A phase 1 clinical-laboratory study of clofarabine followed by cyclophosphamide for adults with refractory acute leukemias

Karp, Judith E.; Ricklis, Rebecca M.; Balakrishnan, Kumudha; Briel, Janet; Greer, Jacqueline M.; Gore, Steven D.; Smith, B. Douglas; McDevitt, Michael A.; Carraway, Hetty E.; Levis, Mark J.; Gandhi, Varsha

doi:10.1182/blood-2007-03-081364

Cited by 79 publications

(59 citation statements)

References 28 publications

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“…Thus, further therapeutic strategies (mainly allo-HCT) seem necessary to achieve long-term remissions in these patients [12]. In the adult setting, data regarding safety and efficacy of clofarabine-based schemes in relapsed/refractory ALL patients are scarce [15][16][17]. These studies suggest worse tolerability and lower efficacy in adult patients when compared with the reported experience in children, with CR rates under 20%.…”

contrasting

confidence: 44%

“…Hematological and infectious grade 3-5 toxicities were found in 31 (100%) and 21 (68%) patients, while grade 3 or grater hepatic, gastrointestinal, and renal toxicities were less common (16,16, and 0%, respectively). Laboratory features of hepatotoxicity included elevation of transaminases in four patients and high levels of transaminases and bilirubin in one patient.…”

mentioning

confidence: 99%

“…Other studies focused in adult patients reported a relatively more favorable toxicity profile. However, these data come from two controlled prospective clinical trials with younger [16] or relatively fit patients [15]. Our cohort represents a real-life population of ALL patients.…”

mentioning

confidence: 99%

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Clofarabine‐based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience

Barba¹,

Sampol²,

Calbacho³

et al. 2012

American J Hematol

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confidence: 44%

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confidence: 99%

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Clofarabine‐based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience

Barba¹,

Sampol²,

Calbacho³

et al. 2012

American J Hematol

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“…Conversely, the use of clofarabine prior to cyclophosphamide appeared to augment both cyclophosphamide-induced DNA damage (by phosphorylated H2AX) and apoptosis (by sub-2N DNA) [75].…”

Section: Page 30 Of 53mentioning

confidence: 92%

Mechanisms of anti-cancer action and pharmacology of clofarabine

Zhenchuk

Lotfi

Juliusson

et al. 2009

Biochemical Pharmacology

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114

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“…It has clinical activity when used as a single agent against adult leukemias at tolerable doses. Exploration of additional schedules, routes of administration and combinations (45)(46)(47) could exploit the full potential of clofarabine in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs

Roth¹,

Kurtzberg²,

Rouleau³

et al. 2009

Int J Oncol

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Abstract. Nucleoside analogs are rationally designed anticancer agents that disrupt DNA and RNA synthesis. Fludarabine and cladribine have important roles in the treatment of hematologic malignancies. Clofarabine is a next generation nucleoside analog which is under clinical investigation. The bone marrow toxicity, tumor cell cytotoxicity and human tumor xenograft activity of fludarabine, cladribine and clofarabine were compared. Mouse and human bone marrow were subjected to colony forming (CFU-GM) assays over a 5-log concentration range in culture. NCI-60 cell line screening data were compared. In vivo, a range of clofarabine doses was compared with fludarabine for efficacy in several human tumor xenografts. The IC 90 concentrations for fludarabine and cladribine for mouse CFU-GM were >30 and 0.93 μM, and for human CFU-GM were 8 and 0.11 μM, giving mouse to human differentials of >3.8-and 8.5-fold. Clofarabine produced IC 90 s of 1.7 μM in mouse and 0.51 μM in human CFU-GM, thus a 3.3-fold differential between species. In the NCI-60 cell line screen, fludarabine and cladribine showed selective cytotoxicity toward leukemia cell lines while for clofarabine there was no apparent selectivity based upon origin of the tumor cells. In vivo, clofarabine produced a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI-8226 multiple myeloma, and HT-29 colon carcinoma models. The PC3 prostate carcinoma was equally responsive to clofarabine and fludarabine. Bringing together bone marrow toxicity data, tumor cell line cytotoxicity data, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.

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A phase 1 clinical-laboratory study of clofarabine followed by cyclophosphamide for adults with refractory acute leukemias

Cited by 79 publications

References 28 publications

Clofarabine‐based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience

Clofarabine‐based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience

Mechanisms of anti-cancer action and pharmacology of clofarabine

Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs

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