alvocidib and Chromosome-Deletion

Patients with chronic lymphocytic leukemia (CLL) with high-risk genomic features achieve poor outcomes with traditional therapies. A phase I study of a pharmacokinetically derived schedule of flavopiridol suggested promising activity in CLL, irrespective of high-risk features. Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated.. Patients with relapsed CLL were treated with single-agent flavopiridol, with subsequent addition of dexamethasone to suppress cytokine release syndrome (CRS). High-risk genomic features were prospectively assessed for response to therapy.. Sixty-four patients were enrolled. Median age was 60 years, median number of prior therapies was four, and all patients had received prior purine analog therapy. If patients tolerated treatment during week 1, dose escalation occurred during week 2. Dose escalation did not occur in four patients, as a result of severe tumor lysis syndrome; three of these patients required hemodialysis. Thirty-four patients (53%) achieved response, including 30 partial responses (PRs; 47%), three nodular PRs (5%), and one complete response (1.6%). A majority of high-risk patients responded; 12 (57%) of 21 patients with del(17p13.1) and 14 (50%) of 28 patients with del(11q22.3) responded irrespective of lymph node size. Median progression-free survival among responders was 10 to 12 months across all cytogenetic risk groups. Reducing the number of weekly treatments per cycle from four to three and adding prophylactic dexamethasone, which abrogated interleukin-6 release and CRS (P < or = .01), resulted in improved tolerability and treatment delivery.. Flavopiridol achieves significant clinical activity in patients with relapsed CLL, including those with high-risk genomic features and bulky lymphadenopathy. Subsequent clinical trials should use the amended treatment schedule developed herein and prophylactic corticosteroids.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 17; Dexamethasone; Disease-Free Survival; Female; Flavonoids; Gene Expression Regulation, Leukemic; Genetic Predisposition to Disease; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Logistic Models; Male; Middle Aged; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Recurrence; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Tumor Lysis Syndrome

Topics: Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Biomarkers, Tumor; Cell Cycle Proteins; Chromosome Deletion; Cytogenetic Analysis; DNA-Binding Proteins; Drug Resistance, Neoplasm; Flavonoids; Humans; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Recurrence, Local; Piperidines; Protein Serine-Threonine Kinases; Risk Factors; Survival Rate; Treatment Outcome; Tumor Suppressor Protein p53; Tumor Suppressor Proteins