title: Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Hematology and Oncology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lin
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ruppert
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Beth
authors.initials: B
authors.lastname: Fischer
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Andritsos
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Flynn
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.forename: Weihong
authors.initials: W
authors.lastname: Hu
authors.forename: Mollie E
authors.initials: ME
authors.lastname: Moran
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Mitchell
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Smith
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: Chelsey A
authors.initials: CA
authors.lastname: Raymond
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Schaaf
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D002886:Chromosomes, Human, Pair 17; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000009:adverse effects; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D015275:Tumor Lysis Syndrome / Q000209:etiology / Q000517:prevention & control
chemical_list: D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C077990:alvocidib; D003907:Dexamethasone