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Multicenter Study
. 2025 Oct 14;9(19):5070-5084.
doi: 10.1182/bloodadvances.2025016824.

Characterization and prediction of prolonged severe neutropenia in pediatric patients receiving tisagenlecleucel

Swati Naik  1 , Subodh Selukar  1 , Aimee C Talleur  1 , Samira Deshpande  1 , Gabriela Llaurador Caraballo  2 , Vanessa A Fabrizio  3 , Rayne H Rouce  2 , Xiaopei L Zeng  4 , Anant Vatsayan  5 , Jenna Rossoff  4 , Holly L Pacenta  6 , Samuel John  7 , Christine L Phillips  8 , Julie-An Talano  9 , Amy Moskop  9 , Michael R Verneris  3 , Gary D Myers  10 , Erin Hall  10 , Nicole Karras  11 , Challice L Bonifant  12 , Muna Qayed  13 , Emily Bakinowski  14 , Amy K Keating  14 , Susanne H C Baumeister  14 , Emily Tomilson  15 , Michelle L Hermiston  15 , Prakash Satwani  16 , Christa Krupski  8 , Vasant Chinnabhandar  17 , Heather E Stefanski  17 , Emily Egeler  18 , Kevin J Curran  19 , Theodore W Laetsch  20 , Crystal L Mackall  18 , Snehit Prabhu  18 , Khanh P Nguyen  18 , Christina Baggott  18 , Liora Michal Schultz  18 , Kevin O McNerney  4
Affiliations
Multicenter Study

Characterization and prediction of prolonged severe neutropenia in pediatric patients receiving tisagenlecleucel

Swati Naik et al. Blood Adv. .

Abstract

Hematotoxicity is the most frequent severe toxicity after chimeric antigen receptor T-cell (CAR-T) therapy. However, limited data exist on risk factors and outcomes for hematotoxicity for children and young adults (CAYAs) with B-acute lymphoblastic leukemia treated with tisagenlecleucel. We conducted a multi-institutional study involving 326 CAYAs, with 144 evaluable in an initial training cohort and 141 evaluable in a validation cohort, through the Pediatric Real-World CAR Consortium to characterize the incidence and outcomes of prolonged severe neutropenia (PSN) and to develop a predictive risk score for PSN, tailored for use in this population. The incidence of PSN, defined as an absolute neutrophil count of <0.5 x 103 cells per μL for ≥30 days, was 15.3% in the initial training cohort and 21% in the validation cohort. Development of PSN was associated with inferior overall survival (P < .001), relapse-free survival (P = .01), higher nonrelapse mortality (P = .003), and a greater risk of infections within 30 days (P = .03). Multivariable penalized regression analysis identified key risk factors for PSN, which included preinfusion C-reactive protein and bone marrow disease burden, and postinfusion peak ferritin and occurrence of severe cytokine release syndrome, which were used to create the CytoRisk score. In the validation cohort, the CytoRisk score discriminated between patients with and without PSN (area under the curve, 0.90; specificity, 93%; sensitivity, 71%; positive predictive value, 74%; and negative predictive value, 92%). The CytoRisk score may be used to a priori identify patients at highest risk of PSN and overall worse outcomes.

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Conflict of interest statement

Conflict-of-interest disclosure: C.L.M. holds multiple patents related to chimeric antigen receptor (CAR) T-cell therapies; receives royalties for CD22-CAR from CARGO Therapeutics; holds equity in CARGO Therapeutics, Link Cell Therapies, GBM NewCo, and Ensoma; consults for CARGO Therapeutics, Link Cell Therapies, GBM NewCo, Ensoma, Immatics, and AstraZeneca; and receives research funding from Tune Therapeutics. R.H.R. has received honoraria from Novartis; and consulting fees from Pfizer. V.A.F. consults for Adaptimmune. T.W.L. holds equity in Advanced Microbubbles; consults for Bayer, Massive Bio, AI Therapeutics, Jazz Pharmaceuticals, GentiBio, ITM Oncologics, and GlaxoSmithKline; and receives research funding from Pfizer, Bayer, Turning Point Therapeutics, Lilly, Roche/Genentech, Taiho, Advanced Accelerator Applications/Novartis, BioAtla, Hoffman-La Roche, Exelixis, and Adaptimmune. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
CONSORT diagram.
Figure 2.
Figure 2.
Neutrophil recovery and survival data. (A) Estimate of cumulative incidence of recovery to ANC of >0.5 x 103/μL among patients experiencing grade 4 neutropenia. (B) Estimate of cumulative incidence of recovery to ANC of >0.5 x 103/μL among patients experiencing grade 4 neutropenia restricted to the first 100 days. (C) ANC median (solid lines) and interquartile range (shaded region) by PSN status. (D) Bar plot of number of patients by PSN status. (E) OS probability estimates by PSN status. (F) RFS probability estimates by PSN status. (G) Estimate of cumulative incidence of NRM by PSN status. (H) Estimate of cumulative incidence of relapse by PSN status.
Figure 3.
Figure 3.
Development of CytoRisk score and validation. (A) Initial 2-point preinfusion system. (B) Initial 5-point preinfusion and postinfusion system. (C) Validation receiver operating characteristic (ROC) curves for initial 2-point preinfusion, initial 5-point preinfusion and postinfusion, and CAR-HEMATOTOX systems. ∗For all risk scores, the AUC was significantly different from 0.50 (P < .001). (D) Optimized 4-point preinfusion system. (E) Optimized 7-point preinfusion and postinfusion system. (F) Validation ROC curves for optimized 4-point preinfusion, optimized 7-point preinfusion and postinfusion, and CAR-HEMATOTOX systems. ∗For all risk scores, the AUC was significantly different from 0.50 (P < .001). (G) Prediction performance for all candidate systems at the respective proposed threshold for high risk.
Figure 4.
Figure 4.
Violin plots of weekly ANC for each candidate system categorized by the respective high-risk grouping. Systems including postinfusion variables are restricted to weeks 2 to 4 when the highest risk grouping could be determined for all patients in the data set. Orange line overlaid at 500. (A) Violin plots of weekly ANC stratified by CAR-HEMATOTOX. (B) Violin plots of weekly ANC stratified by 2-point preinfusion variables. (C) Violin plots of weekly ANC stratified by 5-point preinfusion and postinfusion variables. (D) Violin plots of weekly ANC stratified by 4-point preinfusion variables. (E) Violin plots of weekly ANC stratified by 7-point preinfusion variables.
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