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Profile of obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Hill BT, Kalaycio M - Onco Targets Ther (2015)

Bottom Line: This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities.Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL.Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

ABSTRACT
Chronic lymphocytic leukemia (CLL) is a hematologic malignancy derived from a clonal population of mature B-lymphocytes characterized by relatively low CD20 antigen expression. Although the disease often takes an indolent course, the majority of patients will eventually require therapy. Standard treatment for medically fit patients includes purine analogs and/or alkylating agents in addition to the type I anti-CD20 monoclonal antibody, rituximab. This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities. Historically, treatment options for the elderly or frail patient population were limited to mono-therapy with the oral alkylating agent, chlorambucil, rituximab, or another type I anti-CD20 monoclonal antibody ofatumumab. Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL. Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies. A large Phase III prospective randomized clinical trial for older patients with impaired renal function and/or significant medical comorbidities demonstrated that when compared to conventionally-dosed rituximab and chlorambucil, the combination of chlorambucil and obinutuzumab administered at a dose and schedule involving early loading doses improved response rates and progression-free survival without significantly increasing toxicity. Results of this pivotal trial led to the FDA (US Food and Drug Administration) approval of obinutuzumab in combination with chlorambucil for frontline treatment of CLL. Obinutuzumab expands the armamentarium of active and less-toxic targeted agents in the evolving treatment landscape of CLL, providing physicians and patients with an additional therapeutic option.

No MeSH data available.


Related in: MedlinePlus

Structure of CD20 and epitope targets of ofatumumab, rituximab, and obinutuzumab (GA101).Notes: The CD20 transmembrane receptor is shown with epitopes for binding of ofatumumab, rituximab, and obinutuzumab. Adapted with permission from Klein C, Lammens A, Schafer W, et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs. 2013;5(1):22–33.15
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f1-ott-8-2391: Structure of CD20 and epitope targets of ofatumumab, rituximab, and obinutuzumab (GA101).Notes: The CD20 transmembrane receptor is shown with epitopes for binding of ofatumumab, rituximab, and obinutuzumab. Adapted with permission from Klein C, Lammens A, Schafer W, et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs. 2013;5(1):22–33.15

Mentions: Given the additive benefit of rituximab to chemotherapy regimens, there has been considerable interest in improving anti-CD20 monoclonal antibody technology for therapeutic benefit. In particular, rituximab may not be the optimal agent to target CLL cells, which are characterized by relatively low cell surface expression of CD20. The first so-called second-generation anti-CD20 monoclonal antibody was ofatumumab. Ofatumumab is a fully humanized anti-CD20 monoclonal antibody whose epitope is a small loop of the extracellular domain of CD20, distinct from the binding site for rituximab (Figure 1).6,15 Preclinical studies suggested that ofatumumab has higher CD20 avidity than rituximab, possibly leading to more CMC.16


Profile of obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Hill BT, Kalaycio M - Onco Targets Ther (2015)

Structure of CD20 and epitope targets of ofatumumab, rituximab, and obinutuzumab (GA101).Notes: The CD20 transmembrane receptor is shown with epitopes for binding of ofatumumab, rituximab, and obinutuzumab. Adapted with permission from Klein C, Lammens A, Schafer W, et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs. 2013;5(1):22–33.15
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562745&req=5

f1-ott-8-2391: Structure of CD20 and epitope targets of ofatumumab, rituximab, and obinutuzumab (GA101).Notes: The CD20 transmembrane receptor is shown with epitopes for binding of ofatumumab, rituximab, and obinutuzumab. Adapted with permission from Klein C, Lammens A, Schafer W, et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs. 2013;5(1):22–33.15
Mentions: Given the additive benefit of rituximab to chemotherapy regimens, there has been considerable interest in improving anti-CD20 monoclonal antibody technology for therapeutic benefit. In particular, rituximab may not be the optimal agent to target CLL cells, which are characterized by relatively low cell surface expression of CD20. The first so-called second-generation anti-CD20 monoclonal antibody was ofatumumab. Ofatumumab is a fully humanized anti-CD20 monoclonal antibody whose epitope is a small loop of the extracellular domain of CD20, distinct from the binding site for rituximab (Figure 1).6,15 Preclinical studies suggested that ofatumumab has higher CD20 avidity than rituximab, possibly leading to more CMC.16

Bottom Line: This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities.Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL.Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

ABSTRACT
Chronic lymphocytic leukemia (CLL) is a hematologic malignancy derived from a clonal population of mature B-lymphocytes characterized by relatively low CD20 antigen expression. Although the disease often takes an indolent course, the majority of patients will eventually require therapy. Standard treatment for medically fit patients includes purine analogs and/or alkylating agents in addition to the type I anti-CD20 monoclonal antibody, rituximab. This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities. Historically, treatment options for the elderly or frail patient population were limited to mono-therapy with the oral alkylating agent, chlorambucil, rituximab, or another type I anti-CD20 monoclonal antibody ofatumumab. Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL. Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies. A large Phase III prospective randomized clinical trial for older patients with impaired renal function and/or significant medical comorbidities demonstrated that when compared to conventionally-dosed rituximab and chlorambucil, the combination of chlorambucil and obinutuzumab administered at a dose and schedule involving early loading doses improved response rates and progression-free survival without significantly increasing toxicity. Results of this pivotal trial led to the FDA (US Food and Drug Administration) approval of obinutuzumab in combination with chlorambucil for frontline treatment of CLL. Obinutuzumab expands the armamentarium of active and less-toxic targeted agents in the evolving treatment landscape of CLL, providing physicians and patients with an additional therapeutic option.

No MeSH data available.


Related in: MedlinePlus