Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study

Ann Hematol. 2018 Oct;97(10):1825-1839. doi: 10.1007/s00277-018-3380-z. Epub 2018 Jun 4.


Despite recent advances, chemoimmunotherapy remains a standard for fit previously untreated chronic lymphocytic leukaemia patients. Lenalidomide had activity in early monotherapy trials, but tumour lysis and flare proved major obstacles in its development. We combined lenalidomide in increasing doses with six cycles of fludarabine and rituximab (FR), followed by lenalidomide/rituximab maintenance. In 45 chemo-naive patients, included in this trial, individual tolerability of the combination was highly divergent and no systematic toxicity determining a maximum tolerated dose was found. Grade 3/4 neutropenia (71%) was high, but only 7% experienced grade 3 infections. No tumour lysis or flare > grade 2 was observed, but skin toxicity proved dose-limiting in nine patients (20%). Overall and complete response rates after induction were 89 and 44% by intention-to-treat, respectively. At a median follow-up of 78.7 months, median progression-free survival (PFS) was 60.3 months. Minimal residual disease and immunoglobulin variable region heavy chain mutation state predicted PFS and TP53 mutation most strongly predicted OS. Baseline clinical factors did not predict tolerance to the immunomodulatory drug lenalidomide, but pretreatment immunophenotypes of T cells showed exhausted memory CD4 cells to predict early dose-limiting non-haematologic events. Overall, combining lenalidomide with FR was feasible and effective, but individual changes in the immune system seemed associated with limiting side effects. clinicaltrials.gov (NCT00738829) and EU Clinical Trials Register ( www.clinicaltrialsregister.eu , 2008-001430-27).

Keywords: CLL; Combination; Fludarabine; Lenalidomide; Rituximab.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Consolidation Chemotherapy
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Eruptions / etiology
  • Female
  • Hematologic Diseases / chemically induced
  • Humans
  • Immunity, Cellular / drug effects
  • Immunologic Memory / drug effects
  • Immunotherapy
  • Kaplan-Meier Estimate
  • Lenalidomide
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Lymphocyte Count
  • Maintenance Chemotherapy
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Remission Induction
  • Rituximab / administration & dosage
  • Rituximab / adverse effects
  • T-Lymphocyte Subsets / drug effects
  • Thalidomide / administration & dosage
  • Thalidomide / adverse effects
  • Thalidomide / analogs & derivatives
  • Thalidomide / pharmacology
  • Treatment Outcome
  • Vidarabine / administration & dosage
  • Vidarabine / adverse effects
  • Vidarabine / analogs & derivatives


  • Rituximab
  • Thalidomide
  • Lenalidomide
  • Vidarabine
  • fludarabine

Associated data

  • ClinicalTrials.gov/NCT00738829