Efficacy and Safety of Brexucabtagene Autoleucel for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Patients Aged 60 and Above
Authors: Muhsen Ibrahim , Advani Anjali S. , Roloff Gregory W , Jeyakumar Nikeshan , Miller Katharine , Zhang Amy , Sutherland Katherine C. , Grunwald Michael R. , Kota Vamsi K. , Boccucci Jacob , Ulrickson Matthew , Sasine Joshua , Aldoss Ibrahim , Othman Tamer , Vasu Sumithira , Reshef Ran , Luskin Marlise R. , Chen Evan C. , Lin Chenyu , Langston Amelia , Cassaday Ryan D. , Kopmar Noam E. , Tsai Stephanie B. , O'Connor Timothy E , Hilal Talal , Faramand Rawan , Park Jae H. , Valtis Yannis K. , Solh Melhem M. , Bezerra Evandro , Leonard Jessica T. , Dekker Simone E. , Majhail Navneet , Battiwalla Minoo , Malik Shahbaz A. , Mathews John , Shaughnessy Paul , Mountjoy Luke , Hoeg Rasmus T. , Oliai Caspian H. , Gupta Vishal , Koura Divya , Dykes Kaitlyn C , Logan Aaron C. , Kumaran Muthu V. , Stock Wendy , Schwartz Marc , Bachanova Veronika , Tracy Sean , O'Dwyer Kristen M. , Moore Jozal , Lee Catherine J. , Bobillo Maria Silvina Odstrcil , Frey Noelle , Connor Matthew P , Jamy Omer , Daunov Michael , Ladha Abdullah , Yaghmour George , Jackson Clayton , Irrizary Gatell Vivian , Oluwole Olalekan O. , Dholaria Bhagirathbhai , Pullarkat Vinod , Merchant Akil , Shah Bijal D , Muffly Lori , Hill LaQuisa 
Published: December 2024

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 &gt;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 &lt;60 yo; p=0.004).
Pre-apheresis, 33 pts (45%) had active disease (&gt;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 &lt;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 &lt;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 &lt;60, p=0.049). Grade 3-4 ICANS were similar between the groups: 33%, 27% and 29% in the ≥70, 60-69, and &lt;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 &lt;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 &lt;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 &lt;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 &lt;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 &lt;60, p=0.14) or 12-months OS (61% in ≥ 70 vs. 69% in 60-69 vs. 73% in &lt;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.