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Acute Leukemias

A multi-center phase I study of clofarabine, etoposide and cyclophosphamide in combination in pediatric patients with refractory or relapsed acute leukemia

Leukemia volume 23, pages 2259–2264 (2009)Cite this article

Abstract

This Phase I study of clofarabine with etoposide and cyclophosphamide for children with relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities and the recommended phase 2 doses (RP2Ds). All three drugs were administered for five consecutive days in induction and four consecutive days in consolidation, for a maximum of eight cycles. A total of 25 patients (20 ALL and 5 AML) were enrolled in five cohorts. An MTD was not reached. The RP2Ds of clofarabine, cyclophosphamide and etoposide were 40, 440 and 100 mg/m2/day, respectively. Complete remission (CR) was achieved in 10 patients (ALL: nine; AML: one), and CR without platelet recovery in six patients (ALL: two; AML: four) for an overall response rate of 64% (ALL: 55%; AML: 100%). Of the 16 responders, 9 patients proceeded to hematopoietic stem cell transplantation. In conclusion, the combination of clofarabine, etoposide and cyclophosphamide was well tolerated and effective in pediatric patients with relapsed/refractory leukemia. Of note, the phase II portion of the trial was amended after the occurrence of unexpected hepatotoxicity. The ongoing phase II study will evaluate the efficacy and safety of this regimen in ALL patients.

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References

  1. McNeil DE, Cote TR, Clegg L, Mauer A . SEER update of incidence and trends in pediatric malignancies: acute lymphoblastic leukemia. Med Pediatr Oncol 2002; 39: 554–557.

    Article  Google Scholar 

  2. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71–96.

    Article  Google Scholar 

  3. Gaynon PS . Childhood acute lymphoblastic leukaemia and relapse. Br J Haematol 2005; 131: 579–587.

    Article  Google Scholar 

  4. Montgomery JA, Shortnacy-Fowler AT, Clayton SD, Riordan JM, Secrist III JA . Synthesis and biologic activity of 2′-fluoro-2-halo derivatives of 9-beta-D-arabinofuranosyladenine. J Med Chem 1992; 35: 397–401.

    Article  CAS  Google Scholar 

  5. 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: 784–789.

    Article  CAS  Google Scholar 

  6. Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 2006; 24: 1917–1923.

    Article  CAS  Google Scholar 

  7. Parker WB, Shaddix SC, Chang CH, White EL, Rose LM, Brockman RW et al. Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5′-triphosphate. Cancer Res 1991; 51: 2386–2394.

    CAS  PubMed  Google Scholar 

  8. Parker WB, Shaddix SC, Rose LM, Shewach DS, Hertel LW, Secrist III JA et al. Comparison of the mechanism of cytotoxicity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine, 2-chloro-9-(2-deoxy-2-fluoro- beta-D-ribofuranosyl)adenine, and 2-chloro-9-(2-deoxy-2,2-difluoro- beta-D-ribofuranosyl)adenine in CEM cells. Mol Pharmacol 1999; 55: 515–520.

    CAS  PubMed  Google Scholar 

  9. Xie C, Plunkett W . Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoro-beta-D- arabinofuranosyl)-adenine in human lymphoblastoid cells. Cancer Res 1995; 55: 2847–2852.

    CAS  PubMed  Google Scholar 

  10. Xie KC, Plunkett W . Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine. Cancer Res 1996; 56: 3030–3037.

    CAS  PubMed  Google Scholar 

  11. Mansson E, Flordal E, Liliemark J, Spasokoukotskaja T, Elford H, Lagercrantz S et al. Down-regulation of deoxycytidine kinase in human leukemic cell lines resistant to cladribine and clofarabine and increased ribonucleotide reductase activity contributes to fludarabine resistance. Biochem Pharmacol 2003; 65: 237–247.

    Article  CAS  Google Scholar 

  12. Yamauchi T, Nowak BJ, Keating MJ, Plunkett W . DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4-hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine. Clin Cancer Res 2001; 7: 3580–3589.

    CAS  PubMed  Google Scholar 

  13. Hilden JM, Dinndorf PA, Meerbaum SO, Sather H, Villaluna D, Heerema NA et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 2006; 108: 441–451.

    Article  CAS  Google Scholar 

  14. 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: 3971–3978.

    Article  CAS  Google Scholar 

  15. Hijiya N, Franklin J, Rytting M, Cooper T, Chu R, Barry E et al. A phase I study of clofarabine in combination with cyclophosphamide and etoposide: a new regimen in pediatric patients with refractory or relapsed acute leukemia. ASCO Meet Abstr 2007; 25 (18_suppl): 9529.

    Google Scholar 

  16. Hijiya N, Gaynon PS, Fernandez M, Silverman LB, Thomson B, Chu R et al. Durable remissions observed in a Phase I/II Study of Clofarabine in Combination with Etoposide and Cyclophosphamide in Pediatric Patients with Refractory or Relapsed Acute Leukemia. Blood (ASH Annu Meet Abstr) 2008; 112: 2925.

    Google Scholar 

  17. 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: 1167–1173.

    Article  CAS  Google Scholar 

  18. Kornblau SM, Cortes-Franco J, Estey E . Neurotoxicity associated with fludarabine and cytosine arabinoside chemotherapy for acute leukemia and myelodysplasia. Leukemia 1993; 7: 378–383.

    CAS  PubMed  Google Scholar 

  19. Cheson BD, Vena DA, Foss FM, Sorensen JM . Neurotoxicity of purine analogs: a review. J Clin Oncol 1994; 12: 2216–2228.

    Article  CAS  Google Scholar 

  20. Webb DK, Wheatley K, Harrison G, Stevens RF, Hann IM . Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party. Leukemia 1999; 13: 25–31.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Isabelle Gaston, PhD, Manuel Fernandez and Jo-Anne Paul for assistance in developing this paper. We would also like to thank additional investigators involved in this study: Dr Roger Berkow (University of Alabama, AL, USA); Dr Stanley Chaleff (Children's Memorial Hospital, IL, USA); Dr Gary Dahl (Stanford University, CA, USA); Dr Michael Isakoff (Children's Hospital, CT, USA); Dr Bassem Razzouk (St Vincent Children's Hospital, IN, USA); Dr Gerardo Quezada (Methodist Children's Hospital, TX, USA); Dr Neerav Shulka (Memorial Sloan Kettering Hospital, NY, USA) and Dr Sergey Yurasov (Memorial Sloan Kettering Hospital, NY, USA).

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Authors and Affiliations

  1. Department of Pediatric Hematology Oncology, Children's Memorial Hospital/Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    N Hijiya

  2. Children's Hospital Los Angeles, Los Angeles, CA, USA

    P Gaynon

  3. Genzyme Corporation, Cambridge, MA, USA

    E Barry & R Abichandani

  4. Dana Farber Cancer Institute, Boston, MA, USA

    L Silverman

  5. Seattle Children's Hospital Regional Medical Center, Seattle, WA, USA

    B Thomson

  6. Children's Hospital of Michigan, Detroit, MI, USA

    R Chu

  7. Children's Healthcare of Atlanta, Atlanta, GA, USA

    T Cooper

  8. Rady Children's Hospital, San Diego, CA, USA

    R Kadota

  9. The University of Texas MD Anderson Cancer Center, Pediatrics, Houston, TX, USA

    M Rytting

  10. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    P Steinherz

  11. Children's Hospital of Orange County, Orange, CA, USA

    V Shen

  12. St Jude Children's Research Hospital, Memphis, TN, USA

    S Jeha

  13. NYU Cancer Institute, NY, NY, USA

    W L Carroll

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  1. N Hijiya
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Correspondence to N Hijiya.

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Hijiya, N., Gaynon, P., Barry, E. 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 23, 2259–2264 (2009). https://doi.org/10.1038/leu.2009.185

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