Pre- or post-CAR-T allogeneic hematopoietic cell transplant provides relapse-free survival benefit for R/R Philadelphia negative B-cell acute lymphoblastic leukemia (B-ALL) successfully treated with brexucabtagene autoleucel in the real world
Abstract
Abstract Introduction: Brexucabtagene autoleucel (Brexu-cel) is a CD19-targeted chimeric antigen receptor (CAR-)T cell therapy approved for treatment of relapsed/refractory (r/r) B-ALL. Brexu-cel's approval was founded on data from the ZUMA-3 trial, in which 78 patients (pts) were treated at the pivotal dose of 1x10e6 CAR-T cells/kg, resulting in a complete remission (CR) rate of 73%. Three-year follow-up from ZUMA-3 demonstrated median relapse-free and overall survival (RFS/OS) of 11.6 and 25.6 months (mos) for all treated pts. Amongst responders, the median OS was 60.4 mos for those who did not receive a subsequent allogeneic hematopoietic cell transplant (HCT) (n=43), but only 36.3 months for those who did (n=14). This has led some to conclude that HCT may not be beneficial following brexu-cel therapy for r/r B-ALL; however, it must be noted that 29 (37%) of the pts treated on ZUMA-3 received brexu-cel for post-HCT relapse. T cells collected from individuals who relapse in the post-HCT setting are largely of donor origin, making the CAR-T product comparable to a genetically modified donor lymphocyte infusion (DLI). The immunology at play in this scenario may be different from that in which CAR-T cells are of truly autologous origin. Methods: The Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database includes pt characteristics and outcomes of brexu-cel therapy given as standard-of-care across 41 US institutions. We identified pts who achieved an MRD negative (neg) CR by either flow cytometry (minimum sensitivity 10e-4) or NGS following brexu-cel for r/r Ph neg B-ALL and categorized them into three groups with regard to use of HCT: Never HCT, Pre-CAR HCT, or Post-CAR HCT. Pts who received second HCT following brexu-cel for post-HCT relapse (n=9) were excluded. Pt/disease characteristics, RFS, and OS were assessed for each group, landmarked at 73 days after brexu-cel infusion (the median time to consolidative allogeneic HCT). Results: In the ROCCA database we identified 165 pts who achieved MRD neg CR following brexu-cel, amongst whom 69 never underwent HCT, 49 were transplanted pre-CAR (ie, brexu-cel served as a genetically modified DLI), and 47 underwent post-CAR consolidative HCT while in CR. The median follow-up is 373 days. The median age was higher in the Never HCT group (49, range 19-83) in comparison with the Pre-CAR HCT (40, 24-72) and Post-CAR HCT (34, 18-70) groups. Thirty-five percent were >60yo in the Never HCT group vs 20% in the Pre-CAR HCT and 9% in the Post-CAR HCT groups. Ph-like disease was present in 38%, 29%, and 43% of the Never HCT, Pre-CAR HCT, and Post-CAR HCT groups, respectively (p=0.35). No significant differences were observed in pre-apheresis bone marrow blasts, presence of CNS disease at apheresis, prior blinatumomab or inotuzumab treatment, or use of bridging therapy across the groups, though there was a higher prevalence of non-CNS extramedullary disease in the Pre- and Post-CAR HCT groups (32, 39%) vs the Never HCT group (13%) (p=0.004). A minority of pts in all groups were deemed to be in MRD neg CR prior to apheresis (6-20%). Median RFS was 260 days in the Never HCT group and not reached in the Pre- and Post-CAR HCT groups (p=0.002), with respective 1-yr RFS of 38%, 64%, and 67%. Median OS was not reached in any group and was similar for all at 1-yr at 68-79% (p=0.13). Characteristics of those in the Never HCT group who were least likely to relapse included age >60 (OR 0.22, CI 0.07-0.73 vs age 18-39, p=0.024) and those with non-Ph-like B-ALL (OR 0.33, CI 0.12-0.94, vs Ph-like, p=0.037) in univariate analyses. Conclusions: Real-world data regarding outcomes following brexu-cel therapy allow evaluation of the role for consolidative allogeneic HCT, which remains one of the most important unresolved questions in the use of CAR-T therapy for r/r B-ALL. This analysis demonstrates that a first consolidative HCT after achieving MRD neg CR with brexu-cel is associated with a significant decrease in relapse. Additionally, use of brexu-cel for post-HCT relapse is also associated with a significantly lower risk of relapse compared with those who never received an allogeneic HCT. With the current duration of followup, OS is not significantly different across the three groups. These data suggest there is a benefit for relapse-free survival in pts receiving an allogeneic HCT at some point in the course of treatment for r/r Ph neg B-ALL.
Article Details
Authors (73)
Aaron Logan
1University of California, San Francisco, Hematology, Blood and Marrow Transplantation, and Cellular Therapy Program, San Francisco, United States
Fevzi Yalniz
40Division of Hematology and Blood Marrow Transplantation, Department of Medicine, University of Kentucky College of Medicine, Lexington, KY
Amy Zhang
Katharine Miller
3Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, CA
Katherine Sutherland
6Stanford University School of Medicine, Palo Alto, United States
Nikeshan Jeyakumar
1University of California, Los Angeles, Los Angeles, United States
Hrishikesh Srinagesh
6Stanford University School of Medicine, Palo Alto, United States
Michael Grunwald
4Division of Leukemia, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NC
Vamsi Kota
7Georgia Cancer Center at Augusta University, Hematology/Oncology, Augusta, United States
Jacob Boccucci
7Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
Matthew Ulrickson
28Banner MD Anderson Cancer Center, Gilbert, AZ
Ali Al-Darobi
9Banner MD Anderson Cancer Center, Gilbert, United States
Joshua Sasine
29Division of Hematology and Cellular Therapy, Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA
LaQuisa Hill
9Section of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX
Ibrahim Muhsen
10Baylor College of Medicine, Houston, United States
Anjali Advani
6Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
Ibrahim Aldoss
Tamer Othman
36Hematology, Blood and Marrow Transplantation, and Cellular Therapy Program, University of California San Francisco, San Francisco, CA
Karamjeet Sandhu
11Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA
Ran Reshef
13Division of Hematology/Oncology, Blood and Marrow Transplantation and Cell Therapy Program, Columbia University Irving Medical Center, New York, NY
Marlise Luskin
15Dana-Farber Cancer Institute, Boston, United States
Evan Chen
Chenyu Lin
Department of Earth and Planetary Sciences, Harvard University
Ryan Cassaday
1University of Washington, Medicine (Hematology/Oncology), Seattle, United States
Noam Kopmar
17University of Washington, Seattle, United States
Melhem Solh
14Bone marrow Transplant Group of Georgia, Atlanta, United States
Catherine Lee
Silvina Odstrcil Bobillo
20Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT
Stephanie Tsai
21Loyola University Medical Center, Maywood, United States
Timothy O'Connor
10Division of Hematology/Oncology, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL
Talal Hilal
13Mayo Clinic, Phoenix, AZ
Jae Park
1Memorial Sloan Kettering Cancer Center, Medicine, New York, United States
Yannis Valtis
5Memorial Sloan Kettering Cancer Center, New York City, United States
Sumithira Vasu
29Department of Internal Medicine, The Ohio State University, Columbus, OH
Evandro Bezerra
2The Ohio State University Comprehensive Cancer Center - James Cancer Hospital, Columbus, United States
Eunice Wang
13Roswell Park Comprehensive Cancer Center, Buffalo, United States
Jessica Leonard
1Oregon Health and Science University, Portland, United States
Virginia Tan
27Knight Cancer Institute, Department of Medical Oncology, Oregon Health and Science University, Portland, OR
Kristen O'Dwyer
22University of Rochester, Wilmot Cancer Institute, Rochester, United States
Jozal Moore
45Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute of University of Rochester, Rochester, NY
Ross McCauley
28Division of Hematology and Oncology, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
Navneet Majhail
26Sarah Cannon Cancer Network, Nashville, United States
Luke Mountjoy
28Sarah Cannon Transplant and Cellular Therapy Program at Colorado Blood Cancer Institute, Denver, United States
Aravind Ramakrishnan
Shahbaz Malik
29Sarah Cannon Transplant and Cellular Therapy Program at Texas Transplant Institute, Austin, United States
Minoo Battiwalla
19Sarah Cannon Transplant and Cellular Therapy Program at TriStar Centennial Medical Center, HCA Healthcare, Nashville, TN
Paul Shaughnessy
30Sarah Cannon Transplant and Cellular Therapy Program at Methodist Hospital, San Antonio, United States
John Mathews
31Sarah Cannon Transplant and Cellular Therapy Program at Texas Oncology, Dallas, United States
Omer Jamy
15Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, AL
Razan Mohty
32Division of Hematology and Oncology, O’Neal Comprehensive Cancer Center, The University of Alabama, Birmingham, AL
Muthu Kumaran
33University of Arkansas for Medical Sciences, Little Rock, United States
Rasmus Hoeg
34University of California, Davis, Davis, United States
Wendy Stock
Gregory Roloff
1University of Chicago, Chicago, United States
Caspian Oliai
Georgia Lill
35UCLA Medical Center, Los Angeles, United States
Marc Schwartz
Divya Koura
6University of California San Diego Moores Cancer Center, San Diego, CA
Kaitlyn Dykes
37University of California, San Diego, San Diego, United States
Michael Daunov
9University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH
Ken Byrd
40University of Kansas Cancer Center, Kansas City, United States
Veronika Bachanova
Sean Tracy
41Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN
Punita Grover
42University of Minnesota, Minneapolis, United States
Noelle Frey
Department of Medicine, Division of Hematology–Oncology, Hospital of the University of Pennsylvania, Philadelphia
Matthew Connor
5Division of Hematology and Oncology, Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, PA
George Yaghmour
University of Southern California, Los Angeles, California, United States
Vivian Irizarry Gatell
11Department of Medicine, University of Texas Southwestern, Dallas, TX
Clayton Jackson
45UT Southwestern, Dallas, United States
Olalekan Oluwole
1Vanderbilt University Medical Center, Department of Hematology/Oncology, Nashville, United States
Bhagirathbhai Dholaria
Rawan Faramand
24Moffitt Cancer Center and Research Institute, Tampa, FL
Lori Muffly
1Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford University, Stanford, CA