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)
Highlights
Treatment of chronic lymphocytic leukaemia (CLL) in previously untreated patients has improved remarkably over the past 10 to 15 years [1]
While ibrutinib is licenced for the treatment of previously untreated patients regardless of the physical fitness, the use of idelalisib/rituximab or venetoclax in front-line treatment is restricted to CLL patients with del17p that are not suitable for other therapies
We found that high-risk FISH cytogenetics affected progression-free survival (PFS) (median PFS 46.4 months vs 70.5 months p = 0.037; HR 2.33 (Fig. 3c))
Summary
Treatment of chronic lymphocytic leukaemia (CLL) in previously untreated patients has improved remarkably over the past 10 to 15 years [1]. Recently gained insights into the pathobiology of CLL suggest that targeted treatment of CLL may be feasible by either attacking specific intracellular pathways or using substances that modify the microenvironment more globally [3]. Examples of the former (such as ibrutinib, idelalisib, or venetoclax) have entered the clinical field in relapsed/ refractory patients [4, 5] and have entered initial therapy. Among the options for microenvironment modification, lenalidomide has attracted interest for a number of years (reviewed in Kater et al.) [6]
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