title: Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia.
abstract: OBJECTIVE
  Lenalidomide is an oral immunomodulatory drug with multiple effects on the immune system and tumor cell microenvironment leading to inhibition of malignant cell growth. Based on encouraging reports of lenalidomide in relapsed and refractory chronic lymphocytic leukemia (CLL), we investigated the first-line use of single-agent lenalidomide in CLL.
  
  
  METHODS
  Using a starting dose of lenalidomide 10 mg/d for 21 days of a 28-day cycle and weekly 5-mg dose escalations to a target of 25 mg, we encountered severe toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and the protocol amended to a more conservative regimen: starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg, and extended tumor lysis prophylaxis and monitoring. Gene expression profiles from patient samples before and after 7 days of lenalidomide were performed.
  
  
  RESULTS
  Twenty-five patients were enrolled on the amended protocol. No further tumor lysis events were reported. Tumor flare was common (88%) but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of febrile neutropenia. The overall response rate was 56% (no complete responses). Although rapid peripheral lymphocyte reductions were observed, rebound lymphocytoses during the week off-therapy were common. Lenalidomide-induced molecular changes enriched for cytoskeletal and immune-related genes were identified.
  
  
  CONCLUSIONS
  Lenalidomide is clinically active as first-line CLL therapy and is well-tolerated if a conservative approach with slow dose escalation is used. A lenalidomide-induced molecular signature provides insights into its immunomodulatory mechanisms of action in CLL.
authors.affiliation: Princess Margaret Hospital/Ontario Cancer Institute, Toronto, Ontario, Canada. Christine.chen@uhn.on.ca
authors.forename: Christine I
authors.initials: CI
authors.lastname: Chen
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: Harminder
authors.initials: H
authors.lastname: Paul
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Anthea
authors.initials: A
authors.lastname: Lau
authors.forename: Nimisha
authors.initials: N
authors.lastname: Dave
authors.forename: Vishal
authors.initials: V
authors.lastname: Kukreti
authors.forename: Ellen
authors.initials: E
authors.lastname: Wei
authors.forename: Chungyee
authors.initials: C
authors.lastname: Leung-Hagesteijn
authors.forename: Zhi Hua
authors.initials: ZH
authors.lastname: Li
authors.forename: Joseph
authors.initials: J
authors.lastname: Brandwein
authors.forename: Mariela
authors.initials: M
authors.lastname: Pantoja
authors.forename: James
authors.initials: J
authors.lastname: Johnston
authors.forename: Spencer
authors.initials: S
authors.lastname: Gibson
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hernandez
authors.forename: David
authors.initials: D
authors.lastname: Spaner
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics* / Q000378:metabolism; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012074:Remission Induction; D015996:Survival Rate; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007155:Immunologic Factors; D013792:Thalidomide; D000077269:Lenalidomide