Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes

Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes .

This approach has been used to treat various Myelodysplastic Syndromes in patients ranging in age from 1 month to older than 70 years.416–418 It remains the only treatment with curative potential for Myelodysplastic Syndromes. Conditioning regimens have consisted of cyclophosphamide plus irradiation or busulfan plus cyclophosphamide. Most patients have received transplants from histocompatible sibling donors, although some experience with partially mismatched, related, and unrelated donors has been reported. A good representation of the results of this traditional approach using marrow stem cells is a study of 93 patients (age range: 1 month to older than 60 years; median age: 30 years).419 The most favorable results were seen in patients younger than age 40 years with shorter duration of disease and with less than 5 percent blast cells in the marrow at the time of transplant. These patients may have a disease-free survival of 60 percent at 4 years and an overall disease-free survival estimated at 40 percent. Older patients had higher peritransplantation mortality and relapse rates. Actuarial relapse probability at 4 years was 30 percent for the entire group and 50 percent for patients with greater than 5 percent marrow blasts. Cytogenetic abnormalities did not predict outcome in this study, but adverse cytogenetics were an important prognostic factor in other studies. With targeted busulfan therapy, stem cell transplantation can be successfully performed in patients as old as 66 years of age.420,421 Numerous factors such as disease stage, patient age, comorbidities, prior therapies, type of donor, and source of stem cells need to be weighed when recommending stem cell transplantation to Myelodysplastic Syndromes patients.

An International Bone Marrow Transplant Registry report of 452 patients with Myelodysplastic Syndromes who received allogeneic transplantation found that young age and platelet counts greater then 100 x 109/L prior to transplantation were associated with lower transplantation mortality, higher disease-free survival, and overall survival. Patients with higher percentage of blasts and high IPSS scores had higher relapse rates.422 Blood or marrow stem cell sources can be utilized. One report showed superior results with mobilized blood versus marrow stem cells.423

The National Marrow Donor Program transplantation experience in Myelodysplastic Syndromes included 510 patients. Median age was 38 years, and the probability of disease-free survival at 2 years was 29 percent (confidence interval [CI] 25–33%). The 2-year incidence of treatment-related mortality was 54 percent, which was the major barrier to success in this patient population.424 Unrelated cord blood transplantation for adult and pediatric patients with Myelodysplastic Syndromes has been successfully performed,425 but results with unrelated marrow donors are inferior to the results of matched sibling transplants. It is anticipated that these results will improve in the era of high-resolution HLA matching between donor and recipient.426

Stem cell transplantation for Myelodysplastic Syndromes should be performed before the disease progresses to AML.427 When T-cell depletion is used to prevent graft-versus-host disease, the best outcomes occur in those who are transplanted while in remission.428 Poor cytogenetics may impact risk of relapse but not nonrelapse mortality.429 In one retrospective series, blast percentage less than 5 percent at time of transplantation was the best predictor of improved disease-free survival, and myeloablative conditioning was associated with lower relapse risk but could not overcome increased disease burden.430 Patients with secondary Myelodysplastic Syndromes have comparable outcomes after stem cell transplantation as those with de novo Myelodysplastic Syndromes when high-risk cytogenetics are considered.431,432 Pretransplantation neutropenia is also associated with inferior outcomes as a result of infection-related mortality.433 Prior therapy with demethylating agents does not appear to increase the toxicity of transplantation and whether it will improve outcomes by decreasing disease burden remains to be studied systematically.434 The morbidity and mortality of various transplantation approaches remain high, and some patients are not candidates for ablative transplantation because of age or comorbid conditions.435

Reduced-intensity conditioning with allogeneic hematopoietic stem cell transplantation from HLA-identical family members or unrelated donors has been examined for Myelodysplastic Syndromes treatment.436 In one series of 16 patients (median age: 54 years) receiving a conditioning regimen of fludarabine and cyclophosphamide, no day 100 transplantation-related mortality was observed, and the 2-year actuarial event-free survival was 56 percent (CI 30–68%). Other fludarabine-containing conditioning regimens have been reported.437,438 One series compared reduced intensity to standard transplantation in Myelodysplastic Syndromes patients and noted similar 2-year overall and disease-free survival with different patterns of toxicity.439 In some series, patients older than 70 years of age have undergone transplantation440; the future role this will play in therapy of older Myelodysplastic Syndromes patients is under investigation.441 For those patients who relapse after reduced-intensity stem cell transplantation, salvage therapy with donor lymphocyte infusions, second transplantations, or chemotherapy may be feasible.442,443

Autologous Stem Cell Infusion for Myelodysplastic Syndromes .

Patients with oligoblastic leukemia have been infused with their own stem cells after intensive chemotherapy.444 The approach may be limited by contamination of the stem cell product with a repopulating leukemic cell and the absence of a graft-versus-leukemia effect. The absence of a graft-versus-host reaction makes the approach more applicable to the age group usually affected. In selected patients, peritransplantation mortality with intensive therapy and stem cell rescue has been approximately 10 percent, and approximately 50 percent of selected patients had extended survivals.445 The more advanced the disease at the time of treatment, the worse the outcome. With the increasing use of reduced-intensity allogeneic transplantation, autologous stem cell transplantation has been used less often. Interestingly, when autologous transplantations for AML are performed in patients with antecedent myelodysplasia, no impact on stem cell mobilization or hematopoietic recovery has been noted.446