A Combination of Fludarabine/Rituximab with Escalating Doses of Lenalidomide in Previously Untreated Chronic Lymphocytic Leukemia (CLL): The REVLIRIT CLL5 AGMT Phase I/II Study, Clinical and Exploratory Analyses of Induction Results

CLL cells derive essential cues from their microenvironment, that may be targets for therapy. To this end the immunomodulatory drug Lenalidomide has shown remarkable clinical activity in monotherapy trials in CLL. However, tumor lysis and tumor flare have been major obstacles in development and marked and unexplained differences in the individual tolerance of the substance remains an unsolved problem. Furthermore, the potential for interaction with standard treatment for CLL is unknown. We employed the combination of Fludarabine and Rituximab for early reduction of tumorload and used it as a backbone to establish a tolerable Lenalidomide dose in combination.

In the induction phase a maximal tolerated dose (MTD) of Lenalidomide in combination with FR was to be determined during 6 cycles of Fludarabine (40mg/m2 po d1-3 q28d) and Rituximab (375mg/m2 iv d4 cycle 1; 500mg/m2 iv d1 cycles 2–6, q28d). In cycle 1 Lenalidomide was added day 7–21 at 2,5 mg. Toxicity permitting, Lenalidomide dose was escalated to 5, 10, 15, 20 and 25mg d1-21 over cycles 2–6. Data from this phase are presented in this planned analysis. Data from a 6 month Lenalidomide/Rituximab maintenance phase will be presented later.

The median age of the 45 recruited patients was 66 years (range 43–79). Half of the patients were in stages Rai III/IV and the median β2-MG was 4.4 mg/l. At least one high risk feature from CD38, FISH analysis and mutation status was present in 64% of patients. Five patients stopped treatment during induction (Two due to rashes, two as patient's choice and one due to early Richter's transformation). No systematic toxicity determining an MTD, the primary study endpoint, was found. In striking contrast to a small previous report, 34% of our patients proceeded through dose escalation steps as planned to receive a dose of 25mg of Lenalidomide with their last cycle of FR. The individual MTD was equal or higher than 10mg in 73% of ITT patients and 71% in this group were dose-limited due to individual differences in myelotoxicity. In ITT analysis 27% of patients had an MTD of less than 10mg. Grade 3 and 4 neutropenia was expected in this combination and observed in 88% of patients in any cycle. While it was not used as a dose limiting toxicity per se, 42% of patients were dose-limited due to myelotoxicity at some level. Infectious episodes of grade 3 severity were observed in 5 patients (11%), resulting in a relatively mild rate given the observed myelotoxicity and the phase I/II design. Surprisingly, 1/3 of the patients experienced greater than G2 skin toxicity and this was deemed dose-limiting in nine patients. No tumor lysis or greater than G2 flare reactions were observed. Full response assessment for induction treatment is available for 39 patients. Complete responses were observed in 49% and partial responses in 38% of the ITT population. In 35 patients flow MRD is available and 10 patients have reached MRD negativity. Response quality was not associated with risk factors, age or with lenalidomide dose in those receiving 6 cycles of treatment. Remarkably, one of three patients with deletion 17 achieved an MRD negative CR. Since we could not define a clinical predictor for the patients' tolerance of lenalidomide, we performed extensive immunophenotyping of T cells in pretreatment samples, using markers for functional T cells subsets, their Th polarity and for suppressive or exhausted T cell subsets. Employing a combined endpoint including non-hematological dose-limiting events or MTD < 10mg as a comparator, we identified a fraction of non-exhausted memory CD4 cells as highly significant predictor of dose-limiting non-hematologic events (p<0,005). Using a cut-off the T cell fraction has an 85% NPV for such events, possibly allowing for future identification of patients that will have difficulty with higher lenalidomide doses.

A combination of Lenalidomide with FR seems clinically feasible. While no clear dose dependent limiting toxicity has uniformly emerged in this combination, more than a third of patients had to be dose-limited due to not clearly dose-dependent non-hematologic toxicities (mostly skin-related). Novel biomarkers may be efficient in identifying those patients. In addition, the regimen shows encouraging clinical efficacy with limited clinical complication, particularly in the patients tolerating doses above 5mg. A follow-up study with higher starting dose is planned.

Egle:Celgene: Consultancy, Research Funding, Speakers Bureau; Roche: Speakers Bureau. Off Label Use: Use of Lenalidomide in CLL. Steurer:Roche: Speakers Bureau. Fridrik:Roche: Speakers Bureau. Thaler:Roche: Speakers Bureau. Lang:Roche: Speakers Bureau. Greil:Roche: Speakers Bureau.