Targeted therapy of lymphoid malignancies.

摘要

Lymphoid malignancies including non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and hairy cell leukemia are often cited as the most treatable forms of cancer. Unfortunately, there has been no improvement in survival for patients with these diseases for more than two decades; however, our understanding of the biology of lymphoid malignancies has improved and suggests several ways to target the treatment of these diseases. The purine nucleoside analogs pentostatin and fludarabine, the anti-CD20 monoclonal antibody rituximab, and Epstein-Barr virus (EBV) specific cytotoxic lymphocytes target unique biologic features of different lymphoid malignancies. The efficacy of these therapies was tested in four studies. The long-term follow-up of hairy cell leukemia patients treated with pentostatin was analyzed and this study demonstrated that durable remissions are achievable and these patients have a survival similar to patients without hairy cell leukemia. Unfortunately, most patients with other indolent lymphoid malignancies do not achieve a complete remission with pentostatin or other nucleoside analog. Laboratory data suggests that combining fludarabine with cyclophosphamide may improve the response rate over single agent fludarabine. A phase II study of fludarabine was conducted and revealed a 51% complete response rate with tolerable toxicity. The use of high dose therapy with autologous stem cell transplant is another approach to the treatment of lymphoid malignancies, however the majority of patients who undergo this procedure are destined to relapse. The causes of relapse include residual neoplastic cells persisting despite high dose therapy and the reintroduction of malignant cells into the host with the stem cell graft. A phase II study was conducted using rituximab as an in vivo purging agent and post-transplant adjuvant. This study revealed that this approach is well tolerated and demonstrated preliminary evidence of efficacy. Targeting malignancies with cellular therapy is another immunotherapeutic approach to cancer and an alternative to antibody-based therapies. Epstein-Barr virus specific cytotoxic lymphocytes from partially matched HLA donors were used to treat patients with EBV-associated malignancies. This study demonstrated that this approach was safe; however, the efficacy was limited by the short survival of the infused cells. Further testing and improvements are needed in the above approaches before they can be considered standard therapy. A randomized phase III study of fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia is currently ongoing. A randomized phase III trial of rituximab with autologous stem cell transplantation is currently being planned. Finally, a study examining the effect of increased immunosuppression with a non-myeloablative bone marrow transplant regimen on EBV-CTL engraftment is also planned.