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

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

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Free PMC article
Clinical Trial

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

Alexander Egle et al. Ann Hematol. .
Free PMC article

Erratum in

Abstract

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.

Conflict of interest statement

Conflict of interest

A.E. reports speaker’s fees, travel support and research support from Celgene and Roche and consulting fees from Celgene outside the submitted work. R.Gr. reports personal fees and other from Bristol-Myers-Squibb; grants, personal fees and other from Cephalon; grants and personal fees from Amgen, Mundipharma, Genentech and Pfizer; personal fees from Eisai, Merck, Janssen-Cilag, Novartis, AstraZeneca, Boehringer Ingelheim, Roche and Sanofi Aventis; grants and other from Celgene and grants from GSK and Ratiopharm outside the submitted work. A.P. reports personal fees from Roche and Clegene outside the submitted work. M.G. reports personal fees from Basilea, MSD, Roche, Otsuka, Lilly, Merck, Celgene and Lipomed and non-financial support from Bayer, Amgen and Celgen outside the submitted work. M.S. reports personal fees from Roche and Celgene outside the submitted work. All other authors have no competing interests.

Figures

Fig. 1
Fig. 1
CONSORT diagram of patient disposition throughout the trial. Patient disposition is shown and further explained in the text
Fig. 2
Fig. 2
Achievable lenalidomide doses in combination treatment throughout the trial. a Maximum tolerated doses in induction combination with fludarabine and rituximab established by individual per patient dose finding. b Dose administered with the last of six cycles of FR (includes dose reductions after two stable cycles at the established MTD). c Fraction of on-trial patients per individual dose level per cycle of treatment
Fig. 3
Fig. 3
Kaplan-Meier estimates of a overall survival, b progression-free survival (PFS), c PFS by cytogenetic subgroup, d PFS by mutations state, e PFS by number of gene mutations and f PFS by MRD state after induction
Fig. 4
Fig. 4
T cell subsets predict intolerance for higher lenalidomide doses. a Gating strategy to identify naïve and memory subsets and to measure PD-1 expression; b percentage of PD1-positive cells in CD4+ cells, CD 4 memory T cells and central and effector memory subgroups from pretreatment samples from 41 patients treated in the trial. Patients were categorised into two groups depending on whether they reached a composite endpoint of observed non-haematologic dose-limiting toxicities or inability to escalate dose beyond 5 mg lenalidomide

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