Skip to main content

Advertisement

SpringerLink
Log in

Combination of clofarabine, etoposide, and cyclophosphamide in adult relapsed/refractory acute lymphoblastic leukemia: a phase 1/2 dose-escalation study by the Japan Adult Leukemia Study Group

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

This phase 1/2 study aimed to identify the maximum tolerated dose, the recommended phase 2 dose (RP2D), and efficacy of the clofarabine, etoposide, and cyclophosphamide combination regimen in adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients aged ≥ 15 years with relapsed/refractory ALL were enrolled. Escalating doses of clofarabine (20–30 mg/m2/day × 5 days), etoposide (50–100 mg/m2/day × 5 days), and cyclophosphamide (200–440 mg/m2/day × 5 days) were administered. Dose-limiting toxicity was defined as Grade 3 or more non-hematological toxicities and others. A total of 18 patients (B-ALL; n = 13, T-ALL; n = 5) were recruited in phase 1; however, the protocol was amended to close study without proceeding to phase 2. Three patients were enrolled in cohort 1, three in cohort 2, six in cohort 3, and six in cohort 4. The RP2D of clofarabine, etoposide, and cyclophosphamide was 30, 100, and 440 mg/m2 daily, respectively. Complete remission (CR) was achieved in four patients (22%) and CR without platelet recovery in four patients (22%), with an overall response rate of 44%. The RP2D of the combination therapy was successfully determined in this study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dianne P, Adam G, Hermann B. Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century. Blood. 2009;113:1408–11.

    Article  Google Scholar 

  2. Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009;27:911–8.

    Article  CAS  Google Scholar 

  3. Sakura T, Hayakawa F, Sugiura I, Murayama T, Imai K, Usui N, et al. High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. Leukemia. 2018;32:626–32.

    Article  CAS  Google Scholar 

  4. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Medical Research Council of the United Kingdom Adult ALL Working Party; Eastern Cooperative Oncology Group. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944–50.

    Article  CAS  Google Scholar 

  5. Gökbuget N, Dombret H, Ribera JM, Fielding AK, Advani A, Bassan R, et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016;101:1524–33.

    Article  Google Scholar 

  6. Kako S, Kanamori H, Kobayashi N, Shigematsu A, Nannya Y, Nakamae M, et al. Outcome after first relapse in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia. Br J Haematol. 2013;161:95–103.

    Article  Google Scholar 

  7. Frey NV, Luger SM. How I treat adults with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood. 2015;126:589–96.

    Article  CAS  Google Scholar 

  8. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836–47.

    Article  CAS  Google Scholar 

  9. DeAngelo DJ, Stock W, Stein AS, Shustov A, Liedtke M, Schiffer CA, et al. Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. Blood Adv. 2017;15:1167–80.

    Article  Google Scholar 

  10. 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 

  11. Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004;103:784–9.

    Article  CAS  Google Scholar 

  12. Koh K, Ogawa C, Okamoto Y, Kudo K, Inagaki J, Morimoto T, et al. Phase 1 study of clofarabine in pediatric patients with relapsed/refractory acute lymphoblastic leukemia in Japan. Int J Hematol. 2016;104:245–55.

    Article  CAS  Google Scholar 

  13. Hijiya N, Gaynon P, Barry E, Silverman L, Thomson B, Chu R, et al. A multi-center phase I study of clofarabine, etoposide and cyclophosphamide in combination in pediatric patients with refractory or relapsed acute leukemia. Leukemia. 2009;23:2259–64.

    Article  CAS  Google Scholar 

  14. Kantarjian HM, Gandhi V, Kozuch P, Faderl S, Giles F, Cortes J, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol. 2003;21:1167–73.

    Article  CAS  Google Scholar 

  15. Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003;102:2379–86.

    Article  CAS  Google Scholar 

  16. Hijiya N, Thomson B, Isakoff MS, Silverman LB, Steinherz PG, Borowitz MJ, et al. Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. Blood. 2011;118:6043–9.

    Article  CAS  Google Scholar 

  17. Storer BE. Design and analysis of phase I clinical trials. Biometrics. 1989;45:925–37.

    Article  CAS  Google Scholar 

  18. Rijneveld AW, Holt B, Weerdt O, Biemond BJ, Loosdrecht A, Petersen E, et al. Clofarabine added to standard treatment in adult patients with newly diagnosed ALL: first results of the randomized phase III HOVON-100 Study. Blood. 2017;130(Supplement 1):2606.

    Google Scholar 

  19. Koller CA, Kantarjian HM, Thomas D, O’Brien S, Rios MB, Kornblau S, et al. The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia. Leukemia. 1997;11:2039–44.

    Article  CAS  Google Scholar 

  20. Camera A, Annino L, Chiurazzi F, Fazi P, Cascavilla N, Fabbiano F, et al. GIMEMA ALL—rescue 97: a salvage strategy for primary refractory or relapsed adult acute lymphoblastic leukemia. Haematologica. 2004;89:145–53.

    CAS  PubMed  Google Scholar 

  21. Specchia G, Pastore D, Carluccio P, Liso A, Mestice A, Rizzi R, et al. FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia. Ann Hematol. 2005;84:792–5.

    Article  CAS  Google Scholar 

  22. Möttönen M, Uhari M, Lanning M, Tuokko H. Prospective controlled survey of viral infections in children with acute lymphoblastic leukemia during chemotherapy. Cancer. 1995;75:1712–7.

    Article  Google Scholar 

  23. Jabbour E, Ravandi F, Kebriaei P, Huang X, Short NJ, Thomas D, et al. Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: a phase 2 clinical trial. JAMA Oncol. 2018;4:230–4.

    Article  Google Scholar 

  24. Gossai N, Verneris MR, Karras NA, Gorman MF, Patel NJ, Burke MJ. A clofarabine-based bridging regimen in patients with relapsed ALL and persistent minimal residual disease (MRD). Bone Marrow Transplant. 2014;49:440–2.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank all investigators and members of participating hospitals in ALL studies conducted by the JALSG.

Funding

This work was supported in part by a grant for Practical Research for Innovative Cancer Control Grant No. JP19ck0106331 from the Japan Agency for Medical Research and Development (AMED).

Author information

Authors and Affiliations

  1. Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan

    Takeshi Saito & Yuichi Yahagi

  2. Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan

    Yoshihiro Hatta

  3. Division of Cellular and Genetic Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Fumihiko Hayakawa

  4. Department of Oncology/Hematology, Shimane University Hospital, Izumo, Japan

    Tsutomu Takahashi

  5. Department of Hematology and Clinical Immunology, Yokohama City University School of Medicine, Yokohama, Japan

    Maki Hagihara

  6. National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Hiroatsu Iida

  7. Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan

    Koichiro Minauchi

  8. Clinical Laboratory Department, Yokohama City University Hospital, Yokohama, Japan

    Etsuko Yamazaki

  9. Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan

    Isamu Sugiura

  10. Department of Hematology, Hyogo Cancer Center, Akashi, Japan

    Tohru Murayama

  11. Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan

    Toru Sakura

  12. Department of Hematology, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan

    Naoki Mori

  13. Department of Hematology, Otaru General Hospital, Otaru, Japan

    Kiyotoshi Imai

  14. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Yoshiko Atsuta

  15. Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Akiko Moriya Saito

  16. Division of Biostatics and Data Science, Clinical Research Center, Tokyo Medical and Dental University, Tokyo, Japan

    Akihiro Hirakawa

  17. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Hitoshi Kiyoi

  18. Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osaka, Japan

    Itaru Matsumura

  19. Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan

    Yasushi Miyazaki

Authors
  1. Takeshi Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshihiro Hatta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fumihiko Hayakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tsutomu Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maki Hagihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroatsu Iida
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Koichiro Minauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Etsuko Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Isamu Sugiura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tohru Murayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Toru Sakura
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Naoki Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kiyotoshi Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yuichi Yahagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yoshiko Atsuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Akiko Moriya Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Akihiro Hirakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Hitoshi Kiyoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Itaru Matsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Yasushi Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Japan Adult Leukemia Study Group

Contributions

Administrative support: all authors. Conception and design: all authors. Provision of study materials or patients: all authors. Collection and assembly of data: AMS. Data analysis and interpretation: AH. Manuscript writing: all authors. Final approval of manuscript: all authors.

Corresponding author

Correspondence to Takeshi Saito.

Ethics declarations

Conflict of interest

Hitoshi Kiyoi reports research funding from Chugai Pharmaceutical, Kyowa Kirin, Zenyaku Kogyo, FUJIFILM, Daiichi Sankyo, Astellas Pharma, Otsuka Pharmaceutical, Nippon Shinyaku, Eisai, Pfizer Japan, Takeda Pharmaceutical, Novartis Pharma, Sumitomo Dainippon Pharma, Sanofi, Perseus Proteomics and Celgene, and consulting fees from Astellas Pharma, Amgen Astellas BioPharma, and Daiichi Sankyo, and honoraria from Bristol-Myers Squibb, Astellas Pharma, and Novartis Pharma. Yasushi Miyazaki reports research funding from Sumitomo Dainippon Pharma, Pfizer Japan, Chugai Pharmaceutical, and Takeda Pharmaceutical, and honoraria from Chugai Pharmaceutical, Kyowa Kirin, Astellas Pharma, Otsuka Pharmaceutical, Nippon Shinyaku, Novartis Pharma, Sumitomo Dainippon Pharma, and Celgene. Other authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saito, T., Hatta, Y., Hayakawa, F. et al. Combination of clofarabine, etoposide, and cyclophosphamide in adult relapsed/refractory acute lymphoblastic leukemia: a phase 1/2 dose-escalation study by the Japan Adult Leukemia Study Group. Int J Hematol 113, 395–403 (2021). https://doi.org/10.1007/s12185-020-03032-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-020-03032-3

Keywords

Search

Navigation