Efficacy and Safety of Brexucabtagene Autoleucel for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Patients Aged 60 and Above

Introduction:

Brexucabtagene Autoleucel (brexu-cel) is the first CD19-targeting chimeric antigen receptor (CD19.CAR) T-cell therapy approved for the treatment of relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in adult (≥18 yo) patients (pts) based on results from the ZUMA-3 trial. However, data on the safety and efficacy of CAR-T cells in older pts (≥60 yo) remains limited, with only 8 pts >65 yo enrolled in the ZUMA-3 trial. We evaluated the treatment characteristics and outcomes with use of brexu-cel amongst patients ≥60 yo in the Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database.

Methodology:

ROCCA is a consortium of over 30 U.S.-based institutions with a database of adult pts with B-ALL who received brexu-cel as standard of care therapy. We identified pts ≥60 yo and further stratified them into two cohorts: 60-69 yo and ≥70 yo. Outcomes of interest included OS, PFS, ORR, and toxicities (CRS and ICANS). Both OS and PFS were calculated from the day of brexu-cel infusion. Response assessment occurred on day +28, and MRD evaluation was per institutional practices. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria.

Results:

Of 280 brexu-cel recipients in the ROCCA database, 73 (26%) were ≥60 yo, of which 58 (79%) were between 60-69 yo and 15 (21%) were ≥70 yo. Among pts ≥60 yo, the median age at infusion was 65 (range 60-81). Pts were heavily pretreated with a median of 3 prior lines of therapy (range 2-9). Prior therapies included: allogeneic HSCT (38%), inotuzumab ozogamicin (41%), and blinatumomab (62%). Forty pts (55%) had Ph-negative B-ALL, 24 (33%) had Ph+ B-ALL and 9 (12%) had Ph-like B-ALL. When grouped by HCT-CI equal to 0, 1-2 or ≥3, a higher proportion of pts ≥60 yo had HCT-CI ≥3 (19% vs. 7% in <60 yo; p=0.004).

Pre-apheresis, 33 pts (45%) had active disease (>5% marrow blasts or extramedullary disease), 34 (47%) were in CR (of whom 14 were MRD-negative) and 6 had unknown disease status. Following brexu-cel, 43 (59%) achieved MRD-negative CR, 20 (27%) had MRD + or CR with unknown MRD status, 6 (8%) had refractory disease and 5 had no disease evaluation available. The ORR was similar between pts 60-69 and ≥70 yo (MRD-negative CR rate: 58% vs 61%, r/r to brexu-cel: 9% vs 6%) and was comparable to pts <60 yo (MRD-negative CR 66%; r/r disease of 9%).

The rate of all grade ICANS was higher in pts ≥70 (77%) than in pts 60-69 (47%) or pts <60 (49%), with grade 1-2 ICANS occurring at a significantly higher rate in pts ≥70 (44% vs. 20% in 60-69 and 20% in <60, p=0.049). Grade 3-4 ICANS were similar between the groups: 33%, 27% and 29% in the ≥70, 60-69, and <60 groups, respectively. Conversely, rates of CRS were similar across age groups (80-84%). There was no statistically significant difference in the rate of grade 3-4 CRS which was 17% in pts ≥70, 4% in pts 60-69, and 11% in pts <60 yo.

With a median follow-up of 332 days (range 8-936 days) from infusion, pts ≥60 yo had a median PFS of 395 days compared to 547 days in pts <60 yo. Median PFS was lower in the ³70 yo (231 days) compared to 677 in the 60-69 yo cohort. No statistically significant difference was found between the <60 and ≥60groups in 6- and 12-month PFS rates (6 months PFS: 66% vs 64%, p=0.77 and 12 months PFS: 57% vs 57%, p=1.00). When pts ≥60 yo were stratified by age, pts ≥70 yo had similar 6-month PFS compared to other age groups but significantly lower 12-month PFS (38%; vs. 64% in pts 60-69and 57% in pts <60, p=0.001).

Median OS was not reached in any of the age groups, and there was no statistically significant difference in 6-month OS (72% in ≥ 70 vs. 82% in the 60-69 vs. 82% in <60, p=0.14) or 12-months OS (61% in ≥ 70 vs. 69% in 60-69 vs. 73% in <60, p=0.18).

Conclusion:

This is the largest study to date of older B-ALL pts receiving CAR-T cells. We observed that older pts, particularly those aged 60-69, have similar outcomes to younger pts. However, pts ≥70 yo had lower median and 12-month PFS when compared to younger patients. Additionally, pts ≥70 yo had higher rates of grades 1-2 ICANS. An important limitation of this analysis is the potential selection bias among clinicians when selecting older patients for this treatment. Longer follow-up, including inclusion of additional pts ≥70 yo is needed to confirm these results, and further studies are needed to identify the optimal approach for use of CAR T-cell therapy in patients in this age group.

Advani:Wolters Kluwer: Honoraria; MJH Life: Honoraria; Kite: Consultancy, Research Funding; Immunogen: Research Funding; Wiley: Honoraria; Springer: Honoraria; Glycomimetics: Research Funding; Macrogenics: Research Funding; MD Education: Honoraria; American Society of Hematology: Honoraria; Amgen: Research Funding; Pfizer: Other: Manuscript help, Research Funding; Incyte: Research Funding; Servier: Research Funding; BEAM: Other: Research support, Research Funding; OBI: Research Funding; Seattle Genetics: Research Funding; Kura: Research Funding; Novartis: Consultancy; PER: Honoraria; Emmes: Honoraria; Web MD: Honoraria. Roloff:Kite: Honoraria. Sutherland:Orca Bio, Inc.: Consultancy. Grunwald:Janssen: Research Funding; Merck: Research Funding; Genetech: Consultancy; GSK: Consultancy; Amgen: Consultancy; Bristol Myers Squibb: Consultancy; Aptitude Health: Consultancy; Ajax: Research Funding; Astellas Pharma: Consultancy; Sobi: Consultancy; Medtronic: Current holder of stock options in a privately-held company; Blueprint Medicines: Consultancy; Cardinal Health: Consultancy; Daiichi Sankyo: Consultancy; Incyte Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; OncLive: Consultancy; Pfizer: Consultancy; Premier: Consultancy; Sanofi: Consultancy; Servier: Consultancy. Kota:Kite Pharma: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Ulrickson:Autolus: Consultancy; Stemline: Consultancy; Bristol Myers Squibb: Consultancy; ADC Therapeutics.: Consultancy; Miltenyi Biomedicine: Honoraria. Sasine:Kite Pharma: Consultancy; Genmab: Consultancy; Autolus: Consultancy. Aldoss:AbbVie: Other: research support; Sobi: Other: consulting fees; Jazz Pharmaceuticals: Other: consulting fees; Takeda Pharmaceuticals: Other: consulting fees; Kite Pharma: Other: consulting fees; Pfizer: Honoraria, Other: consulting fees; Syndax Pharmaceuticals, Inc.: Other: consulting fees; Amgen: Honoraria, Other: consulting fees. Vasu:Sanofi Inc: Research Funding; Alexion Inc: Other: Advisory Board; Lentigen/Miltenyi Biotec: Research Funding. 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Park:Takeda: Consultancy; Curocell: Current equity holder in publicly-traded company; Autolus, Fate Therapeutics, Genentech, InCyte, Servier, Sobi, Takeda (Institution): Research Funding; Adaptive Biotechnologies, Affyimmune, Allogene, Amgen, Artiva Biotherapeutics, Autolus, Bright Pharmaceutical Services, BMS, Caribou Biosciences, Curocell, Galapagos, Gilead Sciences, Intellia, In8Bio, Kite, Novartis, Pfizer, Servier, Sobi, Synthekine: Consultancy. Valtis:EastRx: Consultancy. Solh:GlaxoSmithKline: Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Sanofi: Consultancy. Bezerra:Kyverna Inc: Honoraria, Other: Advisory Board, ; Novartis: Honoraria, Other: Advisory Board; Kite Therapeutics: Honoraria, Other: Advisory Board. Leonard:Pfizer: Consultancy, Honoraria; France Foundation: Honoraria; Takeda: Consultancy; Kite/Gilead: Consultancy; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, accommodations, and expenses. Majhail:Caribou Biosciences: Research Funding; Anthem: Consultancy. Battiwalla:Kite/Gilead: Research Funding; Astra Zeneca/Gracell: Research Funding; Fate Therapeutics: Research Funding; JNJ/Janssen: Research Funding. Shaughnessy:Autolus, Sanofi: Consultancy; Sanofi: Speakers Bureau; BMS: Speakers Bureau. Hoeg:Orca Bio: Research Funding. Oliai:Orca Bio: Research Funding; Pfizer: Research Funding; Arog: Research Funding; Ascentage: Research Funding; Jazz Pharmaceuticals: Research Funding; Amgen: Research Funding; Roche: Research Funding; University of California, LA: Current Employment. Koura:BMS: Other: ad board. Logan:Abbvie: Consultancy; Amgen: Consultancy; Amphivena: Research Funding; Astellas: Research Funding; Autolus: Research Funding; Jazz: Research Funding; Kadmon: Research Funding; Kite: Research Funding; Pfizer: Consultancy; Pharmacyclics: Research Funding. 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Oluwole:Gilead Sciences: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; ADC: Consultancy, Speakers Bureau; Bioheng: Consultancy; Cargo: Consultancy; Caribou Biosciences: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Nektar: Consultancy; Novartis: Consultancy; TGR: Consultancy; Daichi Sankyo: Research Funding; Allogene: Research Funding. Pullarkat:Abbvie: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Amgen: Speakers Bureau; Sobi: Speakers Bureau; Jazz: Speakers Bureau; Alexion: Honoraria; Rigel: Consultancy, Honoraria. Merchant:BMS: Speakers Bureau; Innate Pharma: Research Funding; IMMpact Bio: Research Funding; Oncovalent: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Genmab: Consultancy, Speakers Bureau; Amgen: Consultancy. Shah:Pepromene Bio: Other: DSMB; Autolus, Beigene, Century Therapeutics, Deciphera, Jazz, Kite/Gilead, Pfizer, Precision Biosciences, Novartis, Takeda: Consultancy; Kite Pharma: Consultancy; Eli Lilly: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Jazz Pharmaceuticals, Kite-Gilead, Servier: Research Funding; Amgen: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy. Muffly:Vor: Consultancy, Research Funding; Cargo Therapeutics: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Autolus: Consultancy; Adaptive: Research Funding; Wugen: Research Funding; Jasper: Research Funding; Bristol Myers Squibb: Consultancy; Astellas: Consultancy. Hill:March Biosciences: Consultancy; Gilead Sciences: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau.