Significant Suppression of the Colony Forming Capacity of Erythroid Progenitors by Iron Overload in Patients with MDS and Sequential Anlyses of BFU-E Under Chelation Therapy.

The majority of patients with MDS depend on regular blood cell (RBC) transfusions during the course of their disease. Patients with lower-risk MDS are at particularly high risk of developing iron overload because of their longer median survival. Transfusional iron overload is known to be associated with increased morbidity mainly due to cardiac and/or hepatic damage. As a result an excess mortality rate in polytransfused pts. has been demonstrated. A negative prognostic impact of transfusion need is a proven independent marker for a bad prognosis. Jensen et al. (1996) demonstrated that an adequate chelation therapy could improve the transfusion need of pts. with MDS significantly (Br J Haematol 1996, 94, 288-299). This observation was supported by recent findings of another group (Messa, Acta Haematol, 2008, 120, 70-4) with improvement of transfusion need under adequate chelation therapy. Thus iron overload might not only be harmful to hepatocytes and cardiomyocytes but also to bone marrow progenitor cells. Their function is intrinsically impaired by MDS itself and might be further affected by a “second hit” in the form of toxic iron overload which might additionally impair their colony forming capacity.

We performed colony assays from the peripheral blood from 52 pts. with MDS (RA/RARS: n=18, RCMD/RS: 12, RAEB-I/II: 13, 5q-syndrome: 3, MDS-U: 2, CMML: 1, and others: 2; age: 39 – 86 yrs. (median: 68 yrs.); cytogenetics: normal: 26, 5q-: 6, -7/7q-: 2, complex: 4, others: 4) with (serum ferritin ≥250 μg/L, range: 273 – 6267 μg/L, median: 664 μg/L) and without iron overload (range: 11 – 213 μg/L). Only pts. without hepatic and/or active infectious diseases, without chemotherapy/epigenetic therapy during the last 6 months and without cytokine and/or corticoid therapy during the last 3 months before performance of colony assays were considered. BFU-E and CFU-GM were analysed by the same person (U.S.) after 12 – 16 days in cultures from peripheral blood, performed as described (Leuk Res, 2001; 25(11):955-9) in 14 (BFU-E)/ 12 (CFU-GM) pts. with normal ferritin-values (normal range: 20-250 μg/L) in comparison to 38/32 pts. with ferritin values surmounting 250 μg/L. Pts. with diffuse growth or cluster formation (leukemic growth) were excluded. Statistical evaluation was performed with SAS 9.1 software using Wilcoxon-Mann-Whitney tests. The results were regarded as significant if the p-value was under 5%. Both patient subgroups were balanced according to cytogenetics, age and MDS WHO-subtype.

In the patients subgroup with normal ferritin (n=14) the numbers of BFU-E ranged between 0 and 76 (std.dev. 19.63) with a median of 3.5 and a mean of 10.7, the numbers of CFU-GM ranged between 0.5 and 38.5 (std.dev. 13.23), with a median of 6.75 and a mean of 13.2. In the patients with elevated serum ferritin (n=38) the numbers of BFU-E ranged between 0 and 250 (std.dev.40.47) with a median of 0.5 and a mean of 8.86, the numbers of CFU-GM ranged between 0 and 120 (std.dev. 29.62) with a median of 3.0 and a mean of 18.94). Statistical comparison of the numbers of BFU-E and CFU-GM between patients with normal and elevated serum ferritin yielded a highly significant difference (p=0.001348) for BFU-E and no difference for CFU-GM (p=0.570296).

Our data provide further evidence that in MDS iron overload significantly impairs bone marrow function by suppression of the burst forming activity of erythroid progenitors. If this iron is removed by adequate chelation burst forming activity might be partially restored. Myeloid progenitors do not seem to be affected by iron overload.

To address the question whether chelation therapy could improve erythropoiesis we performed 4 colony assays at minimum as follow up in 32pts the analysis of which is under way. In this group 8 pts. showed a normal ferritin while 26 pts. had an elevated ferritin (> 250 μg/L). Of these, pts. 10 were treated with chelation therapy. Furthermore, 9 pts. were monitored by magnetic resonance imaging (MRT). The results of these examinations will be related to the other parameters evaluated in this study and presented in detail.

Haase:Novartis Oncology, Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.