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2133 Risk Factors and Outcomes for Hematotoxicity Following Tisagenlecleucel for Pediatric B-Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Session: 705. Cellular Immunotherapies: Late Phase and Commercially Available Therapies: Poster I
Hematology Disease Topics & Pathways:
Research, Biological therapies, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Clinical Research, real-world evidence, Immunotherapy, Therapies, Adverse Events
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Kevin O. McNerney, MD, MSc1,2*, Vanessa A. Fabrizio, MD3, Aimee C. Talleur, MD4, Stephanie Si Lim, MD5*, Alexandra Dreyzin, MD6,7*, Christina Baggott, PhD8*, Anant Vatsayan, MBBS9, Jenna Rossoff, MD10, Snehit Prabhu, PhD11*, Holly L. Pacenta, MD12*, Christine L Phillips, MD13, Julie-An Talano, MD14, Amy Moskop, MD15*, Michael R Verneris, MD16, Douglas Myers, MD17*, Nicole Karras, MD18*, Challice L. Bonifant, MD, PhD19, Muna Qayed, MD20, Michelle L. Hermiston, MD, PhD21, Prakash Satwani, MD, MBBS22, Christa Krupski, DO, MPH23*, Amy Keating, MD24*, Susanne H.C. Baumeister, MD25, Vasant Chinnabhandar, MD, MBBS26*, Emily Egeler27*, Kevin J Curran, MD28, Crystal L. Mackall, MD29, Theodore W. Laetsch, MD30*, Liora Michal Schultz, MD31 and Swati Naik, MBBS32

1Hematology, Oncology, Neuro-oncology, and Stem Cell Transplant, Lurie Children's Hospital, Chicago, IL
2Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
3University of Colorado Anschutz, Denver, CO
4Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN
5Division of Oncology, John A. Burns School of Medicine, Honolulu, HI
6Center for Cancer and Blood Disorders, Children's National Hospital, Washington, DC
7Pediatric Oncology Branch, National Institute of Health, Bethesda, MD
8Stanford university, san francisco
9Children's National Medical Center, Washington, DC
10Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
11Center for Cancer Cell Therapy, Stanford University, Stanford, CA
12Cook Children's Hospital, Fort Worth, TX
13Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
14Medical College of WI, Milwaukee, WI
15CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
16Children's Hospital Colorado, University of Colorado At Denver, Aurora, CO
17Childrens Mercy Hospital, Kansas City, MO
18City of Hope, Duarte, CA
19Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
20Emory University, Atlanta, GA
2120University of California San Francisco Benioff Children’s Hospital, San Francisco, CA
22Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Columbia University Medical Center, New York, NY
23Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
24The Childrens Hospital University of Colorado Denver, Aurora, CO
25Division of Pediatric Oncology, Dana Farber Cancer Inst./Children's Hospital Boston, Boston, MA
26Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN
27Stanford University School of Medicine, Palo Alto, CA
28Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
29Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA
30Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
31Stanford University School of Medicine, Department of Pediatrics, Division of Hematology and Oncology, Palo Alto, CA
32Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TX


Hematotoxicity following chimeric antigen receptor (CAR) T-cell therapy is increasingly recognized as a distinct adverse event. The CAR-HEMATOTOX score has been developed as a prognostic tool for subsequent development of prolonged cytopenias in adults with lymphoma. However, risk factors in children and young adults (CAYA) with B-acute lymphoblastic leukemia (B-ALL) receiving CAR T cell therapy are less well-defined. We sought to describe incidence, outcomes, and risk factors for prolonged severe neutropenia in CAYA treated with tisagenlecleucel.


This was a multi-institutional retrospective study involving CAYA ≤26 years of age with B-ALL treated with tisagenlecleucel who underwent leukapheresis and manufacturing between August 2017 and March 2020, with data collected through the Pediatric Real World CAR Consortium (PRWCC). Of 185 patients infused, 41 patients were excluded from analysis due to missing data (n=10), refractory disease/death from leukemia (n=27) or non-relapse mortality (n=4) prior to day 35 post-CAR T. Severe prolonged neutropenia was defined as absolute neutrophil count (ANC) <500 cells/mm3 for ≥30 days. For those with severe neutropenia pre-CAR T, day 0 of severe neutropenia was considered the day of CAR T-cell infusion. Statistical analyses included comparisons using Mann-Whitney and Fisher’s exact tests, receiver operating characteristic (ROC) curves to determine cut points with optimal sensitivity and specificity, univariate logistic regression, Kaplan-Meier curves for recovery from neutropenia, overall survival (OS) and relapse free survival (RFS).


Of 144 patients, 23 (15.9%) met the definition of severe prolonged neutropenia and 121 (84%) did not. For lymphodepleting chemotherapy, 139 (96.5%) received standard fludarabine (30mg/m2/dose x 4) and cyclophosphamide (500mg/m2 x 2). Pre- and post-infusion characteristics are shown in Table 1. Pre-infusion, higher pre-infusion C-reactive protein (CRP), ferritin, bone marrow disease burden, and lower ANC and platelet counts were associated with severe prolonged neutropenia. Post-infusion, any grade cytokine release syndrome (CRS), severe CRS, CRS with hemophagocytic lymphohistiocytosis (HLH)-like manifestations, any grade neurotoxicity, peak CRP and ferritin, use of tocilizumab and steroids, and presence of infections within 30 days were associated with severe prolonged neutropenia. With univariate logistic regression, pre-infusion inflammatory markers, cytopenias, and bone marrow disease burden associated with severe prolonged neutropenia and of these, disease burden >15% had the highest odds ratio (Figure 1). Post-infusion infections and inflammatory toxicities, particularly CRS with HLH-like toxicities, as well as peak CRP, and peak ferritin, were associated with severe prolonged neutropenia. Peak ferritin >3800 ng/ml had the highest odds ratio. In patients with severe prolonged neutropenia, OS was inferior (p<0.0001) and RFS trended towards being inferior (p=0.052), compared to those without. Groups with or without severe prolonged neutropenia were also subdivided into >15% or ≤15% pre-infusion bone marrow disease burden subgroups. OS was similar between patients without severe prolonged neutropenia that had >15% or ≤15% pre-infusion disease burden, but patients with severe prolonged neutropenia and >15% disease burden had inferior OS, suggesting prolonged severe neutropenia may have independent prognostic value. Conversely, RFS was inferior in patients in the subgroups with >15% disease burden compared to those with ≤15%, regardless of occurrence of severe prolonged neutropenia.


We describe incidence, risk factors and outcomes for the development of severe prolonged neutropenia in CAYA with B-ALL following tisagenlecleucel. While there are similarities in risk factors with the CAR-HEMATOTOX score that has been validated in adults, in CAYA with B-ALL high disease burden pre-infusion and severe inflammation post-infusion were identified as the strongest risk factors for prolonged neutropenia. Identification of risk factors unique to the CAYA B-ALL population allows for tailored risk mitigation in higher risk patients and may help improve outcomes in CAYA at increased risk of prolonged severe neutropenia following tisagenlecleucel.

Disclosures: McNerney: Eli Lilly: Current equity holder in publicly-traded company; ImmunoGen: Current equity holder in publicly-traded company. Fabrizio: Adaptimmune: Consultancy. Vatsayan: Illumina: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. Rossoff: Novartis: Consultancy. Verneris: Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medexus: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Qihan: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Allovir: Consultancy; Forge: Consultancy; Omeros: Consultancy. Bonifant: Merck: Research Funding; Sharpe: Research Funding; NA: Other: Patents pending on use of engineered cellular therapies for cancer; Dohme, Inc.: Research Funding; Bristol Myers Squibb: Research Funding. Qayed: Novartis: Honoraria; Vertex: Honoraria. Baumeister: Takeda: Other: Husband is an employee at Takeda. Curran: Cellectis: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Research Funding; Atara: Consultancy, Research Funding; Turn Bio: Consultancy. Mackall: Mammoth: Consultancy, Current equity holder in private company; Lyell Immunopharma: Current equity holder in private company, Research Funding; Link Cell Therapies: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; CARGO: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Consultancy; Immatics: Consultancy. Laetsch: Bayer: Consultancy; AITherapeutics: Consultancy; Menarini: Consultancy; Massive Bio: Consultancy; Treeline Bio: Consultancy; Pyramid Biosciences: Consultancy; Advanced Microbubbles: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; GentiBio: Consultancy. Schultz: Novartis: Consultancy; cargo: Consultancy.

*signifies non-member of ASH