title: Clofarabine in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin) in patients with previously untreated intermediate and bad-risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): phase I results of an ongoing phase I/II study of the leukemia groups of EORTC and GIMEMA (EORTC GIMEMA 06061/AML-14A trial).
abstract: This study aims to determine the maximum tolerated dose (MTD) of clofarabine combined with the EORTC-GIMEMA 3 + 10 induction regimen (idarubicin + cytosine arabinoside) in adults with untreated acute myelogenous leukemia or high-risk myelodysplastic syndrome. In this phase I trial, 25 patients (median age 56 years) received 5 days of clofarabine as 1-h infusion (arm A) or push injection (arm B) at the dose level of 5 × 10 or 5 × 15 mg/m(2)/day in an algorithmic dose escalation 3 + 3 design. A consolidation course (intermediate dose cytosine arabinoside, idarubicin) was planned for patients in complete remission (CR). Primary endpoint was safety and tolerance as measured by dose limiting toxicity (DLT); secondary endpoints were response rate, other grade III/IV toxicities, and hematological recovery after induction and consolidation. Five DLTs were observed (in arm A: one DLT at 10 mg/m(2)/day, three at 15 mg/m(2)/day; in arm B: one DLT at 15 mg/m(2)/day). Three patients receiving 15 mg/m(2)/day were withdrawn due to adverse events not classified as DLT. Prolonged hypoplasia was observed in five patients. CR + complete remission with incomplete recovery were achieved in 21 patients (11/12 (92 %) receiving clofarabine 10 mg/m(2)/day; 10/13 (77 %) receiving clofarabine 15 mg/m(2)/day). Clofarabine, 5 × 10 mg/m(2)/day, resulted in one DLT and no early treatment withdrawals. MTD of clofarabine combined with cytosine arabinoside and idarubicin is 5 × 10 mg/m(2)/day.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands, r.willemze@lumc.nl.
authors.forename: R
authors.initials: R
authors.lastname: Willemze
authors.forename: S
authors.initials: S
authors.lastname: Suciu
authors.forename: P
authors.initials: P
authors.lastname: Muus
authors.forename: C J M
authors.initials: CJ
authors.lastname: Halkes
authors.forename: G
authors.initials: G
authors.lastname: Meloni
authors.forename: L
authors.initials: L
authors.lastname: Meert
authors.forename: M
authors.initials: M
authors.lastname: Karrasch
authors.forename: J
authors.initials: J
authors.lastname: Rapion
authors.forename: M
authors.initials: M
authors.lastname: Vignetti
authors.forename: S
authors.initials: S
authors.lastname: Amadori
authors.forename: T
authors.initials: T
authors.lastname: de Witte
authors.forename: J P
authors.initials: JP
authors.lastname: Marie
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage / Q000009:adverse effects; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000009:adverse effects; D000077866:Clofarabine; D060830:Consolidation Chemotherapy; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D006932:Hyperbilirubinemia / Q000139:chemically induced; D015255:Idarubicin / Q000008:administration & dosage / Q000009:adverse effects; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D012074:Remission Induction; D012306:Risk; D016896:Treatment Outcome
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D003561:Cytarabine; D000077866:Clofarabine; D006918:Hydroxyurea; D015255:Idarubicin