title: Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL).
abstract: Tumor necrosis factor alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) play an important role in the biology of chronic lymphocytic leukemia (CLL) cells. Thalidomide is a first-generation immuno-modulating agent that down-regulates TNF-alpha and VEGF. We initiated a phase 1/2 clinical trial to determine the safety and efficacy of combining thalidomide with fludarabine in patients with treatment-naïve CLL. Patients received 6 months of continuous daily thalidomide with standard monthly doses of fludarabine. Three dose levels of thalidomide (100, 200, and 300 mg) were studied. Results from the phase 1 part of this study are reported here. Thirteen patients were enrolled in the phase 1 component of the study. Dose-limiting toxicity was not reached. The most common toxicities noted were fatigue, constipation, and peripheral sensory neuropathy. Overall response rate was 100% with 55% of patients achieving complete remissions. At a median follow-up of 15+ months none of the patients have had a relapse and the median time to disease progression has not yet been reached. Responses were noted at all dose levels. Thalidomide given up to 300 mg/day concurrently with fludarabine in patients with previously untreated CLL shows encouraging clinical efficacy and acceptable toxicity. An ongoing phase 2 part of this study will help validate the clinical efficacy of this regimen.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14051, USA. chanan-khan@roswellpark.org.
authors.forename: Asher
authors.initials: A
authors.lastname: Chanan-Khan
authors.forename: Kena C
authors.initials: KC
authors.lastname: Miller
authors.forename: Kenichi
authors.initials: K
authors.lastname: Takeshita
authors.forename: Alexandra
authors.initials: A
authors.lastname: Koryzna
authors.forename: Kathleen
authors.initials: K
authors.lastname: Donohue
authors.forename: Zale P
authors.initials: ZP
authors.lastname: Bernstein
authors.forename: Alice
authors.initials: A
authors.lastname: Mohr
authors.forename: Donald
authors.initials: D
authors.lastname: Klippenstein
authors.forename: Paul
authors.initials: P
authors.lastname: Wallace
authors.forename: Jerome B
authors.initials: JB
authors.lastname: Zeldis
authors.forename: Christine
authors.initials: C
authors.lastname: Berger
authors.forename: Myron S
authors.initials: MS
authors.lastname: Czuczman
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D012074:Remission Induction / Q000379:methods; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide; D014740:Vidarabine; C024352:fludarabine