CRS/ICANS Prophylaxis does not Improve Outcomes in adult patients with Relapsed/Refractory B-cell acute lymphoblastic leukemia (B-ALL) treated with brexucabtagene autoleucel
Abstract
Abstract Introduction: CD19-directed CAR T-cell (CAR-T) therapy has substantially improved clinical outcomes for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, notable toxicities are associated with CAR-T, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Variable practice patterns have emerged regarding the use of CRS/ICANS prophylaxis (ppx) via corticosteroids and/or other pharmacologic agents, but the utility of these approaches on reducing CRS or ICANS following CAR-T in B-ALL remains unknown. Thus, we utilized the Real-World Outcomes Collaborative for CAR T in ALL (ROCCA) database to evaluate associations between ppx and the development and severity of CRS or ICANS following brexucabtagene autoleucel (brexu-cel) for B-ALL. Methods: Adult patients (pts) who received standard-of-care brexu-cel for relapsed/refractory B-ALL across 40+ US centers were included. Primary endpoints were the incidence of CRS and ICANS within 28 days of CAR-T infusion. Secondary endpoints included timing of CRS and ICANS onset, progression-free survival (PFS) and overall survival (OS). Univariable and multivariable logistic regression evaluated associations between ppx and incidence of CRS/ICANS; KM and log-rank methods were used for survival analyses. Results: A total of 378 pts were included: 53 pts (14.0%) received CRS/ICANS ppx and 325 (86.0%) received no ppx. Ppx agents included steroids only (26.4%), steroid and anakinra (52.8%), anakinra only (15.1%), and steroid and tocilizumab (5.7%). Pts in the ppx group had a higher proportion of Hispanic pts (64% vs 34%), Ph-like (36% vs 19%) and a lower proportion had 0-5% bone marrow blasts at apheresis (38% vs 53%). The ppx and no ppx groups were similar in age, prior therapies, CAR-T indication, and marrow blasts >50%. Cumulative incidence of any grade (gr) CRS was 94% with ppx and 86% with no ppx (p=0.025), of any gr ICANS was 53% with ppx and 51% with no ppx (0= 0.85). Cumulative incidence of gr 3-4 CRS was 9% in the ppx group and 10% in the no ppx group (p=1.00), of gr 3-4 ICANS was 26% in the ppx group and 29% in the no ppx group (p=0.71). Median time to onset for any gr CRS or any gr ICANS was identical in the ppx and no ppx cohorts (CRS: 5 days, range ppx 1-9 days, no ppx 0-14 days; ICANS: 7 days, ppx 1-20 days, no ppx 0-16 days). Univariate logistic regression analyses showed no significant association between ppx and the incidence of gr 2-4 CRS (OR 1.34, 95% CI: 0.75-2.40, p=0.326) or gr 3-4 ICANS (OR 0.88, 95% CI: 0.46-1.70, p=0.708). Multivariate analysis adjusting for ethnicity, leukemia genetic sub-type, and pre-apheresis disease burden similarly found no significant associations between ppx and gr 2-4 CRS (adjusted OR 1.06, 95% CI: 0.55-2.01, p=0.870) or gr 3-4 ICANS (OR 1.23, 95% CI: 0.59-2.55, p=0.584). When comparing steroid-only ppx (N=14) to steroid combinations or other drug ppx (N=39), there was no significant differences in gr 2-4 CRS (57% vs 44%, p=0.345) or gr 3-4 ICANS (43% vs 21%, p=0.115). Comparing cumulative incidence of dexamethasone (dex) exposure, pts in the ppx group had numerically greater dex exposure than pts in the no ppx group, with median (range) dosing of 182 mg (10-1386mg) and 100mg (1-4000mg), respectively. Finally, we found no significant differences in PFS or OS based on ppx. Median PFS was 9.6 months in the ppx group vs 13.3 months in the no ppx group (p=0.646) and median OS was 17.2 months in the ppx group vs 34.4 months in the no ppx group (p=0.170). Conclusions: In this large cohort of adult patients with R/R ALL receiving brexu-cel CAR-T therapy, prophylaxis intended to prevent CRS/ICANS was ineffective at reducing CRS/ICANS incidence, time to onset, or overall steroid exposure. Furthermore, PFS and OS were comparable between patients who received prophylaxis and those who did not. In the absence of prospective trials in B-ALL, these data suggest that current strategies of CRS/ICANS prophylaxis has limited benefit.
Article Details
Authors (72)
Ross McCauley
28Division of Hematology and Oncology, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
Amy Zhang
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
Michael Grunwald
4Division of Leukemia, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NC
Matthew Ulrickson
28Banner MD Anderson Cancer Center, Gilbert, AZ
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
Ibrahim Aldoss
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
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
Silvina Odstrcil Bobillo
20Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT
Stephanie Tsai
21Loyola University Medical Center, Maywood, United States
Talal Hilal
13Mayo Clinic, Phoenix, AZ
Bijal Shah
16H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Rawan Faramand
24Moffitt Cancer Center and Research Institute, Tampa, FL
Jae Park
1Memorial Sloan Kettering Cancer Center, Medicine, New York, United States
Yannis Valtis
5Memorial Sloan Kettering Cancer Center, New York City, United States
Tamer Othman
36Hematology, Blood and Marrow Transplantation, and Cellular Therapy Program, University of California San Francisco, San Francisco, CA
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
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
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
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
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
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
Ali Al-Darobi
9Banner MD Anderson Cancer Center, Gilbert, United States
Evan Chen
Catherine Lee
Timothy O'Connor
10Division of Hematology/Oncology, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL
Bhagirathbhai Dholaria
Veronika Bachanova
Sean Tracy
41Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN
Hrishikesh Srinagesh
6Stanford University School of Medicine, Palo Alto, United States
Katharine Miller
3Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, CA
Katherine Sutherland
6Stanford University School of Medicine, Palo Alto, United States
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
Shahbaz Malik
29Sarah Cannon Transplant and Cellular Therapy Program at Texas Transplant Institute, Austin, United States
Aravind Ramakrishnan
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
Eunice Wang
13Roswell Park Comprehensive Cancer Center, Buffalo, United States
Minoo Battiwalla
19Sarah Cannon Transplant and Cellular Therapy Program at TriStar Centennial Medical Center, HCA Healthcare, Nashville, TN
Gregory Roloff
1University of Chicago, Chicago, United States
Lori Muffly
1Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford University, Stanford, CA