Low Intensity Mini-Hypercvd (mHCVD), Inotuzumab Ozogamicin (Ino) with/without Blinatumomab (Blina) in Older Patients with Newly Diagnosed Philadelphia Negative B-Cell Acute Lymphoblastic Leukemia (B-ALL): 10 Years Update

Background:

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.

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:Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Astyex/Taiho: Research Funding; BMS: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Amgen: 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.