Radioimmunotherapy for B-Cell Non-Hodgkin Lymphomas
Radioimmunotherapy for B-Cell Non-Hodgkin Lymphomas
Background: Radioimmunotherapy (RIT) is a safe and effective therapeutic option for patients with indolent B-cell non-Hodgkin lymphomas (NHL), in both up-front and relapsed/refractory settings. Two approved agents (Y-ibritumomab tiuxetan and I-tositumomab) are available in the United States. Both target CD20 with similar clinical outcomes but with unique clinical considerations and radiation precautions due to the use of varying radioisotopes.
Methods: This paper reviews the available evidence for these approved RIT agents and examines the recently published and ongoing clinical trials of potential novel indications for aggressive B-cell NHL.
Results: A pretreatment biodistribution evaluation required before administering the Y-ibritumomab tiuxetan therapeutic dose has been removed, which once limited its usage. The potential clinical applications of RIT include relapsed/refractory indolent B-cell NHL, diffuse large B-cell lymphoma, indolent lymphoma in the front-line setting, and mantle cell lymphoma. Multiple novel RIT agents are in preclinical and clinical development, and the addition of radiosensitizers or external-beam radiotherapy may act in synergy with RIT for both indolent and aggressive lymphomas. The risk of treatment-related myelodysplastic syndrome does not appear to be higher in patients treated with RIT over those receiving chemotherapy alone.
Conclusions: RIT is a safe, effective, and significantly underutilized therapy for patients with B-cell NHL, and many studies have demonstrated the efficacy of Y-ibritumomab tiuxetan and 131I-tositumomab for relapsed/refractory indolent B-cell lymphomas. Continued research to establish its efficacy for other lymphoma subtypes is warranted.
The treatment of B-cell non-Hodgkin lymphoma (NHL) has undergone significant transformation since the approval of rituximab in 1997 by the US Food and Drug Administration (FDA). This chimeric monoclonal antibody is specifically targeted to the CD20 molecule on the surface of mature B cells and B-cell lymphomas. While the endogenous role of CD20 is incompletely defined, evidence suggests a role in B-cell cycle progression as well as regulation of calcium influx necessary for B-cell activation. Rituximab exerts a cytotoxic effect via numerous different mechanisms including induction of apoptosis, antibody-dependent cell-mediated toxicity, and complement-mediated cytotoxicity. However, this cytotoxic response requires the physical association of the monoclonal antibody with the particular target cell. Thus, a fractionated approach is necessary as evidenced by the approved regimens for rituximab as sole therapy and in combination with chemotherapy.
It was recognized early that the addition of a radionuclide to monoclonal antibodies would be a rational approach to achieving additional cytotoxic effects, particularly given the inherent radiosensitivity of most lymphomas. This approach, termed radioimmunotherapy (RIT), allows for the delivery of radionuclides directly to the surface of target tumor cells. Over time, as the radionuclide decays, the particles released cross several cell diameters, leading to a significant radiation exposure to cells not bound by the antibody. This "crossfire effect" is thought to lead to a significantly higher penetration within involved lymphoma lesions, particularly in the setting of bulky disease or in poorly perfused regions. To date, two RIT agents have been approved by the FDA for the treatment of B-cell NHL: yttrium-90 (Y)- ibritumomab tiuxetan (Zevalin) and iodine-131 (I)- tositumomab (Bexxar). Both agents are indicated for the treatment of relapsed or refractory CD20-positive lymphomas. In addition, Y-ibritumomab tiuxetan has an indication in the front-line setting following a complete response (CR) or a partial response (PR) to cytotoxic systemic therapy. I-tositumomab carries an additional indication for the treatment of transformed B-cell NHL. Both agents utilize radionuclides that decay by releasing beta particles (high-energy electrons) that exert lethal effects by causing double-strand DNA breaks in tumor cells.
Abstract and Introduction
Abstract
Background: Radioimmunotherapy (RIT) is a safe and effective therapeutic option for patients with indolent B-cell non-Hodgkin lymphomas (NHL), in both up-front and relapsed/refractory settings. Two approved agents (Y-ibritumomab tiuxetan and I-tositumomab) are available in the United States. Both target CD20 with similar clinical outcomes but with unique clinical considerations and radiation precautions due to the use of varying radioisotopes.
Methods: This paper reviews the available evidence for these approved RIT agents and examines the recently published and ongoing clinical trials of potential novel indications for aggressive B-cell NHL.
Results: A pretreatment biodistribution evaluation required before administering the Y-ibritumomab tiuxetan therapeutic dose has been removed, which once limited its usage. The potential clinical applications of RIT include relapsed/refractory indolent B-cell NHL, diffuse large B-cell lymphoma, indolent lymphoma in the front-line setting, and mantle cell lymphoma. Multiple novel RIT agents are in preclinical and clinical development, and the addition of radiosensitizers or external-beam radiotherapy may act in synergy with RIT for both indolent and aggressive lymphomas. The risk of treatment-related myelodysplastic syndrome does not appear to be higher in patients treated with RIT over those receiving chemotherapy alone.
Conclusions: RIT is a safe, effective, and significantly underutilized therapy for patients with B-cell NHL, and many studies have demonstrated the efficacy of Y-ibritumomab tiuxetan and 131I-tositumomab for relapsed/refractory indolent B-cell lymphomas. Continued research to establish its efficacy for other lymphoma subtypes is warranted.
Introduction
The treatment of B-cell non-Hodgkin lymphoma (NHL) has undergone significant transformation since the approval of rituximab in 1997 by the US Food and Drug Administration (FDA). This chimeric monoclonal antibody is specifically targeted to the CD20 molecule on the surface of mature B cells and B-cell lymphomas. While the endogenous role of CD20 is incompletely defined, evidence suggests a role in B-cell cycle progression as well as regulation of calcium influx necessary for B-cell activation. Rituximab exerts a cytotoxic effect via numerous different mechanisms including induction of apoptosis, antibody-dependent cell-mediated toxicity, and complement-mediated cytotoxicity. However, this cytotoxic response requires the physical association of the monoclonal antibody with the particular target cell. Thus, a fractionated approach is necessary as evidenced by the approved regimens for rituximab as sole therapy and in combination with chemotherapy.
It was recognized early that the addition of a radionuclide to monoclonal antibodies would be a rational approach to achieving additional cytotoxic effects, particularly given the inherent radiosensitivity of most lymphomas. This approach, termed radioimmunotherapy (RIT), allows for the delivery of radionuclides directly to the surface of target tumor cells. Over time, as the radionuclide decays, the particles released cross several cell diameters, leading to a significant radiation exposure to cells not bound by the antibody. This "crossfire effect" is thought to lead to a significantly higher penetration within involved lymphoma lesions, particularly in the setting of bulky disease or in poorly perfused regions. To date, two RIT agents have been approved by the FDA for the treatment of B-cell NHL: yttrium-90 (Y)- ibritumomab tiuxetan (Zevalin) and iodine-131 (I)- tositumomab (Bexxar). Both agents are indicated for the treatment of relapsed or refractory CD20-positive lymphomas. In addition, Y-ibritumomab tiuxetan has an indication in the front-line setting following a complete response (CR) or a partial response (PR) to cytotoxic systemic therapy. I-tositumomab carries an additional indication for the treatment of transformed B-cell NHL. Both agents utilize radionuclides that decay by releasing beta particles (high-energy electrons) that exert lethal effects by causing double-strand DNA breaks in tumor cells.
