Background:
The incorporation of novel agents such as NEL and PEG to frontline therapy has been associated with improved outcomes in pediatric patients (pts) with T-ALL/LBL, but has not been extensively studied in the adult pts. BCL-2 upregulation has been demonstrated in T-lymphoblasts, especially of the early T-cell precursor (ETP) ALL and addition of VEN (BCL-2 inhibitor) may be beneficial.
Methods:
Pts with previously untreated or minimally pre-treated T-ALL/LBL were eligible if they had an ECOG PS ≤3, creatinine ≤ 2 mg/dL, total bilirubin ≤ 2 mg/dL and ALT/AST ≤ 4 x ULN. Pts received 8 cycles (C) of HCVAD (C 1,3, 5, 7) alternating with high dose Ara-C and methotrexate (MTX) (C 2, 4, 6, 8) at approximately 3-week intervals. Two cycles of NEL (650 mg/m 2 daily x 5) were initially administered after C8 (cohort 1). Later, after a protocol amendment, they were administered after C4 and C5 (cohort 2). Subsequently, the protocol was amended to add PEG (1500 IU/m 2 capped at 3750 IU; for pts age 60 or older, dose was 1000 IU/m 2, capped at 2000 IU) on day 5 of the NEL cycles (cohort 3) and more recently, VEN 400 mg daily was added on the first 7 days of each of 8 cycles of therapy (cohort 4); this was later modified to be given for 7 days during the induction cycle to all pts and reduced to 3 days per post-induction cycle only in pts with ETP-ALL or those with persistent measurable residual disease (MRD) and all other pts did not receive VEN after C1 (cohort 5). Pts with ETP-ALL were referred for allogeneic stem cell transplant (allo-SCT) in first complete remission (CR). After the completion of the intensive phase; pts in all cohorts received 30 cycles of maintenance therapy with monthly POMP (prednisone, vincristine, MTX, prednisone) and early intensification with NEL/PEG on C6 and 7 and late intensification with MTX/PEG in C18 and HCVAD on C19. All pts received 8 intrathecal chemotherapy with MTX alternating with Ara-C and mediastinal radiation was considered in pts with bulky mediastinal disease.
Results:
Between 7/2007 and 12/2022, 133 pts were enrolled in the 5 study cohorts sequentially (cohort 1= 30, 2= 49, 3=17, 4=16, 5=21) (Table 1). Eighty pts (60%) had T-ALL, 52 T-LBL (39%) and 1 pt had ETP/myeloid bi-phenotypic leukemia. The median age for the entire cohort was 35 years (yrs) (range 18-78), 102 pts were male (77%), 83 pts (62%) were white and 18 pts (14%) had PS ≥2. Overall, 24 pts (18%) had an ETP phenotype and another 19 pts (14%) had a near-ETP phenotype. Six pts (5%) had central nervous system disease at diagnosis, 72 pts (54%) had mediastinal disease, 49 of 80 (61%) T-ALL pts had extramedullary disease and 20 pts (15%) were in complete remission (CR) at trial enrollment after minimal pre-enrollment therapy. Overall response (CR+CRp+CRi+PR) on trial was attained in 109/113 (95%) pts [CR= 101 (89%), CRi/CRp= 3 (3%), PR=5 (4%)]. CR/CRi/CRp was attained in 36/41 (88%) pts with ETP/near-ETP ALL and 60/64 (94%) of confirmed near-ETP ALL pts ( p=0.31). At a median follow-up of 62 months (mos), the median overall survival (OS) was not reached (NR), 3-yr OS was 71% and 5-yr OS was 64% . The 3-yr OS for pts treated with HCVAD+NEL (cohort 1+2), HCVAD+NEL+PEG (Cohort 3) and HCVAD+NEL+PEG+VEN (Cohort 4+5) were 66%, 88% and 76% respectively (Figure 1). Median OS was not reached for both VEN cohorts, while 3-yr OS was 72% in cohort 4 compared to 88% in cohort 5 ( p=0.51), with significantly shorter follow-up for the latter (33 mos vs. 15 mos). Amongst the 124 pts who had CR/CRp/CRi, the median RFS was NR and 5-yr RFS was 68%. 24 (18%) pts underwent SCT in first remission, including 20 (83%) with ETP or near-ETP ALL. The median OS was shorter in the 44 ETP/near-ETP pts compared to the 77 pts with non-ETP phenotype (71 mos vs. NR, p=0.08). 30 and 60-day mortality was 0% and 1%. 10 pts (7.5%) died in remission (3, 5 and 2 pts in cohorts 1, 2 and 4 respectively) including 1 after SCT, 4 after developing therapy-related acute myeloid leukemia and 5 from infectious complications.
Conclusion: The ongoing phase 2 trial of NEL, ASP, VEN added to the HCVAD regimen shows promising long-term survival in adult pts with T-ALL/LBL with 3-yr OS of 76%-88% in pts treated with HCVAD+NEL+PEG +/- VEN. Larger prospective trials and longer follow-up are needed to demonstrate further benefit.
Disclosures
Senapati:Kite Pharma: Other: Advisory Board. Kantarjian: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; Pfizer: Honoraria; Taiho Pharmaceutical: Honoraria; Precision Biosciences: Honoraria; Shenzhen Target Rx: Honoraria; Abbvie (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Amgen (Inst): Research Funding; Bristol-Myers Squibb (Inst): Research Funding; Novartis (Inst): Research Funding. Jabbour:Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Kadia:Celgene: Research Funding; Iterion: Research Funding; Sanofi-Aventis: Consultancy; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Genzyme: Honoraria; Hikma Pharmaceuticals: Speakers Bureau; Amgen, Inc.: Research Funding; Astellas Pharma Global Development: Research Funding; Novartis: Consultancy; Cellenkos Inc.: Research Funding; Cure: Speakers Bureau; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Janssen Research and Development: Research Funding; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Liberum: Consultancy; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Glycomimetics: Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Agios: Consultancy; Genentech: Consultancy, Research Funding; Delta-Fly Pharma, Inc.: Research Funding; GenFleet Therapeutics: Research Funding; Cyclacel: Research Funding; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage Pharma Group: Research Funding; Regeneron Pharmaceuticals: Research Funding; SELLAS Life Sciences Group: Research Funding; Servier: Consultancy; Pinotb-Bio: Consultancy; BMS: Consultancy, Research Funding; Astex: Honoraria. Borthakur:Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; 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. Konopleva:Reata Pharmaceuticals.: Current holder of stock options in a privately-held company, Patents & Royalties; Abbvie, Allogene Therapeutics, Cellectis, Forty Seven, Gilead Sciences, Genentech, Sanofi, MEI Pharma, Rafael Pharmaceuticals, Daiichi Sankyo Pharmaceutical, AstraZeneca Co., Menarini, Precision BioSciences.: Research Funding; AbbVie, Forty Seven, Precision Biosciences, Gilead Sciences, Genentech, Janssen, Sanofi, MEI Pharma, Daiichi Sankyo Pharmaceutical, AstraZeneca Co., Menarini.: Consultancy. Wierda:NIH P30 CA016672/MDACC Cancer Center Support Grant: Research Funding; GSK/Novartis: Research Funding; Nurix THerapeutics: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; Numab THerapeutics: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Juno Therapeutics: Research Funding; Janssens Biotech: Research Funding; Cyclacel: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Janssens Biotech Inc: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Research Funding; Accutar Biotechnology: Research Funding; National Comprehensive Cancer Network: Other: Nonrelevant Financial Relationship/Chair, CLL). Supported by the NIH/NCI under award number P30 CA016672 and used MDACC Cancer Center Support Grant (CCSG) shared resources; Miragen: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding. Burger:Abbvie, Beigene: Research Funding; Janssen: Other: Speaker fees and Travel Support; AstraZeneca, Pharmacyclics: Other: Advisory Board, Research Funding. Issa:Merck: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding; Syndax: Research Funding; NuProbe: Consultancy; Celgene: Research Funding. Maiti:Lin BioScience: Research Funding; Celgene: Research Funding. Ferrajoli:Beigene: Research Funding; GenMab: Research Funding; Genetech: Honoraria; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria. Garcia-Manero:Genentech: Research Funding; Bristol Myers Squibb: Other: Medical writing support, Research Funding; AbbVie: Research Funding. Alvarado Valero:Jazz: Research Funding; FibroGen: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Sun Pharma: Consultancy, Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding. Kebriaei:Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Short:AstraZeneca: Consultancy; Takeda: Consultancy, Research Funding; Astellas: Research Funding; Amgen: Honoraria; Stemline therapeutics: Research Funding; Novartis: Consultancy; Pfizer: Consultancy. Jain:Cellectis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TransThera Sciences: Research Funding; Mingsight: Research Funding; BMS: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Dialectic Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Novalgen: Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; CareDX: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; MEI Pharma: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Research Funding; Ipsen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Medisix: Research Funding; Pfizer: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Loxo Oncology: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Genentech: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Beigene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Newave: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Incyte: Research Funding; Servier: Research Funding; Aprea Therapeutics: Research Funding; ADC Therapeutics: Research Funding. Ravandi:Prelude: Research Funding; Biomea fusion: Honoraria, Research Funding; Xencor: Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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