PF390 FIRST-LINE TREATMENT WITH LENALIDOMIDE DOES IMPROVE OUTCOME IN ELDERLY/UNFIT PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: J. Driessen, M.J. Kersten, A.P. Kater
Journal: HemaSphere (2019)

Background: Chronic Lymphocytic Leukemia (CLL) treatment is evolving rapidly. But, except for a small subset of patients undergoing allogenic stem cell transplantation, CLL is still not curable. Therefore, new therapies are needed that improve survival outcomes without increasing toxicity. Lenalidomide (Len) is an oral immunomodulatory drug with multiple effects on the immune system. High response rates are observed in early trials, however, exact place and duration of len treatment is still not optimized. Aims: The aim of this systematic review and meta-analysis was to provide overview of efficacy and safety of len as induction and consolidation therapy compared to standard treatment in previously untreated CLL patients. Methods: A systematic review and meta-analysis on len induction and consolidation treatment in elderly/unfit and young/fit first-line patients was performed. PubMed, EMBASE, Clinicaltrials.gov and Cochrane were searched for relevant cohort studies. Both randomized and non-randomized studies were included. Overall response rates (ORR), progression free survival (PFS) and safety outcomes were compared to standard CLL treatment, i.e. FCR for young/fit and rituximab or obinutuzumab with chlorambucil (R-Clb, G-Clb) for elderly/unfit patients, of which results were used from the large CLL11 and CLL10 studies of the German CLL Study Group. A meta-analysis was performed on ORR for len induction treatment. For studies investigating consolidation treatment, results were compared descriptively. Results: Ten studies, of which 9 non-randomized studies and 1 randomized study, with a total of 571 patients that received len induction treatment were included in the meta-analysis. A subgroup analysis was performed for patients undergoing len monotherapy (Len-mono) and len combination therapy (Len-combo). The summarized ORR using the random effects model of the two Len-combo in elderly/unfit studies was higher compared to standard treatment with a pooled ORR of 82% [95% CI: 72 - 89%] compared to 65.7% for R-Clb and 77.3% for G-Clb (Fig1A). The summarized ORR of Len-combo in the 5 young/fit studies was 87% [95% CI: 70 – 95%] compared to 90.4% for FCR, however, the chemotherapy regimens differ between the studies (Fig1B). Treatment with Len-mono was not superior compared to standard treatment in both elderly/unfit and young/fit patients (Fig1A+B). Seven studies, including 2 randomized studies, with a total of 305 patients that received len consolidation treatment were compared descriptively. All studies showed an improvement in response or PFS during consolidation with len. Moreover, one placebo-controlled study showed a significant PFS advantage for patients treated with lenalidomide consolidation, although no difference in overall survival was found. Toxicity was slightly increased with len therapy. Neutropenia was the most common toxicity but was usually manageable. Tumor lysis syndrome and tumor flare response grade 3/4 occurred rarely when individualized dose escalation of len was performed and thrombo-embolic events occurred in less than 5% when aspirin prophylaxis was given.Summary/Conclusion: This meta-analysis demonstrates that elderly/unfit CLL patients benefit from treatment with len in combination with rituximab/chlorambucil compared to R-Clb and G-Clb. In young/fit patients, standard FCR treatment remains superior. When len was given as consolidation treatment after induction treatment, responses increased and PFS was prolonged. Toxicity was higher compared to standard treatment, but was manageable when adequate prophylaxis was used.