Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia

Jeha, Sima; Gandhi, Varsha; Chan, Ka Wah; McDonald, Lisa; Ramírez, Isabel; Madden, Renee; Rytting, Michael; Brandt, Mark; Keating, Michael J.; Plunkett, William; Kantarjian, Hagop

doi:10.1182/blood-2003-06-2122

Cited by 211 publications

(163 citation statements)

References 18 publications

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“…29,30,33,34 Although heterogeneity among individuals was common, in both trials, dose-dependent increases of clofarabine in plasma and accumulation of clofarabine triphosphate in leukemic blasts could be demonstrated. Comparison of the triphosphate concentration in leukemic blasts of each patient at the end of the infusion relative to that present at 24 hours indicated retention of Ͼ 50% of the initial concentration of clofarabine triphosphate at 24 hours, irrespective of lymphoid or myeloid lineage.…”

Section: Clinical Development Phase I Studies In Adult and Pediatric mentioning

confidence: 99%

“…Both patients who had CRs The pediatric Phase I study was restricted to children with advanced acute leukemias. 33 Six dose levels, starting at 11.25 mg/m 2 and escalating up to a dose of 70 mg/m 2 , were evaluated in 25 patients (8 patients with AML and 17 patients with ALL). The treatment schedule was identical to that used in the adult study.…”

Section: Clinical Development Phase I Studies In Adult and Pediatric mentioning

confidence: 99%

“…24,33 In both adult and pediatric studies, clofarabine was given as a 1-hour infusion daily for 5 days. However, the starting doses differed (15 mg/m 2 per dose in adults and 11.25 mg/m 2 per dose in children), partly because the adult study preceded the pediatric trial and served as a reservoir experience for subsequent clinical studies.…”

Section: Clinical Development Phase I Studies In Adult and Pediatric mentioning

confidence: 99%

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The role of clofarabine in hematologic and solid malignancies—Development of a next‐generation nucleoside analog

Faderl

Gandhi

Keating

et al. 2005

Cancer

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Clofarabine is a new-generation nucleoside analog that has been synthesized to combine the most favorable pharmacokinetic properties of its congeners fludarabine and cladribine. In addition to inhibition of DNA polymerases and DNA synthesis, clofarabine acts as a strong inhibitor of ribonucleotide reductase (RnR), an enzyme involved in regulating intracellular deoxynucleotide pools, and has a high affinity to the enzyme deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation.A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) data base and from abstracts based on the publication of meeting materials.Although it was synthesized early in the 1980s, the development of clofarabine was stalled until

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Section: Clinical Development Phase I Studies In Adult and Pediatric mentioning

confidence: 99%

Section: Clinical Development Phase I Studies In Adult and Pediatric mentioning

confidence: 99%

Section: Clinical Development Phase I Studies In Adult and Pediatric mentioning

confidence: 99%

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The role of clofarabine in hematologic and solid malignancies—Development of a next‐generation nucleoside analog

Faderl

Gandhi

Keating

et al. 2005

Cancer

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“…Clofarabine showed promising activity in phase 1 and 2 studies in patients with relapsed and refractory acute leukemias in adults and children. (Kantarjian et al, 2003a;2003b;Jeha et al, 2004;Styczynski et al, 2009). Clofarabine has also shown activity in combination with high dose ARA-C in relapsed or refractory younger and older patients with AML (Tse et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Clofarabine in the Treatment of Elderly Patients with Acute Myeloid Leukemia

Aleem

Anjum²,

Algahtani³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Elderly patients with acute myeloid leukemia (AML) have a poor outcome because of comorbidities, poor tolerance to intensive chemotherapy and inherently more resistant disease. Clofarabine is a second generation nucleoside analogue which has shown promising activity in elderly patients with AML. This study was conducted to review the outcome of treatment with clofarabine in a group of such patients. Methods: The records of 5 elderly patients who were diagnosed to have AML and treated with clofarabine over a 12 month period were reviewed retrospectively. Results: There were 2 female and 3 male patients with a median age of 68 years (range 65-82). At the time of treatment, 2 patients had newly diagnosed AML not considered suitable for intensive therapy, while 3 patients had partial or no response to conventional chemotherapy. The overall response rate was 100%, all patients achieving a complete remission. Induction and consolidation were well tolerated. All patients developed neutropenia with a median duration of 20 days (range 17-42). One patient developed hand and foot syndrome and a generalized rash but recovered. There was no mortality and all patients remained in remission after a median follow-up of 5.2 months (Range 3-10). Conclusion: Clofarabine (alone or in combination) is active in elderly AML patients with an acceptable safety profile and should be considered a potential option in this group.

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“…In particular, deoxyadenosine-based analogues such as cladribine and fludarabine ( Figure 1) have both been shown to be active against various forms of leukemias and lymphomas (reviewed in [1]). Clofarabine, a second generation chemotherapeutic agent developed following the effectiveness of fludarabine, is active against several hematological malignancies, including acute and chronic leukemias (reviewed in [2]), myelodysplastic syndromes [3], and advanced pediatric acute leukemias [4].…”

Section: Introductionmentioning

confidence: 99%

Polyadenylation inhibition by the triphosphates of deoxyadenosine analogues

2008

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The nucleotide substrate specificity of yeast poly(A) polymerase (yPAP) was examined with various ATP analogues of clinical relevance. The triphosphate derivatives of cladribine (2-CldATP), clofarabine (Cl-F-ara-ATP), fludarabine (F-ara-ATP), and related derivatives were incubated with yPAP and 32 P-radiolabeled RNA oligonucleotide primers in the absence of ATP to assay polyadenylation. While 2-Cl-ATP resulted in primer elongation, ara-ATP and F-ara-ATP were poor substrates for yPAP. In contrast, the triphosphate derivatives of cladribine (2-Cl-dATP), clofarabine (Cl-F-ara-ATP) and its corresponding deoxyribose derivative (Cl-F-dATP) were substrates and caused chain termination in the absence of ATP. We further investigated whether analog incorporation at the 3′-terminus of RNA primers negatively impacts polyadenylation with ATP by generating RNA oligonucleotides containing either a terminal clofarabine, Cl-F-dAdo, or cladribine residue. Incorporation of any of these analogs blocks the ability of yPAP to extend RNA past the analog site, impeding the addition of a poly(A)-tail. To determine whether modified ATP analogues exhibit a concentration dependent effect on polyadenylation, poly(A)-tail synthesis by yPAP with modified ATP analogues in combination with a constant level of ATP was also examined. With all the ATP analogues assayed in these studies, there was a significant reduction in poly(A)-tail length with increasing amounts of analog triphosphate. Taken together, our results suggest that polyadenylation inhibition may be a component in the mechanism of action of adenosine analogues.

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Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia

Cited by 211 publications

References 18 publications

The role of clofarabine in hematologic and solid malignancies—Development of a next‐generation nucleoside analog

The role of clofarabine in hematologic and solid malignancies—Development of a next‐generation nucleoside analog

Clofarabine in the Treatment of Elderly Patients with Acute Myeloid Leukemia

Polyadenylation inhibition by the triphosphates of deoxyadenosine analogues

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