Immunomodulatory Drugs and Active Immunotherapy for CLL
Background: The last decade witnessed the emergence of several therapeutic options for patients with chronic lymphocytic leukemia (CLL) for first-line and relapsed settings. The vast majority of patients with relapsed or refractory CLL carry poor prognostic features, which are strong predictors of shorter overall survival and resistance to first-line treatment, particularly fludarabine-based regimens.
Methods: This article highlights the current role of immunomodulatory drugs (IMiDs) and active immunotherapy as treatment options for this select group. The rationale of using IMiDs is discussed from the perspective of lenalidomide as a novel active agent. Relevant clinical trials using IMiDs alone or in combinations are discussed. New immunotherapeutic experimental approaches are also described.
Results: As a single agent, lenalidomide offers an overall response rate of 32% to 47% in patients with relapsed/refractory disease. Recent studies have shown promising activity as a single agent in treatment-naive patients. The combination of lenalidomide with immunotherapy (rituximab and ofatumumab) has also shown clinical responses. Encouraging preclinical and early clinical data have been observed with different immunotherapeutic approaches.
Conclusions: The use of IMiDs alone or in combination with immunotherapy represents a treatment option for relapsed/refractory or treatment-naive patients. Mature data and further studies are needed to validate overall and progression-free survival. The toxicity profile of lenalidomide might limit its use and delay further studies. Immunotherapy offers another potential alternative, but further understanding of the immunogenicity of CLL cells and the mechanisms of tumor flare reaction is needed to improve the outcomes in this field.
Prognostic factors, discussed in a separate article in this issue (Sagatys EM, Zhang L; pp 18–25), are strong predictors of progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed chronic lymphocytic leukemia (CLL). Patients with poor prognostic features are more likely to be refractory to first-line treatment, or they relapse early, requiring salvage therapies. Although several alternative therapies are available, none offers a durable response. Even with current standard therapies, there are still clearly unmet needs. Therefore, the treatment of relapsed or refractory CLL has become a challenge. For these reasons, considerable effort is aimed toward the development and use of different therapeutic agents for this population.
Immunotherapy is an appealing alternative and appears to offer a logical approach if we consider the biology of CLL. The tumor microenvironment and different cytokines play an important role in the evolution of this disease. Immunomodulatory drugs (IMiDs) offer different biologic effects on cytokine and cell-mediated responses. This article reviews the use of this new class of drugs for the treatment of relapsed and refractory CLL and also discusses new immunotherapeutic approaches.
Abstract and Introduction
Abstract
Background: The last decade witnessed the emergence of several therapeutic options for patients with chronic lymphocytic leukemia (CLL) for first-line and relapsed settings. The vast majority of patients with relapsed or refractory CLL carry poor prognostic features, which are strong predictors of shorter overall survival and resistance to first-line treatment, particularly fludarabine-based regimens.
Methods: This article highlights the current role of immunomodulatory drugs (IMiDs) and active immunotherapy as treatment options for this select group. The rationale of using IMiDs is discussed from the perspective of lenalidomide as a novel active agent. Relevant clinical trials using IMiDs alone or in combinations are discussed. New immunotherapeutic experimental approaches are also described.
Results: As a single agent, lenalidomide offers an overall response rate of 32% to 47% in patients with relapsed/refractory disease. Recent studies have shown promising activity as a single agent in treatment-naive patients. The combination of lenalidomide with immunotherapy (rituximab and ofatumumab) has also shown clinical responses. Encouraging preclinical and early clinical data have been observed with different immunotherapeutic approaches.
Conclusions: The use of IMiDs alone or in combination with immunotherapy represents a treatment option for relapsed/refractory or treatment-naive patients. Mature data and further studies are needed to validate overall and progression-free survival. The toxicity profile of lenalidomide might limit its use and delay further studies. Immunotherapy offers another potential alternative, but further understanding of the immunogenicity of CLL cells and the mechanisms of tumor flare reaction is needed to improve the outcomes in this field.
Introduction
Prognostic factors, discussed in a separate article in this issue (Sagatys EM, Zhang L; pp 18–25), are strong predictors of progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed chronic lymphocytic leukemia (CLL). Patients with poor prognostic features are more likely to be refractory to first-line treatment, or they relapse early, requiring salvage therapies. Although several alternative therapies are available, none offers a durable response. Even with current standard therapies, there are still clearly unmet needs. Therefore, the treatment of relapsed or refractory CLL has become a challenge. For these reasons, considerable effort is aimed toward the development and use of different therapeutic agents for this population.
Immunotherapy is an appealing alternative and appears to offer a logical approach if we consider the biology of CLL. The tumor microenvironment and different cytokines play an important role in the evolution of this disease. Immunomodulatory drugs (IMiDs) offer different biologic effects on cytokine and cell-mediated responses. This article reviews the use of this new class of drugs for the treatment of relapsed and refractory CLL and also discusses new immunotherapeutic approaches.
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