ALBERT

Beschreibung: Background: Many patients (pts) with myelodysplastic syndromes (MDS) [particularly those with Low- or Int-1-risk] are susceptible to iron overload from ongoing blood transfusions and increased dietary iron absorption. Deferasirox (Exjade®) has shown efficacy in maintaining or reducing body iron (assessed by liver iron concentration [LIC] and serum ferritin [SF]) in MDS pts. More recently, the efficacy and safety of deferasirox in pts with various underlying anemias, including MDS, was evaluated in the large EPIC study. Data for MDS pts are presented here. Methods: The EPIC study was a 1-yr, openlabel, single-arm, multicenter trial. Pts with transfusion-dependent MDS and SF ≥1000 ng/ mL, or SF 20 transfusions or 100 mL/kg of blood and an R2 MRI-confirmed LIC 〉2 mg Fe/g dry weight (dw), received an initial deferasirox dose of 10–30 mg/kg/day. SF was assessed monthly and protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 mths based on SF trends and safety markers. Primary efficacy endpoint was the change in SF from baseline at 12 mths. Safety assessments included monitoring of adverse event (AE) and laboratory parameters. Results: 341 MDS pts (204 M, 137 F; mean age 67.9 yrs, range 11–89 yrs) with median baseline SF of 2730 (range 951–9465) ng/mL were enrolled. Mean transfusion duration was 3.6 yrs, and pts received a mean of 116.4 mL/kg of blood in the previous yr. Almost half (48.4%) of all pts had not received any prior chelation therapy; 40.0% had previously received deferoxamine (DFO), 4.1% deferiprone, 7.0% combination DFO/ deferiprone, and 0.3% other therapy. Overall, mean actual dose of deferasirox over 1 yr of treatment was 19.2±5.4 mg/kg/day. At 12 mths, there was a significant reduction in median SF from baseline (by LOCF: –253.0 ng/mL; P=0.0019). Median SF (range) ng/mL values at baseline, 3, 6, 9 and 12 mths were 2729.5 (951–9465; n=336), 2358.0 (534–46569; n=263), 2209.5 (357–10066; n=230), 2076.0 (358–25839; n=197) and 1903.5 (141–10155; n=174), respectively. Overall, 48.7% of pts (n=166) discontinued therapy. Reasons for withdrawal included AEs [n=78, 23% (n=44, 13% for drug-related AEs)], consent withdrawal (n=33, 10%), unsatisfactory therapeutic effect (n=6, 2%), lost to follow-up (n=2, 33% above baseline (in normal range), 10.6% had two values above ULN, and 24.9% had both two consecutive values 〉33% and 〉ULN; 19 pts had dose decreases and 10 dose interruptions due to abnormal creatinine; there were no progressive increases. One patient (10xULN on two consecutive visits. Conclusions: In this large cohort of MDS pts with iron overload, deferasirox provided significant reduction in SF levels over 1-yr treatment with appropriate dose adjustments every 3 mths based on SF trends and safety markers. The AE profile in this study is consistent with previously reported deferasirox data in MDS pts. The discontinuation rate was higher in this subgroup. Investigations are ongoing to assess possible contributing factors including associated comorbidities, age of pts, and others.

Beschreibung: The del(5q) is the most commonly reported deletion in de novo MDS and is found in 10–15% of all patients. Our group demonstrated haploinsufficiency for the ribosomal gene RPS14, which is required for the maturation of 40S ribosomal subunits and maps to the commonly deleted region in patients with the 5q- syndrome (Boultwood et al, Br J Haematol2007, 139:578–89). Haploinsufficiency of RPS14 has been shown to be the mechanism underlying the erythroid defect in this disorder (Ebert et al, Nature2008, 451:335–9). We have recently shown that haploinsufficiency of RPS14 in patients with the 5q- syndrome is associated with deregulated expression of ribosomal- and translation-related genes, suggesting that the 5q- syndrome represents a disorder of aberrant ribosome biogenesis (Pellagatti et al, Br J Haematol2008, 142:57–64). The del(5q) in the 5q-syndrome is cytogenetically indistinguishable from the del(5q) found in other MDS and in the vast majority of these patients the CDR of the 5q- syndrome will be deleted (and therefore one allele of RPS14 will be lost). We are investigating the hypothesis that haploinsufficiency of RPS14 and consequent deregulated ribosome biogenesis may also play a role in the pathogenesis of non-5q- syndrome MDS patients with del(5q). Using Affymetrix U133 Plus2.0 arrays, we have studied the expression profiles of a group of 579 ribosomal- and translation-related genes in the CD34+ cells of 21 non-5q- syndrome MDS patients with del(5q) and 95 MDS patients without del(5q). 168 of 579 ribosomal-and translation-related probe sets were found to be significantly differentially expressed between these two groups, with approximately 90% of these showing lower expression levels in patients with del(5q). Hierarchical clustering using this set of 168 genes gave a good separation between patients with and without the del(5q). RPS14 was one of the most significant differentially expressed genes, with lower expression levels in patients with del(5q) confirming its haploinsufficient status in these patients. Other significant differentially expressed genes include the ribosomal protein RPL22L1, and the translation initiation factors EIF4EBP3 and EIF4B. Interestingly, when samples from 16 patients with 5q- syndrome were included in the analysis, hierarchical clustering using significantly differentially expressed ribosomal- and translation-related genes showed that most patients with 5q- syndrome and most patients with del(5q) clustered together. We are currently using polysome profile analysis on bone marrow cells to examine the levels of the 40S ribosomal subunit in patients with del(5q) and without del(5q). Our results support the hypothesis that haploinsufficiency of RPS14 and deregulation of ribosomal- and translation-related genes contribute to disease pathogenesis in MDS patients with del(5q). An exciting possibility is that other MDS with the del(5q) and the 5q- syndrome share a related molecular basis in that they are all disorders of defective ribosomal biogenesis.

Beschreibung: Abstract 2912 Background: Improvements in hematologic parameters and/or reductions in transfusion requirements have been associated with iron chelation therapy in transfusion-dependent patients with MDS; however, data has been limited to case reports/small studies (Jensen P et al. Br J Hematol 1996; Messa E et al. Acta Haematol 2008; Okabe H et al. Rinsho Ketsueki 2009; Oliva E et al. Transfusion 2010; n=1–11). The 1-year prospective EPIC study (Cappellini MD et al. Haematologica 2010) enrolled 341 transfusion-dependent MDS patients with iron overload. Patients were chelated with deferasirox leading to reductions in serum ferritin, an indicator of body iron burden (Gattermann N et al. Leuk Res 2010). During the EPIC study, transfusions were recorded and pretransfusion blood counts were assessed. Here we report a post-hoc analysis evaluating hematologic responses in a large cohort of MDS patients enrolled in EPIC using the IWG 2006 criteria (Cheson B et al. Blood 2006). Methods: Full study design and inclusion/exclusion criteria for EPIC have previously been described (Cappellini MD et al. Haematologica 2010; Gattermann N et al. Leuk Res 2010). Patients with a life expectancy of

Beschreibung: Abstract 3803 Poster Board III-739 Background Transfusional iron overload can cause hepatocellular injury, which manifests as increased liver transaminase levels and, in some cases, may progress to cirrhosis. The once-daily oral iron chelator deferasirox (Exjade®) has been shown to reduce iron overload in patients with various transfusion-dependent anemias, and a previous analysis demonstrated a correlation between decreased iron overload and improved transaminase levels [Brissot P et al. Blood 2006;108(11):abst 3817]. As liver dysfunction is a common complication in patients with myelodysplastic syndromes (MDS), this analysis evaluates the relationship between serum ferritin (as a marker of iron overload) and alanine aminotransferase (ALT; as a marker of liver function) during deferasirox treatment in a large MDS population. Methods This analysis is based on data from iron overloaded MDS patients aged ≥2 years who were enrolled in the 1-year multicenter EPIC study; patients with a life expectancy

Beschreibung: Abstract 3806 Poster Board III-742 Background Although iron overload in patients with myelodysplastic syndromes (MDS) is a negative prognostic factor for survival, many chronically transfused patients are not regularly evaluated for iron overload and remain unchelated. The once-daily oral iron chelator deferasirox (Exjade®) maintains or reduces body iron in patients with MDS, however, it has not previously been assessed based on chelation history. This analysis therefore evaluates the efficacy and safety of deferasirox in a large population of chelation-naïve and previously chelated patients with MDS. Methods This analysis is based on data from iron overloaded MDS patients aged ≥2 years who were enrolled in the 1-year multicenter EPIC study; patients with a life expectancy 10 × ULN on two consecutive visits. Conclusions Although baseline serum ferritin levels were 〉2500 ng/mL, almost 50% of patients were chelation-naive, suggesting that the importance to treat iron overload continues to be underestimated in the MDS population. For previously chelated patients these data suggest that iron burden was not adequately managed with previous regimens. Irrespective of chelation history, with appropriate dosing based on transfusion requirements, serum ferritin levels and safety markers, deferasirox effectively decreased serum ferritin to

Beschreibung: The myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic malignancies, characterized by blood cytopenias, ineffective hematopoiesis and a hypercellular bone marrow. We have investigated the gene expression profiles of a large group of patients with MDS in order to better understand the molecular pathogenesis of this disorder. The CD34+ cells obtained from 154 MDS patients and 17 healthy individuals were analyzed using Affymetrix U133 Plus2.0 arrays. 38 genes were up-regulated by 〉2-fold in at least 77 MDS patients, and pathway analysis using these genes showed that the interferon signalling pathway was significantly deregulated (p=0.0006). Indeed IFIT1, the most up-regulated gene (up-regulated in 110 of 154 MDS patients), is an interferon-stimulated gene (ISG). Other ISGs, which mediate growth inhibitory effects of interferon, such as IFITM1, IFI44L and IFIT3, were markedly up-regulated in the majority of MDS patients. Up-regulation of ISGs is a major feature of MDS and may be responsible for some of the hematological characteristics of this disorder, such as peripheral blood cytopenias. We investigated differences in gene expression that could distinguish MDS patients according to their FAB subtype classification (48 patients with RA, 44 patients with RARS and 62 patients with RAEB). Hierarchical clustering performed using the 773 significantly differentially expressed probe sets identified showed that MDS patients with RARS constitute the most homogeneous group, while MDS patients with RA and RAEB show more overlap. RARS gene expression profile was characterized by up-regulation of mitochondrial-related genes and by down-regulation of ABCB7, a gene mutated in the rare inherited X-linked sideroblastic anemia with ataxia (XLSA/A). Moreover, a good separation between the 20 patients with RARS and the 20 patients with RCMD-RS was obtained by hierarchical clustering using the 86 significantly differentially expressed genes between these two WHO subgroups. One of the most significant genes was MFN1, which is essential for mitochondrial fusion and maintenance of mitochondrial morphology. The association of distinct gene expression profiles with specific cytogenetic groups was also determined, and we were able to separate by hierarchical clustering MDS patients with del(5q), patients with −7/del(7q) and patients with trisomy 8. The expression profile of patients with the del(5q) was characterized by down-regulation of genes mapping to chromosome 5q. Genes differentially expressed in patients with −7/del(7q) include LOX and UBE2H, while genes differentially expressed in patients with trisomy 8 include HRSP12 and TPM4. These findings suggest distinct molecular pathogenetic pathways for MDS patients with del(5q), −7/del(7q) and trisomy 8. In order to identify differences in gene expression associated with MDS disease progression, we compared the 48 patients with early MDS (RA) and the 35 patients with advanced MDS (RAEB2). Hierarchical clustering performed using 1081 significantly differentially expressed probe sets resulted in a good separation between MDS patients with RA and patients with RAEB2. LEF1, a regulator of neutrophilic granulopoiesis, was the most significant differentially expressed gene with higher expression levels in patients with RA and decreasing in patients with RAEB2. Other genes showing higher expression levels in patients with RA, decreasing in patients with RAEB2, include CASC5, a cancer susceptibility candidate gene, and RBBP8, a gene that plays a role in DNA-damage-induced cell cycle checkpoint control. Several genes mapping to the cell cycle pathway were significantly deregulated between early and advanced MDS. This study provides new important insights into the pathophysiology of MDS and represents a first step towards determining pathway signatures in MDS as a guide to targeted therapies.