Ofatumumab as Front-Line Therapy in Untreated CLL
Ofatumumab as Front-Line Therapy in Untreated CLL
Ofatumumab is a fully human IgG1 type I anti-CD20 monoclonal antibody that binds to both the small and large loop of the membrane antigen CD20. Much of its therapeutic efficacy is derived through complement-dependent cytotoxicity, although it also appears to operate via induction of caspase-dependent apoptosis and shows potent antibody-dependent cellular phagocytosis. CD20 is an important but sometimes difficult antigen to effectively target in chronic lymphocytic leukemia (CLL) secondary to its overall dim expression in CLL cells. Currently, ofatumumab is approved in the USA and EU for fludarabine- and alemtuzumab-refractory CLL patients. However, the experience with ofatumumab in untreated CLL patients is mounting and shows competitive response and survival rates with an acceptable adverse event profile. Herein, we outline the efficacy and toxicities of ofatumumab alone and in combination for the front-line treatment of CLL.
Chronic lymphocytic leukemia (CLL) is characterized by proliferation and accumulation of malignant mature monoclonal B lymphocytes. CLL is the most common chronic leukemia diagnosed in adults in western countries. As of 2010, the prevalence of CLL in the USA was estimated at approximately 120,000 individuals. In the USA, 15,680 new cases of CLL were diagnosed in 2013, 9720 in men and 5960 in women for a men-to-women ratio of 1.6:1. Additionally, 4580 deaths from CLL have been estimated in the USA in 2013, with 2750 deaths in men and 1830 in women. The median age at CLL diagnosis is 72 years, and the incidence increases with age. Other factors associated with an increased risk of CLL are a family history of hematologic malignancy, and possibly red blood cell transfusions.
The clinical course of CLL is variable but typically characterized by a chronic, indolent course that can progress for years to decades. A large proportion of patients will be asymptomatic and diagnosed incidentally while undergoing routine physical examination. Symptoms associated with CLL progression are varied and may include fever, night sweats and unintentional weight loss (i.e., B symptoms), but also lymphadenopathy, hepatosplenomegaly, and fatigue, infections and bleeding associated with decreased production of normal blood cell components or autoimmune processes.
The diagnosis of CLL is established by the presence of B-cell lymphocytosis >5000 cells/μl in peripheral blood for longer than 3 months. The characteristic immunophenotype of CLL cells shows a coexpression of the T-cell antigen CD5 along with the B-cell antigens CD19, CD20 (dim) and in most cases CD23. Monoclonality can be determined by immunoglobulin light chain restriction, cytogenetic abnormalities and/or immunoglobulin gene rearrangements. The prognosis of CLL relies on the clinical stage at presentation (e.g., early stage has a survival of >10 years while advanced stage of <3 years) and cytogenetic abnormalities (e.g., 17p deletions are associated with worse survival rates), among other factors.
Given the chronicity and incurability of CLL, it is a standard approach to delay therapy until patients are symptomatic from the disease; hence, most of the patients do not need therapy at the time of diagnosis. Once initiated, the main objective of CLL therapy is to improve symptoms and quality of life. New chemoimmunotherapy combinations have shown progression-free survival (PFS) and even overall survival (OS) benefit in younger patients, in particular those individuals who attained low levels of minimal residual disease. Despite these important advances there still remains no current curative therapy for CLL. Survival benefits are less clear in older patients who cannot tolerate the side effects of chemoimmunotherapy.
Abstract and Introduction
Abstract
Ofatumumab is a fully human IgG1 type I anti-CD20 monoclonal antibody that binds to both the small and large loop of the membrane antigen CD20. Much of its therapeutic efficacy is derived through complement-dependent cytotoxicity, although it also appears to operate via induction of caspase-dependent apoptosis and shows potent antibody-dependent cellular phagocytosis. CD20 is an important but sometimes difficult antigen to effectively target in chronic lymphocytic leukemia (CLL) secondary to its overall dim expression in CLL cells. Currently, ofatumumab is approved in the USA and EU for fludarabine- and alemtuzumab-refractory CLL patients. However, the experience with ofatumumab in untreated CLL patients is mounting and shows competitive response and survival rates with an acceptable adverse event profile. Herein, we outline the efficacy and toxicities of ofatumumab alone and in combination for the front-line treatment of CLL.
Introduction
Chronic lymphocytic leukemia (CLL) is characterized by proliferation and accumulation of malignant mature monoclonal B lymphocytes. CLL is the most common chronic leukemia diagnosed in adults in western countries. As of 2010, the prevalence of CLL in the USA was estimated at approximately 120,000 individuals. In the USA, 15,680 new cases of CLL were diagnosed in 2013, 9720 in men and 5960 in women for a men-to-women ratio of 1.6:1. Additionally, 4580 deaths from CLL have been estimated in the USA in 2013, with 2750 deaths in men and 1830 in women. The median age at CLL diagnosis is 72 years, and the incidence increases with age. Other factors associated with an increased risk of CLL are a family history of hematologic malignancy, and possibly red blood cell transfusions.
The clinical course of CLL is variable but typically characterized by a chronic, indolent course that can progress for years to decades. A large proportion of patients will be asymptomatic and diagnosed incidentally while undergoing routine physical examination. Symptoms associated with CLL progression are varied and may include fever, night sweats and unintentional weight loss (i.e., B symptoms), but also lymphadenopathy, hepatosplenomegaly, and fatigue, infections and bleeding associated with decreased production of normal blood cell components or autoimmune processes.
The diagnosis of CLL is established by the presence of B-cell lymphocytosis >5000 cells/μl in peripheral blood for longer than 3 months. The characteristic immunophenotype of CLL cells shows a coexpression of the T-cell antigen CD5 along with the B-cell antigens CD19, CD20 (dim) and in most cases CD23. Monoclonality can be determined by immunoglobulin light chain restriction, cytogenetic abnormalities and/or immunoglobulin gene rearrangements. The prognosis of CLL relies on the clinical stage at presentation (e.g., early stage has a survival of >10 years while advanced stage of <3 years) and cytogenetic abnormalities (e.g., 17p deletions are associated with worse survival rates), among other factors.
Given the chronicity and incurability of CLL, it is a standard approach to delay therapy until patients are symptomatic from the disease; hence, most of the patients do not need therapy at the time of diagnosis. Once initiated, the main objective of CLL therapy is to improve symptoms and quality of life. New chemoimmunotherapy combinations have shown progression-free survival (PFS) and even overall survival (OS) benefit in younger patients, in particular those individuals who attained low levels of minimal residual disease. Despite these important advances there still remains no current curative therapy for CLL. Survival benefits are less clear in older patients who cannot tolerate the side effects of chemoimmunotherapy.
