Nonmyeloablative Allogeneic Stem-Cell Transplantation
Background: Increasingly, clinicians advocate the use of nonmyeloablative allogeneic stem-cell transplants (NM-allo-SCTs, "mini-transplants") to manage hematologic malignancies. They hypothesize that NM-allo-SCT is equally efficacious to standard allo-SCT but produces less regimen-related toxicity.
Methods: To analyze available evidence on the benefits and harms of "mini-transplants," we identified 23 manuscripts, 1 abstract, and 1 letter that reported the outcome of mini-transplants in hematologic malignancies.
Results: Data were compiled on 603 treated patients, with 118 transplants using stem cells from matched unrelated donors. All studies were small prospective case series, and most lacked concurrent or historical controls. Outcomes of interest were not uniformly reported. The studies were heterogeneous and used different patient selection criteria, conditioning regimens, and timing of transplant with respect to disease status. The transplant-related mortality rate was 32%, the relapse rate was 15%, and toxicities included acute and chronic graft-vs-host disease and veno-occlusive disease. The aggregate rate of complete remission was 45%. Survival at 1 year or longer ranged from 30% to 60% at 1 to 5 years of follow-up. All studies reported successful chimerism.
Conclusions: Disease-specific studies with longer follow-up are needed to evaluate this potentially promising therapy.
Allogeneic Stem-Cell Transplantation. Allogeneic stem-cell transplantation (allo-SCT) utilizes hematopoietic stem cells from a nonidentical twin, another sibling or relative, or an unrelated donor to rescue patients from the myelotoxicity caused by high-dose chemotherapy (HDC). Allo-SCT is one method of hematopoietic stem-cell transplantation (HSCT). Another approach to HSCT utilizes autologous stem cells (ie, cells harvested from the patient) for rescue after myeloablative therapy -- HDC with autologous stem-cell support. This method produces no graft-vs-malignancy effect, and virtually all of the therapeutic efficacy results from the high-dose regimen. In general, HSCT takes advantage of a steep dose-response curve associated with chemotherapy, radiation therapy, or both. Otherwise, without a transplant, such high doses would cause severe myelosuppression.
An antitumor immunologic response (graft-vsmalignancy effect) may be associated with allo-SCT. Although there is strong evidence of a graft-vs-leukemia effect in allogeneic transplants for patients with chronic myeloid leukemia (CML), evidence is limited for comparable immunologic responses in patients with multiple myeloma (MM), acute lymphocytic leukemia (ALL), acute myelocytic leukemia (AML), or other hematologic malignancies.
In standard allo-SCT, hematopoietic growth factors are usually given to stimulate engraftment and hematopoietic recovery after infusing the donor cells. Immunosuppressants are administered at the time of stem-cell infusion to reduce the incidence of graft-vs-host disease (GVHD), which is a major complication of allo-SCT. Matching donors with recipients according to class I and II HLAs affects the occurrence and severity of acute and chronic GVHD and thus affects the out-come of allo-SCT. Hematopoietic stem cells for allogeneic transplantation may be harvested from bone marrow or peripheral blood. Umbilical cord blood also may be used as a source of stem cells but is not reviewed here.
Nonmyeloablative Conditioning With Allo-SCT. Myeloablative HDC/allo-SCT is associated with a high risk of treatment-related morbidity and mortality (TRM). Even in patients who are otherwise eligible for this procedure, myeloablative HDC/allo-SCT can be toxic. As shown in Table 1 ,TRM is high in patients with MM, non-Hodgkin's lymphoma (NHL), and Hodgkin's disease (HD). In addition, many patients with malignancies that could potentially be treated with HDC/allo-SCT are not eligible for the procedure due to age (55 years of age is the most common upper limit for eligibility in clinical trials of allo-SCT) or due to coincident disease or poor organ function, which increases the risk for an adverse outcome as a result of treatment-related toxicity. Therefore, treatments are needed that would maintain the high efficacy of myeloablative HDC/allo-SCT with reduced toxicity. For these patients, a nonmyeloablative preparative regimen followed by allogeneic stem-cell transplant (NM-allo-SCT, also known as a "mini-transplant" or "transplant lite") has been proposed to decrease the treatment-related morbidity associated with myeloablative chemotherapy while attempting to improve disease-free survival.
In recent years, the need for high-dose conditioning regimens has been challenged. Cures have been observed in patients with advanced malignancies, such as those in whom several courses of aggressive chemotherapy or standard allo-SCT have failed, with adoptive immunotherapy only (ie, using donor-lymphocyte infusion). This observation led to the hypothesis that the efficacy of allo-SCT may derive more from a "graft-vs-leukemia" effect than from the conditioning regimen. If so, long-term disease control might be feasible with less aggressive conditioning regimens. In turn, this might foster the development of safer allo-SCT that can be used for older patients and for those with preexisting organ dysfunction who are currently ineligible for standard HDC/allo-SCT.
Donor allogeneic stem cells can engraft in recipients with the use of less intensive but sufficiently immunosuppressive conditioning regimens to allow graft-host tolerance that yields stable mixed donor-host hematopoietic chimerism. After chimerism develops, donor-lymphocyte infusion can be given safely to eradicate malignant cells. Nonmyeloablative preparative regimens have been developed to enable mixed donor-host hematopoietic chimerism while minimizing the toxicity of standard, high-dose preparative regimens (Figure 1). These nonmyeloablative approaches can be divided in three categories : (1) reduced-intensity allo-SCT, (2) pre-allo-SCT host immunosuppression with post-allo-SCT immunosuppression directed at host and donor immune cells, and (3) high-intensity auto-SCT followed by an immunosuppressive cytotoxic allo-BMT alone.
(Enlarge Image)
Principle of nonmyeloablative allogeneic stem-cell transplantation. The goal of conditioning regimen (chemotherapy, radiation therapy or combination) is not to eradicate malignancy but to provide sufficient immunosuppression to prevent graft rejection and allow tolerance between donor and recipients (as measured by the existence of mixed chimerism). The purpose of donor T lymphocytes infusion (DLI) is to eradicate malignant clone. It is believed that mixed chimerism is sufficient to correct some nonmalignant disorders. Modified from McSweeney PM, Storb R. Establishing mixed chimerism with immunosuppressive, minimally myelosuppressive conditioning: preclinical and clinical studies. Hematology. Washington, DC: American Society of Hematology Education Program Book; 1999:396-405. American Society of Hematology, with permission.
In all of these settings, NM-allo-SCT serves as the basis for subsequent adoptive immunotherapy of the underlying malignancies using donor-lymphocyte infusion. It is important to note that a consistent definition of "nonmyeloablative" regimens is lacking with respect to drug classes, doses, and durations. Multiple regimens have been described, ranging from low-dose total-body irradiation (2 Gy) plus immunosuppressive agents such as mycophenolate mofetil and cyclosporine to regimens using combinations of drugs in doses similar to standard allo-SCT. Thus, these regimens comprise a continuum that overlaps with standard myeloablative regimens.
Background: Increasingly, clinicians advocate the use of nonmyeloablative allogeneic stem-cell transplants (NM-allo-SCTs, "mini-transplants") to manage hematologic malignancies. They hypothesize that NM-allo-SCT is equally efficacious to standard allo-SCT but produces less regimen-related toxicity.
Methods: To analyze available evidence on the benefits and harms of "mini-transplants," we identified 23 manuscripts, 1 abstract, and 1 letter that reported the outcome of mini-transplants in hematologic malignancies.
Results: Data were compiled on 603 treated patients, with 118 transplants using stem cells from matched unrelated donors. All studies were small prospective case series, and most lacked concurrent or historical controls. Outcomes of interest were not uniformly reported. The studies were heterogeneous and used different patient selection criteria, conditioning regimens, and timing of transplant with respect to disease status. The transplant-related mortality rate was 32%, the relapse rate was 15%, and toxicities included acute and chronic graft-vs-host disease and veno-occlusive disease. The aggregate rate of complete remission was 45%. Survival at 1 year or longer ranged from 30% to 60% at 1 to 5 years of follow-up. All studies reported successful chimerism.
Conclusions: Disease-specific studies with longer follow-up are needed to evaluate this potentially promising therapy.
Allogeneic Stem-Cell Transplantation. Allogeneic stem-cell transplantation (allo-SCT) utilizes hematopoietic stem cells from a nonidentical twin, another sibling or relative, or an unrelated donor to rescue patients from the myelotoxicity caused by high-dose chemotherapy (HDC). Allo-SCT is one method of hematopoietic stem-cell transplantation (HSCT). Another approach to HSCT utilizes autologous stem cells (ie, cells harvested from the patient) for rescue after myeloablative therapy -- HDC with autologous stem-cell support. This method produces no graft-vs-malignancy effect, and virtually all of the therapeutic efficacy results from the high-dose regimen. In general, HSCT takes advantage of a steep dose-response curve associated with chemotherapy, radiation therapy, or both. Otherwise, without a transplant, such high doses would cause severe myelosuppression.
An antitumor immunologic response (graft-vsmalignancy effect) may be associated with allo-SCT. Although there is strong evidence of a graft-vs-leukemia effect in allogeneic transplants for patients with chronic myeloid leukemia (CML), evidence is limited for comparable immunologic responses in patients with multiple myeloma (MM), acute lymphocytic leukemia (ALL), acute myelocytic leukemia (AML), or other hematologic malignancies.
In standard allo-SCT, hematopoietic growth factors are usually given to stimulate engraftment and hematopoietic recovery after infusing the donor cells. Immunosuppressants are administered at the time of stem-cell infusion to reduce the incidence of graft-vs-host disease (GVHD), which is a major complication of allo-SCT. Matching donors with recipients according to class I and II HLAs affects the occurrence and severity of acute and chronic GVHD and thus affects the out-come of allo-SCT. Hematopoietic stem cells for allogeneic transplantation may be harvested from bone marrow or peripheral blood. Umbilical cord blood also may be used as a source of stem cells but is not reviewed here.
Nonmyeloablative Conditioning With Allo-SCT. Myeloablative HDC/allo-SCT is associated with a high risk of treatment-related morbidity and mortality (TRM). Even in patients who are otherwise eligible for this procedure, myeloablative HDC/allo-SCT can be toxic. As shown in Table 1 ,TRM is high in patients with MM, non-Hodgkin's lymphoma (NHL), and Hodgkin's disease (HD). In addition, many patients with malignancies that could potentially be treated with HDC/allo-SCT are not eligible for the procedure due to age (55 years of age is the most common upper limit for eligibility in clinical trials of allo-SCT) or due to coincident disease or poor organ function, which increases the risk for an adverse outcome as a result of treatment-related toxicity. Therefore, treatments are needed that would maintain the high efficacy of myeloablative HDC/allo-SCT with reduced toxicity. For these patients, a nonmyeloablative preparative regimen followed by allogeneic stem-cell transplant (NM-allo-SCT, also known as a "mini-transplant" or "transplant lite") has been proposed to decrease the treatment-related morbidity associated with myeloablative chemotherapy while attempting to improve disease-free survival.
In recent years, the need for high-dose conditioning regimens has been challenged. Cures have been observed in patients with advanced malignancies, such as those in whom several courses of aggressive chemotherapy or standard allo-SCT have failed, with adoptive immunotherapy only (ie, using donor-lymphocyte infusion). This observation led to the hypothesis that the efficacy of allo-SCT may derive more from a "graft-vs-leukemia" effect than from the conditioning regimen. If so, long-term disease control might be feasible with less aggressive conditioning regimens. In turn, this might foster the development of safer allo-SCT that can be used for older patients and for those with preexisting organ dysfunction who are currently ineligible for standard HDC/allo-SCT.
Donor allogeneic stem cells can engraft in recipients with the use of less intensive but sufficiently immunosuppressive conditioning regimens to allow graft-host tolerance that yields stable mixed donor-host hematopoietic chimerism. After chimerism develops, donor-lymphocyte infusion can be given safely to eradicate malignant cells. Nonmyeloablative preparative regimens have been developed to enable mixed donor-host hematopoietic chimerism while minimizing the toxicity of standard, high-dose preparative regimens (Figure 1). These nonmyeloablative approaches can be divided in three categories : (1) reduced-intensity allo-SCT, (2) pre-allo-SCT host immunosuppression with post-allo-SCT immunosuppression directed at host and donor immune cells, and (3) high-intensity auto-SCT followed by an immunosuppressive cytotoxic allo-BMT alone.
(Enlarge Image)
Principle of nonmyeloablative allogeneic stem-cell transplantation. The goal of conditioning regimen (chemotherapy, radiation therapy or combination) is not to eradicate malignancy but to provide sufficient immunosuppression to prevent graft rejection and allow tolerance between donor and recipients (as measured by the existence of mixed chimerism). The purpose of donor T lymphocytes infusion (DLI) is to eradicate malignant clone. It is believed that mixed chimerism is sufficient to correct some nonmalignant disorders. Modified from McSweeney PM, Storb R. Establishing mixed chimerism with immunosuppressive, minimally myelosuppressive conditioning: preclinical and clinical studies. Hematology. Washington, DC: American Society of Hematology Education Program Book; 1999:396-405. American Society of Hematology, with permission.
In all of these settings, NM-allo-SCT serves as the basis for subsequent adoptive immunotherapy of the underlying malignancies using donor-lymphocyte infusion. It is important to note that a consistent definition of "nonmyeloablative" regimens is lacking with respect to drug classes, doses, and durations. Multiple regimens have been described, ranging from low-dose total-body irradiation (2 Gy) plus immunosuppressive agents such as mycophenolate mofetil and cyclosporine to regimens using combinations of drugs in doses similar to standard allo-SCT. Thus, these regimens comprise a continuum that overlaps with standard myeloablative regimens.