Commentary (Sahebi/Forman): The Role of Hematopoietic Stem Cell Transplantation in Myelodysplastic Syndrome

Drs. Thompson and Luger have written a thoughtful and comprehensive review of the therapeutic options and issues facing physicians caring for patients with myelodysplastic syndrome (MDS). In our commentary, we would like to highlight and expand on several areas of their analysis. Conventional Myeloablative vs Reduced-Intensity Conditioning
As outlined by the authors, there is general agreement that in patients with advanced disease (high International Prognostic Scoring System [IPSS] category) or those who have developed the disease at a young age, allogeneic stem cell transplant is the treatment of choice. For less advanced disease and older patients without a human leukocyte antigen (HLA)-matched sibling donor, this approach has remained controversial. What requires further discussion is the fact that the results of conventional allogeneic stem cell transplant using myeloablative conditioning have shown some improvement in recent years. The European Bone Marrow Transplant (EBMT) Group analyzed the transplantation outcome in 885 patients with MDS and secondary acute myelogenous leukemia (AML) who were transplanted with matched sibling stem cells.[1] The 3-year survival and disease-free survival (DFS) rates were better in patients undergoing transplants after 1989 (DFS = 39%) than in patients transplanted before 1989 (DFS = 31%). These findings were associated with a decrease in treatment-related mortality from 50% to 36% in recent years. Seattle investigators also recently reported favorable results in MDS patients treated with a targeted busulfan (Busulfex, Myleran)/cyclophosphamide conditioning regimen. They noted a 3-year relapse-free survival rate of 56% for related and 59% for unrelated recipients. Nonrelapse mortality was 12% at day 100 and 28% at 3 years for related recipients, compared with 13% at day 100 and 30% at 3 years for unrelated recipients.[2] Previously, the same group had reported a favorable outcome, with an overall survival of 44% in patients 55 to 66 years old undergoing conventional allogeneic and syngeneic marrow transplants.[3] These data suggest that conventional allogeneic stem cell transplant can be offered to appropriate patients up to age 65. Although the graft-vs-leukemia effect is a major factor in how patients are cured by an allogeneic transplant, the relative importance of transplant regimen intensity in MDS has been studied in retrospective analysis of transplant trials in MDS. The M. D. Anderson group reviewed their experience with MDS patients treated using reduced-intensity and nonmyeloablative conditioning regimens.[4] The nonmyeloablative group included more patients in remission, more sibling recipients, and more bone marrow recipients than those treated with reduced-intensity conditioning. Despite these differences, the investigators observed a higher relapse rate with the nonmyeloablative regimen (61%) than with the reduced-intensity regimen (30%). However, overall survival was similar between the two groups. This was likely due to significantly higher incidence of relapse mortality in the nonmyeloablative group and higher incidence of nonrelapse mortality in the reduced-intensity group. The more intensive conditioning provided better disease control at a cost of increased treatment-related mortality but suggested that the graft-vs-leukemia effect may not be adequate in patients with high-risk disease. Other Retrospective Comparisons
Three other groups reported retrospective comparisons of reducedintensity and myeloablative conditioning regimens for patients with AML or MDS in abstract form. The EBMT group published their results in 739 patients with MDS (196 reduced- intensity and 543 myeloablative).[ 5] The reduced-intensity group included older patients, more patients with prior autologous stem cell transplant, and more peripheral stem cell transplant recipients, whereas the ablative group had more T-cell depleted allografts. There was no significant difference in 1-year transplant-related mortality, disease-free survival, or overall survival. Investigators at the Dana-Farber Cancer Institute also retrospectively compared 39 patients with nonmyeloablative allografts to 273 with myeloablative allografts.[6] The 1-year overall survival was similar for both groups. The primary cause of treatment failure was relapse, which occurred in 57% of the reduced-intensity group vs 31% of the myeloablative group. The Seattle investigators reported a retrospective comparison of 132 patients over age 40 with MDS or AML treated with conventional myeloablative transplant to 40 patients treated with nonmyeloablative transplant.[7] The nonmyeloablative group included older patients and high-risk patients by IPSS. Among patients with more advanced disease, 87% of the nonmyeloablative group and 39% of the myeloablative group received induction chemotherapy prior to transplant. Overall survival, relapse-free survival, and nonrelapse mortality did not differ significantly between the myeloablative and nonmyeloablative groups. In patients who achieved a complete remission with induction chemotherapy, there was no difference between the two conditioning regimens, suggesting that disease burden at the time of transplant influenced the outcome. These studies suggest that reducedintensity transplantation could be considered as a reasonable alternative for older patients or those at high risk for complications of myeloablative transplant. Prospective randomized studies comparing reduced-intensity transplant to myeloablative transplant are needed to determine the optimal transplant conditioning regimen. The EBMT has initiated one such study comparing these two approaches in patients over age 50. Role of Induction Treatment Prior to Transplant
The IPSS score was originally developed in nontransplanted patients with de novo MDS to evaluate prognosis. Recent reports suggest that IPSS score is also a useful predictor of transplant outcome. For instance, an increase in marrow blasts to more than 5% has been shown to have a negative impact on disease-free survival after transplantation, with the inferior outcome resulting mainly from an increase in relapse after transplant. The question of whether patients with refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-t) AML should receive remission- induction therapy remains controversial. Treatment-related toxicities, infectious complications, and the lack of beneficial response in highrisk patients may preclude transplant of some patients receiving induction chemotherapy prior to transplant. Often, analysis of prognostic features for successful induction, such as poorrisk cytogenetics with a long history of MDS, influence the decision to pursue induction chemotherapy before transplant. The design of new protocols for patients with advanced MDS using novel drugs such as hypomethylating agents or farnesyl transferase inhibitors as induction therapy may improve both transplant opportunities and outcome by cytoreducing the disease with fewer toxicities prior to transplant. When to Transplant
Because MDS is a heterogeneous disease with median survival varying from a few months to several years, the best timing for transplant remains to be determined. Several studies have reported improved disease-free survival if allogeneic stem cell transplant is performed early in the disease course. However, a recent analysis by the International Bone Marrow Transplant Registry, as outlined in details by the authors, demonstrated that the life expectancy of patients in low-risk and intermediate-1-risk IPSS categories was higher when transplant was delayed but still performed prior to the development of AML. This was particularly true for patients under age 40. In the intermediate-2- and highrisk groups, transplantation soon after diagnosis resulted in maximal life expectancy. This analysis was limited to patients undergoing HLA-matched sibling allogeneic stem cell transplant. In view of the higher morbidity and mortality rates associated with unrelated donor stem cell transplant, using the same strategy based on the disease risks and patient age would be very reasonable. In the absence of randomized studies, these data serve as a useful guide for treatment decision- making. Therapy-Related Disease
Therapy-related MDS and AML have emerged in the past few decades as a significant long-term complication of cancer treatment, as more cancer patients are successfully treated and surviving. In particular, this is a major problem for patients who have undergone autologous transplant for lymphoma and Hodgkin's disease. When compared to primary MDS, several studies have reported lower eventfree survival in patients undergoing transplant for treatment with secondary therapy-related MDS/AML. In the largest such study, reported by the French Society of Bone Marrow Transplant, 70 patients received sibling or unrelated donor bone marrow transplant.[8] These investigators reported a 2-year overall survival of 30%, event-free survival of 28%, relapse rate of 40%, and transplantation- related mortality of 49%. The complete remission status at the time of bone marrow transplant and goodrisk IPSS were associated with a favorable outcome. In contrast, an EBMT analysis reported a similar outcome after transplant for patients with therapy-related MDS/AML and those with primary MDS.[1] The use of prior chemotherapy, radiotherapy, and in particular previous transplantation put these patients at increased risk of transplantrelated morbidity and mortality with myeloablative allogeneic stem cell transplant. Several groups including our own[10] have reported encouraging results in patients with relapsed AML or MDS after autologous hematopoietic cell transplant using a reduced-intensity allograft from a sibling or unrelated donor. Autologous Transplant
The EBMT group reported their experience with autologous stem cell transplant, noting a disease-free survival rate of 30% at 3 years,[1] which is comparable to the 29% rate reported by the National Marrow Donor Program for unrelated donor recipients.[ 9] The high incidence of relapse in autologous stem cell transplant is counterbalanced by the high therapyrelated mortality in unrelated donor allografts. Achievement of complete remission and harvest of a sufficient number of autologous stem cells are prerequisites for autologous transplant, which makes this a very limited option for the vast majority of patients with MDS. Conclusions
Recent advances in allogeneic stem cell transplantation and the development of nonmyeloablative and reduced- intensity conditioning regimens have expanded the use of transplantation to patients with advanced age or comorbid illnesses who previously had limited treatment options. Future studies are needed to determine the contribution of newer novel therapies and reduced-intensity transplant in the treatment of patients with MDS. Conventional allogeneic stem cell transplant is the preferred treatment option for appropriate patients with an available matched sibling donor. Patients without a matched sibling donor may be considered for unrelated donor or autologous stem cell transplantation if complete remission is achieved with treatment and a sufficient number of autologous stem cells are procured.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. de Witte J, Hermans J, Vossen J, et al: Haematopoietic stem cell transplantation for patients with myelodysplastic syndromes, and secondary acute myelogenous leukemia: A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 110:620-630, 2000.
2. Deeg HJ, Storer B, Slattery T, et al: Conditioning with targeted busulfan and cyclophosphamide for hematopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastc syndrome. Blood 100:1201-1207, 2002.
3. Deeg HJ, Shulman HM, Anderson JE, et al: Allogeneic and syngeneic marrow transplantation of myelodysplastic syndrome in patients 55 to 66 years of age. Blood 95:1188-1193, 2000.
4. de Lima M, Anagnostopoulos A, Munsell M, et al: Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: Dose is relevant for longterm disease control after allogeneic stem cell transplantation. Blood 104:865-872, 2004.
5. Martino R, Van Biezen A, Iacobelli S, et al: Reduced-intensity conditioning (RIC) for allogeneic hematopoietic stem cell transplantation (HSCT) from HLA identical siblings in adults with myelodysplastic syndromes (MDS): A comparison with standard myeloablative conditioning (abstract 642). Blood 102:184a, 2003.
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8. Yakoub-Agha I, de La Solmoniere P, Ribaud P, et al: Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: A longterm study of 70 patients. Report of the French Society of Bone Marrow Transplantation. J Clin Oncol 19:963-971, 2000.
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