Conditioning Regimens

The conditioning regimen administered before stem cell infusion plays several potential roles in promoting the success of transplantation. Cytoreduction of the endogenous malignancy with high-dose chemo/radiotherapy has traditionally been central to transplantation and is the major mode by which autologous transplantation benefits patients. Typical conditioning regimens for autologous transplantation include cyclophosphamide/total-body irradiation (Cy/TBI), cyclophosphamide/busulfan (Bu/Cy), cyclophosphamide/ BCNU/VP-16 (CBV), BCNU/etoposide, ara-C, melphalan (BEAM), VP-16/busulfan, and cyclophosphamide/thiotepa/ carboplatin (CTCb). It is not clear if one particular regimen is superior in a particular clinical circumstance, although it is generally assumed that results with current standard regimens are reasonably equivalent.

For allogeneic transplantation, the conditioning regimen not only reduces the disease burden but also suppresses the host to facilitate donor engraftment. The most common ablative combinations have been cyclophosphamide/total-body irradiation or cyclosphosphamide/busulfan. Several randomized studies of Cy/TBI and Bu/Cy have been conducted in patients with AML and CML.60-62 Socie et al. summarized the long-term results of four of these studies.63 With more than 7 years of follow-up in each study, no differences in long-term outcome were noted for patients with CML. They noted a nonsignificant 10% improvement for AML patients receiving Cy/TBI compared to Bu/Cy. The development of intravenous busulfan and strict pharmacokinetic monitoring to target

TABLE 6.1. Comparison of autologous and allogeneic transplantation.

Autologous

Allogeneic

Advantages 1. No HLA matching requirement

2. No graft-versus-host disease (GVHD)

3. No need for immunosuppression

Disadvantages 1. ? Stem cell damage from prior therapy leading to delayed engraftment or myelodysplasia

2. ? Graft contamination with tumor

3. No graft-versus-tumor effect

Lower risk of complications Higher risk of relapse

1. Stem cells have not been exposed to chemotherapy

2. Stem cells free of tumor

3. Graft-versus-tumor activity

1. Donor availability uncertain

2. GVHD

3. Infectious complications

Higher risk of complications Lower risk of relapse plasma levels of the drug has helped optimize efficacy and limit toxicity of the Bu/Cy regimen.28,64

Attempts to escalate doses of the conditioning have been disappointing. In several studies in which TBI dose intensity was increased to more than 1,500 cGy, modest decreases in relapse rates were offset by increases in regimen-related morbidity and mortality.65-67 The introduction of monoclonal antibodies directed at marrow elements linked to radioisotopes in hopes of targeting only marrow and not vital organs may offer hope of providing truly selective myeloablation.68 The lack of benefit of conditioning regimen dose intensification and the recognition of the contribution of graft-versus-tumor activity to disease eradication prompted the development of low-dose, nonmyeloablative regimens. These regimens are designed not to have direct antitumor activity but rather to provide sufficient host suppression to permit engraftment of donor hematopoietic and lymphoid effector cells. Many regimens ranging from nearly myeloablative to minimally myelosuppressive have been piloted. Most regimens have combined a purine analogue, such as fludarabine, with an alkylating agent or low-dose TBI with or without anti-T-cell antibodies such as thymoglobulin or alte-muzumab.69-73 Studies indicate that these nonmyeloablative regimens can facilitate full donor engraftment with much decreased upfront toxicity, allowing transplantation to be performed in older patients or those with contraindications to high-dose therapy. Unfortunately, GVHD still is a problem. One-hundred-day transplant-related mortality is low in recipients of nonmyeloablative conditioning, but later morbidity and mortality, usually from GVHD, can be substantial.74 Several retrospective comparative studies have suggested similar overall outcomes in recipients of myeloablative and nonmyeloablative transplants, but prospective randomized studies are needed to determine the impact of these less-intensive regimens on toxicity and disease control.

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