Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias

Stefan Faderl, Varsha Gandhi, Susan O'Brien, Peter Bonate, Jorge Cortes, Elihu Estey, Miloslav Beran, William Wierda, Guillermo Garcia-Manero, Alessandra Ferrajoli, Zeev Estrov, Francis J. Giles, Min Du, Monica Kwari, Michael Keating, William Plunkett, Hagop Kantarjian

Research output: Contribution to journalArticle

Abstract

Clofarabine (2-chloro-2′-fluoro-deoxy-9-β-D- arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myejoid leukemia (CML).1 Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m2 per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m 2 per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.

Original languageEnglish (US)
Pages (from-to)940-947
Number of pages8
JournalBlood
Volume105
Issue number3
DOIs
StatePublished - Feb 1 2005

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Cytarabine
Refractory materials
Leukemia
Vidarabine
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Intravenous Infusions
Arabinofuranosylcytosine Triphosphate
Blast Crisis
Ribonucleotide Reductases
Mucositis
Myelodysplastic Syndromes
Platelets
clofarabine
Exanthema
Nucleosides
Acute Myeloid Leukemia
Liver
Nausea
Vomiting
Diarrhea

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. / Faderl, Stefan; Gandhi, Varsha; O'Brien, Susan; Bonate, Peter; Cortes, Jorge; Estey, Elihu; Beran, Miloslav; Wierda, William; Garcia-Manero, Guillermo; Ferrajoli, Alessandra; Estrov, Zeev; Giles, Francis J.; Du, Min; Kwari, Monica; Keating, Michael; Plunkett, William; Kantarjian, Hagop.

In: Blood, Vol. 105, No. 3, 01.02.2005, p. 940-947.

Research output: Contribution to journalArticle

Faderl, S, Gandhi, V, O'Brien, S, Bonate, P, Cortes, J, Estey, E, Beran, M, Wierda, W, Garcia-Manero, G, Ferrajoli, A, Estrov, Z, Giles, FJ, Du, M, Kwari, M, Keating, M, Plunkett, W & Kantarjian, H 2005, 'Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias', Blood, vol. 105, no. 3, pp. 940-947. https://doi.org/10.1182/blood-2004-05-1933
Faderl, Stefan ; Gandhi, Varsha ; O'Brien, Susan ; Bonate, Peter ; Cortes, Jorge ; Estey, Elihu ; Beran, Miloslav ; Wierda, William ; Garcia-Manero, Guillermo ; Ferrajoli, Alessandra ; Estrov, Zeev ; Giles, Francis J. ; Du, Min ; Kwari, Monica ; Keating, Michael ; Plunkett, William ; Kantarjian, Hagop. / Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. In: Blood. 2005 ; Vol. 105, No. 3. pp. 940-947.
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abstract = "Clofarabine (2-chloro-2′-fluoro-deoxy-9-β-D- arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myejoid leukemia (CML).1 Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m2 per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m 2 per day for 5 days. Among all patients, 7 (22{\%}) achieved complete remission (CR), and 5 (16{\%}) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38{\%}. No responses occurred in 3 patients with ALL and CML. One patient (3{\%}) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.",
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AU - Cortes, Jorge

AU - Estey, Elihu

AU - Beran, Miloslav

AU - Wierda, William

AU - Garcia-Manero, Guillermo

AU - Ferrajoli, Alessandra

AU - Estrov, Zeev

AU - Giles, Francis J.

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