 and 7 of POMP as early intensification. Late intensification consisted of MTX/PEG replacing cycle 18 and HCVAD replacing cycle 19 of POMP. CNS prophylaxis included 8 intrathecal doses of MTX alternating with ara-C. Pts with bulky mediastinal disease were considered for local radiation therapy prior to starting POMP maintenance.

Results: Between August 16, 2007 and March 6, 2019, we enrolled 96 pts with T-ALL (n=57) and T-LBL (n=39). Median age was 35 yrs (range 18-78), 75 pts were male (78%) and 83 pts (86%) had PS 0-1. In pts with T-ALL, median bone marrow blast % was 79% (range 0-96), 70 pts (73%) had extramedullary disease with mediastinal involvement in 48 pts and CNS involvement in 5 pts. 60 pts (63%) had diploid cytogenetics, 13 pts (14%) had complex cytogenetics, 19 pts had miscellaneous abnormalities and 4 pts had insufficient metaphases. Based on immunophenotype, pts were further characterized as thymic (n=38), early T-cell precursor (ETP; n=38), mature (n=10), not otherwise specified (NOS; n=9), and early-non-ETP (n=3). 12 pts had received prior therapy with HCVAD (n=8), asparaginase-based regimen (n=2), and others (n=2). 30-day mortality was 0%. 9 pts were in CR at enrollment. There were 242 grade 3/4 non-hematological treatment-emergent adverse events (TEAE) with the most frequent grade 3/4 TEAEs being neutropenic infections in 74 pts (77%), hypokalemia in 42 pts (44%), hypophosphatemia in 42 pts (44%) and elevated ALT in 28 pts (29%). Overall response rate was 98% (85/87 pts) with CR in 95% pts (n=83), PR in 2% (n=2), and no response in 2% (n=2). The median no. of cycles to response was 1 (range 1-10) with CR reported based on achieving PET negativity as well as standard response criteria. CR rate in T-ALL was 88% (43/49) and T-LBL was 100% (38/38). At a median follow-up of 58.8 months (mo; 95% CI 42.2, 67.6), 61 pts (63%) are alive with a median PFS and OS of 135.3 and 135.1 mo, respectively (Fig 1a, b) and 55 pts (57%) remain in CR. For pts who received NEL after HCVAD cycle 4, the 7-year OS was 61% compared to 52% who received NEL after cycle 8, hazard ratio 0.91, 95% CI 0.46, 1.82, p=0.7. For pts receiving PEG in addition to NEL, the 2yr OS was 86% (Fig 1c). 30 pts (31%) relapsed and 35 pts (37%) have died including 9 pts who died in CR. 17 pts (18%) pts underwent allogeneic stem cell transplantation, 6 have relapsed, 10 are alive, and 1 pt died in remission. Rate of relapse was 37% with NEL after cycle 8, 33% (16/49) with NEL after cycle 4 and 21% (3/14) with NEL/PEG (p=.38).

Conclusion: HCVAD with NEL with or without PEG is safe and effective as frontline therapy of adults with newly diagnosed T-ALL/LBL. Addition of PEG appears to confer a benefit.

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Disclosures

Maiti: Celgene: Research Funding. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; BMS: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Borthakur:FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Cyclacel: Research Funding; PTC Therapeutics: Consultancy; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; BioLine Rx: Consultancy; Novartis: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; GSK: Research Funding; PTC Therapeutics: Research Funding; Polaris: Research Funding; BioTherix: Consultancy; Argenx: Consultancy; Incyte: Research Funding. Kadia:Incyte: Research Funding; Abbvie: Honoraria, Research Funding; Astellas: Research Funding; Astra Zeneca: Research Funding; Cyclacel: Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; Novartis: Honoraria; Pulmotec: Research Funding. Burger:TG Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Beigene: Research Funding, Speakers Bureau; Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Speakers Bureau. Konopleva:Kisoji: Consultancy; Agios: Research Funding; Genentech: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Amgen: Consultancy; Calithera: Research Funding; Cellectis: Research Funding; Ablynx: Research Funding; AbbVie: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Rafael Pharmaceutical: Research Funding; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; BerGenBio ASA: Research Funding; Sun Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. O'Brien:Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Kite, Regeneron, Acerta: Research Funding. Daver:Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding. Pemmaraju:Plexxikon: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Pacylex Pharmaceuticals: Consultancy; Celgene: Honoraria; Daiichi Sankyo: Research Funding; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding; LFB Biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria. Bose:Astellas Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Promedior, Inc.: Research Funding; NS Pharma: Research Funding. Thompson:AbbVie: Research Funding; Pharmacyclics: Research Funding; Janssen-Cilag: Honoraria; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Ascentage: Research Funding; Immunogen: Research Funding; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; BMS: Research Funding; Jazz: Research Funding. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria.