Iron Support in Erythropoietin Treatment in Myelodysplastic Syndrome Patients Affected by Low-Risk Refractory Anaemia: Real-Life Evidence from an Italian Setting.

Refractory anaemia (RA) among myelodysplastic syndrome (MDS) is associated with a partial functional iron deficit and may require transfusions. In low-risk lymphoma and solid tumour patients, iron support improves erythropoietin (EPO) cost-effectiveness in treating anaemia. The aim of this study is to see if oral sucrosomial iron support improves the cost-effectiveness of EPO treatment in MDS patients affected by low-risk RA. We treated patients with EPO only or with EPO plus oral sucrosomial iron or intravenous (i.v.) iron. The need for transfusions was lowest in the group taking oral iron (p = 0.016) or not receiving supplementation at all (p = 0.022). We compared costs of EPO with i.v. ferric gluconate or oral sucrosomial iron supplementation or no iron supplementation. The oral iron group had fewer side effects, fewer patient medical visits in the out-patient setting, and fewer transfusions; this led to higher savings on direct hospital costs and indirect patient costs (lost days at work) and translated into a 50% abatement of overall expenditures. EPO treatment-related expenditures in MDS-RA patients were lowest with oral sucrosomial iron supplementation (Sideral®), with a longer interval between EPO administration in maintenance treatment, quicker hemoglobin recovery, lower ferritin increase and fewer blood transfusions.

Role of microRNA-29b in myelodysplastic syndromes during transformation to overt leukaemia.

Chromosome 7q32 is a frequently deleted region in myelodysplastic syndromes (MDSs) and encodes the microRNAs (miRNAs) miR-29a/miR-29b. Both miR-29s down-regulate the anti-apoptotic protein myeloid cell leukaemia 1 (MCL-1) in acute myeloid leukaemia. Thus, to investigate the role of miR-29s in the transformation of MDS to overt leukaemia (OL), we analysed the relationship between miR-29 expression and MCL-1 expression. MiR-29b expression was down-regulated in refractory anaemia and OL bone marrow as compared to that in control bone marrow. MCL-1 expression level in OL was significantly higher than that in refractory anaemia with excess blasts and a negative correlation was observed between miR-29b and MCL-1 messenger RNA expression levels in OL samples. Immunohistochemical analysis showed that the MCL-1 positive rate among MDS bone marrow CD34 positive cells significantly increased during transformation to OL. Additionally, MCL-1 positive cells were negative for cleaved caspase 3, which indicated that these cells avoided apoptosis. Reduced miR-29b expression in MDS bone marrow cells might trigger transformation to OL via overexpression of MCL-1 in blastic cells.

Steroid-responsive anemia in patients of Ghosal hematodiaphyseal dysplasia: simple to diagnose and easy to treat.

Ghosal hematodiaphyseal dysplasia (GHDD) is a recently recognized cause of steroid-responsive anemia. We would like to report 3 cases of GHDD who presented in early childhood with moderate to severe anemia, splenomegaly, and a hypocellular marrow with increased reticulin. They were easily diagnosed with long-bone x-rays showing diaphyseal and metaphyseal widening and loss of diaphyseal constriction. All cases dramatically responded to oral steroid and no longer needed blood transfusion. They required steroid at low doses for long term (up to 5 y). GHDD is easy to diagnose with long-bone radiography and consistently responds to steroid. It should therefore be considered as a differential diagnosis of unusual anemia in early childhood, especially in children from the Middle East or the Indian subcontinent.

Hyperuricemia and acute kidney injury secondary to spontaneous tumor lysis syndrome in low risk myelodysplastic syndrome.

BACKGROUND: This is a rare instance of acute kidney injury caused by hyperuricemia due to spontaneous tumor lysis syndrome and also the first case of spontaneous tumor lysis syndrome reported in association with myelodysplastic syndrome. CASE PRESENTATION: A 53-year-old man presented with abrupt oliguria. Laboratory findings on admission included hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis and rapidly rising serum creatinine, which were consistent with acute tumor lysis syndrome in the absence of precipitating chemotherapy or radiotherapy. After hemodialysis and oral uric acid lowering therapy, serum uric acid levels returned to normal range and renal function rapidly recovered. The patient was diagnosed as myelodysplastic syndrome eleven months later. CONCLUSIONS: Occult malignancy including solid tumors and hematological malignancies should be carefully evaluated in the case of unexplainable acute kidney injury with hyperuricemia. Aggressive investigations should be thoroughly considered and repeated in this population.

Correlation between dysplastic lineage and type of cytopenia in myelodysplastic syndromes patients with refractory anemia according to the FAB classification.

OBJECTIVES: To analyze the correlation between dysplastic lineage and type of cytopenia in myelodysplastic syndromes. METHODS: We analyzed the correlation between dysplasia and cell count using the data set of our previous morphologic study. RESULTS: There were no correlations between dysgranulopoiesis of 10% or more and absolute neutrophil count (ANC). Similarly, hyposegmented mature neutrophils (Pelger) of 10% or more were not related to ANC. Interestingly, the platelet count of patients with dysmegakaryopoiesis (dys Mgk) was higher than that of patients without dys Mgk (dys Mgk ≥10% vs <10%, P = .08; dys Mgk ≥40% vs <40%, P = .02; micromegakaryocytes ≥10% vs <10%, P = .004). CONCLUSIONS: Since low cell counts did not correlate with the presence of dysplastic features, we suggest that dysplastic features do not directly relate to apoptosis.

Age, JAK2(V617F) and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis.

Refractory anaemia with ring sideroblasts (RARS) and marked thrombocytosis (RARS-T) is a provisional entity in the World Health Organisation 2008 classification and has previously been shown to have a high proportion of JAK2(V617F) (Janus Kinase 2) and SF3B1 (Splicing Factor 3B subunit 1) mutations. The purpose of the present study was to analyse the frequency of SF3B1 mutations in a large cohort of 111 patients with RARS-T and 33 patients with RARS and to explore the prognostic impact of SF3B1 mutational status on RARS-T. The frequency of SF3B1 mutations in RARS-T (96/111, 86.5%) and RARS (28/33, 84.8%) was similar. In RARS-T, median survival was better in SF3B1-mutated patients than in SF3B1-non-mutated patients (6.9 and 3.3 years, respectively, P=0.003). RARS can be differentiated from RARS-T by the frequency of JAK2(V617F) (0% vs 48.6%). In RARS-T patients, SF3B1 (P=0.021) and JAK2 mutations (P=0.016) were independent factors for a better prognosis. Altogether, our results confirm that RARS-T is an independent entity that should be recognised by the next World Health Organisation classification. The assessment of SF3B1 mutations is of prognostic interest in RARS-T patients. Younger age, JAK2(V617F) and SF3B1 mutations are the main predicting factors for survival in RARS-T.

Refractory anemia with ringed sideroblasts and thrombocytosis without JAK2 V617F mutation: report of three cases.

In the WHO classification, there is a provisional entity called Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable (MDS/MPN, U). Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T) was included in this category. Recently published studies report a small percentage of patients with RARS-T. Sixty percent of these have JAK2 V617F mutation, which can suggest the coexistence of two pathological conditions (MDS and MPN). In this paper, we analyzed three patients diagnosed with RARS-T in the Department of Hematology, "Fundeni" Clinical Institute, Bucharest, Romania, during the period 2005-2011. The patients were investigated with cytogenetic exam and molecular biology. In these three cases were identified morphological features of multilineage dysplasia (two-lineage dysplasia in two cases and three-lineage dysplasia in one case). In two cases, thrombocytosis was under 1000×10(3)/µL and clinical evolution was similar to the myelodysplastic syndrome (transfusion dependent anemia with response to administration of erythropoietin). In the third case, the platelets were over 1000×10(3)/µL and with response to the treatment with Hydrea, which improved anemia. JAK2 V617F mutation was not identified in any case. RARS-T remains a provisional entity and requires a complex investigation of patients for the correct diagnosis of these patients. Therapeutic options should be personalized to each case in part because there is not yet a standardized treatment of these patients.

Refractory anemia with ring sideroblasts.

Refractory anemia with ring sideroblasts (RARS) is a subtype of myelodysplastic syndrome (MDS) characterized by 15% or more ring sideroblasts in the bone marrow according to the WHO classification. After Perls staining, ring sideroblasts are defined as erythroblasts in which there are 5 or more siderotic granules covering at least a third of the nuclear circumference. The iron deposited in perinuclear mitochondria of ring sideroblasts is present in the form of mitochondrial ferritin. The molecular basis of MDS with ring sideroblasts has remained unknown until recently. In 2011, whole exome sequencing studies revealed somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in myelodysplasia with ring sideroblasts. The close relationship between SF3B1 mutation and ring sideroblasts is consistent with a causal relationship, and makes SF3B1 the first gene to be associated with a specific morphological feature in MDS. RARS is mainly characterized by isolated anemia due to ineffective erythropoiesis, and its clinical course is generally benign, although there is a tendency to worsening of anemia in most patients over time. By contrast, refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) is characterized by pancytopenia and dysplasia in two or more myeloid cell lineages. More importantly, patients with RCMD-RS have a higher risk of developing bone marrow failure or progressing to acute myeloid leukemia (AML). Refractory anemia with ring sideroblasts (RARS-T) associated with marked thrombocytosis is a myelodysplastic/myeloproliferative neoplasm associated with both SF3B1 and JAK2 or MPL mutations. RARS-T may develop from an SF3B1 mutated RARS through the acquisition of a JAK2 or MPL mutations in a subclone of hematopoietic cells.

Ghosal hematodiaphyseal dysplasia with myelofibrosis.

Diaphyseal dysplasia with refractory anemia requiring blood transfusion is a relatively new entity having possible autosomal recessive inheritance. Prednisolone therapy alleviates the need for repeated transfusion. One such case is being reported here.

Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis.

BACKGROUND: Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. DESIGN AND METHODS: We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases. RESULTS: In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600 × 10(9)/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia (P<0.001) but better survival (P<0.001) and a higher risk of thrombosis (P=0.039) than patients with refractory anemia with ring sideroblasts. CONCLUSIONS: The clinical course of refractory anemia with ring sideroblasts and marked thrombocytosis is better than that of refractory anemia with ring sideroblasts and worse than that of essential thrombocythemia. The higher risk of thrombotic events in this disorder suggests that anti-platelet therapy might be considered in this subset of patients. From a clinical point of view, it appears to be important to consider refractory anemia with ring sideroblasts and marked thrombocytosis as a distinct entity.