ABSTRACT: High-dose myeloablative therapy with allogeneic hematopoietic transplantation is an effective treatment for hematologic malignancies, but this approach is associated with a high risk of complications. The use of relatively nontoxic, nonmyeloablative, or reduced-intensity preparative regimens still allows engraftment and the generation of graft-vs-malignancy effects, is potentially curative for susceptible malignancies, and reduces the risk of treatment-related morbidity. Two general strategies along these lines have emerged, based on the use of (1) immunosuppressive chemotherapeutic drugs, usually a purine analog in combination with an alkylating agent, and (2) lowdose total body irradiation, alone or in combination with fludarabine (Fludara).
High-dose myeloablative therapy with allogeneic hematopoietic transplantation is an effective yet risky treatment for hematologic malignancies. This strategy is associated with a high risk of treatment-related complications, ranging from 10% to > 50%, depend depending on histocompatibility, age comorbidities, and disease factors. The initial concept of allogeneic transplantation for treatment of cancer was to use the transplant for supportive care, as a means to restore hematopoiesis after myeloablative doses of chemotherapy and/or total body irradiation. The pretransplant "preparative regimen" was intended to eradicate the malignancy as well as provide sufficient immunosuppression to prevent graft rejection.
The therapeutic benefit of allogeneic marrow transplantation for many diagnoses is largely related to an associated immune-mediated graftvs- malignancy effect.[2,3] This realization has recently led to the use of less toxic, nonmyeloablative preparative regimens to achieve engraftment and allow development of graft-vs-malignancy effects as a primary form of therapy. For nonmalignant disorders, it is not necessary to ablate diseased tissues; it is only necessary to achieve mixed chimerism to provide a source of normal hematopoietic cells.
Two general strategies have emerged. One approach is based on the use of immunosuppressive chemotherapeutic drugs, usually a purine analog in combination with an alkylating agent.[5-7] The other technique is based on the immunosup pressive effects of low-dose total body irradiation, alone or in combination with fludarabine (Fludara).
Nonmyelablative vs Reduced-Intensity Regimens
Several regimens have been proposed to reduce the toxicity associated with allogeneic transplantation. The relative myelosuppressive and immunosuppressive effects of these regimens are summarized in Figure 1.
As a working definition, a truly nonmyeloablative regimen should not eradicate host hematopoiesis and should allow relatively prompt hematopoietic recovery (< 28 days) without a transplant. Upon engraftment, mixed chimerism should be present, with both donor- and recipient- derived cells detectable. If the graft is rejected, prompt autologous recovery should occur. This category includes the fludarabine/cyclophosphamide (Cytoxan, Neosar), fludarabine/idarubicin (Idamycin)/ cytarabine(Drug information on cytarabine), and 2-Gy total body irradiation-based regimens.
The general treatment scheme of a nonablative regimen is illustrated in Figure 2. The nonablative preparative regimen does not completely eliminate host normal and malignant cells. An allogeneic graft-vs-hematopoietic effect occurs in which donor cells eradicate residual host hematopoiesis. Graft-vs-malignancy effects generally occur after the development of full donor T-cell chimerism.
An ablative regimen requires hematopoietic transplantation for recovery, and only donor-derived cells should be detectable after engraftment. Many of the lower-dose regimens designed to reduce toxicity- including combinations of intermediate doses of melphalan(Drug information on melphalan) (Alkeran) or busulfan(Drug information on busulfan) (Busulfex, Myleran) with fludarabine[5,7]-have been referred to as nonmyeloablative, but do not actually meet nonmyeloablative criteria. These regimens require a transplant for hematologic recovery, and if the graft is rejected, prolonged aplasia typically occurs. They should be referred to as reduced-intensity ablative regimens.
The intensity of immunosuppression required for engraftment depends on the immunocompetence of the recipient, histocompatibility, and the composition of the transplant. Initial studies focused on patients with a human leukocyte antigen (HLA)- matched sibling donor. More intensive regimens are required for engraftment in settings of greater genetic disparity, including unrelated-donor or HLAnonidentical transplants.
Advantages of Nonablative Regimens
Nonablative regimens have been studied as a means to reduce regimen- related toxicity. This approach allows hematopoietic transplantation in patients considered ineligible for myeloablative preparative regimens because of advanced age or the presence of comorbidities. Nonablative transplants are also associated with a reduced incidence and severity of acute graft-vs-host disease (GVHD). Several factors likely contribute to this observation. The clinical manifestations of acute GVHD partly result from the toxicity of the preparative regimen and subsequent cytokine release as well as the alloreactivity of the graft. Residual host T cells may produce a "veto" effect that also inhibits development of GVHD, and GVHD is less severe in the setting of mixed chimerism.
Infectious complications also appear to be reduced. Neutropenia is reduced or eliminated by most nonablative regimens. In addition, since the nonablative preparative regimen does not immediately eliminate host-derived immunocompetent cells, these cells can contribute to host defense in the early posttransplant period.
Disadvantages of Nonablative Transplants
There are also potential disadvantages of using nonablative preparative regimens. Higher doses of busulfan or total body irradiation have been shown to reduce the risk of relapse in chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML).[14-16] Approximately one-third of patients with good risk leukemias are cured with high-dose therapy and syngeneic transplants in which graft-vsleukemia (GVL) effects would not be expected to occur. Young patients without comorbidities tolerate supralethal regimens well, and reducing toxicity may not improve their survival. Given these considerations, nonablative regimens should be reserved for diagnoses that are exquisitely sensitive to graft-vs-malignancy effects, for older patients, or for those with comorbidities who would not be able to tolerate an ablative regimen.
Disease Susceptibility to Graft-vs-Malignancy Effects
Malignancies differ greatly in their susceptibility to GVL effects and, hence, their sensitivity to nonmyeloablative allogeneic transplants (see Table 1). Three general categories,based on levels of sensitivity to GVL effects, can be defined.
• Highly Sensitive Malignancies—CML is the disease in which GVL effects have been best documented.[ 18] The majority of CML patients who relapse into chronic phase following an allogeneic transplant achieve a durable complete remission with donor lymphocyte infusions. Indolent lymphoid malignancies also appear to be very sensitive to graft-vs-malignancy effects, as evidenced by durable remissions to donor lymphocyte infusions or modulation of immunosuppression in patients who have relapsed after an allogeneic transplant. Allogeneic transplants are associated with a substantially lower relapse rate than purged autologous transplants.
Selected patients with chronic lymphocytic leukemia or low-grade lymphoma have responded to donor lymphocyte infusions or modification of immunosuppressive therapy. In preliminary studies of nonablative allogeneic transplants, many patients with low-grade lymphoma, mantle cell lymphoma, or chronic lymphocytic leukemia have achieved durable remissions.[6,21,22]
These highly sensitive malignancies share several common characteristics. In CML and lymphoma, the malignant cells are derived from antigen-presenting cells-B-lymphocytes in the case of lymphoid malignancies, and dendritic cells generated from CML. Their responsiveness to GVL may, in part, relate to effective in vivo antigen presentation.
• Intermediate Sensitivity to GVL—A second category of malignancies, including AML, multiple myeloma, Hodgkin's disease, and intermediate- grade lymphoma, have intermediate sensitivity to GVL effects. In these diagnoses, allogeneic transplants produce a greater frequency of durable remissions than syngeneic or autologous transplants, but these disorders less frequently respond to donor lymphocyte infusions, and responses are usually transient. Nonablative transplants are most effective for these diagnoses when the malignancy is in a minimal disease state. In patients with resistant or bulky disease, the nonablative or reduced- intensity preparative regimens do not substantially cytoreduce the malignancy, resulting in a high rate of disease recurrence.
• Relatively Insensitive Malignancies—Acute lymphocytic leukemia and high-grade lymphoma appear to be relatively insensitive to GVL effects,[ 24] although patients with GVHD do have a reduced risk of relapse. The malignant lymphoblasts typically lack costimulatory molecules and do not effectively stimulate an immune response. The rapid rate of proliferation of these malignancies may also outpace a developing immune response; only rare patients have responded to donor lymphocyte infusions.
• Graft-vs-Tumor Effects—Graft-vs-tumor effects may also occur against solid tumors, although few studies of allogeneic transplantation in this setting have been performed. Pilot studies in breast cancer have reported antitumor responses in patients with GVHD, suggesting a graftvs- adenocarcinoma effect. Major antitumor responses have been reported in renal cell carcinoma, usually concomitant with the development of acute GVHD. Further studies are required to determine whether graft-vs-tumor effects are sufficiently active to justify the added morbidity related to allogeneic transplantation.