Session: 613. Acute Lymphoblastic Leukemias: Therapies Excluding Allogeneic Transplantation: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphoid Leukemias, ALL, Combination therapy, Drug development, Elderly, Clinical Research, Supportive Care, Diseases, Therapy sequence, Treatment Considerations, Lymphoid Malignancies, Adverse Events, Study Population, Human, Measurable Residual Disease
Older patients (pts) with B-ALL have historically had poor outcomes from adverse disease biology and inability to tolerate intensive chemotherapy and asparaginase. Addition of B-cell targeted agents to low-intensity chemotherapy could lead to tolerable regimens with possibility of improved outcomes in these pts. Herein we are reporting the long-term safety and efficacy of InO with/without Blina added to mHCVD regimen as frontline therapy in older adults (≥60 yrs) with Philadelphia (Ph) negative B-ALL with 10-year follow-up.
Methods:
Pts ≥60 yrs with Ph-ve B-ALL were eligible if untreated or had received ≤2 cycles of previous therapy, ECOG PS ≤3 and adequate organ function. The chemotherapy backbone was mHCVD (mHCVD: cyclophosphamide 150mg/m2 q12h [day] D1-3, dexamethasone 20mg/day D1-4, 11-14, and vincristine 2 mg D1, 8; alternating with methotrexate (MTX) 250mg/m2 D1 & cytarabine 500mg/m2 q12h D2, 3) for up to 8 cycles (C). 12 doses of intrathecal IT MTX /cytarabine were given for CNS prophylaxis; pts with CNS disease had IT hydrocortisone, MTX, and cytarabine 2/week till CNS clearance, then weekly x 4. 8 doses of rituximab 375mg/m2 were given on D1, 8 of C1-4 if CD20 was ≥20% by flow cytometry (FCM). Initially, InO was dosed at 1.3-1.8mg/m2 on D3 of C1 and 1.0-1.3mg/m2 on D3 in C2-4. After protocol amendment from pt#50 onwards in Mar 2017, InO was administered in fractionated doses with a max cumulative dose of 2.7mg/m2 (0.6 mg/m2 on D2 of C1, 0.3 mg/m2 on D8 of C1, 0.3 mg/m2 on D2/D8 of C2-4). Ursodeoxycholic acid was given to all pts. 4 cycles of Blina 28µg/day replaced C5-8 of mHCVD. Maintenance was initially with vincristine 2mg D1, prednisolone 50mg daily D1-5, 6-mercaptopurine 50mg BID & MTX 10mg/m2 weekly (POMP) for 3 years. After the mentioned protocol amendment, this was reduced to 12 cycles of POMP, with 1 cycle of Blina given after every 3 POMP cycles (total 4 Blina cycles).
Results:
From Dec 2011-Aug 2022, 83 pts at a median (med) age of 67 years (60-88 years) were treated (28 [34%] ≥70 yrs], 6 of whom were in complete remission (CR) at start (5 of 6 were MRD+ve) at enrollment. 49 (59%) were male. Amongst 48 evaluated pts, 7 (14%) had CRLF2 positive and amongst 64 evaluated pts 25 (39%) had a TP53 mutation. 5 pts (65) had prior multiple myeloma. Cytogenetic (CTG) data was available in 67/83 pt; 27 had a diploid karyotype and 19 pts (28%) had high-risk (HR) CTG (12 hypodiploid, 4 tetraploid, 4 complex, 1 KMT2A rearranged). Four pts (5%) had CNS disease at baseline. A best response of CRc was attained in 76 of 77 pts not in CR at enrollment (99%) (CR=69, CRi=7) and a best response of MRD negativity by FCM was attained in 75 of 81 (5 CR-MRD+ve at enrollment + 76 CRc on study) evaluable pts (93%). MRD-ve rate after course 1 was 75% (56/75 evaluable). Amongst 17 pts evaluated by NGS for MRD (sensitivity= 10-6), 16 (94%) became undetectable, none of whom relapsed, at a med FU of 37 mos; the NGS MRD+ pt was consolidated with SCT. Amongst blina treated pts 3/38 (8%) had MRD+ve by FCM before Blina initiation.
At a med estimated F/U of 121 mos (95% CI 61-129 mos), (129 mos pre-amendment and 46 mos post-amendment pts), the med PFS was 47 mos (95%CI 22-71 mos), OS 62 mos (95%CI 22-72 mos) and continuous remission duration (CRD) not reached (95% CI NR-NR). 5-year rates were 46%, 50% and 79% resp. The 3-year PFS and OS pre and post amendment were 49% vs. 65% (p=0.56) and 57% vs. 65% (p=0.88) respectively. Med PFS and OS in pts 60-69 yrs and ≥70 yrs was 70 vs. 34 mos (p=0.1) and 75 vs. 36 mos (p=0.09) resp. 5 pts (7%) underwent an SCT in CR, 4 for HR-genomics and 1 for persistent MRD+ disease. 9 pts (11%) developed a secondary myeloid neoplasm after a med of 33 mos from therapy initiation (range, 3-66 mos), 6 on ALL therapy and 2 post ALL therapy; 5 of 8 evaluated had a TP53 mutation at ALL diagnosis which persisted.
6 pts (7%) developed hepatic SOS (4 pre, 1 post amendment), one after SCT and 5 without. 7 pts (8%) had grade 3 CNS events with Blina, but no seizures. At data cutoff, 33 pts (40%) are alive; of 50 pts who died, 1 was a non-responder, 11 died after relapse, and 38 in CR (secondary myeloid neoplasms=9, infectious complications=9 [6 on study, 3 off-study], SOS=4, miscellaneous=16).
Conclusion:
mHCVD-InO ± Blina is an efficacious and tolerable regimen with promising PFS and OS benefit even on long-term F/U. Further reduction of chemo doses and assessment of mutations that increase risk of myeloid neoplasms, especially in pts ≥70 years of age, is prudent to reduce non-relapse mortality.
Disclosures: Jabbour: AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Jain: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; CareDx: Consultancy, Honoraria, Other: Travel Support; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; ADC Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; Fate Therapeutics: Research Funding; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Loxo Oncology: Research Funding; Newave: Research Funding; Dialectic Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; TransThera Sciences: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; NovalGen: Research Funding; Servier: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Medisix: Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; Incyte: Research Funding; Takeda: Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; MingSight: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding. Garcia-Manero: Aprea: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Curis: Research Funding; H3 Biomedicine: Research Funding; Janssen: Research Funding; Onconova: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; Astex: Research Funding; Astex: Other: Personal fees; Forty Seven: Research Funding; Novartis: Research Funding; Merck: Research Funding; Helsinn: Research Funding; Helsinn: Other: Personal fees; Amphivena: Research Funding; Genentech: Other: Personal fees. Daver: Astellas: Consultancy, Research Funding; Menarini Group: Consultancy; Arog: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Trovagene: Research Funding; Hanmi: Research Funding; Jazz: Consultancy; Trillium: Consultancy, Research Funding; KITE: Research Funding; Celgene: Consultancy; Novimmune: Research Funding; Novartis: Consultancy; Genentech: Consultancy, Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Agios: Consultancy; Glycomimetics: Research Funding; Servier: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding. Kadia: Ascentage: Research Funding; Servier: Consultancy; Pfizer: Research Funding; Amgen: Research Funding; Cellenkos: Research Funding; Incyte: Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; DrenBio: Consultancy, Research Funding; Sellas: Consultancy, Research Funding; AstraZeneca: Research Funding; JAZZ: Research Funding; Novartis: Honoraria; Regeneron: Research Funding; ASTEX: Research Funding; Rigel: Honoraria; Abbvie: Consultancy, Research Funding. Ravandi: Astellas: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding; Syndax: Honoraria; Abbvie: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Research Funding; Xencor: Research Funding; Astyex/Taiho: Research Funding. Sasaki: Pfizer: Consultancy; Enliven: Research Funding; Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Otsuka: Other: Lecture fees; Chugai: Other: Lecture fees. DiNardo: Abbvie: Consultancy, Honoraria, Research Funding; GenMab: Consultancy, Honoraria, Other: data safety board; Jazz: Consultancy, Honoraria; Foghorn: Research Funding; Cleave: Research Funding; Stemline: Consultancy; Astellas: Consultancy, Honoraria; Riegel: Honoraria; Schrodinger: Consultancy, Honoraria; Rigel: Research Funding; GSK: Consultancy, Honoraria; Amgen: Consultancy; ImmuneOnc: Research Funding; Loxo: Research Funding; Immunogen: Honoraria; Notable Labs: Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Astex: Research Funding; Gilead: Consultancy; Genetech: Honoraria; AstraZeneca: Honoraria; BMS: Consultancy, Honoraria, Research Funding. Montalban-Bravo: Takeda: Research Funding; Rigel: Research Funding. Short: Astellas Pharma, Inc.: Honoraria, Research Funding; BeiGene: Honoraria; Autolus: Honoraria; Sanofi: Honoraria; Xencor: Research Funding; Novartis: Honoraria; Takeda Oncology: Honoraria, Research Funding; Amgen: Honoraria; GSK: Consultancy, Research Funding; Stemline Therapeutics: Research Funding; NextCure: Research Funding; Adaptive Biotechnologies: Honoraria; Pfizer Inc.: Honoraria.