Allogeneic stem cell transplantation

Allogeneic stem cell transplantation, using myeloablative doses of chemotherapy and/or radiation followed by infusion of allogeneic stem cells, remains the only proven curative therapy for CML. Stem cells used for allogeneic transplantation may be obtained from either the bone marrow or the peripheral blood of the donor. Allogeneic stem cell transplantation in CML has a long-term survival rate of 55-80%, with median survival of more than 10 years for patients transplanted during chronic phase with non-T-cell-depleted marrow, using modern GVHD and cytomegalovirus prophylaxis. Results with allogeneic stem cell transplantation are much better for patients in chronic-phase CML than for those in the accelerated or blastic phase of the disease. Long-term overall survival rates are 15-20% for patients transplanted during the accelerated phase and below 10% for patients transplanted during the blastic phase.

The major causes of treatment failure are relapse and transplant-related mortality. Relapse rates are lowest for chronic-phase patients (10-20%), intermediate for patients transplanted in the accelerated phase (approximately 40%), and highest for patients allografted during the blastic phase, for whom relapse rates in excess of 60% are reported. The majority of relapses occur within the first 3 years after transplantation, though late relapses can occur.

Allogeneic stem cell transplantation is associated with high early rates of morbidity and mortality due to regimen-related toxicity, GVHD, and infectious complications. This early mortality is highly dependent on patient age and the degree of graft mismatch. Transplant-related mortality also increases with the interval from diagnosis of CML and with the stage of disease. Patients younger than 20 years with an HLA-matched sibling donor have a transplant-related mortality of 5-10%, with a long-term disease survival of 60-80% in most studies. Patients over the age of 40 have a risk of transplant-related mortality double that of patients under age 20. However, data from the Fred Hutchinson Cancer Research Center show that selected patients in the 50- to 60-year age group may have a disease-free survival at 4 years of approximately 80%.

The widespread application of stem cell transplantation has been limited by donor availability and the high toxicity of the procedure in older patients. Ongoing advances in alternative donor sources (including unrelated donors and, to a lesser degree, cord blood), more accurate molecular HLA typing, and less toxic regimens, including reduced intensity or non-myeloablative transplants, are broadening the potential use of this treatment modality.

Fig. 7.7 The IBMTR (International Bone Marrow Transplant Registry) experience of CML chronic-phase patients

The curves demonstrate both the effect of a related versus unrelated donor and the benefit of early transplantation for survival.

HLA-identical sibling, <1y (N = 2876)

HLA-identical sibling, >1y (N = 1391)

Unrelated, <1y (N = 613) Unrelated, >1y (N =936)

Years

CML is the most frequent indication for an unrelated donor transplant because of the lethality of the disease and the fact that disease progression is typically slow enough to allow adequate time for identification of a suitable donor. The use of volunteer unrelated donor transplants is associated with a higher incidence of viral infections, extensive chronic GVHD (up to 50%) and engraftment failure (16%) compared with related donor transplants. Recent reports show disease-free survival rates of 57-64% at 4 or 5 years after unrelated donor transplantation. In highly selected patients under age 50 who are transplanted within 1 year of diagnosis, a 74% survival rate at 5 years has been reported.

T-cell depletion of the unrelated allograft has been used in an effort to decrease the incidence of GVHD. Although this strategy does effectively reduce the incidence and severity of GVHD, it results in increased graft failure and relapse.

Non-myeloablative approaches use less intensive conditioning therapy than the standard allogeneic stem cell transplantation. The primary aim of non-myeloablative approaches is the induction of sufficient immunosuppression in the recipient to allow durable engraftment of both donor stem cells and donor lymphocytes, which can then exert a potent graft-versus-leukemia effect. However, GVHD remains a major limiting factor in this approach. It is not clear which patients should undergo a standard allogeneic transplant as opposed to a non-myeloablative transplant.

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