Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study

Purpose Acadesine has shown in vitro to selectively induce apoptosis in B cells from chronic lymphocytic leukemia (CLL) patients. We conducted a phase I/II open-label clinical study, to determine the safety and tolerability of acadesine given intravenously as a 4-h infusion to CLL patients. Methods...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2013-03, Vol.71 (3), p.581-591
Main Authors: Van Den Neste, Eric, Cazin, Bruno, Janssens, Ann, González-Barca, Eva, Terol, María José, Levy, Vincent, Pérez de Oteyza, Jaime, Zachee, Pierre, Saunders, Andrew, de Frias, Mercè, Campàs, Clara
Format: Article
Language:English
Subjects:
Aged
Aminoimidazole Carboxamide - adverse effects
Aminoimidazole Carboxamide - analogs & derivatives
Aminoimidazole Carboxamide - pharmacokinetics
Aminoimidazole Carboxamide - therapeutic use
Anemia
Antineoplastic agents
B-Lymphocytes - drug effects
Biological and medical sciences
Cancer Research
Cohort Studies
Drug Resistance, Neoplasm
Female
Hematologic and hematopoietic diseases
Humans
Karnofsky Performance Status
Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Lymph - cytology
Lymph - drug effects
Lymphocyte Count
Male
Maximum Tolerated Dose
Medical sciences
Medicine
Medicine & Public Health
Middle Aged
Oncology
Original
Original Article
Pharmacology. Drug treatments
Pharmacology/Toxicology
Recurrence
Ribonucleosides - adverse effects
Ribonucleosides - pharmacokinetics
Ribonucleosides - therapeutic use
T-Lymphocytes - drug effects
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Summary:Purpose Acadesine has shown in vitro to selectively induce apoptosis in B cells from chronic lymphocytic leukemia (CLL) patients. We conducted a phase I/II open-label clinical study, to determine the safety and tolerability of acadesine given intravenously as a 4-h infusion to CLL patients. Methods Patient population included CLL patients with relapsed/refractory disease who had received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen. Twenty-four patients were included: eighteen in Part I treated at single doses of 50–315 mg/kg, and six in Part II, three with two doses at 210 mg/kg and three with five doses at 210 mg/kg. Results A manageable and predictable safety profile was demonstrated for acadesine at single doses between 50 and 210 mg/kg; 210 mg/kg was the maximum tolerated dose (MTD) and optimal biological dose (OBD). Grade ≥2 hyperuricemia occurred commonly but was not clinically significant and resolved with the administration of prophylactic allopurinol. Other adverse events included transient anemia and/or thrombocytopenia (not clinically significant), renal impairment, and transient infusion-related hypotension (clinically significant). Trends of efficacy such as a reduction of peripheral CLL cells and reduction in lymphadenopathy were observed; however, the results were variable due to the small population and the range of doses tested. Conclusions A MTD of 210 mg/kg was established with single acadesine dose. Multiple dose administrations at the OBD were tested with an acceptable safety profile, showing that acadesine might be a valuable agent for the treatment of relapsed/refractory CLL patients.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-012-2033-5