A Phase 1/2 Study Of The Safety and Activity Of Escalating Doses Of Lenalidomide Plus Rituximab For Patients With Refractory Or Relapsed Chronic Lymphocytic Leukemia (LLC-Lenar-08)

Phase II trials have shown that lenalidomide alone is active in relapsed and refractory CLL. When the initially dose is reduced from 25mg to 5-10mg associated toxicities as the tumor lysis syndrome (TLS) or tumor flare reaction (TFR) nearly disappeared (J Clin Oncol 2006,24:5343). There is synergistic activity between rituximab and lenalidomide against CLL and non-Hodgkin lymphoma cells in vitro, and recently a Phase II study demonstrated that the combination of lenalidomide and Rituximab is active in patients with recurrent CLL (J Clin Oncol, 2012,31: 584). However neither the dose of lenalidomide nor the optimal schedule of administration has been defined. Furthermore since median age of CLL patients is high the emergence of a nonchemotherapy containing regimen with a lower toxicity seems an attractive approach for them. In 2008 we designed a trial that explore the optimal doses of lenalidomide in combination with rituximab for patients with relapsed or refractory CLL and analized also its safety and efficacy (ClinicalTrials.gov:NCT01185262). Our primary endpoint was to define the recommended dosage regimen for the combination of lenalidomide plus rituximab in patients with relapsed/refractory CLL. From June 2009 to November 2012 a dose escalation study was performed starting at a lenalidomide daily dose of 2,5mg and rituximab (375mg/m2 cycle 1 and 500mg/m2 cycles 2-6/28 days) with cohorts of 3 patients (if no DLT move to a higher dose; if one DLT ocurred in the cohort expand 3 more patients)(Tables 1 and 2). 29 patients has been registered in the trial. 4 of them were screening failures either because did not fullfilled criteria (2) or early withdrawal of patient consent before receiving treatment(2). Median age was 75 years (45-86). Median number of previous lines of treatment were 2 (1-4) and all but 2 patients were treated previously with fludarabine. In the first cohort of 2.5 mg we treated 6 patients and because of persistent neutropenia (more than 7 days grade 4) MTD ocurred. This was because the original protocol did not accept the prohylactic use of G-CSF. From that moment the use of G-CSF was free and based on the investigator criteria but mandatory for all those patients that started with less than 1000 neutrophils/mm3. A total of 33 SAEs were recorded among the 25 patients included in the two periods of the study (before and after the free use of G-CSF)(7/26 respectively) and during all the treatment. Main SAEs were as follows: Infections (23 SAEs with one case of Multifocal leukcoencephalophaty), constipation (2), autoimmune hemolytic anemia (1), allergic reaction to rituximab infusion (1), amyotrophic lateral sclerosis (1), gastrointestinal bleeding(1) and others (4). No case of TLS has been reported and only one case of mild TFR. By June 1st 2013 9/29 patients included has died and one is still receiving treatment. Causes of death were disease progression (5) and infection (4). In our experience the combination of lenalidomide and rituximab was a well tolerated regimen for this old (median age 75y) and heavely pre-treated population. In our experience lenalidomide at 15 mg was defined at the MTD. Neutropenia was the main adverse event associated with the regimen and nearly all patients needed G-CSF support. Clinical eficacy data is on evaluation.