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4674 Obesity Associates with Inferior Outcomes and Toxicity in Pediatric and Young Adult Patient with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia Treated with Commercially Manufactured Tisagenlecleucel

Program: Oral and Poster Abstracts
Session: 705. Cellular Immunotherapies: Late Phase and Commercially Available Therapies: Poster III
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Biological therapies, Chimeric Antigen Receptor (CAR)-T Cell Therapies, pediatric, Diseases, Therapies, Lymphoid Malignancies, Adverse Events, young adult , Study Population, Human
Monday, December 12, 2022, 6:00 PM-8:00 PM

Anthony J Ross, MD1, Christina Baggott, RN, PhD2*, Snehit Prabhu, PhD2*, Holly Pacenta, MD3, Christine Philips4*, Jenna Rossoff, MD5, Heather E Stefanski, MD6, Julie-An Talano, MD 7, Amy Moskop, MD, MS8, Susanne H.C. Baumeister, MD9, Michael R Verneris, MD10, Gary Douglas Myers, MD11*, Nicole Karras, MD12*, Muna Qayed, MD, MSc13, Michelle L. Hermiston, MD, PhD14, Prakash Satwani, MD15*, Christa Krupski, DO, MPH16*, Amy K. Keating, MD17*, Rachel Wilcox18*, Vanessa A Fabrizio, MD19, Vasant Chinnabhandar, MD20*, Kevin J. Curran, MD21, Crystal L. Mackall, MD22, Theodore W. Laetsch, MD23*, Sandra K Althouse, PhD24*, Shannon L. Maude, MD25, Curtis J Henry, PhD26, Liora M. Schultz, MD27 and Jodi L. Skiles, MD28*

1Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, IN
2Stanford University School of Medicine, Stanford, CA
3Cook Children's Medical Center, Fort Worth, TX
4Cincinnati Children's Hospital Medical Center, Cincinnati, OH
5Division of Pediatric Hematology/Oncology/Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
6CIBMTR® (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program®/Be The Match®, Mendota Heights, MN
7Department of Pediatrics, Hematology/Oncology and BMT, Medical College of WI, Milwaukee, WI
8CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
9Division of Pediatric Oncology, Dana Farber Cancer Inst./Children's Hospital Boston, Boston, MA
10Children's Hospital Colorado, University of Colorado At Denver, Aurora, CO
11Children's Mercy of Kansas City, Kansas City, MS
12Department of Pediatrics, City of Hope National Medical Center, Duarte, CA
13Emory University, Atlanta, GA
14Pediatric Hematology Oncology, University of California San Francisco, San Francisco, CA
15Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Columbia University Medical Center, New York, NY
16Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
17Pediatric Blood and Marrow Transplantation, University of Colorado, Anschutz Medical Campus, Colorado Children’s Hospital, Aurora, CO
18Childern's Mercy Hospital, Kansas
19University of Colorado, Anschutz Medical Campus, Colorado Children's Hospital, Aurora, CO
20Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, University of Minnesota Medical School, Minneapolis, MN
21Department of Pediatrics, BMT Service, Memorial Sloan Kettering Cancer Center, New York, NY
22Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA
23Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
24Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN
25Division of Oncology, Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children's Hospital of Philadelphia, Philadelphia, PA
26Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
27Department of Pediatrics, Division of Hematology and Oncology, Stanford University School of Medicine, Palo Alto, CA
28Riley Hospital for Children, Indianapolis, IN

Introduction: The incidence of obesity continues to rise with over 50% of the world’s population predicted to be overweight/obese by the year 2030. There is emerging epidemiological evidence suggesting that obesity is a risk factor for developing hematological malignancies, and previous data shows acute lymphoblastic leukemia (ALL) treatment is associated with the development of obesity. Alarmingly, the survival outcomes for obese children/young adults with B-ALL are historically inferior to those observed in healthy weight peers when treated with traditional chemotherapy regimens leading to the need for alternative therapeutic approaches. Chimeric antigen receptor T-cell therapy redirects the cytotoxicity of a T-cell towards a cancer cell and has been shown to induce remission in patients who have previously been treatment-refractory or multiply relapsed. Unfortunately, T-cell dysfunction has been reported in obesity. The impact of obesity on T-cell immunotherapies is currently unknown.

Objective: Establish real world disease response and toxicity outcomes experienced by overweight/obese pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) treated with chimeric antigen receptor T-cell therapy (tisagenlecleucel), compared to their healthy weight peers.

Design/Methods: Retrospective data was collected from Pediatric Real World CAR Consortium (PRWCC) institutions (n=15) on 168 pediatric/young adult patients (age 2-22), evaluable for BMI measure, who underwent infusion of commercially manufactured tisagenlecleucel for r/r B-ALL. Weight categories were established using CDC growth charts with gender/age specific BMI cutoffs (healthy 5th to 85th percentile; overweight/obese >85th percentile). Efficacy outcomes include relapse-free survival (RFS) and overall survival (OS). Toxicity endpoints include cytokine release syndrome (CRS) and neurotoxicity (ICANS). Demographic, baseline characteristics, and toxicities were summarized as median (range) for continuous variables and number and percentage for categorical variables. Comparisons between groups were done using Chi-square tests for categorical variables, or Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze RFS and OS using the log rank test to compare weight groups. Hazard ratios with 95% confidence intervals were calculated. Univariable and multivariable analyses were performed.

Results: Of 168 patients included in the analysis, 88 were in the healthy weight category and 80 were in the overweight/obese category. There was no difference in baseline characteristics between groups (age at infusion, gender, race/ethnicity, Down syndrome, marrow morphology prior to infusion (M1 vs >M1 marrow), CNS status prior to infusion, or transplant following infusion). Overweight/obese patients had statistically significant inferior RFS at 6 months (61.9% vs 81.5%), 12 months (51.4% vs 70%), and 24 months (31.1% vs 64.7%). Relapse hazard ratio for obese/overweight patients was 2.04 (95% CI 1.2, 3.45: p = 0.006). Overall survival of overweight/obese patients was not statistically different than healthy weight patients but trended towards decreased OS in overweight/obese patients at 6 months (82.4% vs 89.6%), 12 months (70.3% vs 77.5%) and 24 months (46.4% vs 64.7%). OS hazard ratio for obese/overweight patients was 1.54 (95% CI 0.85, 2.78: p = 0.149). Additionally, overweight/obese patients showed a trend towards higher grade toxicity than healthy weight patients with CRS grade ≥ 3 seen in 22.8% vs 14.8% (p = 0.272) and ICANS grade ≥ 3 seen in 11.4% vs 3.4% (p = 0.108), respectively.

Conclusion: This retrospective, multi-institutional analysis highlights the high incidence of obesity among patients who are candidates for tisagenlecleucel. Furthermore, it shows that overweight/obese patients treated with tisagenlecleucel for r/r B-ALL have inferior outcomes (particularly RFS) and potential for increased toxicity compared to their healthy weight peers. Additional research is needed to interrogate generalizability of findings to immunotherapy recipients of all ages, across cancer subtypes, and illicit the mechanism of obesity induced immune dysfunction and related mitigating strategies.

Disclosures: Stefanski: Novartis: Other: Ad Board, Speakers Bureau. Verneris: Up-To-Date: Consultancy; Bmogen: Consultancy, Current equity holder in private company; Fate Therapeutics: Consultancy, Current equity holder in private company; Novartis: Membership on an entity's Board of Directors or advisory committees. Myers: Eliana Trial: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Qayed: Vertex: Honoraria; Novartis: Honoraria. Hermiston: Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Satwani: Takeda: Honoraria; Mesoblast: Honoraria. Curran: Novartis: Consultancy, Research Funding. Mackall: Immatics: Consultancy; Medimmune Tech: Consultancy; Nektar: Consultancy; Syncopation: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Link: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Ensoma: Divested equity in a private or publicly-traded company in the past 24 months; Mammoth: Divested equity in a private or publicly-traded company in the past 24 months; BMS: Consultancy; Apricity: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; GSK: Consultancy; Lyell Pharmaceuticals: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months. Laetsch: Novartis: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Cellectis: Consultancy; Pfizer: Research Funding; Advanced Microbubbles: Current holder of stock options in a privately-held company; AI Therapeutics: Consultancy; Deciphera: Consultancy; GentiBio: Consultancy; Jazz Pharmaceuticals: Consultancy; Jumo Health: Consultancy; Massive Bio: Consultancy; Menarini: Consultancy; Pyramid Biosciences: Consultancy; y-mAbs Therapeutics: Consultancy. Maude: Novartis Pharmaceuticals: Consultancy, Other: study steering committee, Patents & Royalties: Patent pending and licensed to Novartis Pharmaceuticals for PCT/US2017/044425: Combination Therapies of Car and PD-1 Inhibitors , Research Funding; Wugen: Research Funding. Henry: PureTech Health: Research Funding. Schultz: Novartis: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH