Nonmyeloablative Allogeneic Stem Cell Transplantation From HLA-Matched Unrelated Donor for the Treatment of Hematologic Disorders

Allogeneic Transplantation and the Graft versus Disease Effect Over the past three decades, the transplantation of allogeneic marrow grafts has emerged as a uniquely effective therapy for patients with hematologic malignancies, marrow failure syndromes, and other lethal genetic and acquired diseases of hematopoiesis.1-9 Allogeneic transplantation potentially results in curative outcomes for patients with acute leukemia, chronic myelogenous leukemia, aplastic anemia, and lymphoid malignancies for whom standard therapies may not be effective. The anti-tumor effect mediated by allogeneic lymphocytes is an essential factor in eliminating residual disease post-transplant and preventing subsequent relapse.10-14 Numerous observations in patients undergoing allogeneic bone marrow transplant for hematological malignancies have convincingly demonstrated evidence of a graft-versus-disease (GVD) effect mediated by lymphocytes present in the donor graft. Supportive evidence for the importance of this phenomenon includes: 1) relapse rates of syngeneic BMT recipients are greater than in allogeneic recipients; 2) allogeneic BMT recipients who do not develop graft-versus-host disease (GVHD) have a significantly greater relapse rate than allogeneic BMT-recipients who do develop GVHD; 3) complete remissions have been observed in patients with relapsed disease after allogeneic BMT in association with flares of GVHD; 4) recipients of T-cell depleted BMT, a method of GVHD prophylaxis, relapse more frequently than recipients of non-T-cell depleted BMT; and 5) the use of an unrelated marrow graft in both non-T-cell depleted and T-cell depleted allogeneic BMT is associated with a reduced incidence of relapse.

The most direct evidence for the role of allogeneic lymphocytes in mediating an antitumor effect has been that patients who experience relapse following allogeneic transplantation may be successfully treated by the infusion of donor leukocytes.15-22 Summarizing the European experience, Kolb et al reported that the over 80% of patients with CML who relapse into the chronic phase following transplant may achieve a second complete remission after the infusion of donor leukocytes infusion in treating relapsed CML following transplant. Complete remissions with the use of DLI for the treatment of relapsed acute leukemias, chronic lymphocytic leukemia, myelodysplastic syndromes, multiple myeloma, and polycythemia vera, although lower than those seen in CML, have been well demonstrated by several groups. Additionally, a potent graft versus disease effect associated with allogeneic transplantation and donor leukocyte infusion has been observed in patients with non-Hodgkin's lymphoma and multiple myeloma.23-25 Thus, allogeneic transplantation offers a uniquely effective approach to eradicating hematological malignancy in which myeloablative therapy results in profound tumor cytoreduction and donor lymphocytes subsequently eliminate minimal residual disease via immunological mechanisms.

Limitations in the Application of Allogeneic Transplantation The use of allogeneic BMT has been limited by the significant treatment related morbidity and mortality associated with this procedure. Patients often experience significant organ dysfunction as a result of regimen related toxicity. Moderate to severe graft versus host disease occurs in approximately 40% of patients undergoing matched sibling conventional transplants and increases in incidence in older patients and those receiving unrelated or mismatched grafts.26-28 Opportunistic infections due to immune dysfunction remains a major source of morbidity and mortality particularly in older patients. The application of allogeneic transplantation is therefore restricted to younger patients with normal underlying organ function. Because the median age of many hematological malignancies may exceed 60 years of age, a majority of patients with these disorders are not considered candidates for this procedure.

The difficulty in applying allogeneic transplantation in patients with hematological malignancies is particularly highlighted in patients with lymphoid malignancies such as multiple myeloma, chronic lymphocytic leukemia and low-grade lymphoma. These disorders are incurable with standard dose chemotherapy but may follow a relatively indolent course for several years before patients develop progressive chemoresistant disease. Allogeneic transplantation has been associated with long-term disease free survival in these settings but is associated with a high incidence of upfront transplant related mortality. Strategies to limit transplant related toxicity are essential to translate the decreased incidence of relapse into an improvement in overall survival in this patient population.

Nonmyeloablative Allogeneic Transplantation One approach to limit the toxicity of allogeneic transplantation has been the use of nonmyeloablative regimens preceding the infusion of allogeneic cells.29-33 With this strategy, patients receive immunosuppressive therapy that allows for the engraftment of donor cells without the immediate eradication of patient hematopoiesis. The primary mechanism by which the underlying disease is eradicated is not through chemotherapy-mediated cytoreduction, but rather through the donor lymphocyte mediated graft versus tumor effect. As a result, patients experience far less regimen related toxicity. Therefore, the adoption of this strategy may allow for the use of allogeneic transplantation in disease settings and patient populations for which it had not been readily applicable in the past.