title: Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia.
abstract: OBJECTIVE
  Lenalidomide is a novel therapeutic agent with uncertain mechanism of action that is clinically active in myelodysplastic syndrome (MDS) and multiple myeloma (MM). Application of high (MM) and low (MDS) doses of lenalidomide has been reported to have clinical activity in CLL. Herein, we highlight life-threatening tumor flare when higher doses of lenalidomide are administered to patients with CLL and provide a potential mechanism for its occurrence.
  
  
  METHODS
  Four patients with relapsed CLL were treated with lenalidomide (25 mg/d for 21 days of a 28-day cycle). Serious adverse events including tumor flare and tumor lysis are summarized. In vitro studies examining drug-induced apoptosis and activation of CLL cells were also performed.
  
  
  RESULTS
  Four consecutive patients were treated with lenalidomide; all had serious adverse events. Tumor flare was observed in three patients and was characterized by dramatic and painful lymph node enlargement resulting in hospitalization of two patients, with one fatal outcome. Another patient developed sepsis and renal failure. In vitro studies demonstrated lenalidomide-induced B-cell activation (upregulation of CD40 and CD86) corresponding to degree of tumor flare, possibly explaining the tumor flare observation.
  
  
  CONCLUSIONS
  Lenalidomide administered at 25 mg/d in relapsed CLL is associated with unacceptable toxicity; the rapid onset and adverse clinical effects of tumor flare represent a significant limitation of lenalidomide use in CLL at this dose. Drug-associated B-cell activation may contribute to this adverse event. Future studies with lenalidomide in CLL should focus on understanding this toxicity, investigating patients at risk, and investigating alternative safer dosing schedules.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Andritsos
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: Cheryl
authors.initials: C
authors.lastname: Kefauver
authors.forename: Farrukh
authors.initials: F
authors.lastname: Awan
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Smith
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
authors.forename: Sarah E
authors.initials: SE
authors.lastname: May
authors.forename: Chelsey A
authors.initials: CA
authors.lastname: Raymond
authors.forename: Da-Sheng
authors.initials: DS
authors.lastname: Wang
authors.forename: Robert D
authors.initials: RD
authors.lastname: Knight
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ruppert
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D013792:Thalidomide; D000077269:Lenalidomide