Prognostic Pre-Transplant Factors in Myelodysplastic Syndromes Primarily Treated by Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Study on Behalf of the MDS Subcommittee of the Chronic Leukaemia Working Party of the EBMT

Allogeneic hematopoietic stem cell transplantation (SCT) is associated with iron overload and iron toxicity, especially in patients with myelodysplastic syndromes (MDS). Causes of this increased iron load are transfusions, ineffective erythropoiesis and, myelosuppressive therapy. Investigators found that iron toxicity (often using serum ferritin as a surrogate marker of iron burden) was associated with an adverse effect on non-relapse mortality (NRM) and overall survival (OS). As pre-transplant anti-leukemic treatment may lead to organ damage which may influence outcome after SCT, our study aimed to minimize the role of previous treatment toxicity by only including MDS patients who had not received intensive anti-leukemic treatment prior to SCT conditioning, allowing more insight in the role of iron toxicity in allogeneic SCT. A retrospective analysis of data from the EBMT registry was carried out after an additional survey within selected EBMT centers.

This report describes the effect of iron toxicity on OS, NRM and relapse during treatment with myeloablative (MAC) allogeneic SCT in previously untreated adults with MDS.

The Chronic Leukemia Working Party of the EBMT collected data of 201 adult patients with cytological proven MDS, according to the WHO classification, who received allogeneic SCT after myeloablative conditioning in 2000–2005. Data were available from 201 patients transplanted in 34 centers. All clinical variables were measured at time of transplantation. Fifty-nine percent of the patients were male (n=119). The median patient age was 49 years (range 18–70). Median time between diagnosis and transplantation was 8 months (range 0, 3–274). WHO classification at transplantation was RA/RARS/5q- 36% (n=72), RCMD 7% (n=15), RAEB-1 17% (n=34), RAEB-2 20% (n=39) and sAML 20% (n=41). A composite iron parameter based on the serum iron levels, transferrin saturation and serum ferritin levels prior to the SCT was used to define a high risk group with serum ferritin >1, 500 ng/ml, and/or transferrin saturation >80% and/or serum >200 mg/l (low/intermediate/high 30% / very high 12% / missing 58%). Variables analyzed were WHO classification groups, iron load, amount of red blood cell (RBC) transfusions prior to SCT (≤20 RBC units 43% / >20 RBC units 20% / missing 37%), age (≤50 years 58% / >50 years 42%), cytogenetics (normal 31% / abnormal 46% / 23% not performed or missing), donor type (HLA id.Sibling 55% / Unrelated44%), match sex recipient-donor (male-female 23% /other 77%), time between diagnosis and transplantation (≤6 months 40% / >6 months 60%), co morbidity (no 45% / yes 26%, missing 29%). Univariate analysis for OS showed a significant impact of WHO-classification (p=0.04), iron load (p=0.055) and, amount of RBC transfusions (p=0.02) but were not significant for age (p=0.23), cytogenetics (p=0.39), donor type (p=0.75), match sex recipient-donor (p=0.82), time between diagnosis and transplantation (p=0.30), and comorbidity scores (p=0, 11). The high risk iron load group show decreased 2-year OS (29% versus 59% in the low risk group) due to a combined higher relapse risk and NRM.

These data show that disease stage has a significant impact on outcome. In addition a high number of RBC transfusions has a negative influence on OS, NRM and relapse. Iron load, when adjusted for transfusion numbers does not influence outcome. In our study with relatively low co-morbidity due to short interval between diagnosis and SCT (median 8 months) and the exclusion of patients who received anti-leukemic therapy prior to SCT the influence of co-morbidity on outcome was not significant.

No relevant conflicts of interest to declare.