Skip to main content
Top
Published in: International Journal of Hematology 6/2017

01-06-2017 | Original Article

Clofarabine-based chemotherapy as a bridge to transplant in the setting of refractory or relapsed acute myeloid leukemia, after at least one previous unsuccessful salvage treatment containing fludarabine: a single institution experience

Authors: Alfredo Molteni, Marta Riva, Emanuele Ravano, Laura Marbello, Valentina Mancini, Giovanni Grillo, Elisa Zucchetti, Rosa Greco, Roberto Cairoli

Published in: International Journal of Hematology | Issue 6/2017

Login to get access

Abstract

For refractory or relapsed acute myeloid leukemia patients, allogeneic hematopoietic stem cell transplantation is the only curative treatment option, but the disease must be in remission before this can be attempted. “Salvage” therapy regimens containing high-dose cytarabine plus fludarabine or cladribine with or without anthracyclines or plus mitoxantrone and etoposide fail in 30–50% of cases. We report the outcome of 14 patients treated with a clofarabine-based treatment administered after at least one failed fludarabine-based “salvage” attempt in a “real life” (outside a clinical trial) context. No death related to the clofarabine-based treatment was observed. Four of the 14 patients (29%) reached complete remission and one (7%) achieved a reduction of marrow blasts to fewer than 10%. Three of these five patients were successfully transplanted and have shown a long-term survival. The small number of this group of patients does not permit the identification of clinical features clearly related to a favorable outcome, but we note that all the three long-term survivals were FLT3 wild type. Clofarabine-based “salvage therapy” in patients with very poor expectancy is feasible even after a fludarabine-based salvage attempt, albeit with success only in a small percentage of cases (3/14 = 21%).
Literature
1.
go back to reference Schiffer CA. Acute myeloid leukemia in adults: where do we go from here? Cancer Chemother Pharmacol. 2001;48(suppl):S45–52.CrossRefPubMed Schiffer CA. Acute myeloid leukemia in adults: where do we go from here? Cancer Chemother Pharmacol. 2001;48(suppl):S45–52.CrossRefPubMed
2.
go back to reference Mandelli F, Vignetti M, Suciu S, Stasi R, Petti MC, Meloni G, et al. Daunorubicin versus mitoxantrone versus idarubicin as induction an consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol. 2009;27:5397–403.CrossRefPubMedPubMedCentral Mandelli F, Vignetti M, Suciu S, Stasi R, Petti MC, Meloni G, et al. Daunorubicin versus mitoxantrone versus idarubicin as induction an consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol. 2009;27:5397–403.CrossRefPubMedPubMedCentral
3.
go back to reference Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, et al. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMAAML-12 Trial. J Clin Oncol. 2014;32(3):219–28.CrossRefPubMed Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, et al. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMAAML-12 Trial. J Clin Oncol. 2014;32(3):219–28.CrossRefPubMed
4.
go back to reference Löwenberg B, Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C, et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011;364(11):1027–36.CrossRefPubMed Löwenberg B, Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C, et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011;364(11):1027–36.CrossRefPubMed
5.
go back to reference Gardin C, Turlure P, Fagot X, Thomas X, Terre C, Contentin T, et al. Postremission treatment of elderly patients with AML in first CR after IC: results of the multicenter randomized ALFA 9803 trial. Blood. 2007;109:5129–35.CrossRefPubMed Gardin C, Turlure P, Fagot X, Thomas X, Terre C, Contentin T, et al. Postremission treatment of elderly patients with AML in first CR after IC: results of the multicenter randomized ALFA 9803 trial. Blood. 2007;109:5129–35.CrossRefPubMed
6.
go back to reference Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Hołowiecki J, et al. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008;80:115–26.CrossRefPubMed Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Hołowiecki J, et al. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008;80:115–26.CrossRefPubMed
7.
go back to reference Montillo M, Mirto S, Petti MC, Latagliata R, Magrin S, Pinto A, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol. 1998;58:105–9.CrossRefPubMed Montillo M, Mirto S, Petti MC, Latagliata R, Magrin S, Pinto A, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol. 1998;58:105–9.CrossRefPubMed
8.
go back to reference Parker JE, Pagliuca A, Mijovic A, Cullis JO, Czepulkowski B, Rassam SM, et al. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol. 1997;99:939–44.CrossRefPubMed Parker JE, Pagliuca A, Mijovic A, Cullis JO, Czepulkowski B, Rassam SM, et al. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol. 1997;99:939–44.CrossRefPubMed
9.
go back to reference Amadori S, Arcese W, Isacchi G, Meloni G, Petti MC, Monarca B, et al. Mitoxantrone, etoposide, and intermediate dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991;9:1210–4.CrossRefPubMed Amadori S, Arcese W, Isacchi G, Meloni G, Petti MC, Monarca B, et al. Mitoxantrone, etoposide, and intermediate dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991;9:1210–4.CrossRefPubMed
10.
go back to reference Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, et al. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high risk myelo high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol. 2004;22(6):1078–86.CrossRefPubMed Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, et al. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high risk myelo high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol. 2004;22(6):1078–86.CrossRefPubMed
11.
go back to reference Pastore D, Specchia G, Carluccio P, Liso A, Mestice A, Rizzi R, et al. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol. 2003;82(4):231.PubMed Pastore D, Specchia G, Carluccio P, Liso A, Mestice A, Rizzi R, et al. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol. 2003;82(4):231.PubMed
12.
go back to reference Price SL, Lancet JE, George TJ, Wetzstein GA, List AF, Ho VQ, et al. Salvage chemotherapy regimens for acute myeloid leukemia: Is one better? Efficacy comparison between CLAG and MEC regimens. Leuk Res. 2011;35:301–4.CrossRefPubMed Price SL, Lancet JE, George TJ, Wetzstein GA, List AF, Ho VQ, et al. Salvage chemotherapy regimens for acute myeloid leukemia: Is one better? Efficacy comparison between CLAG and MEC regimens. Leuk Res. 2011;35:301–4.CrossRefPubMed
13.
go back to reference Montgomery JA, Shortnacy-Fowler AT, Clayton SD, Riordan JM, Secrist JA. Synthesis and biologic activity of 2-fluoro-2-halo derivatives of 9-beta-d-arabinofuranosyladenine. J Med Chem. 1992;35:397–401.CrossRefPubMed Montgomery JA, Shortnacy-Fowler AT, Clayton SD, Riordan JM, Secrist JA. Synthesis and biologic activity of 2-fluoro-2-halo derivatives of 9-beta-d-arabinofuranosyladenine. J Med Chem. 1992;35:397–401.CrossRefPubMed
14.
go back to reference Cooper T, Ayres M, Nowak B, Ganchi V. Biochemical modulation of cytarabine triphosphate by clofarabine. Cancer Chemother Pharmacol. 2005;55:361–8.CrossRefPubMed Cooper T, Ayres M, Nowak B, Ganchi V. Biochemical modulation of cytarabine triphosphate by clofarabine. Cancer Chemother Pharmacol. 2005;55:361–8.CrossRefPubMed
15.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
16.
go back to reference Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, et al. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013;122:1384–94.CrossRefPubMed Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, et al. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013;122:1384–94.CrossRefPubMed
17.
go back to reference Faderl S, Wetzler M, Rizzieri D, Schiller G, Jagasia M, Stuart R, et al. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol. 2012;30:2492–9.CrossRefPubMedPubMedCentral Faderl S, Wetzler M, Rizzieri D, Schiller G, Jagasia M, Stuart R, et al. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol. 2012;30:2492–9.CrossRefPubMedPubMedCentral
18.
go back to reference Scappini B, Gianfaldoni G, Caracciolo F, Mannelli F, Biagiotti C, Romani C, et al. Cytarabine and clofarabine after high-dose cytarabine in relapsed or refractory AML patients. Am J Hematol. 2012;87:1047–51.CrossRefPubMed Scappini B, Gianfaldoni G, Caracciolo F, Mannelli F, Biagiotti C, Romani C, et al. Cytarabine and clofarabine after high-dose cytarabine in relapsed or refractory AML patients. Am J Hematol. 2012;87:1047–51.CrossRefPubMed
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
go back to reference Kantarjian HM, Erba HP, Claxton D, Arellano M, Lyons RM, Kovascovics T, et al. Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol. 2010;28:549–55.CrossRefPubMed Kantarjian HM, Erba HP, Claxton D, Arellano M, Lyons RM, Kovascovics T, et al. Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol. 2010;28:549–55.CrossRefPubMed
21.
go back to reference Faderl S, Gandhi V, O’Brien S, Bonate P, Cortes J, Estey E, et al. Results of a phase 1–2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005;105:940–7.CrossRefPubMed Faderl S, Gandhi V, O’Brien S, Bonate P, Cortes J, Estey E, et al. Results of a phase 1–2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005;105:940–7.CrossRefPubMed
22.
go back to reference Becker PS, Kantarjian HM, Appelbaum FR, Petersdorf SH, Storer B, Pierce S, et al. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol. 2011;155:182–9.CrossRefPubMedPubMedCentral Becker PS, Kantarjian HM, Appelbaum FR, Petersdorf SH, Storer B, Pierce S, et al. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol. 2011;155:182–9.CrossRefPubMedPubMedCentral
23.
go back to reference Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642–9.CrossRefPubMed Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642–9.CrossRefPubMed
24.
go back to reference Roberts DA, Wadleigh M, McDonnell AM, DeAngelo DJ, Stone RM, Steensma DP. Low efficacy and high mortality associated with clofarabine treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes. Leuk Res. 2015;39(2):204–10.CrossRefPubMed Roberts DA, Wadleigh M, McDonnell AM, DeAngelo DJ, Stone RM, Steensma DP. Low efficacy and high mortality associated with clofarabine treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes. Leuk Res. 2015;39(2):204–10.CrossRefPubMed
25.
go back to reference Middeke JM, Herbst R, Parmentier S, Bug G, Hänel M, Stuhler G, et al. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial. Leukemia. 2016;30(2):261–7.CrossRefPubMed Middeke JM, Herbst R, Parmentier S, Bug G, Hänel M, Stuhler G, et al. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial. Leukemia. 2016;30(2):261–7.CrossRefPubMed
26.
go back to reference Schlenk RF, Döhner K, Mack S, Stoppel M, Király F, Götze K, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German–Austrian trial AMLHD98A. J Clin Oncol. 2010;28(30):4642–8.CrossRefPubMed Schlenk RF, Döhner K, Mack S, Stoppel M, Király F, Götze K, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German–Austrian trial AMLHD98A. J Clin Oncol. 2010;28(30):4642–8.CrossRefPubMed
27.
go back to reference Sierra J, Storer B, Hansen JA, Bierke JW, Martin PJ, Petersdorf EW, et al. Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: the effect of leukemic burden, donor HLA- matching, and marrow cell dose. Blood. 1997;89(11):4226–35.PubMed Sierra J, Storer B, Hansen JA, Bierke JW, Martin PJ, Petersdorf EW, et al. Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: the effect of leukemic burden, donor HLA- matching, and marrow cell dose. Blood. 1997;89(11):4226–35.PubMed
28.
go back to reference Hemmati PG, Terwey TH, Na IK, Jehn CF, le Coutre P, Vuong LG, Dörken B, et al. Allogeneic stem cell transplantation for refractory acute myeloid leukemia: a single center analysis of long-term outcome. Eur J Hematol. 2015;95(6):498–506.CrossRef Hemmati PG, Terwey TH, Na IK, Jehn CF, le Coutre P, Vuong LG, Dörken B, et al. Allogeneic stem cell transplantation for refractory acute myeloid leukemia: a single center analysis of long-term outcome. Eur J Hematol. 2015;95(6):498–506.CrossRef
Metadata
Title
Clofarabine-based chemotherapy as a bridge to transplant in the setting of refractory or relapsed acute myeloid leukemia, after at least one previous unsuccessful salvage treatment containing fludarabine: a single institution experience
Authors
Alfredo Molteni
Marta Riva
Emanuele Ravano
Laura Marbello
Valentina Mancini
Giovanni Grillo
Elisa Zucchetti
Rosa Greco
Roberto Cairoli
Publication date
01-06-2017
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 6/2017
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-017-2198-0

Other articles of this Issue 6/2017

International Journal of Hematology 6/2017 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine