NGS MRD Negativity on Day 28 after Brexu Cel in Adults with R/R ALL Is Associated with Favorable Progression Free Survival

Introduction: Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Some patients (pts) proceed with a consolidative allogeneic hematopoietic cell transplant (HCT) after breux cel. We do not know which pts can safely avoid a consolidative HCT and its associated morbidity. Methods: We conducted a retrospective cohort study utilizing the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) dataset. ROCCA is a registry of brexu cel pts in 32 centers in North America. We defined complete remission (CR) as < 5% blasts in the bone marrow and no central nervous system (CNS) or extramedullary (EM) disease on or around D28 after brexu cel. We defined measurable residual disease negative (MRD-) CR as CR and no abnormal blasts in the bone marrow by multiparameter flow cytometry, quantitative polymerase chain reaction, ClonoSeq next generation sequencing (NGS), or other sequencing modalities with lower sensitivity. ClonoSeq NGS has a sensitivity of 10-6, while the other modalities have a sensitivity of at least 10-4. We defined progression free survival (PFS) as the time from CAR-T infusion to relapse or death, censored at the date of last follow-up. Statistical analyses were performed in R. Univariable Cox proportional hazards regression analyses were performed to determine the association of pre-specified variables with PFS. Variables known to be associated with CAR T outcomes in ALL were entered into a multivariable model. HCT was incorporated as a time-varying covariate. Results: During the study period, 281 pts were infused with brexu cel. We focused our analysis on 172 (61%) pts with confirmed MRD- CR on D28, as that is the group with clinical equipoise regarding maintenance strategy. 38 (22%) of those pts received a consolidative HCT, 30 (17%) received another form of maintenance therapy (primarily tyrosine kinase inhibitors for Philadelphia (Ph)-chromosome positive ALL), and 104 (60%) pts received no maintenance therapy. Pts who underwent consolidative HCT were younger (median age 35 years) than those who received no maintenance (42y) (p = 0.023) and were less likely to have a history of prior HCT (13% vs. 47%, p < 0.001). No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel. We performed univariable Cox proportional hazard regression analyses among pts in MRD- CR on D28, excluding those who received other maintenance therapy besides HCT; the median follow up was 8.1 months. In univariable analyses, D28 MRD negativity by ClonoSeq NGS (versus MRD negativity by other, less sensitive methods), development of CRS, and pre-CAR BM blasts < 5% were associated with improved PFS; prior ino exposure was negatively associated with PFS (p < 0.05). Age, sex, Ph status, TP53 status, and neurotoxicity development were not associated with PFS. In a multivariable model incorporating ALL type, prior HCT, prior ino/blina, and pre-CAR blast burden, as well as consolidative HCT as a time-varying covariate, only MRD negativity by ClonoSeq NGS with at least 10-6 sensitivity retained statistical significance (PFS hazard ratio 0.34, 95% confidence interval (CI) 0.15-0.77, p = 0.005). Pts who were MRD- by ClonoSeq NGS on D28 and received no maintenance had favorable 6m PFS of 76% (95% CI: 59-98%) and OS of 100% with a median follow up of 6.3 months in this subgroup. Among those in MRD- CR by NGS, HCT as a time-varying covariate was not associated with improved PFS (HR 0.6, p = 0.6). Conclusions: In a large real-world cohort of adults with R/R B-ALL infused with brexu cel, we identified practice variation regarding the use of consolidative HCT. Among brexu cel recipients who entered an MRD- CR, we identified ClonoSeq NGS MRD negativity as a novel predictive factor of favorable oncologic outcomes, even without a consolidative HCT. Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative.

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Blood
Published
2024-11-05
DOI
https://doi.org/10.1182/blood-2024-201610
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2
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Adenosine and Purinergic Signaling
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0.80

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article

NGS MRD Negativity on Day 28 after Brexu Cel in Adults with R/R ALL Is Associated with Favorable Progression Free Survival

Jozal Moore, Lori S. Muffly, Melhem Solh, Rawan Faramand et al.
2 citations
Blood
Adenosine and Purinergic Signaling
0.80
article

NGS MRD Negativity on Day 28 after Brexu Cel in Adults with R/R ALL Is Associated with Favorable Progression Free Survival

Jozal Moore, Lori S. Muffly, Melhem Solh, Rawan Faramand, Wendy Stock, Maria Odstrcil Bobillo, Joshua Sasine, Norbert Frey, Catherine J. Lee, Simone E. Dekker, Matthew L. Ulrickson, George Yaghmour, Paul Shaughnessy, Navneet S. Majhail, Divya Koura, Marlise Rachael Luskin, Matthew P. Connor, Vinod A. Pullarkat, Bijal Shah, Omer Jamy, Marc S. Schwartz, Luke Mountjoy, Caspian Oliai, Jessica Leonard, Evandro D. Bezerra, Tamer Adel Othman, Akil Merchant, Ibrahim Taha Aldoss, Olalekan O. Oluwole, Michael R. Grunwald, Gregory W. Roloff, Noam E. Kopmar, Evan Chris Chen, Amelia Langston, Rasmus T. Hoeg, LaQuisa C. Hill, Bhagirathbhai Dholaria, Kristen M. O'Dwyer, Ibrahim N. Muhsen, Vamsi Kota, Muthu V. Kumaran, Veronika Bachanová, Sang‐Bing Tsai, Talal Hilal, Clayton Jackson, Chenyu Lin, Aaron C. Logan, Ryan D. Cassaday, Minoo Battiwalla, Sean Tracy, Kaitlyn C. Dykes, John A. Mathews, David Nemirovsky, Abdullah Ladha, Anjali S. Advani, Ran Reshef, Yannis K. Valtis, Michael Daunov, Timothy E. O’Connor, Nikeshan Jeyakumar, Vishal Gupta, Amy Zhang, Jae H. Park, Sumithira Vasu, Shabaz Malik, Katherine C. Sutherland, Sean Devlin, Katharine Miller, Jacob Boccucci, Vivian Irrizary Gatell
article en
2 citations

Abstract

Introduction: Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Some patients (pts) proceed with a consolidative allogeneic hematopoietic cell transplant (HCT) after breux cel. We do not know which pts can safely avoid a consolidative HCT and its associated morbidity. Methods: We conducted a retrospective cohort study utilizing the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) dataset. ROCCA is a registry of brexu cel pts in 32 centers in North America. We defined complete remission (CR) as < 5% blasts in the bone marrow and no central nervous system (CNS) or extramedullary (EM) disease on or around D28 after brexu cel. We defined measurable residual disease negative (MRD-) CR as CR and no abnormal blasts in the bone marrow by multiparameter flow cytometry, quantitative polymerase chain reaction, ClonoSeq next generation sequencing (NGS), or other sequencing modalities with lower sensitivity. ClonoSeq NGS has a sensitivity of 10-6, while the other modalities have a sensitivity of at least 10-4. We defined progression free survival (PFS) as the time from CAR-T infusion to relapse or death, censored at the date of last follow-up. Statistical analyses were performed in R. Univariable Cox proportional hazards regression analyses were performed to determine the association of pre-specified variables with PFS. Variables known to be associated with CAR T outcomes in ALL were entered into a multivariable model. HCT was incorporated as a time-varying covariate. Results: During the study period, 281 pts were infused with brexu cel. We focused our analysis on 172 (61%) pts with confirmed MRD- CR on D28, as that is the group with clinical equipoise regarding maintenance strategy. 38 (22%) of those pts received a consolidative HCT, 30 (17%) received another form of maintenance therapy (primarily tyrosine kinase inhibitors for Philadelphia (Ph)-chromosome positive ALL), and 104 (60%) pts received no maintenance therapy. Pts who underwent consolidative HCT were younger (median age 35 years) than those who received no maintenance (42y) (p = 0.023) and were less likely to have a history of prior HCT (13% vs. 47%, p < 0.001). No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel. We performed univariable Cox proportional hazard regression analyses among pts in MRD- CR on D28, excluding those who received other maintenance therapy besides HCT; the median follow up was 8.1 months. In univariable analyses, D28 MRD negativity by ClonoSeq NGS (versus MRD negativity by other, less sensitive methods), development of CRS, and pre-CAR BM blasts < 5% were associated with improved PFS; prior ino exposure was negatively associated with PFS (p < 0.05). Age, sex, Ph status, TP53 status, and neurotoxicity development were not associated with PFS. In a multivariable model incorporating ALL type, prior HCT, prior ino/blina, and pre-CAR blast burden, as well as consolidative HCT as a time-varying covariate, only MRD negativity by ClonoSeq NGS with at least 10-6 sensitivity retained statistical significance (PFS hazard ratio 0.34, 95% confidence interval (CI) 0.15-0.77, p = 0.005). Pts who were MRD- by ClonoSeq NGS on D28 and received no maintenance had favorable 6m PFS of 76% (95% CI: 59-98%) and OS of 100% with a median follow up of 6.3 months in this subgroup. Among those in MRD- CR by NGS, HCT as a time-varying covariate was not associated with improved PFS (HR 0.6, p = 0.6). Conclusions: In a large real-world cohort of adults with R/R B-ALL infused with brexu cel, we identified practice variation regarding the use of consolidative HCT. Among brexu cel recipients who entered an MRD- CR, we identified ClonoSeq NGS MRD negativity as a novel predictive factor of favorable oncologic outcomes, even without a consolidative HCT. Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative.

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University of Southern California (US), Cedars-Sinai Medical Center (US), City Of Hope National Medical Center (US), University of Minnesota (US), Loyola University Medical Center (US), Cleveland Clinic (US), Memorial Sloan Kettering Cancer Center (US), The University of Texas MD Anderson Cancer Center (US), Emory University (US), University of California, Los Angeles (US), Oregon Health & Science University (US), Duke University (US), University of California, San Francisco (US), Baylor College of Medicine (US), University of Washington (US), University of Utah (US), Augusta University (US), Columbia University Irving Medical Center (US), Huntsman Cancer Institute (US), WinnMed (US), University of Rochester Medical Center (US), Moffitt Cancer Center (US), University of Alabama at Birmingham (US), University of California San Diego (US), University of Chicago (US), Augusta University Health (US), Centennial Medical Center (US), Fred Hutch Cancer Center (US), Levine Cancer Institute (US), Sarah Cannon (US), Methodist Hospital (US), City of Hope (US), USC Norris Comprehensive Cancer Center (US), Dana-Farber Cancer Institute (US), University Hospitals Seidman Cancer Center (US), St David's Medical Center (US), Methodist Hospital (US), Stanford Blood Center (US), Colorado Blood Cancer Institute (US), University of Minnesota Medical Center (US), Presbyterian St. Luke's Medical Center (US), Mayo Clinic in Florida (US), Banner MD Anderson Cancer Center, Southwestern Medical Center (US), Moores Cancer Center, Winship Cancer Institute, The Ohio State University (US), University of Pennsylvania (US), University of Arkansas for Medical Sciences (US), University of California, Davis (US), The University of Texas Southwestern Medical Center (US), Vanderbilt University Medical Center (US), University of Colorado Denver (US), Stanford University (US)
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