Allogeneic stem cell transplantation (allo-SCT) is a potentially curative procedure for a variety of malignant and nonmalignant conditions. Historically, allo-SCT was developed to rescue patients from the toxic side effects of lethal doses of radiation and chemotherapy given for malignancies. Hematopoietic stem cell transplants (HSCTs) have the ability to reconstitute hematopoiesis and immunity in the recipient. The role of allo-SCT has expanded owing to advances in conditioning, supportive care, management of complications, and the use of related and unrelated donor stem cells from a number of sources.

The objectives of HSCT are to eradicate the malignant cells and replace them with healthy cells. The process involves delivering chemotherapy/radiation to destroy tumor cells and suppress the recipient's immunity to prevent rejection of the transplant. This treatment also destroys normal hematopoietic cells. The healthy cells for transplant can be from the patient (ie, autologous [after he/she achieves a complete response] or allogeneic [from a donor]). Bone marrow, peripheral blood progenitor cells from a related or unrelated adult donor, or cord blood cells provide the cell source.[1] This activity will be limited to discussing allogeneic transplant.

This slide illustrates the recipient (R) with residual tumor cells (RL) who receives a preparative regimen followed by donor cells (D) from a human leukocyte antigen (HLA) compatible source. The end result should be reconstitution of hematopoiesis with healthy donor cells. The limitations for having a successful allo-SCT depend on finding an HLA-compatible donor, reducing transplant-related complications, and augmenting the graft-vs-tumor effect to prevent disease relapse. For patients in whom allo-SCT is indicated but who lack HLA-matched related or unrelated donors, alternative stem cell sources are available and should be considered. These include HLA-haploidentical family members, HLA-mismatched donors, or umbilical cord blood.[1]

This slide highlights 2009 data from the Center for International Blood and Marrow Transplant Research (CIBMTR) indicating the number of hematopoietic cell transplants (HCTs) conducted for hematologic malignancies. The most common indications for HCT in the United States in 2009 were multiple myeloma and lymphoma, accounting for 60% of all HCTs. Multiple myeloma continues to be the most common indication for autotransplantation and acute myeloid leukemia for allogeneic transplantation.[2]

Allo-SCT is an effective but toxic treatment for hematopoietic malignancies. It is associated with a high risk for morbidity and mortality. The choice for allo-SCT depends on the disease characteristics. In certain diseases for which chemotherapy followed by autologous transplant will not result in a cure, allo-SCT may be the only option.[3]

Transplant-related complications include graft rejection, acute or chronic graft-vs-host disease (GVHD), and opportunistic infections. Success of transplant depends on the effectiveness of conditioning regimens, the composition of the graft for durable engraftment and chimerism, and immune suppression to prevent graft rejection and create "space" for engraftment. To eliminate tumor cells of host origin several methods have been studied including cell therapy with alloreactive donor lymphocytes,[4,5] infusion of NK cells,[4] and T-cell depletion of the graft prior to transplant. Maintenance therapy following transplant is also a tactic to eradicate minimal residual disease (MRD).[6]

Hematopoietic transplants initially involved high-dose myeloablative treatment designed to maximally cytoreduce the malignancy. Myeloablative treatment has substantial toxicity. Much of the benefit in nonmyeloablative regimens results from immune-mediated graft-vs-malignancy effect and total elimination of the malignancy by the preparative regimen is not necessary. Reduced-intensity conditioning (RIC) or nonmyeloablative conditioning regimens have been developed that reduce the toxicity and treatment-related mortality. This has made allo-SCT available for older and medically infirm patients. Progression-free survival rates are similar to those achieved with myeloablative regimens.[7]

The myeloablative conditioning[8] regimen ablates the marrow, so it is reserved for healthy patients age ≤ 55 years. Examples are total body irradiation (TBI) ≥ 5 Gy single dose or ≥ 8 Gy fractionated radiation; busulfan (Bu) > 8 mg/kg orally or the intravenous equivalent. Combinations that deliver myeloablation may include Bu (IV) and cyclophosphamide (Cy); Cy/TBI (TBI dose > 500 cGy); Bu (oral or IV) and TBI or Bu/Cy/melphalan. Nonablative regimens[1] have reduced toxicity, resulting in reduced GVHD. Although similar infections occur in these patients, they generally respond to therapy. Their advantage is that there is lower treatment-related mortality and the use of HSCT can be extended to patients up to 75 years of age.

These data from CIBMTR illustrate the probability of overall survival (OS) after myeloablative allo-SCT. Results of allogeneic hematopoietic transplants have improved over time with refinement of preparative regimens, and better control of GVHD and infections. Data updated until November 2008.[9]

Nonmyeloablative and RIC regimens are less dependent on the cytotoxic effects of the conditioning regimen but rely on donor cellular immune effects to eradicate the underlying disease.[1,7] This approach is based on the induction of host tolerance to donor cells followed by the administration of scheduled donor T-lymphocyte infusions.

A nonmyeloablative regimen,[10] by definition, does not destroy the recipient's hematopoiesis and autologous recovery should occur without a hematopoietic transplant or if the graft is rejected. This regimen is designed to provide sufficient immunosuppression to prevent graft rejection.

A nonmyeloablative regimen results in reversible myelosuppression (usually within 28 days) when given without stem cell support, results in mixed chimerism in a proportion of patients at the time of first assessment, and is associated with a low rate of nonhematologic toxicity.[11] RIC is associated with higher relapse and lower nonrelapse mortality. Survival is not significantly different between the 2 regimens.[12]

Results of disease-free survival with alternative myeloablative regimens of Bu (16 mg/kg) and Cy (120 mg/kg) (Bu/Cy2) or Bu (16 mg/kg) and Cy (200 mg/kg) (Bu/Cy4) when compared with cyclophosphamide-TBI (Cy/TBI) conditioning in transplants for chronic myeloid leukemia (CML) indicate that Bu/Cy regimens are as effective as Cy/TBI regimens.[13,14] As the metabolism of Bu and Cy use glutathione it is an important consideration to avoid toxicity by staggering the dosing and measuring pharmacokinetic levels in patients.

BuCy is a commonly used preparative regimen BuCy is a commonly used preparative regimen. Recently busulfan has been combined with fludarabine (Bu-Flu), particularly in reduced-intensity regimens.[15,16] Results show that Bu-Flu compares favorably with BuCy2 as conditioning for patients with AML/MDS.[17] Purine analogues ( ie, fludarabine and cladribine) have been shown to be effective, but have been associated with an increased incidence of serious infection and severe acute GVHD.[18] Kaplan-Meier estimates for the probabilities of OS and nonrelapse related survival indicate that Bu-Flu treatment is associated with improved survival in this studied patient population. Pharmacokinetic-guided dosing will avoid unnecessary toxicity with Bu-Flu regimens.

This slide shows results (overall survival and event-free survival) with Bu-Flu conditioning in patients with AML and MDS. Patients with active disease at the time of HSCT were divided into 2 subgroups according to the presence or absence of circulating blasts. The outcome of patients with refractory disease without circulating blasts was significantly better than that of patients with peripheral blood disease. In patients with MDS, if extramedullary hematopoiesis in the liver is a factor, care has to be used in monitoring for additional toxicity.[19]

The intrapatient variability with drug exposure with administration of busulfan is shown here. Oral busulfan is erratically absorbed, resulting in unpredictable pharmacokinetics. The IV busulfan formulation avoids this problem and first-pass metabolism in the liver, providing more reliable dosing. There is still variability in clearance of busulfan and many centers use pharmacokinetic dose adjustment to ensure optimal drug levels.[20]

Patients clear busulfan at different rates via hepatic metabolism Patients clear busulfan at different rates via hepatic metabolism. Pharmacokinetic testing and dose adjustment to target a specific area under the curve ensure reproducible drug effects. This improves outcomes by ensuring adequate drug exposure to the malignancy and preventing toxicities in patients who slowly clear the drug. Inadequate drug exposure leads to less cytoreduction and relapse. Excess drug exposure leads to toxicities and increased probability of treatment-related mortality.

The syndrome of GVHD involves toxicity from chemotherapy/radiation damaging host cells, resulting in production of inflammatory cytokines which amplifies the immune graft-vs-host reaction. Reduced intensity or nonmyeloablative transplants produce less host tissue injury, and in many studies a lower rate of GVHD is observed.[21]

This slide shows relapse-free survival according to whether the patients received a transplant consult, donor, and transplant status. Results show that relapse-free survival was longest in patients who received a transplant. Results were similar with the other groups (ie, if the 13 patients with no, unavailable, or unHLA-typed siblings and the 14 with no sibling donors are considered separately).[22]

There is a potent graft-vs-leukemia (GVL) effect in CML There is a potent graft-vs-leukemia (GVL) effect in CML. Patients with residual disease detected posttransplant may achieve remission either from additional treatment with imatinib or other tyrosine kinase inhibitors or with a donor lymphocyte infusion. With transplant, whether agents are administered at preconditioning (ie, induction) (eg, cytarabine for AML) or posttransplant to eradicate residual disease, toxicities have to be watched carefully. During administration of conditioning regimens pharmacokinetic dosing can be applied, but when postconditioning medications such as those used for GvHD prophylaxis, for fungal infections, and for the treatment of relapse (eg, imatinib for CML) are used, patients should be carefully monitored for toxicities.[23-25]

The ideal nonablative hematopoietic transplant results in no or minimal GVHD, complete immune reconstitution by donor cells, and GVL effect to eradicate the residual malignant cells. In conclusion, the preparative regimen for HCT is designed to cytoreduce the malignancy and to provide immunosuppression to prevent graft rejection. An immune-mediated GVL effect will be able to eradicate drug-resistant cells. Reduced intensity and nonmyeloablative regimens improve toxicity and treatment-related mortality and allow transplants to be performed in older and medically infirm patients.