By Gérard Socié, MD, PhD

2008-09-01

Dr. Socié indicated no relevant conflicts of interest.
 
Alessandrino EP, Della Porta MG, Bacigalupo A, et al. WHO classification and WPSS predict post-transplant outcome in patients with myelodysplastic syndrome: a study from the GITMO. Blood. 2008. [Epub ahead of print]

Currently, allogeneic stem cell transplantation (SCT) is considered to be the only potentially curative therapy for myelodysplastic syndromes (MDS). However, since most patients with MDS are older than 60, few are candidates for myeloablative transplantation. Approximately 25 percent of patients with MDS are younger than 60 and may be considered for transplantation. Trials of SCT demonstrate long-term survival rates between 25 percent and 70 percent. The Inter-national Prognostic Scoring System (IPSS) is reported to be a useful predictor of transplantation outcome.¹ The optimal timing of bone marrow transplantation from HLA-identical siblings or unrelated donors for MDS is unknown. Many patients enjoy a long period after diagnosis without obvious disease progression. For these patients, the risks of immediate morbidity and mortality associated with transplantation are unacceptably high. Eventually, however, most patients with MDS develop symptomatic cytopenias, or their disease evolves to a more aggressive phenotype or transforms into AML, at which time SCT is less likely to be successful. Prospective comparisons of different transplantation timing strategies are not available and, unfortunately, are unlikely to be performed.

In a decision analysis, Cutler, et al. reported analyses using individual patient risk-assessment data from transplantation and non-transplantation registries performed for all four IPSS risk groups with adjustments for quality of life (QoL).¹ For low and intermediate-1 IPSS groups, they reported that delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of years of life than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. Thus, the authors claimed that for low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.¹

In 2002, the WHO formulated a new proposal for the classification of MDS. The distinction of multi-lineage dysplasia and the recognition of two categories of RAEB represented an improvement in the ability to predict survival and leukemic evolution. Data have also emerged on the ability of the WHO classification to guide clinical decision-making regarding therapeutic choice. A WHO classification-based prognostic scoring system (WPSS) has been recently defined and validated in untreated patients. The WPSS is based on WHO categories, karyotype abnormalities, and transfusion requirement, and is able to identify five risk groups of MDS patients with difference in survival and risks of leukemic progression. The impact of WHO classification and WPSS on the outcome of MDS patients receiving allogeneic SCT remains, however, to be clarified.

In their study, Alessandrino, et al., for the Italian group for transplantation (GITMO), studied the impact of WHO classification and WPSS on the outcome of patients with MDS receiving allogeneic SCT. They studied 365 patients reported to the GITMO between 1990 and 2006. Five-year overall survival (OS) was 80 percent in refractory anemia, 57 percent in refractory cytopenias with multilineage dysplasia, 51 percent in RAEB-1, 28 percent in RAEB-2, and 25 percent in acute leukemia from MDS (p=0.001). Five-year probability of relapse was 9 percent, 22 percent, 24 percent, 56 percent, and 53 percent, respectively (p<0.001), while five-year transplant-related mortality (TRM) was 14 percent, 39 percent, 38 percent, 34 percent, and 44 percent, respectively. In multivariate analysis, WHO classification showed a significant effect on OS and probability of relapse. Transfusion-dependency was associated with a reduced OS and increased TRM. In multivariate analysis, WPSS showed a prognostic significance on both OS and probability of relapse. In patients without excess blasts, multilineage dysplasia and transfusion-dependency significantly affected OS and were associated with an increased TRM. In patients without excess blasts, WPSS identified two groups of patients (low vs. intermediate risk) with a significant difference in OS and TRM, while in the same group of patients, IPSS failed to stratify the prognosis.

Interestingly, both WHO and WPSS maintained their prognostic effect on post-transplantation outcome also in specific subsets of patients, such as subjects older than 50 as well as patients receiving reduced-intensity conditioning (RIC) regimen. This is clearly relevant in light of the increased number of RIC regimens performed in MDS in most recent years, after the demonstration of their efficacy in allowing engraftment and in decreasing TRM in patients ineligible for standard conditioning allogeneic SCT. Whether there is any advantage in administering chemotherapy to achieve remission before transplantation for MDS is the subject of debate. The GITMO data suggest that in patients with high-risk MDS according to WHO criteria (i.e., RAEB-1, RAEB-2), achieving a complete remission before a standard allogeneic SCT seems not to be associated with a better post-transplant outcome. In patients receiving RIC, complete remission was associated with a trend to a reduced relapse rate. As expected, a significant impact of disease status at transplant was present in patients affected with AML from MDS (formerly classified as RAEB-t according to FAB criteria).

Nowadays, however, the real question is what the impact of new chemotherapeutic agents in MDS before SCT, such as 5-azacytidine, will be. These new drugs seem to be able to increase the survival of patients with MDS; their role, if any, before SCT is still under investigation.

References

1. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104:579-85.

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