The use of higher dose clofarabine in adults with relapsed acute lymphoblastic leukemia (original) (raw)
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Clinical lymphoma, myeloma & leukemia, 2014
Clofarabine is a nucleoside analogue with activity in children with acute lymphoblastic leukemia (ALL). Based on the hypothesis that clofarabine inhibits DNA repair after exposure to DNA-damaging agents, we designed a phase I and extension study to evaluate the combination of clofarabine and cyclophosphamide in adult patients with relapsed/refractory ALL. The continual reassessment method (CRM) was used to define the maximum tolerated dose (MTD). Fifty patients with a median age of 30 years (range, 21-72 years) were enrolled, 30 of whom were part of the phase I group. Clofarabine 40 mg/m(2) intravenously daily × 3 days and cyclophosphamide 200 mg/m(2) intravenously every 12 hours × 3 days were established as the MTDs. Dose limiting toxicity (DLT) included diarrhea, transaminase elevations, and skin rashes. The response rate of the whole study group was 14%, including 10% of patients who achieved complete remission (CR) or CR without platelet recovery (CRp). Three responses occurred ...
International journal of hematology, 2016
A phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), efficacy and pharmacogenetic characteristics of clofarabine in seven Japanese pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients in Cohort 1 received clofarabine 30 mg/m(2)/day for 5 days, followed by 52 mg/m(2)/day for 5 days in subsequent cycles. Cohort 2 patients were consistently treated with 52 mg/m(2)/day for 5 days. No more than six cycles were performed. Every patient had at least one ≥Grade 3 adverse event (AE). AEs (≥Grade 3) related to clofarabine were anaemia, neutropenia, febrile neutropenia, thrombocytopenia, alanine aminotransferase increased, aspartate aminotransferase increased, haemoglobin decreased, and platelet (PLT) count decreased. C max and AUC of clofarabine increased in a dose-dependent fashion, but its elimination half-life (T 1/2) did not appear to be dependent on dose or duration of treatment. Clofarabine at 52 mg/m(2)/day shows similarly tol...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2003
The purpose of our study was to investigate the pharmacology of clofarabine and its triphosphate and the pharmacodynamic actions in circulating blasts obtained from acute leukemia patients who entered a Phase I clinical trial of clofarabine. Adults with refractory acute leukemias including lymphoblastic (ALL), myelogenous (AML) and chronic myelogenous leukemia in blastic phase (CML-BP) received clofarabine from 4 mg/m(2) to 55 mg/m2/day for 5 days as a 1-h i.v. infusion. A total of 26 of the 32 patients were studied for pharmacological investigations. The maximum tolerated dose was 40 mg/m2/day for 5 days. Plasma pharmacology studies done in 25 patients indicate a linear increase in the plasma clofarabine concentration with increasing doses. At 40 mg/m2 the median plasma clofarabine level was 1.5 micro M (range, 0.42-3.2 micro M; n = 7). Cellular pharmacokinetic studies done at the end of the first clofarabine infusion in 26 patients appeared dose proportional but showed a wide vari...
Phase I Study of Clofarabine in Adult Patients with Acute Myeloid Leukemia in Japan
Japanese Journal of Clinical Oncology, 2013
There are limited treatment options for relapsed/refractory acute myeloid leukemia patients or previously untreated elderly (!60 years) patients with acute myeloid leukemia. In Phase II studies from the USA and Europe, single-agent clofarabine demonstrated activity and acceptable toxicity in elderly patients with previously untreated acute myeloid leukemia. This Phase I, multicenter study assessed the maximum-tolerated dose, safety, pharmacokinetics and efficacy of clofarabine in Japanese adults with acute myeloid leukemia. Methods: Intravenous clofarabine (20, 30 and 40 mg/m 2 /day) was administered for 5 days to Japanese adult patients with relapsed or refractory acute myeloid leukemia or elderly patients with newly diagnosed acute myeloid leukemia. Results: Fourteen patients, median age of 67.5 (59-72) years, were enrolled in this study. Eleven out of 14 patients had relapsed/refractory acute myeloid leukemia. Three patients received clofarabine at 20 mg/m 2 , six at 30 mg/m 2 and five at 40 mg/m 2. Frequently reported treatment-related adverse events included thrombocytopenia (100%), anemia (93%), neutropenia (86%), nausea (86%), alanine aminotransferase increase (71%), headache (71%) and febrile neutropenia (57%). Three patients experienced reversible dose-limiting toxicities; two had increased alanine aminotransferase with 30 and 40 mg/m 2 and one had Grade 3 elevation of serum amylase with 40 mg/m 2. The maximum-tolerated dose was 30 mg/m 2 /day. C max and exposure area under the curve 0224h increased with increasing dose and were proportional to dose through the tested dose range. Among the 14 assessable patients, four (29%) achieved complete remission and two (14%) complete remission without platelet recovery. The overall remission rate was 43%. Conclusions: These results demonstrate safety and preliminary, promising activity of clofarabine in Japanese patients with acute myeloid leukemia. Further investigation is warranted.
Anticancer research, 2009
Clofarabine is a second-generation nucleoside analogue. The aim of the study was the analysis of ex vivo activity of clofarabine and 14 other anticancer drugs in pediatric and adult acute lymphoblastic (ALL) and myeloid (AML) leukemia. The ex vivo drug resistance profile was analyzed in 282 patients, including 201 children with ALL de novo, 24 children with relapsed ALL, 25 children with AML de novo and 32 adults with AML. Cellular ex vivo drug resistance was tested by means of the MTT assay. Clofarabine had comparable ex vivo activity against lymphoblasts and myeloblasts, both on initial diagnosis and at relapse, both in children and in adults. Its activity in acute myeloid leukemia was independent of patient age. No significant differences in drug resistance to clofarabine between pediatric age-based subgroups of ALL were detected, while it was observed for most of other drugs. An activity of clofarabine in relapsed pediatric ALL patients was as good as in newly-diagnosed ones. In...
Clofarabine Experience in Children with Multi-Relapsed Acute Leukemia
Turkish Journal of Hematology, 2014
Although clofarabine is known as an effective novel agent in relapsed acute leukemia , determining the optimum combination with other agents and the optimum time to use remains a challenge. Clofarabine is recommended to be used after 2 protocol regimens in patients with relapsed leukemia . We want to add our experience with clofarabine in children with multi-relapsed acute lymphoblastic and myeloblastic leukemia. We analyzed the data of 12 children (1-13 years old) treated with the CLOVE protocol [clofarabine (4 mg/m 2 ), cyclophosphamide (440 mg/m 2 ), and etoposide (100 mg/m 2 ) for 5 days] [2,3,4] for relapsed or refractory acute leukemia between 2009 and 2013. We used this therapy in a third or more of cases of relapsed acute leukemia. Bone marrow relapses were eligible for the treatment protocol. Seven of 12 patients had acute lymphoblastic leukemia (ALL) and 5 had acute myeloid leukemia (AML) ( . Patients with relapsed ALL were treated with 1 or 2 cycles of FLAG after applying the BFM-95 REZ protocol. Patients with no response were administered clofarabine. Patients with relapsed AML were treated with 2 cycles of FLAG after applying the MRC protocol. Patients without response were given clofarabine in 1 or 2 cycles. The required permission for all patients was received from the Ministry of Health.
Haematologica, 2021
Novel treatment strategies are needed to improve cure for all children with acute lymphoblastic leukemia. To this end, we investigated the therapeutic potential of clofarabine in primary acute lymphoblastic leukemia in trial CoALL 08-09. The primary study objective was the minimal residual disease (MRD)-based comparative assessment of cytotoxic efficacies of clofarabine 5x40 mg/m2 versus high-dose cytarabine (HIDAC) 4x3g/m2, both in combination with PEG-ASP 2500 IU/m2 as randomized intervention in early consolidation. The secondary objective was an outcome analysis focused on treatment-arm dependence and MRD after randomized intervention. In B-cell precursor (BCP)-ALL, eradication of MRD was more profound after clofarabine compared to cytarabine, with 93 vs 79 of 143 randomized patients per arm reaching MRD-negativity (Chi-square test P=.03, left-sided P(Fisher's exact test)=.04). MRD status of BCP-ALL after randomized intervention maintained its prognostic relevance, with a sig...