Clofarabine-induced Acral Erythema During the Treatment of Patients with Myelodysplasia and Acute Leukemia: Report of Two Cases

Chiao, Nor; Bumgardner, Amy; Duvic, Magdeleine

doi:10.1080/1042819031000090183

Cited by 12 publications

(4 citation statements)

References 10 publications

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“…The regimen was well tolerated despite the presence of comorbidities, with transient transaminitis, skin rash, and anorexia as the chief regimen-related toxicities. These toxicities were consistent with prior reports of clofarabine monotherapy [19,30,[34][35][36]. The transaminitis seen with clofarabine did not translate to hepatic toxicity (eg, sinusoidal obstructive syndrome) and elevated transaminases resolved early after transplantation.…”

Section: Discussionsupporting

confidence: 90%

Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study

Soni

Abdel‐Azim

McManus

et al. 2017

Biology of Blood and Marrow Transplantation

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Clofarabine is a purine nucleoside analog with immunosuppressive and antileukemic activity and its inclusion in reduced-intensity regimens could potentially improve outcomes. We performed a prospective phase I study of clofarabine combined with 2 Gy total body irradiation (TBI) as a nonmyeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients who were considered at high risk of mortality from standard myeloablative regimens. The main goal of the study was to delineate the maximum feasible dose (MFD) of clofarabine in combination with 2 Gy TBI. Eighteen patients, 1 to 21 years of age and in complete remission, were enrolled in 2 strata (matched related donor and unrelated donor) and evaluated for day100 dose-limiting events (DLE) (nonengraftment, nonrelapse mortality [NRM], and severe renal insufficiency) after receiving clofarabine at the starting dose level of 40 mg/m. All 6 patients (3 in each stratum) engrafted with no day 100 DLE seen in the first cohort. The dose was increased to 52 mg/m in the next and an expanded cohort (total of 12 patients) and no DLE were observed at day 100 and at the 1-year study endpoint. The regimen was well tolerated with transient transaminitis and gastrointestinal and skin reactions as the common reversible toxicities observed with clofarabine. The dose of 52 mg/m of clofarabine was deemed the MFD. Disease relapse led to mortality in 6 (33%) patients during follow-up with 1-year event-free survival and overall survival of 60% (95% confidence interval [CI], 34 to 79) and 71% (95% CI, 44 to 87), respectively. This regimen leads to successful engraftment using both related and unrelated donors with exceptionally low rates of NRM.

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Section: Discussionsupporting

confidence: 90%

Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study

Soni

Abdel‐Azim

McManus

et al. 2017

Biology of Blood and Marrow Transplantation

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“…In phase I clinical trials in patients with solid and hematologic cancers, the dose limiting toxicities of clofarabine were myelosupression and thrombocytopenia (42). However, in patients with myelodysplasias and acute leukemias the dose limiting toxicity was hepatotoxcity, which is different from other clinically applied nucleoside analogs (43). Bone marrow granulocyte-macrophage-colony forming unit (CFU-GM) assays comparing the sensitivity of bone marrows across species have been useful in predicting the blood levels of agents that might be tolerated in patients compared with blood levels in preclinical efficacy and safety species (11).…”

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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“…The median time to achieve a platelet count > 100 × 10 9 /l was 31 days in one study [17], whereas results in older patients revealed a median time to a platelet count of 50 × 10 9 /l of 25 days [18]. Other common side effects of clofarabine include skin rash, palmar-plantar erythrodysethesia [19], mucositis, nausea, vomiting and diarrhoea [17].…”

Section: Toxicitiesmentioning

confidence: 97%

Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review

Kline

Larson²

2005

Expert Opinion on Pharmacotherapy

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Clofarabine, a synthesised adenosine nucleoside, has recently demonstrated single-agent activity in the acute leukaemias. Originally developed to capture the best qualities of cladribine and fludarabine, clofarabine contains halogenated carbons, rendering it resistant to inactivating enzymes and maintaining its stability in acidic environments. Like other adenosine nucleosides, clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication and also resulting in premature DNA chain termination. Clofarabine has also been shown to induce apoptosis in transformed cell lines, indicating that clofarabine results in cell death in both cycling and non-cycling cells. Interest in the development of clofarabine was initially hampered by the availability of other active nucleoside analogues for the treatment of haematological malignancies. However, the results of several early-phase trials evaluating the use of clofarabine in acute leukaemias in adults and children have rekindled enthusiasm for further investigation into its use. This article describes the development, pharmacology, toxicity and clinical activity of clofarabine, as well as discuss its potential role in the treatment of acute leukaemia.

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Clofarabine-induced Acral Erythema During the Treatment of Patients with Myelodysplasia and Acute Leukemia: Report of Two Cases

Cited by 12 publications

References 10 publications

Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study

Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study

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

Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review

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