Phase II study of lenalidomide to repair immune synapse response and humoral immunity in early-stage, asymptomatic chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with high-risk genomic features
Hypotheses: Low-dose lenalidomide will enhance the efficacy of vaccination for infectious diseases among patients with CLL as measured by antibody response to pneumonia vaccination with conjugated 13-valent pneumococcal vaccine. Low-dose lenalidomide can also induce complete remissions in asymptomatic patients with high genomic risk CLL, delaying the time to first conventional therapy.
Study Design: Patients are randomized to one of two treatment arms. Oral low-dose lenalidomide is administered daily on a continuous basis for at least 24 28-day courses in the absence of disease progression or unacceptable toxicity. Patients also receive two doses of 13-valent protein-conjugated pneumococcal vaccine (PCV13) intramuscularly concurrent with or sequential to lenalidomide, depending upon treatment arm.
Rationale: OSU-10156 investigates the use of lenalidomide and vaccine therapy for treating early-stage, asymptomatic CLL or SLL. Survival of CLL patients ranges from months to more than 20 years, but infectious complications account for 30-50 percent of deaths. Unfortunately, many of the most common therapies for CLL (e.g., fludarabine, alkylating agents) can increase the risk for infection.
Standard care for CLL involves treating only symptomatic disease. Routine treatment of early-stage CLL is generally not considered beneficial. However, a subgroup of patients is at high-risk for early progression and death. For example, patients with CLL cells showing unmutated immunoglobulin heavy-chain genes (IgVH), a complex karyotype and deletions of chromosomes 11q22.3 and 17p13.1 demonstrate a shorter treatment-free interval and impaired survival.
Lenalidomide is a potent immunomodulatory analogue of thalidomide. Its immunomodulatory effects include stimulating T-cell proliferation and production of IL-2, IL-10 and IFN-γ. The agent has shown promising activity in both untreated and relapsed/refractory CLL, including patients with high-risk genomic features.
Evidence suggests that lenalidomide can promote both cellular and innate immune activation, and the drug has effected both remissions and improvement of immune-system parameters when given to patients with symptomatic CLL/SLL. Lenalidomide might further benefit patients if administered earlier in the disease course, when humoral and cellular immune mechanisms are more intact.
The Prevnar 13 (PCV13) vaccine is a conjugate vaccine for prevention of disease caused by the 13 pneumococcal serotypes. Research has shown that such vaccines are not only safe but also potentially more effective in several immunocompromised adult populations. Additionally, preliminary findings from a study of protein-conjugated pneumococcal vaccine and lenalidomide in multiple myeloma patients suggest that the vaccine and lenalidomide interact to boost immune responses.
OSU-10156 will help determine whether early treatment of early-stage, high-risk CLL patients with the PCV13 vaccine and either concurrent or sequential lenalidomide will help prevent immune deterioration in early-stage disease. Key objectives include determining the complete response rate after two years of lenalidomide therapy and determining the incidence of infection, particularly invasive pneumococcal infections.
At a Glance
Trial no.: OSU-10156 (ClinicalTrial.gov identifier NCT01351896
PI: Jeffrey A. Jones, MD, MPH
Phone: 614-293-3507
Email: jeffrey.jones@osumc.edu
Eligibility: Histologically confirmed, asymptomatic CLL/SLL with at least one high-risk genomic feature; age ≥18 years; ECOG performance status ≤ 2; non-pregnant and/or using adequate birth control; no previous treatment for CLL/SLL; no history of AIHA/ITP; no VTE events within 6 months; estimated life expectancy ≥24 months