Tisagenlecleucel utilisation and outcomes across refractory, first relapse and multiply relapsed B-cell acute lymphoblastic leukemia: a retrospective analysis of real-world patterns

Valentin Barsan¹, Yimei Li^{2

3}, Snehit Prabhu¹, Christina Baggott¹, Khanh Nguyen¹, Holly Pacenta^{4

5}, Christine L Phillips^{6

7}, Jenna Rossoff⁸, Heather Stefanski⁹, Julie-An Talano¹⁰, Amy Moskop¹⁰, Susanne Baumeister¹¹, Michael R Verneris¹², Gary Douglas Myers¹³, Nicole A Karras¹⁴, Stacy Cooper¹⁵, Muna Qayed¹⁶, Michelle Hermiston¹⁷, Prakash Satwani¹⁸, Christa Krupski^{6

7}, Amy Keating¹², Vanessa Fabrizio¹², Vasant Chinnabhandar⁹, Michael Kunicki¹, Kevin J Curran¹⁹, Crystal L Mackall^{1

20

21}, Theodore W Laetsch², Liora M Schultz¹

Affiliations

¹ Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, 1000 Welch Road, Suite 300, Palo Alto, CA 94304, USA.
² Department of Pediatrics, Children's Hospital of Philadelphia/University of Pennsylvania, 3401 Civic Center Blvd., Philadelphia, PA 19104, USA.
³ Children's Hospital of Philadelphia, 3401 Civic Center Blvd., Philadelphia, PA 19104, USA.
⁴ Cook Children's Hospital, 1500 Cooper St 5th Floor, Fort Worth, TX 76104, USA.
⁵ Department of Pediatrics, The University of Texas Southwestern Medical Center/Children's Health, 5323 Harry Hines Blvd., Dallas, TX 75390-9063, USA.
⁶ Department of Pediatrics, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229-3026, USA.
⁷ Cincinnati Children's Hospital Medical Center, Cancer and Blood Disease Institute, 3333 Burnet Avenue, Cincinnati, OH 45229-3026, USA.
⁸ Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E Chicago Ave, Chicago, IL 60611, USA.
⁹ Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, 2450 Riverside Ave S AO-102, Minneapolis, MN 55454, USA.
¹⁰ Department of Pediatric Hematology Oncology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.
¹¹ Dana Farber/Boston Children's Hospital, 450 Brookline Avenue Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA.
¹² University of Colorado, Anschutz Medical Campus, Colorado Children's Hospital, 13123 East 16th Avenue, Aurora, CO 80045, USA.
¹³ Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108, USA.
¹⁴ Department of Pediatrics, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010, USA.
¹⁵ Department of Oncology, Sidney Kimmel Cancer Center at John Hopkins School of Medicine, Baltimore, MD, USA.
¹⁶ Emory University and Children's Healthcare of Atlanta, 2015 Uppergate Drive, Atlanta, GA 30322, USA.
¹⁷ University of California San Francisco Benioff Children's Hospital, 1975 4th St., San Francisco, CA 94158, USA.
¹⁸ Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA.
¹⁹ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA.
²⁰ Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford Cancer Institute, 265 Campus Drive, Stanford, CA 94305, USA.
²¹ Division of Blood and Bone Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Room H0101, Stanford, CA 94305-5623, USA.

PMID: 37954907
PMCID: PMC10632672
DOI: 10.1016/j.eclinm.2023.102268

Tisagenlecleucel utilisation and outcomes across refractory, first relapse and multiply relapsed B-cell acute lymphoblastic leukemia: a retrospective analysis of real-world patterns

Valentin Barsan et al. EClinicalMedicine. 2023.

. 2023 Oct 26:65:102268.

doi: 10.1016/j.eclinm.2023.102268. eCollection 2023 Nov.

Authors

Affiliations

¹ Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, 1000 Welch Road, Suite 300, Palo Alto, CA 94304, USA.
² Department of Pediatrics, Children's Hospital of Philadelphia/University of Pennsylvania, 3401 Civic Center Blvd., Philadelphia, PA 19104, USA.
³ Children's Hospital of Philadelphia, 3401 Civic Center Blvd., Philadelphia, PA 19104, USA.
⁴ Cook Children's Hospital, 1500 Cooper St 5th Floor, Fort Worth, TX 76104, USA.
⁵ Department of Pediatrics, The University of Texas Southwestern Medical Center/Children's Health, 5323 Harry Hines Blvd., Dallas, TX 75390-9063, USA.
⁶ Department of Pediatrics, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229-3026, USA.
⁷ Cincinnati Children's Hospital Medical Center, Cancer and Blood Disease Institute, 3333 Burnet Avenue, Cincinnati, OH 45229-3026, USA.
⁸ Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E Chicago Ave, Chicago, IL 60611, USA.
⁹ Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, 2450 Riverside Ave S AO-102, Minneapolis, MN 55454, USA.
¹⁰ Department of Pediatric Hematology Oncology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.
¹¹ Dana Farber/Boston Children's Hospital, 450 Brookline Avenue Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA.
¹² University of Colorado, Anschutz Medical Campus, Colorado Children's Hospital, 13123 East 16th Avenue, Aurora, CO 80045, USA.
¹³ Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108, USA.
¹⁴ Department of Pediatrics, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010, USA.
¹⁵ Department of Oncology, Sidney Kimmel Cancer Center at John Hopkins School of Medicine, Baltimore, MD, USA.
¹⁶ Emory University and Children's Healthcare of Atlanta, 2015 Uppergate Drive, Atlanta, GA 30322, USA.
¹⁷ University of California San Francisco Benioff Children's Hospital, 1975 4th St., San Francisco, CA 94158, USA.
¹⁸ Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA.
¹⁹ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA.
²⁰ Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford Cancer Institute, 265 Campus Drive, Stanford, CA 94305, USA.
²¹ Division of Blood and Bone Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Room H0101, Stanford, CA 94305-5623, USA.

PMID: 37954907
PMCID: PMC10632672
DOI: 10.1016/j.eclinm.2023.102268

Abstract

Background: Tisagenlecleucel was approved by the Food and Drug Administration (FDA) in 2017 for refractory B-cell acute lymphoblastic leukemia (B-ALL) and B-ALL in ≥2nd relapse. Outcomes of patients receiving commercial tisagenlecleucel upon 1st relapse have yet to be established. We aimed to report real-world tisagenlecleucel utilisation patterns and outcomes across indications, specifically including patients treated in 1st relapse, an indication omitted from formal FDA approval.

Methods: We conducted a retrospective analysis of real-world tisagenlecleucel utilisation patterns across 185 children and young adults treated between August 30, 2017 and March 6, 2020 from centres participating in the Pediatric Real-World CAR Consortium (PRWCC), within the United States. We described definitions of refractory B-ALL used in the real-world setting and categorised patients by reported Chimeric Antigen Receptor (CAR) T-cell indication, including refractory, 1st relapse and ≥2nd relapse B-ALL. We analysed baseline patient characteristics and post-tisagenlecleucel outcomes across defined cohorts.

Findings: Thirty-six percent (n = 67) of our cohort received tisagenlecleucel following 1st relapse. Of 66 evaluable patients, 56 (85%, 95% CI 74-92%) achieved morphologic complete response. Overall-survival (OS) and event-free survival (EFS) at 1-year were 69%, (95% CI 58-82%) and 49%, (95% CI 37-64%), respectively, with survival outcomes statistically comparable to remaining patients (OS; p = 0.14, EFS; p = 0.39). Notably, toxicity was increased in this cohort, warranting further study. Interestingly, of 30 patients treated for upfront refractory disease, 23 (77%, 95% CI 58-90%) had flow cytometry and/or next-generation sequencing (NGS) minimum residual disease (MRD)-only disease at the end of induction, not meeting the historic morphologic definition of refractory.

Interpretation: Our findings suggested that tisagenlecleucel response and survival rates overlap across patients treated with upfront refractory B-ALL, B-ALL ≥2nd relapse and B-ALL in 1st relapse. We additionally highlighted that definitions of refractory B-ALL are evolving beyond morphologic measures of residual disease.

Funding: St. Baldrick's/Stand Up 2 Cancer, Parker Institute for Cancer Immunotherapy, Virginia and D.K. Ludwig Fund for Cancer Research.

Keywords: CAR T cells; CD19 CAR T cells; Commercial CAR; First relapse; Immunotherapy; Pediatric oncology; Real-world analysis; Tisagenlecleucel.

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Conflict of interest statement

V.B. serves on the boards of ArsenalBio and Umoja Biopharma and consults or holds stock in Zafrens and Treeline Biosciences which are developing therapies for cancer treatment and Illumina, Invitae, Pacific Biosciences, and Guardant who are developing oncology NGS tests. C.L.M. is an inventor on several patents related to CAR T-cell therapies. C.L.M. is a cofounder of Lyell Immunopharma, CARGO Therapeutics and Link Cell Therapies, which are developing CAR-based therapies, and consults for Lyell, CARGO, Link, Ensoma, Mammoth, Immatics, Apricity, Glaxo Smith Klein, Nektar, Legend and Bristol Myers Squibb. C.L.M receives royalties for CD-22 CAR licensing from NIH, has had grant/contract funding from St. Baldrick’s Foundation, NIH, CIRM, Parker, Tune therapeutics, Lyell Immunopharma, Ludwig Institute, Emerson Collective, Department of Defense and Goldhirsh-Yellin Foundation. She is a member of the Board of Directors of CARGO Therapeutics and Link Cell Therapies and owns stocks in Lyell Immunopharma, CARGO Therapeutics, Link Cell Therapies, Ensoma, Mammoth and Apricity. T.W.L. served on advisory boards or consults for Novartis, Bayer, Aptitude Health, Jumo Health, Massive Bio, Medscape, AI Therapeutics, Jazz Pharmaceuticals, GentiBio, Menarini, Pyramid Biosciences, Targeted Oncology, Treeline Biosciences. He owns stocks/other ownership interest in advanced microbubbles. T.W.L. received research funding from Lily, Roche/Genentech, Taiho Oncology, Advanced Accelerator Applications/Novartis, Bristol-Myers Squibb, BioAtla, Pfizer, Bayer and Turning Point Therapeutics. G.D.M. received funding for medical writing from Novartis. C.L.P. served on an advisory board for Novartis. L.S. served on an advisory board for Novartis. H.S. served on an advisory board for Novartis. M.H. served on editorial advisory board for Novartis and Sobi Pharmaceuticals and is the Vice Chair for COG NHL committee and COG NHL Biology Committee. V.F. consulted for Adaptimmune. S.P. is supported by the UCSF-Stanford CERSI grant UOI FD005978 from the FDA. P.S. served on advisory board for Sobi Pharmaceuticals. A.K. received COG support for meeting attendance. K.J.C. received grant support for an investigator-initiated trial and sat on advisory boards for Novartis and Atara Biotherapeutics. M.R.V. consults for Novartis, Sanofi, Qihan, Forge, Takada and Equillium. M.R.V. has a provisional patent describing methods of producing and using immunotherapy for cancer. M.R.V.participates on the safety monitoring/advisory board for FBX-101 and owns stocks/options for Fate therapeutics.

Figures

**Fig. 1**
Clinical indications and real-world utilisation of Tisagenlecleucel.

**Fig. 2**
**(A)** Response to induction chemotherapy across infused patients. **(B)** Overall-survival (OS), Event-free survival (EFS) and Duration of remission (DOR) across patients with upfront refractory disease who were treated in the upfront refractory setting vs. patients with upfront refractory disease, who only received CAR T-cells upon subsequent relapse(s), using KM curves and log-rank tests. **(C)** Duration of B cell aplasia (DBA) across described cohorts, treating relapse, HSCT and MDS as competing risks, using cumulative incidence curves and Gray’s test. Shaded areas represent the 95% confidence intervals.

**Fig. 3**
**(A)** Overall-Survival (OS), Event-free Survival (EFS) and Duration of Remission (DOR) across patients infused with refractory disease, 1 prior relapse or ≥2 relapses, using KM curves and log-rank tests. **(B)** Duration of B cell Aplasia (DBA) across described cohorts, treating relapse, HSCT and MDS as competing risks and using cumulative incidence curves and Gray’s test. Shaded areas represent the 95% confidence intervals.

See this image and copyright information in PMC

References

1. Parker C., Krishnan S., Hamadeh L., et al. Outcomes of patients with childhood B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses: long-term follow-up of the ALLR3 open-label randomised trial. Lancet Haematol. 2019;6:e204–e216. - PMC - PubMed
1. Bhojwani D., Pui C.H. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 2013;14:e205–e217. - PubMed
1. Lew G., Chen Y., Lu X., et al. Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433. Haematologica. 2021;106:46–55. - PMC - PubMed
1. Hunger S.P., Raetz E.A. How I treat relapsed acute lymphoblastic leukemia in the pediatric population. Blood. 2020;136:1803–1812. - PubMed
1. Oskarsson T., Söderhäll S., Arvidson J., et al. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome. Haematologica. 2016;101:68–76. - PMC - PubMed

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Tisagenlecleucel utilisation and outcomes across refractory, first relapse and multiply relapsed B-cell acute lymphoblastic leukemia: a retrospective analysis of real-world patterns

Affiliations

Tisagenlecleucel utilisation and outcomes across refractory, first relapse and multiply relapsed B-cell acute lymphoblastic leukemia: a retrospective analysis of real-world patterns

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources