Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML

Bob Löwenberg, Thomas Pabst, Johan Maertens, Yvette Van Norden, Bart J. Biemond, Harry C. Schouten, Olivier Spertini, Edo Vellenga, Carlos Graux, Violaine Havelange, Georgine E. De Greef, Okke De Weerdt, Marie Cecile J.C. Legdeur, Juergen Kuball, Marinus Van Marwijk Kooy, Bjorn T. Gjertsen, Mojca Jongen-Lavrencic, Arjan A. Van De Loosdrecht, Daniëlle Van Lammeren-Venema, Beata Hodossy & 6 others Dimitri A. Breems, Yves Chalandon, Jakob Passweg, Peter J.M. Valk, Markus G. Manz, Gert J. Ossenkoppele

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study revealsnodifferences in overall survivalandEFSbetweenthe control (EFS,35%63 [standard error] at 4 years) and clofarabine treatments (38% ± 3) but a markedly reduced relapse rate (44% ± 3 vs 35% ± 3) in favor of clofarabine and an increased death probability in remission (15%±2 vs 22%±3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic riskAML(EFS,26%64 vs40%65 at 4 years;CoxP5.002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% 6 5 vs 40% 6 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.

Original languageEnglish
Pages (from-to)1636-1645
Number of pages10
JournalBlood
Volume129
Issue number12
DOIs
Publication statusPublished - 23 Mar 2017

Cite this

Löwenberg, B., Pabst, T., Maertens, J., Van Norden, Y., Biemond, B. J., Schouten, H. C., ... Ossenkoppele, G. J. (2017). Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. Blood, 129(12), 1636-1645. https://doi.org/10.1182/blood-2016-10-740613
Löwenberg, Bob ; Pabst, Thomas ; Maertens, Johan ; Van Norden, Yvette ; Biemond, Bart J. ; Schouten, Harry C. ; Spertini, Olivier ; Vellenga, Edo ; Graux, Carlos ; Havelange, Violaine ; De Greef, Georgine E. ; De Weerdt, Okke ; Legdeur, Marie Cecile J.C. ; Kuball, Juergen ; Van Marwijk Kooy, Marinus ; Gjertsen, Bjorn T. ; Jongen-Lavrencic, Mojca ; Van De Loosdrecht, Arjan A. ; Van Lammeren-Venema, Daniëlle ; Hodossy, Beata ; Breems, Dimitri A. ; Chalandon, Yves ; Passweg, Jakob ; Valk, Peter J.M. ; Manz, Markus G. ; Ossenkoppele, Gert J. / Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. In: Blood. 2017 ; Vol. 129, No. 12. pp. 1636-1645.
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title = "Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML",
abstract = "Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89{\%}) did not differ but were attained faster with clofarabine (66{\%} vs 75{\%} after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study revealsnodifferences in overall survivalandEFSbetweenthe control (EFS,35{\%}63 [standard error] at 4 years) and clofarabine treatments (38{\%} ± 3) but a markedly reduced relapse rate (44{\%} ± 3 vs 35{\%} ± 3) in favor of clofarabine and an increased death probability in remission (15{\%}±2 vs 22{\%}±3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic riskAML(EFS,26{\%}64 vs40{\%}65 at 4 years;CoxP5.002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18{\%} 6 5 vs 40{\%} 6 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.",
author = "Bob L{\"o}wenberg and Thomas Pabst and Johan Maertens and {Van Norden}, Yvette and Biemond, {Bart J.} and Schouten, {Harry C.} and Olivier Spertini and Edo Vellenga and Carlos Graux and Violaine Havelange and {De Greef}, {Georgine E.} and {De Weerdt}, Okke and Legdeur, {Marie Cecile J.C.} and Juergen Kuball and {Van Marwijk Kooy}, Marinus and Gjertsen, {Bjorn T.} and Mojca Jongen-Lavrencic and {Van De Loosdrecht}, {Arjan A.} and {Van Lammeren-Venema}, Dani{\"e}lle and Beata Hodossy and Breems, {Dimitri A.} and Yves Chalandon and Jakob Passweg and Valk, {Peter J.M.} and Manz, {Markus G.} and Ossenkoppele, {Gert J.}",
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Löwenberg, B, Pabst, T, Maertens, J, Van Norden, Y, Biemond, BJ, Schouten, HC, Spertini, O, Vellenga, E, Graux, C, Havelange, V, De Greef, GE, De Weerdt, O, Legdeur, MCJC, Kuball, J, Van Marwijk Kooy, M, Gjertsen, BT, Jongen-Lavrencic, M, Van De Loosdrecht, AA, Van Lammeren-Venema, D, Hodossy, B, Breems, DA, Chalandon, Y, Passweg, J, Valk, PJM, Manz, MG & Ossenkoppele, GJ 2017, 'Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML' Blood, vol. 129, no. 12, pp. 1636-1645. https://doi.org/10.1182/blood-2016-10-740613

Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. / Löwenberg, Bob; Pabst, Thomas; Maertens, Johan; Van Norden, Yvette; Biemond, Bart J.; Schouten, Harry C.; Spertini, Olivier; Vellenga, Edo; Graux, Carlos; Havelange, Violaine; De Greef, Georgine E.; De Weerdt, Okke; Legdeur, Marie Cecile J.C.; Kuball, Juergen; Van Marwijk Kooy, Marinus; Gjertsen, Bjorn T.; Jongen-Lavrencic, Mojca; Van De Loosdrecht, Arjan A.; Van Lammeren-Venema, Daniëlle; Hodossy, Beata; Breems, Dimitri A.; Chalandon, Yves; Passweg, Jakob; Valk, Peter J.M.; Manz, Markus G.; Ossenkoppele, Gert J.

In: Blood, Vol. 129, No. 12, 23.03.2017, p. 1636-1645.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML

AU - Löwenberg, Bob

AU - Pabst, Thomas

AU - Maertens, Johan

AU - Van Norden, Yvette

AU - Biemond, Bart J.

AU - Schouten, Harry C.

AU - Spertini, Olivier

AU - Vellenga, Edo

AU - Graux, Carlos

AU - Havelange, Violaine

AU - De Greef, Georgine E.

AU - De Weerdt, Okke

AU - Legdeur, Marie Cecile J.C.

AU - Kuball, Juergen

AU - Van Marwijk Kooy, Marinus

AU - Gjertsen, Bjorn T.

AU - Jongen-Lavrencic, Mojca

AU - Van De Loosdrecht, Arjan A.

AU - Van Lammeren-Venema, Daniëlle

AU - Hodossy, Beata

AU - Breems, Dimitri A.

AU - Chalandon, Yves

AU - Passweg, Jakob

AU - Valk, Peter J.M.

AU - Manz, Markus G.

AU - Ossenkoppele, Gert J.

PY - 2017/3/23

Y1 - 2017/3/23

N2 - Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study revealsnodifferences in overall survivalandEFSbetweenthe control (EFS,35%63 [standard error] at 4 years) and clofarabine treatments (38% ± 3) but a markedly reduced relapse rate (44% ± 3 vs 35% ± 3) in favor of clofarabine and an increased death probability in remission (15%±2 vs 22%±3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic riskAML(EFS,26%64 vs40%65 at 4 years;CoxP5.002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% 6 5 vs 40% 6 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.

AB - Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study revealsnodifferences in overall survivalandEFSbetweenthe control (EFS,35%63 [standard error] at 4 years) and clofarabine treatments (38% ± 3) but a markedly reduced relapse rate (44% ± 3 vs 35% ± 3) in favor of clofarabine and an increased death probability in remission (15%±2 vs 22%±3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic riskAML(EFS,26%64 vs40%65 at 4 years;CoxP5.002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% 6 5 vs 40% 6 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.

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Löwenberg B, Pabst T, Maertens J, Van Norden Y, Biemond BJ, Schouten HC et al. Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. Blood. 2017 Mar 23;129(12):1636-1645. https://doi.org/10.1182/blood-2016-10-740613