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Phase 2 study of combination chemotherapy with bortezomib in children with relapsed and refractory acute lymphoblastic leukemia

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Abstract

Treatment outcomes for children with relapsed and refractory acute lymphoblastic leukemia (R/R-ALL) remain poor, and the optimal induction therapy has not been determined. Bortezomib is a proteasome inhibitor that acts synergistically and additively with standard chemotherapy for ALL. We evaluated the efficacy and safety of combination chemotherapy with bortezomib in children with R/R-ALL. This single-arm, multicenter, phase 2 study was conducted in Japan between 2016 and 2020. Eligible patients were divided into two cohorts: a high-risk first-relapse cohort of untreated patients with high-risk first-relapsed ALL and an expansion cohort of patients with refractory ALL, including multiple relapses, relapse after allogeneic hematopoietic cell transplantation, and induction failure. All patients received a single course of chemotherapy as induction therapy. Sixteen patients (10 in the high-risk first-relapse cohort, six in the expansion cohort) were evaluable. The overall remission rate after induction therapy was 60% in the high-risk first-relapse cohort and 16.7% in the expansion cohort. All patients had minimal residual disease. Adverse events were acceptable except for interstitial lung disease and hypoxia in a patient in the expansion cohort, but addition of bortezomib to conventional chemotherapy did not produce obvious improvement in children with R/R-ALL.

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Data availability

The data generated and analyzed in this study are available from the corresponding author on reasonable request.

References

  1. Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children. N Engl J Med. 2015;373:1541–52.

    Article  CAS  PubMed  Google Scholar 

  2. Teachey DT, Pui C-H. Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia. Lancet Oncol. 2019;20:e142–54.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tallen G, Ratei R, Mann G, Kaspers G, Niggli F, Karachunsky A, et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. 2010;28:2339–47.

    Article  CAS  PubMed  Google Scholar 

  4. Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group study. Leukemia. 2008;22:2142–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Eckert C, Henze G, Seeger K, Hagedorn N, Mann G, Panzer-Grumayer 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  PubMed  Google Scholar 

  6. Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. The Lancet. 2010;376:2009–17.

    Article  CAS  Google Scholar 

  7. Hunger SP, Raetz EA. How I treat relapsed acute lymphoblastic leukemia in the pediatric population. Blood. 2020;136:1803–12.

    Article  CAS  PubMed  Google Scholar 

  8. Roy A, Cargill A, Love S, Moorman AV, Stoneham S, Lim A, et al. Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial. Br J Haematol. 2005;130:67–75.

    Article  PubMed  Google Scholar 

  9. Borgmann A, von Stackelberg A, Hartmann R, Ebell W, Klingebiel T, Peters C, et al. Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis. Blood. 2003;101:3835–9.

    Article  CAS  PubMed  Google Scholar 

  10. Bader P, Kreyenberg H, Henze GH, Eckert C, Reising M, Willasch A, et al. Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group. J Clin Oncol. 2009;27:377–84.

    Article  PubMed  Google Scholar 

  11. Eckert C, Hagedorn N, Sramkova L, Mann G, Panzer-Grumayer R, Peters C, et al. Monitoring minimal residual disease in children with high-risk relapses of acute lymphoblastic leukemia: prognostic relevance of early and late assessment. Leukemia. 2015;29:1648–55.

    Article  CAS  PubMed  Google Scholar 

  12. Ko RH, Ji L, Barnette P, Bostrom B, Hutchinson R, Raetz E, et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. J Clin Oncol. 2010;28:648–54.

    Article  PubMed  Google Scholar 

  13. Sun W, Malvar J, Sposto R, Verma A, Wilkes JJ, Dennis R, et al. Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study. Leukemia. 2018;32:2316–25.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Thibaudeau TA, Smith DM. A Practical Review of Proteasome Pharmacology. Pharmacol Rev. 2019;71:170–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vink J, Cloos J, Kaspers GJ. Proteasome inhibition as novel treatment strategy in leukaemia. Br J Haematol. 2006;134:253–62.

    Article  CAS  PubMed  Google Scholar 

  16. Horton TM, Gannavarapu A, Blaney SM, D’Argenio DZ, Plon SE, Berg SL. Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother Pharmacol. 2006;58:13–23.

    Article  CAS  PubMed  Google Scholar 

  17. Horton TM, Pati D, Plon SE, Thompson PA, Bomgaars LR, Adamson PC, et al. A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children’s Oncology Group study. Clin Cancer Res. 2007;13:1516–22.

    Article  CAS  PubMed  Google Scholar 

  18. Messinger YH, Bostrom BC. Bortezomib-based four-drug induction does induce a response in advanced relapsed ALL but cure remains elusive. Pediatr Blood Cancer. 2020;67: e28115.

    Article  PubMed  Google Scholar 

  19. Hasegawa D, Yoshimoto Y, Kimura S, Kumamoto T, Maeda N, Hara J, et al. Bortezomib-containing therapy in Japanese children with relapsed acute lymphoblastic leukemia. Int J Hematol. 2019;110:627–34.

    Article  CAS  PubMed  Google Scholar 

  20. Messinger YH, Gaynon PS, Sposto R, van der Giessen J, Eckroth E, Malvar J, et al. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood. 2012;120:285–90.

    Article  CAS  PubMed  Google Scholar 

  21. Bertaina A, Vinti L, Strocchio L, Gaspari S, Caruso R, Algeri M, et al. The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood. Br J Haematol. 2017;176:629–36.

    Article  CAS  PubMed  Google Scholar 

  22. Horton TM, Whitlock JA, Lu X, O’Brien MM, Borowitz MJ, Devidas M, et al. Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children’s Oncology Group. Br J Haematol. 2019;186:274–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Takahashi H, Kajiwara R, Kato M, Hasegawa D, Tomizawa D, Noguchi Y, et al. Treatment outcome of children with acute lymphoblastic leukemia: the Tokyo Children’s Cancer Study Group (TCCSG) Study L04–16. Int J Hematol. 2018;108:98–108.

    Article  PubMed  Google Scholar 

  24. Eckert C, von Stackelberg A, Seeger K, Groeneveld TW, Peters C, Klingebiel T, et al. Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia - long-term results of trial ALL-REZ BFM P95/96. Eur J Cancer. 2013;49:1346–55.

    Article  CAS  PubMed  Google Scholar 

  25. Raetz EA, Borowitz MJ, Devidas M, Linda SB, Hunger SP, Winick NJ, et al. Reinduction platform for children with first marrow relapse of acute lymphoblastic Leukemia: A Children’s Oncology Group Study[corrected]. J Clin Oncol. 2008;26:3971–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. August KJ, Guest EM, Lewing K, Hays JA, Gamis AS. Treatment of children with relapsed and refractory acute lymphoblastic leukemia with mitoxantrone, vincristine, pegaspargase, dexamethasone, and bortezomib. Pediatr Blood Cancer. 2020;67: e28062.

    Article  PubMed  Google Scholar 

  27. Iguchi A, Cho Y, Sugiyama M, Terashita Y, Ariga T, Hosoya Y, et al. Bortezomib combined with standard induction chemotherapy in Japanese children with refractory acute lymphoblastic leukemia. Int J Hematol. 2017;106:291–8.

    Article  CAS  PubMed  Google Scholar 

  28. Niewerth D, Kaspers GJ, Jansen G, van Meerloo J, Zweegman S, Jenkins G, et al. Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy. J Hematol Oncol. 2016;9:82.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chen YL, Tang C, Zhang MY, Huang WL, Xu Y, Sun HY, et al. Blocking ATM-dependent NF-kappaB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia. Leukemia. 2019;33:2365–78.

    Article  CAS  PubMed  Google Scholar 

  30. Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet. 2017;49:1211–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Belver L, Ferrando A. The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer. 2016;16:494–507.

    Article  CAS  PubMed  Google Scholar 

  32. Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F, et al. Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med. 2007;13:70–7.

    Article  CAS  PubMed  Google Scholar 

  33. Koyama D, Kikuchi J, Hiraoka N, Wada T, Kurosawa H, Chiba S, et al. Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia. Leukemia. 2014;28:1216–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank all patients and parents as well as clinical staff involved in this study. This study was an investigator-initiated clinical trial and supported by a research grant from the Japan Agency for Medical Research and Development (AMED) (Grant number: 20ck0106419h0003). Bortezomib was provided as an investigational agent from Janssen Pharmaceutical K.K. (Tokyo, Japan).

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NM performed the research and data collection as a sub-investigator and wrote the manuscript. CO designed the study and obtained a research grant as a primary investigator. HG, AK, YK, MS, HN, and CO worked as investigators and performed the research and collected data. AO, DT, HT, HH, JH, and SM worked as investigators. All investigators helped with the development and conduct of the study. KY helped with statistical analyses. YIY and MS performed gene analyses. HG and CO assisted with writing the manuscript. All authors contributed to the revision and approval of the final manuscript.

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Correspondence to Naoyuki Miyagawa.

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Miyagawa, N., Goto, H., Ogawa, A. et al. Phase 2 study of combination chemotherapy with bortezomib in children with relapsed and refractory acute lymphoblastic leukemia. Int J Hematol 118, 267–276 (2023). https://doi.org/10.1007/s12185-023-03609-8

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  • DOI: https://doi.org/10.1007/s12185-023-03609-8

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