The REVLIRIT CLL5 AGMT Study - a Phase I/II Trial Combining Fludarabine/Rituximab with Escalating Doses of Lenalidomide Followed by Rituximab/Lenalidomide in Untreated Chronic Lymphocytic Leukemia (CLL): Results of a Planned Interim Analysis.

Increasing insight into the biology of CLL suggests a relevant interplay between tumor cells and the microenvironment. Preclinical data point to the potency of Lenalidomide to favourably modulate such interactions and remarkable clinical activity has been demonstrated in monotherapy trials in pretreated and also in previously untreated CLL patients. However, tumor flare and tumor lysis have been observed as problems and the optimal dose and schedule is still under investigation. In addition, the potential for interaction with effective standard treatment for CLL is unknown. We used a combination of Fludarabine and Rituximab as a backbone to establish a tolerable Lenalidomide dose in a dose escalation design.

The study treatment follows two phases: In the induction phase the maximal tolerated dose (MTD) of Lenalidomide in combination with FR should be determined. The protocol combines 6 cycles of Fludarabine (40mg/m2 po d1-3) and Rituximab (375mg/m2 iv day 4 on cycle 1 and 500mg/m2 iv day 1 on cycles 2-6), both in a 28 day cycle. Lenalidomide is given at a starting dose of 2,5 mg daily (day 7-21 of cycle 1) and with dose escalation steps to 5, 10, 15, 20 and 25mg of Lenalidomide from day 1-21 of the following cycles, if toxicity of the combination permits. In a second phase, Rituximab (375mg/m2 iv) at 2, 4 and 6 months after the last cycle is combined with Lenalidomide (day 1-28 of 28 day cycles) at the last tolerated dose for 6 months of maintenance. 40 patients are planned for this study. We herewith present the planned interim analysis for dose finding and safety endpoints for the induction phase of the first 10 patients recruited into the study.

Mean age of patients was 70 years (range 59-76). Six of 10 patients had stage Rai III/IV and mean WBC count was 159 G/L. Seven of 10 patients had at least one high risk feature from CD38 and FISH analysis or by mutation status. Of the 60 planned cycles 46 (77%) are currently evaluable for this analysis. No systematic toxicity determining MTD was found. 50% of patients proceeded through dose escalation steps as planned. Two patients have already tolerated 25mg of Lenalidomide with their FR cycles. Regarding toxicities, grade 3 and 4 neutropenia was expected in this combination and observed in 7/10 patients. However it was not used as a dose limiting toxicity per se. Still, one 75 year old patient was dose reduced because of febrile neutropenia in the previous cycle. Overall three infectious episodes were observed on treatment. Two patients experienced thrombotic events one of which was then taken off study because of Richter transformation, which might in hindsight have been present from study onset. Surprisingly, 5/10 patients experienced significant skin toxicity, mostly in the form of skin rashes, which was deemed dose limiting in two patients. It was, however, clearly associated with Pneumocystis prophylaxis in one patient, who then went on to receive the full Lenalidomide dose without further rashes. No tumor lysis or flare reaction was observed in the 10 patients reported. Preliminary efficacy data show that all patients achieved at least a PR after 3 cycles of therapy (except for the patient with the Richter transformation). Of the 3 patients currently evaluable after 6 cycles of treatment one CR and two very good PRs were observed before starting the maintenance phase of the study.

The combination of Lenalidomide with Fludarabine and Rituximab seems clinically feasible and no tumor lysis or flare reaction have been observed, possibly due to the Lenalidomide step up design, as well as the initial tumor load reduction by the chemo-immunotherapy backbone. No clear dose dependent toxicity has emerged as dose limiting for Lenalidomide escalation in this combination. However, 50% of patients had to be dose-limited due to not clearly dose-dependent skin and vascular toxicities. A regime of thromboprophylaxis as well as a delayed start of prophylaxis against pneumocystis have since been amended to improve the management of the patients. In addition, and remarkably, the regimen shows clinical efficacy despite controversial in vitro reports, suggesting a potential negative interaction between Lenalidomide and Rituximab. This might be due to the Lenalidomide pause before each Rituximab cycle or may reflect a difference between in vitro and in vivo.

Egle:Roche: Research Funding, Speakers Bureau. Off Label Use: Lenalidomide treatment in CLL, Rituximab maintenance in CLL. Greil:Roche: Honoraria, Research Funding; Celgene: Research Funding.