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ACUTE LYMPHOBLASTIC LEUKEMIA

Outcome of chimeric antigen receptor T-cell therapy following treatment with inotuzumab ozogamicin in children with relapsed or refractory acute lymphoblastic leukemia

Leukemia volume 37, pages 53–60 (2023)Cite this article

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Abstract

Chimeric antigen receptor T cells targeting CD19 (CART-19) have shown remarkable efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We investigated whether prior use of inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, may impact CAR T-cell manufacturing or efficacy via pre-CART-19 depletion of the B-cell compartment. In this international, retrospective analysis, 39 children and young adults receiving InO before (n = 12) and/or after (n = 27) T-cell apheresis as bridging therapy to CART-19 treatment were analyzed. Median age at infusion was 13 years (range 1.4–23 years). Thirty-four out of 39 patients (87.2%) obtained complete remission. With a median follow-up of 18.2 months after CART-19 infusion, 12-month event-free survival (EFS) was 53.3% (95% confidence interval (CI): 38.7–73.4) and overall survival (OS) was 77.8% (95% CI: 64.5–93.9). Seventeen patients (44%) relapsed with a median of 159 days (range 28–655) after CART-19 infusion. No difference in day 28 minimal residual disease negative complete response rate, 12-month OS/EFS, or incidence of CD19-positive or -negative relapses was observed among patients receiving InO before or after apheresis. Compared to published data for patients treated with CART-19 therapy without prior InO exposure, response and OS/EFS for patients treated with InO prior to CART-19 are similar.

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Fig. 1: Outcome of the entire cohort.
Fig. 2: Duration of response after CART-19 infusion.
Fig. 3: Outcome according to prior InO exposure.
Fig. 4: Outcome according to prior blinatumomab exposure.

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References

  1. Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020;105:2524–39.

    Article  CAS  Google Scholar 

  2. Eckert C, Henze G, Seeger K, Hagedorn N, Mann G, Panzer-Grümayer R, et al. Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group. J Clin Oncol. 2013;31:2736–42.

    Article  Google Scholar 

  3. Eckert C, Parker C, Moorman AV, Irving JA, Kirschner-Schwabe R, Groeneveld-Krentz S, et al. Risk factors and outcomes in children with high-risk B-cell precursor and T-cell relapsed acute lymphoblastic leukaemia: combined analysis of ALLR3 and ALL-REZ BFM 2002 clinical trials. Eur J Cancer. 2021;151:175–89.

    Article  CAS  Google Scholar 

  4. Asare JM, Rabik CA, Muller B, Brown PA, Cooper S. Investigational treatment options in phase I and phase II trials for relapsed or refractory acute lymphoblastic leukemia in pediatric patients. Expert Opin Investig Drugs. 2021;30:611–20.

    Article  CAS  Google Scholar 

  5. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740–53.

    Article  CAS  Google Scholar 

  6. Brivio E, Locatelli F, Lopez-Yurda M, Malone A, Díaz-de-Heredia C, Bielorai B, et al. A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study). Blood. 2021;137:1582–90.

    Article  CAS  Google Scholar 

  7. Brivio E, Locatelli F, Thano A, Petit A, Vormoor BJ, Rives S. et al. A phase II study of single-agent inotuzumab ozogamicin in pediatric CD22-positive relapsed/refractory acute lymphoblastic leukemia: results of the ITCC-059 study. Blood. 2020;136(Supplement 1):8–9.

    Article  Google Scholar 

  8. O’Brien MM, Ji L, Shah NN, Rheingold SR, Bhojwani D, Yuan CM, et al. Phase II trial of inotuzumab ozogamicin in children and adolescents with relapsed or refractory B-cell acute lymphoblastic leukemia: Children’s Oncology Group Protocol AALL1621. J Clin Oncol. 2022;40:956–67.

    Article  Google Scholar 

  9. Grupp S, Hu Z-H, Zhang Y, Keating A, Pulsipher MA, Philips C. et al. Tisagenlecleucel chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory children and young adults with acute lymphoblastic leukemia (ALL): real world experience from the Center for International Blood and Marrow Transplant Research (CIBMTR) and Cellular Therapy (CT) Registry. Blood. 2019;134(Supplement_1):2619.

    Article  Google Scholar 

  10. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.

    Article  CAS  Google Scholar 

  11. Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129:3322–31.

    Article  CAS  Google Scholar 

  12. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–28.

    Article  CAS  Google Scholar 

  13. Curran KJ, Margossian SP, Kernan NA, Silverman LB, Williams DA, Shukla N. et al. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL. Blood. 2019;134:2361–8. Blood. 2020;136:1374.

    Article  Google Scholar 

  14. Pasquini MC, Hu ZH, Curran K, Laetsch T, Locke F, Rouce R, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4:5414–24.

    Article  CAS  Google Scholar 

  15. Shah NN, Lee DW, Yates B, Yuan CM, Shalabi H, Martin S, et al. Long-term follow-up of CD19-CAR T-cell therapy in children and young adults with B-ALL. J Clin Oncol. 2021;39:1650–9.

    Article  CAS  Google Scholar 

  16. Kadauke S, Myers RM, Li Y, Aplenc R, Baniewicz D, Barrett DM, et al. Risk-adapted preemptive tocilizumab to prevent severe cytokine release syndrome after CTL019 for pediatric B-cell acute lymphoblastic leukemia: a prospective clinical trial. J Clin Oncol. 2021;39:920–30.

    Article  CAS  Google Scholar 

  17. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.

    Article  Google Scholar 

  18. Rives S, Maude SL, Hiramatsu H, Baruchel A, Bader P, Bittencourt H, et al. Tisagenlecleucel in pediatric and young adult patients (PTS) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL): final analyses from the Eliana Study. EHA Library 2022;S112:356977.

  19. Dourthe ME, Rabian F, Yakouben K, Chevillon F, Cabannes-Hamy A, Mechinaud F, et al. Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia. 2021;35:3383–93.

  20. Barz Leahy A, Devine KJ, Li Y, Liu H, Myers RM, DiNofia A, et al. Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T cell therapy. Blood. 2022;139:2173–85.

  21. Pillai V, Muralidharan K, Meng W, Bagashev A, Oldridge DA, Rosenthal J, et al. CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy. Blood Adv. 2019;3:3539–49.

    Article  Google Scholar 

  22. Myers RM, Taraseviciute A, Steinberg SM, Lamble AJ, Sheppard J, Yates B, et al. Blinatumomab nonresponse and high-disease burden are associated with inferior outcomes after CD19-CAR for B-ALL. J Clin Oncol. 2022;40:932–44.

  23. von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, et al. Phase I/Phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. 2016;34:4381–9.

    Article  Google Scholar 

  24. Bhojwani D, Sposto R, Shah NN, Rodriguez V, Yuan C, Stetler-Stevenson M, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2019;33:884–92.

    Article  CAS  Google Scholar 

  25. O’Brien MM, Ji L, Shah NN, Rheingold SR, Bhojwani D, Yi JS. et al. A Phase 2 trial of inotuzumab ozogamicin (InO) in children and young adults with relapsed or refractory (R/R) CD22+ B-acute lymphoblastic leukemia (B-ALL): results from Children’s Oncology Group Protocol AALL1621. Blood. 2019;134(Supplement_1):741.

    Article  Google Scholar 

  26. Krueger J, Bittencourt HNS, Rives S, Baruchel A, Moerloose BD, Peters C. et al. Tisagenlecleucel (Tisa) for relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL): B2001X study focusing on prior exposure to blinatumomab (BLINA) and inotuzumab (INO). J Clin Oncol. 2020;38(suppl):10518.

    Article  Google Scholar 

  27. Mullanfiroze K, Ottaviano G, Mishra AK, Gabelli M, Lazareva A, Burridge S. et al. Outcomes of children and young adults with acute lymphoblastic leukaemia administered inotuzumab pre CAR-T therapy. Blood. 2021;138(Supplement 1):1743.

    Article  Google Scholar 

  28. Garrett M, Ruiz-Garcia A, Parivar K, Hee B, Boni J. Population pharmacokinetics of inotuzumab ozogamicin in relapsed/refractory acute lymphoblastic leukemia and non-Hodgkin lymphoma. J Pharmacokinet Pharmacodyn. 2019;46:211–22.

    Article  CAS  Google Scholar 

  29. Schultz LM, Baggott C, Prabhu S, Pacenta H, Phillips CL, Rossoff J. et al. Disease burden impacts outcomes in pediatric and young adult B-cell acute lymphoblastic leukemia after commercial tisagenlecleucel: results from the Pediatric Real World CAR Consortium (PRWCC). Blood. 2020;136(Supplement 1):14–5.

    Article  Google Scholar 

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Acknowledgements

All the parents and patients, because with their data, they made this research possible.

Author information

Author notes

  1. These authors contributed equally: Valeria Ceolin, Erica Brivio.

  2. These authors jointly supervised this work: Friso G. Calkoen, Christian Michel Zwaan.

Authors and Affiliations

  1. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Valeria Ceolin, Erica Brivio, Harm van Tinteren, Britta Vormoor, Bianca F. Goemans, Peter Hoogerbrugge, Friso G. Calkoen & Christian Michel Zwaan

  2. Department of Pediatric Oncology/Hematology, Regina Margherita Children’s Hospital, University of Turin, Turin, Italy

    Valeria Ceolin

  3. Department of Pediatric Oncology/Hematology, Erasmus University MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    Valeria Ceolin, Erica Brivio & Christian Michel Zwaan

  4. Division of Pediatric Oncology, Children’s Hospital of Philadelphia, Perelman School of Medicine, Philadelphia, PA, USA

    Susan R. Rheingold & Allison Leahy

  5. Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Maureen M. O’Brien & Jeremy D. Rubinstein

  6. Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland

    Krzysztof Kalwak

  7. Department of Pediatric Oncology/Hematology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

    Barbara De Moerloose

  8. Division of Pediatric Hematology, Oncology and BMT, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Elad Jacoby

  9. Department of Pediatric Oncology/Hematology, Clinic for Children and Youth Medicine, University Hospital Frankfurt, Goethe University, Frankfurt, Germany

    Peter Bader

  10. Pediatric Hematology Unit, Hematology Department, Hospital de Valdecilla, Santander, Spain

    Mónica López-Duarte

  11. Department of Hematology/Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Catholic University of the Sacred Heart, Rome, Italy

    Franco Locatelli

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  1. Valeria Ceolin
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Contributions

Study conception and design: CMZ, EB, PH, FC. Data collection and patient management: SRR, AL, BV, MMO, JDR, KK, BDM, EJ, PB, JLF, BFG, FL, PH, VC, EB, FGC. Data analysis and interpretation: VC, HvT, EB, FGC, CMZ. Manuscript writing: all authors provided substantial contributions in writing the paper, or revising it critically for important intellectual content, and approved the version to be published as well as agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of this work were appropriately investigated and resolved.

Corresponding author

Correspondence to Christian Michel Zwaan.

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Competing interests

SRR: honoraria and research funding Pfizer and Jazz. MMO: honoraria and research funding Pfizer and Jazz. BDM: advisory board Novartis, travel funding Jazz. EJ: honoraria and membership on an entity’s Board of Directors or advisory committees Novartis. FL: honoraria for speakers’ bureau or participation in advisory boards from Amgen, Bellicum Pharmaceutical, Celgene, Jazz Pharmaceutical, Miltenyi, Sanofi and Novartis. PH: honoraria for lectures, consultancy and/or scientific advisory boards from Novartis and BMS. CMZ: consultancy Sanofi, Novartis, Roche, Incyte, travel funding and research funding Jazz, research funding BMS, AbbVie, Kura oncology, Takeda, Pfizer. Other authors have no COI to declare.

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Ceolin, V., Brivio, E., van Tinteren, H. et al. Outcome of chimeric antigen receptor T-cell therapy following treatment with inotuzumab ozogamicin in children with relapsed or refractory acute lymphoblastic leukemia. Leukemia 37, 53–60 (2023). https://doi.org/10.1038/s41375-022-01740-9

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