Clinical trials evaluating a variety of agents in the management of patients with adult T cell leukemia (ATLL) have continued. These trials include evaluations of agents that target CD2 (siplizumab), CD25 (daclizumab) and CD52 (alemtuzumab). The phase I trial of siplizumab completed accrual to its initially planned evaluation of a two or three day course of treatment administered on an every other week basis for up to 16 weeks. Seven cohorts of patients were treated with doses ranging from 0.4 to 4.8 mg/kg. There were no dose-limiting toxicities and both T cell and NK cell depletion were observed. In this cohort of patients there was one patient who developed Epstein Barr Virus (EBV) lymphoproliferative disease nine months after her initial treatment with siplizumab. This was attributed to the agent that she was being treated with at the time. Down modulation of the siplizumab target, CD2, was observed within 24 hours of antibody administration in the peripheral blood and appeared to impair the activity of the administered antibody from producing further decreases in peripheral blood T cell numbers particularly in patients with high white blood cell counts. The protocol was amended to permit accrual of several additional cohorts of patients with doses ranging from 0.8 to 15 mg/kg administered as a single infusion weekly. Three of the six patients entered in this cohort developed EBV lymphoma or lymphoproliferative disease. Although partial and complete responses were observed the sponsor of the trial has elected to close the study. It is possible that EBV lymphoproliferative disease can be prevented by preemptive treatment with rituximab to deplete B cells. A follow up study is planned. The phase II trial of daclizumab has shown that the agent is inactive in patients with lymphomatous and the acute leukemic form of adult T cell leukemia but patients with the smoldering and chronic forms of the disease are responsive to this treatment. It is thought that these earlier forms of ATLL remain dependent on interleukin 2 signaling and that the responses are due to apoptosis due to cytokine deprivation. Accrual continues in our phase II trial of alemtuzumab as responses were observed in patients during the first stage of the trial. Accrual to a total of 29 patients is planned. Responses have been confined to patients with the acute leukemic and chronic forms of the disease but not in the lymphomatous presentation. In an attempt to define the mechanisms responsible for response and resistance to treatment we have begun collaborations with Dr. John Brady and Dr. Jane Trepel to identify new targets for treatment of patients with ATLL. Dr. Brady has observed high levels of the anti-apoptotic protein, survivin in patients with ATLL. Using cDNA microarray Dr. Brady has observed that responding patients treated with daclizumab have reduced levels of survivin message compared with pretreatment samples whereas the malignant cells that are resistant to alemtuzumab have elevated levels of survivin compared with pretreatment samples. A phase I clinical trial of humanized MiK-beta-1, directed at the beta chain of the IL-2 receptor continues accrual in patients with large granular lymphocyte leukemia. No dose-limiting toxicity has been observed and patients are being treated with the highest dose level planned for the study. Reduction in the numbers of peripheral blood malignant cells has been observed. In addition a phase I trial of HeFi-1, a murine monoclonal antibody directed at CD30 has completed accrual. Evidence of tumor regression has been seen in isolated lesions but no partial or complete responses were observed. In our Phase II trial of yttrium labeled Zenapax we have treated 30 patients with Hodgkins disease and other CD25 expressing malignancies. No responses were observed in the non-Hodgkins lymphoma cohort but 70% of patients with Hodgkins disease have achieved partial or complete responses. These responses have been observed in patients whose tumors progressed following autologous and allogeneic stem cell transplantation. Accrual of patients with Hodgkins disease continues and futures studies are planned to move this treatment into an earlier point in the treatment of these patients
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