Thomas A. Waldmann

ABCs of Radioisotopes Used for Radioimmunotherapy: α- and β-Emitters

Although the introduction of the monoclonal antibody rituximab 5 years ago led to a marked improvement in the treatment of non-Hodgkins lymphoma (NHL), most patients do not experience a complete response to therapy, and many who do respond relapse. One way of improving the efficacy of monoclonal antibodies is to use them to deliver cytotoxic agents, such as radionuclides, to the tumor. Monoclonal antibodies armed with radionuclides provide a means of targeting radiation therapy specifically to tumor cells that express the antigen to which the antibody was originally raised. Subsequently, in 2002, the first radiolabeled monoclonal antibody, 90Y-ibritumomab tiuxetan was approved for the treatment of patients with relapsed or refractory low-grade follicular or transformed B-cell NHL, including patients with follicular lymphoma refractory to rituximab. Attempts to optimize the efficacy of radioimmunotherapy are ongoing, however, and there are three factors that need to be considered: choice of antibody/antigen, choice of delivery of system to be used, and choice of radionuclide. CD25 (IL-2Rα) is an ideal choice for a target antigen as it is over-expressed by a number of tumor cells, including adult T-cell leukemia (ATL); 9 of 16 patients with ATL responded to treatment with anti-Tac (which targets the interleukin-2 receptor-α [IL-2Rα]), conjugated to 90Y. The dose of radionuclide that can be delivered to a tumor can be increased dramatically by using a three-step process in which the antibody and radioactivity are delivered separately to the antigen in order to improve tumor-to-normal tissue ratios. The most commonly used radionuclides in radioimmunotherapy to date are β-emitters. However, the pretargeting process makes the use of short-lived α-emitters more feasible. The results of experiments involving this pretargeting process and α- and β-emitting radionuclides in leukemia and lymphoma models suggest that α-emitters may be more effective in the treatment of small tumors, micrometastases and isolated cells, and that β-emitters may be more suitable for use in large tumor masses, such as lymphomas.

Cardiac involvement with human T-cell lymphotrophic virus type-1-associated adult T-cell leukemia/lymphoma: The NIH experience

Malignant cardiac involvement is rare in patients with human T cell lymphotrophic virus type-1-associated adult T cell leukemia/lymphoma (ATLL). We report a single institution experience of eight patients with pathologically documented cardiac involvement with ATLL. Pericardial effusion and tamponade, cardiac valvular infiltration, valve leaflet tumor nodules and endocardial and myocardial tumors were observed. Cardiac involvement with ATLL was most often identified post-mortem; however, three cases were diagnosed clinically. All but one of the patients had the acute or lymphomatous subtypes of ATLL and had progressed through at least one prior systemic therapy. Patients with ATLL-related cardiac disease were also found to have pulmonary involvement suggesting that this may be a sign of increased risk of cardiac involvement. One patient with the chronic form of ATLL remains alive 10 years after undergoing cardiac valve replacement.