Lenalidomide as Single Agent to Control Minimal Residual Disease in Chronic Lymphocytic Leukemia In First Complete Remission: Report of Three cases

Lenalidomide is a novel therapeutic agent with immunomodulatory activity, that is clinically active in myelodysplastic syndrome and multiple myeloma. Recent clinical trials have shown that Lenalidomide may have clinical efficacy also in patients with Chronic Lymphocytic Leukemia (CLL). Studies so far reported have been carried out in patients with refractory or relapsed CLL. Besides its clinical efficacy, some concerns have been raised on the possible toxicity of Lenalidomide, with some unique effects, namely tumor flare reactions and tumor lysis syndrome, observed in CLL patients. A recent pilot study has been started at our Institution aimed to verify safety and efficacy of Lenalidomide given to control persistent minimal residual disease (MRD) in patients with CLL in 1^st Complete Remission (CR). The selection of patients in 1^st CR had a dual advantage: i. the possible use of Lenalidomide as single agent, without any other concurrent chemo-immunotherapeutic drugs that might interact in the clinical response; ii. the presence of low tumor burden, that allows to minimize the risk of severe side effects, in particular the risk of tumor lysis syndrome. So far, three patients have concluded the first year of Lenalidomide. Their clinical outcome, including treatment feasibility and monitoring of MRD, is here reported.

Case # 1: male, aged 53 yrs. in 2002 when he had a diagnosis of B-CLL, with mutated IgH genes; he remained in watchful waiting (w/w) for two yrs., then he received a Fludarabine-based treatment supplemented with Rituximab, achieving CR in September 2005; he then received 2-yr. maintenance with Rituximab; since 2008 he was off-therapy in clinical CR; Case # 2: male, aged 59 yrs. in 2005 when he had a diagnosis of B-CLL, with mutated IgH genes; he remained in w/w for three yrs., then he received a Fludarabine-based treatment supplemented with Rituximab, achieving CR in May 2008; thereafter he was off-therapy in clinical CR; Case # 3: female, aged 38 yrs. in 2002 when she had a diagnosis of B-CLL, with un-mutated IgH genes and she received an induction treatment with Fludarabine supplemented with Rituximab, achieving CR in April 2003; she then received prolonged and intermittent maintenance treatments with Rituximab; since 2008 she was off-therapy in clinical CR. All these patients showed a slow though continuous increase of their clonal B-cell population, identified by cytofluorimetric analysis as CD19+/CD5+ve cells. Based on the increase of the MRD, the patients were placed under Lenalidomide, given at 15 mg/day for 3 weeks/month, until disease progression or discontinuation for severe toxicity. Aspirin at 100 mg. daily was added for thromboembolic prophylaxis. Lenalidomide administration was approved by the Italian National Agency of drugs (AIFA).

Presently, all three patients are under Lenalidomide since 12 consecutive months, according to the planned treatment. There have been no severe toxicities, in particular neither tumor flare nor symptoms related to tumor lysis have been recorded. So far, no patients showed clinical signs of disease progression. MRD has been carefully monitored by immunophenotypic analysis on both bone marrow and peripheral blood. In details, the CD19+/CD5+ve clonal B-cell population progressively decreased under Lenalidomide in two patients, with the following changes over 1 yr. before and 1 yr. after Lenalidomide, respectively: 5 to 66 cells/μ L before, then reduction to 12 cells/μ L, in case #1; 189 to 4,480 cells/μ L before, then reduction to 1,317 cells/μ L, in case #2; the clonal B-cell population is still growing (from 67 to 116 cells/μ L before, and then up to 497/μ L after Lenalidomide) in the third patient, with un-mutated B-CLL. A significant increase of the activated T-cell (CD3+/DR+) population has been observed in all three patients following Lenalidomide.

This pilot study suggests that: i. Lenalidomide can be administered at 15 mg/day, 21 days/month, for over 1 yr. to patients with B-CLL in first CR, with reduced risks of severe side effects; ii. this schedule may be effective to control the expansion of the MRD in patients with B-CLL in clinical CR; iii. further studies on large series should be planned to verify in which patient subsets Lenalidomide might be offered, in order to reduce or even eliminate the MRD that usually persists in B-CLL patients following induction chemo-immunotherapy.

Off Label Use: Lenalidomide in CLL in first CR to control MRD.