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Abstract: Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders that are preferentially diagnosed in the elderly. Aberrant expression of the adhesion receptor CD44 correlates with poor prognosis in various neoplasms. To evaluate the prognostic impact of CD44 in MDS serum levels of soluble CD44 standard (solCD44s) were measured in 130 MDS patients (median age 68 years) using an enzyme-linked immunosorbent assay (ELISA). solCD44s levels were significantly elevated in MDS patients as compared to those of healthy donors (p <0.001) and were found to correlate with distinct FAB and WHO subtypes. The highest levels of solCD44s were found in patients with CMML, in RAEB and in patients with MDS transformed into secondary acute myeloid leukaemia (AML). In univariate analysis elevated levels of solCD44s (cut-off level>688.5ng/ml) correlated significantly with shorter overall survival in MDS patients (12 versus 39 months; p <0.001). In multivariate analysis solCD44s displayed prognostic significance independent of the International Prognosis Scoring System (IPSS). To test for refined prognostication, IPSS risk groups were split into two separate categories based on the solCD44s levels. Using this approach, MDS patients with a shorter survival were identified both in the IPSS low-risk (p =0.037) and in the IPSS intermediate-1-risk group (p =0.015). The CD44s-adjusted IPSS defines a cohort of MDS patients with unfavorable prognosis, which might be helpful in risk stratification and in therapeutic algorithms. [Copyright &y& Elsevier]

Myelodysplastic syndromes (MDS) belong to the most frequent bone marrow disorders with a median age about 70 years. The diagnosis of MDS relies on morphologic features of dysplasia of blood and marrow cytology and histology. Cytogenetic analyses of the marrow cells are mandatory in MDS. The assessment of the correct proportion of blasts and the degree of dysplasia is important for diagnosis as well as prognosis and therapeutic decisions. Patients with unilineage dysplasia (RA/RARS) and patients with a del(5q) Syndrome, have a median survival time of 5 years as compared to only 3 years in patients with multilineage dysplasia (RCMD, RSCMD). An increased proportion of blast up to 9% defines a RAEB I facing a survival time of about 18 months. Patients with RAEB II (medullary blasts >10%) have a bad prognosis of less than one year. We can stratify patients into four risk groups according to the International Prognostic Scoring System (IPSS), which uses medullary blasts, chromosomal findings and number of cytopenia. The WHO adapted Scoring System (WPSS) creates 5 risk groups by calculating survival and AML evolution using WHO type, cytogenetic findings and transfusion need. The prognosis of patients, in whom cytogenetic data are not available, can be assessed by using the Düsseldorf Score that is based on LDH, cell counts and proportion of medullary blasts. The most important clinical parameter is the age at diagnosis. Especially low risk patients aged less than 50 years have a better prognosis as compared to older patients. On the other hand, high risk patients of every age have a poor prognosis. Planning the treatments for MDS patients should take into account other parameters like comorbidity and the wish of the patient. [ABSTRACT FROM AUTHOR]

Median survival is about one year in MDS patients with an unfavourable risk profile. The only curative approach, allogeneic stem cell transplantation, achieves long-term remissions in 30-50% of the few patients eligible for this kind of treatment. Non-myeloablative conditioning, causing less toxicity and treatment-related mortality, has increased the number of transplantation candidates. However, because of an increased risk of relapse, superiority in terms of long-term benefit has not yet been established. Another open question relates to whether induction chemotherapy should be performed prior to allografting in patients with an elevated medullary blast count. Induction chemotherapy followed by consolidation chemotherapy results in long-term remission rates of 15-20%. Standard regimens employ cytarabine in combination with an anthracyclin. It is not advisable to administer induction chemotherapy to MDS patients over 60 years of age who have an unfavourable karyotype, because of low remission rates and a high risk of early relapse. Such patients should be considered candidates for epigenetic treatment. The demethylating agents 5-azacytidine and decitabine have been approved for MDS treatment in the USA since treatment results are superior to best supportive care regarding haematological improvement, risk of leukaemic transformation, and overall survival. Epigenetic treatment, which aims to antagonize abnormal gene silencing, may be augmented by including inhibitors of histone deacetylases. Patients with a high-risk karyotype including a 5q- anomaly should receive a trial of lenalidomide because of impressive responses seen in this cytogenetic subgroup. Thalidomide and farnesyltransferase inhibitors can also be of clinical benefit in a number of high-risk patients. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are categorized into different risk groups according to the International Prognostic Scoring System (IPSS). Patients with low- and intermediate-1-risk disease are usually qualified as low-risk-MDS and treated with common treatment strategies. Recently, a number of new therapies have emerged and proved very promising, both in best supportive care as well as in interventional therapeutic strategies. Given that most patients with early MDS will eventually become transfusion dependent, effective iron chelation is an important part of the therapeutic management. The new iron chelator deferasirox has the advantage of high bioavailability after oral ingestion and leads to effective iron chelation with an acceptable toxicity profile. Other drugs may be used to reduce transfusion-dependence: Lenalidomide has shown astonishing erythroid responses in patients with del(5q) chromosomal abnormality, irrespective of karyotype complexity. Adverse events are manageable, including grade III and IV thrombocytopenia and neutropenia. Erythropoietin ± G-CSF may be used in non-del(5q) patients with low erythropoietin levels and a low pre-therapeutic transfusion dependence. Young patients with low transfusion burden and a HLA-DR15 phenotype may be especially prone to respond to antithymocyte globulin and cyclosporin A treatment. Responders seem to have an improved overall survival compared to non-responding patients. Finally, valproic acid, a histone deacetylase inhibitor, does strengthen the erythroid lineage in a significant part of low-risk IPSS patients and may be used in patients not eligible for other treatment strategies. [ABSTRACT FROM AUTHOR]

One of the hallmarks of myelodysplastic syndromes (MDS) is their morphological heterogeneity which complicates the diagnosis and classification of these bone marrow disorders. The French-American-British (FAB) classification system which is based on cytological findings and the blast cell percentage in the bone marrow (BM) and peripheral blood (PB) was the universally accepted reference standard for categorization of MDS samples from 1982 to 1999 when it was modified by an expert panel of the World Health Organization (WHO). The WHO classification system distinguishes eight subgroups of MDS and is based on three principles: distinction between unilineage and multilineage dysplasia of haematopoietic cells, definition of refined blast cell percentages in BM and PB for diagnosing patients with RAEB and AML, as well as incorporation of genetic data into the classification scheme. When compared to the FAB proposals, the WHO classification appears to define more homogeneous subgroups of patients and to provide greater prognostic power. However, prospective studies of large patient populations will be required to decide whether the WHO classification allows accurate risk assessment and facilitates clinical decision-making for individual MDS patients. [ABSTRACT FROM AUTHOR]

Background: The International Prognostic Scoring System (IPSS) is the golden standard to assess prognosis in myelodysplastic syndromes (MDS). The aim of this analysis was to study age and gender as interacting variables for individualized prognostication. [ABSTRACT FROM PUBLISHER]

Highlights • The IPSS-R is validated as a prognostic tool for patients with MDS and del(5q). • Isolated del(5q) plus one non-chromosome 7 aberration deteriorates the prognosis. • Changes in chromosome 7 in the context of del(5q) lead to a poor prognosis. Abstract The IPSS-R proved to be a powerful tool for the assessment of prognosis in MDS patients. We aimed at a validation of the IPSS-R for patients with MDS harboring deletion (5q) isolated or accompanied by additional aberrations. The study was based on 444 MDS patients from MDS centers in Europe. 67% of the patients were female, median age was 69 years. 43.5% had MDS del(5q), 5.9% were diagnosed with RCUD, 2.0% RARS, 18.4% RCMD, 14.6% RAEB-I and 15.5% RAEB-II. According to the IPSS-R, there were 9.9% very low, 39.6% low, 16.6% intermediate, 12.8% high, 20.9% very high risk patients. For very low risk patients survival was 7.5 years, low 9.0 years, intermediate 6.5 years, high 1.5 years and very high 0.7 years (p < 0.001). For low and intermediate risk, the probability of AML evolution was significantly different (p = 0.03) as well as for high versus very high risk groups (p = 0.002). The IPSS-R proved to be an appropriate prognostic tool for MDS with del(5q). [ABSTRACT FROM AUTHOR]

MDS patients may present with monocytic marrow proliferation not fulfilling criteria for CMML. We analyzed MDS patients with or without a marrow monocytic proliferation by following up the amount of monocytic proliferation and characterizing their molecular profile. 315 MDS patients of Duesseldorf MDS registry were divided into two groups: A) 183 patients with monocytic esterase positive cells in marrow and monocytes between 101 and 900/μl in blood and B) 132 patients without monocytic esterase positive cells in marrow and monocytes in blood ≤100/μl. Twenty patients of each group were screened with regard to ASXL1, TET2, RUNX1, SETBP1, NRAS, and SRSF2 using Illumina myeloid panel. Group A patients were older, had significantly higher WBC, hemoglobin levels, neutrophils and platelets. CMML evolution rates were 4.9% and 1.5%, respectively (p = n.s.). TET2, NRAS and SRFS2 mutation frequencies were higher in group A and four patients had coexisting TET2 and SRFS2 mutation, which was shown to be characteristic but not specific for CMML. MDS patients with marrow monocytic proliferation have a more CMML-like pheno- and genotype and develop CMML more often. Those patients could potentially be very early stages of CMML or represent a CMML-like myeloid neoplasma with marrow adherence of the monocytic cell population. [ABSTRACT FROM AUTHOR]

Since 2001, chronic myelomonocytic leukemia (CMML) is classified by the WHO as myeloproliferative/myelodysplastic neoplasm. Herein we tried to better describe CMML patients with regard to hematological characteristics and prognosis using data of the Duesseldorf registry. We created 6 CMML subgroups, by dividing dysplastic and proliferative CMML at the cut-off of white blood cell count of 13,000/μL and splitting these two groups into 3 subgroups: CMML 0 with <5% blasts ( n = 101), CMML I with 5–9% blasts ( n = 204) and CMML II with 10–19% blasts ( n = 81). For comparison we included patients with RCMD, RAEB I and II. The newly created CMML 0 group had better prognosis than CMML I and II, median survival times were 31 months (ms), 19 ms and 13 ms, respectively ( p < 0.001). Median survival times between the corresponding dysplastic and proliferative subgroups 0 and 1 differed significantly: CMML 0 dysplastic 48 ms and CMML 0 proliferative 17 ms ( p = 0.03), CMML I dysplastic 29 ms and CMML I proliferative 15 ms ( p = 0.008), CMML II dysplastic 17 ms and CMML II proliferative 10 ms ( p = 0.09). Outcome of CMML patients worsens with increasing medullary blasts and when presenting as proliferative type. Therefore it is justified to separate CMML with <5% medullary blasts. [ABSTRACT FROM AUTHOR]

Background: Patients not fulfilling minimal criteria for myelodysplastic syndromes (MDS) but presenting with persisting cytopenia(s) not attributable to a haematological or non-haematological disease are defined as ‘idiopathic cytopenia of undetermined significance’ (ICUS).Design and methods: We retrospectively analysed 67 of 3504 patients from our MDS Registry fulfilling the criteria for ICUS. Furthermore, we used the human androgen receptor gene-based assay (HUMARA) to look for clonality.Results: Of all 67 patients, 66% had unilineage, 18% bilineage and 12% trilineage cytopenias. The majority of patients (67%) presented with anaemia. Median overall survival was 44 months (range: 1–199 months). In the entire group, eight patients (12%) developed acute myeloid leukaemia (AML). Of the 23 patients eligible for HUMARA, 17 had non-clonal X-chromosome inactivation patterns, while 6 patients showed clonal patterns. Two of these six patients developed AML indicating that a clonal stem cell disorder was the reason for the anteceding cytopenia, while there was no AML observed among the 17 patients with non-clonal patterns (P = 0.013).Conclusions: Since some of the ICUS patients had a clonal bone marrow disease when presenting with cytopenia(s) and 8 of 67 patients with ICUS later developed AML, we recommend to follow these patients thoroughly. As demonstrated here, HUMARA can facilitate the discrimination between ICUS and a ‘manifest’ MDS. [ABSTRACT FROM PUBLISHER]

Background: We retrospectively determined whether a 3-day short course of palifermin could reduce the toxicity of high-dose therapy (HDT) and autologous blood stem-cell transplantation (ASCT) in patients with multiple myeloma (MM). Patients and methods: Sixty-seven consecutive patients received 60 μg/kg palifermin for 3 days before HDT with melphalan 200 or 140 mg/m² for patients with renal failure (group A). Granulocyte colony-stimulating factor (G-CSF) was applied after ASCT. Data on haematopoietic reconstitution and toxicity were compared with two previously published patient groups from our institution who had received pegfilgrastim but not palifermin (group B, n = 21) and patients who had received neither palifermin nor G-CSF (group C, n = 21). Results: In group A, patients with renal failure had a significantly higher risk for severe mucositis (64% versus 16%, P < 0.002). Patients with normal renal function who received palifermin experienced significantly less days of hospitalisation (P < 0.05) and less need for narcotic analgesia (P < 0.05), parenteral nutrition (P < 0.05) and erythrocyte transfusions (P < 0.05) in comparison with groups B and C. Time to haematopoietic reconstitution was not compromised by the use of palifermin. Conclusions: In conclusion, a short 3-day course of palifermin may be able to reduce the toxicity of HDT and ASCT in patients with MM. Patients with impaired renal function at the time of HDT need additional strategies to further reduce the incidence of severe mucositis. [ABSTRACT FROM AUTHOR]