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. 2022 Mar 20;40(9):945-955.
doi: 10.1200/JCO.20.03585. Epub 2021 Dec 9.

Disease Burden Affects Outcomes in Pediatric and Young Adult B-Cell Lymphoblastic Leukemia After Commercial Tisagenlecleucel: A Pediatric Real-World Chimeric Antigen Receptor Consortium Report

Liora M Schultz  1 , Christina Baggott  2 , Snehit Prabhu  3 , Holly L Pacenta  4   5 , Christine L Phillips  6   7 , Jenna Rossoff  8 , Heather E Stefanski  9 , Julie-An Talano  10 , Amy Moskop  10 , Steven P Margossian  11 , Michael R Verneris  12 , Gary Douglas Myers  13 , Nicole A Karras  14 , Patrick A Brown  15 , Muna Qayed  16 , Michelle Hermiston  17 , Prakash Satwani  18 , Christa Krupski  6   7 , Amy K Keating  12 , Rachel Wilcox  13 , Cara A Rabik  19 , Vanessa A Fabrizio  20   21 , Rayne H Rouce  22 , Vasant Chinnabhandar  9 , Michael Kunicki  2 , Valentin V Barsan  1 , A Yasemin Goksenin  17 , Yimei Li  23 , Sharon Mavroukakis  2 , Emily Egeler  2 , Kevin J Curran  20   21 , Crystal L Mackall  24   25 , Theodore W Laetsch  4   26   27
Affiliations

Disease Burden Affects Outcomes in Pediatric and Young Adult B-Cell Lymphoblastic Leukemia After Commercial Tisagenlecleucel: A Pediatric Real-World Chimeric Antigen Receptor Consortium Report

Liora M Schultz et al. J Clin Oncol. .

Abstract

Purpose: Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel.

Methods: We conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity.

Results: Intent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; P < .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively.

Conclusion: Commercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.

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Conflict of interest statement

Christine L. PhillipsConsulting or Advisory Role: NovartisTravel, Accommodations, Expenses: Novartis Heather E. StefanskiHonoraria: Novartis Steven P. MargossianConsulting or Advisory Role: NovartisTravel, Accommodations, Expenses: Novartis Michael R. VernerisStock and Other Ownership Interests: Fate TherapeuticsHonoraria: Novartis, Jazz PharmaceuticalsPatents, Royalties, Other Intellectual Property: patent to make innate lymphiod cells. It is not licensed. Gary Douglas MyersHonoraria: NovartisConsulting or Advisory Role: NovartisSpeakers' Bureau: NovartisResearch Funding: Novartis (Inst) Patrick A. BrownConsulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Servier, Kite, a Gilead company Muna QayedConsulting or Advisory Role: Novartis, MesoblastTravel, Accommodations, Expenses: Novartis Michelle HermistonConsulting or Advisory Role: Novartis, SobiPatents, Royalties, Other Intellectual Property: Spouse has patents pending for platform technology with application to oncology, diagnostics, anti-infections and for anti-bleeding technology (I). Prakash SatwaniConsulting or Advisory Role: Mesoblast, TakedaSpeakers' Bureau: SobiOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1047592 Rachel WilcoxResearch Funding: Novartis, AlloVirTravel, Accommodations, Expenses: Novartis Rayne H. RouceHonoraria: Novartis Pharmaceuticals UK Ltd, Kite/GileadResearch Funding: Tessa Therapeutics (Inst) Valentin V. BarsanLeadership: Tessera Therapeutics, NavioStock and Other Ownership Interests: Illumina, Natera, Pacific Biosciences, InVitaeConsulting or Advisory Role: Guardant Health Kevin J. CurranHonoraria: NovartisConsulting or Advisory Role: Novartis, MesoblastResearch Funding: Juno Therapeutics Crystal L. MackallLeadership: Syncopation Life SciencesStock and Other Ownership Interests: Lyell Immunopharma, Alimera Sciences, Vor Pharmaceuticals, Apricity Health, Syncopation Life Sciences, Ensoma, MammothConsulting or Advisory Role: Bryology, Vor Biopharma, Apricity Health, TPG, Alimera Sciences, PACT Pharma, Nektar, Lyell Immunopharma, NeoImmuneTech, Syncopation Life Sciences, Bristol Myers Squibb, Immatics, GlaxoSmithKline, Ensoma, MammothResearch Funding: Lyell ImmunopharmaPatents, Royalties, Other Intellectual Property: I am an inventor on numerous patents related to chimeric antigen receptor therapeutics and received royalties from NIH for the CD22-CAR patent licensed to Juno therapeutics.Travel, Accommodations, Expenses: NeoImmuneTech, Roche, NektarOther Relationship: Lyell Immunopharma, Syncopation Life Sciences Theodore W. LaetschConsulting or Advisory Role: Novartis, Bayer, Cellectis, Aptitude Health, Clinical Education Alliance, Deciphera, Jumo Health, Massive Bio, Med Learning Group, Medscape, Physicans' Education Resource, Y-mAbs TherapeuticsResearch Funding: Pfizer (Inst), Novartis (Inst), Bayer (Inst), AbbVie (Inst), Amgen (Inst), Atara Biotherapeutics (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), Epizyme (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Jubilant Pharmaceuticals (Inst), Novella Clinical (Inst), Servier (Inst), Foundation Medicine (Inst), Merck Sharp & Dohme (Inst)No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Patient flow diagram. aPatients had concurrent disease progression, toxicities from prior therapy and/or death, therefore cumulative sum > 15. bPatients excluded because of incomplete reporting. CAR, chimeric antigen receptor; CRS, cytokine release syndrome; IND, investigational new drug.
FIG 2.
FIG 2.
(A) OS, (B) EFS, (C) DOR, and (D) DBA outcomes of infused cohort. OS and EFS estimates in all infused, evaluable patients. DOR and DBA estimates in patients who achieved morphologic remission. DBA, duration of B-cell aplasia; DOR, duration of remission; EFS, event-free survival; OS, overall survival.
FIG 3.
FIG 3.
Association of baseline characteristics with OS in a multivariate analysis of tisagenlecleucel recipients. AIC, akaike information criterion; HSCT, hematopoietic stem cell transplantation; OS, overall survival.
FIG 4.
FIG 4.
(A) OS, (B) EFS, (C) DOR, and (D) DBA outcomes stratified by disease burden. OS and EFS estimates in all infused patients with measurable disease burden. DOR and DBA estimates in patients who achieved morphologic remisson. (E) Disease burden stratification and day 28 CR rate. BM, bone marrow; CR, complete response; DBA, duration of B-cell aplasia; DOR, duration of remission; EFS, event-free survival; EM, extramedullary; HB, high-disease burden; LB, low-disease burden; MRD, minimal residual disease; OS, overall survival; UD, undetectable disease.
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References

    1. Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373:1541–1552. - PubMed
    1. Pui CH, Yang JJ, Hunger SP, et al. Childhood acute lymphoblastic leukemia: Progress through collaboration. J Clin Oncol. 2015;33:2938–2948. - PMC - PubMed
    1. Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: A report from the children's oncology group. J Clin Oncol. 2012;30:1663–1669. - PMC - PubMed
    1. Pulte D, Gondos A, Brenner H. Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century. Blood. 2009;113:1408–1411. - PubMed
    1. Nguyen K, Devidas M, Cheng SC, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: A Children's Oncology Group study. Leukemia. 2008;22:2142–2150. - PMC - PubMed

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