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; Yimei Li; Snehit Prabhu; Christina Baggott; Khanh Nguyen; Holly Pacenta; Christine L Phillips; Jenna Rossoff; Heather Stefanski; Julie-An Talano; Amy Moskop; Susanne Baumeister; Michael R Verneris; Gary Douglas Myers; Nicole A Karras; Stacy Cooper; Muna Qayed; Michelle Hermiston; Prakash Satwani; Christa Krupski; Amy Keating; Vanessa Fabrizio; Vasant Chinnabhandar; Michael Kunicki; Kevin J Curran; Crystal L Mackall; Theodore W Laetsch; Liora M Schultz

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

EClinicalMedicine. 2023 Oct 26:65:102268. doi: 10.1016/j.eclinm.2023.102268. eCollection 2023 Nov.

Authors

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.

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.

Abstract

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