KMT2Ar, but not other high-risk genetics, adversely impacts outcomes in adult patients with relapsed/refractory (R/R) Philadelphia chromosome negative B-cell acute lymphoblastic leukemia (B-ALL) treated with brexucabtagene autoleucel (Brexu-cel)
Abstract
Abstract Introduction: Brexu-cel is a highly effective treatment for R/R B-ALL, with complete responses achieved in 71% of patients (pts) treated in the pivotal ZUMA-3 trial. Patients with B-ALL with high-risk (HR) genetics are known to have inferior outcomes with chemotherapy, but little is known about the influence of HR ALL genetics on responses to chimeric antigen receptor (CAR)-T in adults. In this study, we assessed the impact of HR ALL genetics on outcomes in a large cohort of adult patients treated with brexu-cel for R/R Philadelphia chromosome (Ph)-negative B-ALL. Methods: Patient characteristics and outcomes were obtained from the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) database which includes data from 40 U.S. centers. NCCN guidelines (NCCN Guidelines in Oncology, ALL v2.2025) were used to define HR B-ALL genetics; lack of HR genetics was defined as standard-risk (SR). The primary outcome was event-free survival (EFS), defined as lack of response, disease progression, or death from any cause. Secondary outcomes were overall survival (OS), relapse free survival (RFS) and response rates including complete response (CR), CR incomplete count recovery (CRi), measurable residual disease negative CR (MRD-) by flow or NGS and progressive disease (PD). Multivariable models were adjusted for age, pre-infusion blast percentage, prior allo-HCT, and post CAR-T allo-HCT (modeled as a time-varying covariate). Results: The cohort included 286 pts: 169 with HR and 117 with SR B-ALL. The HR cohort included TP53m (n=24, 14%), KMT2Ar (n=16, 9%), CRLF2r (n=65, 39%) and other HR genetics such as JAK2 and other Ph-like, IKZF1, complex cytogenetics (n=64, 38%). Relative to SR pts, HR pts were more commonly Hispanic (50% vs 28%). HR and SR pts had similar disease burden pre-apheresis (>5% blasts: 58% vs 53%), prior blinatumomab (60% vs 58%), prior inotuzumab (42% vs 46%), and prior allo HCT (27% vs 37%). The presence of CNS disease (11% HR vs 12% SR) and extramedullary disease (EMD, 22% HR vs 29% SR) at apheresis was also similar. CR/CRi was achieved in 90.5% of evaluable HR pts (n=147) and 90.2% of evaluable SR pts (n=102); MRD- rates were also similar between HR and SR pts at 78.9% and 78.2% respectively. In unadjusted analyses, EFS did not significantly differ between HR pts (median 9.6 mos; 1-yr: 46%, 95% CI 38%-54%) and SR pts (median 11.6 mos; 1-yr: 48%, 95% CI 38%- 58%). Median RFS (HR: 12.2 mos, SR: 13.3 mos) and median OS (HR: 22.4 mos, SR: 21.0 mos) were also similar. Multivariable models demonstrated no significant associations between HR B-ALL and EFS (HR 1.09, 95% CI 0.73-1.63), RFS (HR 1.13, 95% CI 0.71-1.80), or OS (HR 0.96, 95% CI 0.62- 1.48) relative to SR ALL. 28% of HR patients and 21% of SR patients underwent consolidative allo-HCT. Among the HR subgroup, CR/CRi rate was lowest in KMT2Ar (71%) relative to TP53m (95%), CRLF2r (95%), and other HR genetics (89%). The median EFS was lowest in KMT2Ar (4.1 mos), followed by TP53m (6.9 mos), CRLF2r (11.6 mos), and other HR (11.1 mos). Median OS was also lowest in KMT2Ar (6.8 mos) vs 22.4 mos in TP53m and not reached in CRLF2r or other HR. PD was highest in KMT2Ar pts (29%), as compared to 11% HR other, 10% SR, and 5% TP53 and CRLF2r. The rate of relapse among those that achieved CR across the groups was similar and ranged between 28% -40%. Rates of CD19 negative relapse were similar between all subgroups (13%-15%), however 21% of KMT2A pts underwent myeloid transformation as compared 0% for TP53 and CRLF2 pts, and 2% among other HR and SR pts. 25% of KMT2Ar patients underwent consolidative allo-HCT as compared to 32% CRLF2 pts, 29% TP53 pts, 25% other HR pts and 21% SR pts. Multivariable models evaluating the different genomic subgroups demonstrated that relative to SR B-ALL, only KMT2Ar was associated with inferior OS (HR 3.17, 95% CI 1.53-6.58, p=0020). No associations were seen between HR subgroups and EFS. Conclusion: To our knowledge, this analysis represents the largest examination of adult B-ALL recipients of CAR-T assessed by genomic risk group. We found that response rates and survival outcomes following brexu-cel were similar among HR and SR B-ALL pts, including pts with TP53m and CRLF2r. However, pts with KMT2Ar had lower response rates and dismal EFS and OS, with higher rates of PD and myeloid transformation at relapse, suggesting that alternative strategies are necessary to improve outcomes for patients with R/R KMT2Ar B-ALL.
Article Details
Authors (74)
Jessica Leonard
1Oregon Health and Science University, Portland, United States
Abdullah Ladha
2University of Southern California, Keck School of Medicine, Los Angeles, United States
Rawan Faramand
24Moffitt Cancer Center and Research Institute, Tampa, FL
Gregory Roloff
1University of Chicago, Chicago, United States
Yannis Valtis
5Memorial Sloan Kettering Cancer Center, New York City, United States
Virginia Tan
27Knight Cancer Institute, Department of Medical Oncology, Oregon Health and Science University, Portland, OR
Katharine Miller
3Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, CA
Amy Zhang
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
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
Joshua Sasine
29Division of Hematology and Cellular Therapy, Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA
Anjali Advani
6Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
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
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
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
Eunice Wang
13Roswell Park Comprehensive Cancer Center, Buffalo, United States
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
Aravind Ramakrishnan
Luke Mountjoy
28Sarah Cannon Transplant and Cellular Therapy Program at Colorado Blood Cancer Institute, Denver, United States
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
Hrishikesh Srinagesh
6Stanford University School of Medicine, Palo Alto, United States
Katherine Sutherland
6Stanford University School of Medicine, Palo Alto, 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
Caspian Oliai
Georgia Lill
35UCLA Medical Center, Los Angeles, United States
Wendy Stock
Marc Schwartz
Tamer Othman
36Hematology, Blood and Marrow Transplantation, and Cellular Therapy Program, University of California San Francisco, San Francisco, CA
Divya Koura
6University of California San Diego Moores Cancer Center, San Diego, CA
Kaitlyn Dykes
37University of California, San Diego, San Diego, United States
Aaron Logan
1University of California, San Francisco, Hematology, Blood and Marrow Transplantation, and Cellular Therapy Program, San Francisco, 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
Fevzi Yalniz
40Division of Hematology and Blood Marrow Transplantation, Department of Medicine, University of Kentucky College of Medicine, Lexington, KY
Veronika Bachanova
Sean Tracy
41Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN
Punita Grover
42University of Minnesota, Minneapolis, United States
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
Noelle Frey
Department of Medicine, Division of Hematology–Oncology, Hospital of the University of Pennsylvania, Philadelphia
Lori Muffly
1Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford University, Stanford, CA
Bijal Shah
16H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Ibrahim Aldoss