Lower-risk Myelodysplastic Syndromes Patients Research Articles

Research Progress of Thalidomide and Its Derivatives in Treatment of Myelodysplastic Syndrome--Review

Thalidomide and its derivatives have been used in the treatment of myelodysplastic syndrome (MDS) because of their anti-angiogenic and immunomodulatory effects. In recent years, some studies have found that thalidomide and its derivatives not only showed significant efficacy in lower-risk MDS patients with del (5q), but also showed advantages in non-del (5q) MDS patients. In addition, the discovery of its molecular targets and new substrates makes it possible to develop a new generation of immunomodulatory drugs (IMiDs) and to design IMiDs-based proteolysis-targeting chimeras. In this review, the new progress in mechanism and clinical application of thalidomide and its derivatives were summarized briefly, so as to provide a more scientific, reasonable and effective scheme to the treatment of MDS.

Allogeneic Hematopoietic Stem Cell Transplantation (allo HSCT) in Patients with IPSS Low or Intermediate-1 Myelodysplastic Syndrome (MDS): A Prospective Multicenter Phase II Study Based on Donor Availability By the GFM & SFGM-TC “MDS-ALLO-Risk”

Allogeneic Hematopoietic Stem Cell Transplantation (allo HSCT) in Patients with IPSS Low or Intermediate-1 Myelodysplastic Syndrome (MDS): A Prospective Multicenter Phase II Study Based on Donor Availability By the GFM & SFGM-TC “MDS-ALLO-Risk”

Recombinant Human Thrombopoietin Accelerates the Recovery of Platelet in Patients with Lower-Risk Myelodysplastic Syndrome: A Prospective Cohort Study

Aim: The effect of recombinant human thrombopoietin (rhTPO) is largely unknown in lower-risk myelodysplastic syndrome (LR-MDS). This study aimed at investigating the safety and efficacy of rhTPO in patients with LR-MDS.Methods: This was a prospective study. Patients newly diagnosed as LR-MDS patients from 2018 to 2020 were enrolled and randomized into two groups. They were either treated with rhTPO+ stanozolol 2mgtid (rhTPO group) or stanozolol 2mgtid alone (non-rhTPO). rhTPO was given at 15000U qd for 7days/months for at least three months. Patients stopped rhTPO if platelet count was higher than50×10 9/L, or had no effects after 3-month treatment. The overall response (OR), complete response (CR), platelet response, side effects, clone evolution and clinical outcome were evaluated.Result: 35 patients were enrolled, the median age (range) was 55 (41-91) years and 17 patients were males, 18 patients were females. 20 (57.1%) patients were enrolled in rhTPO group and 15 (42.9%) patients in non-rhTPO group. The demographic and baseline characteristic were balanced between the two groups. The platelet response was higher at 1 month and 2 months, as compared with that in non-rhTPO group (40% vs 0%, p = 0.006; 55.0% vs 0%, p = 0.001, respectively). Meanwhile, rhTPO group had a shorter time to achieve platelet transfusion free compared with non-rhTPO group (2 (1-6) months vs 4.5 (2-12) months, p=0.034). No significant difference in overall response, complete response, or hematologic response at 1/2/3/6/12months between the two groups. One patient in rhTPO group evolved into higher risk MDS, one patient died of intracranial hemorrhage. No significant difference in disease progression, infection, gastrointestinal disorders or drug-related liver/renal injuries were found between the two groups (p>0.05).Conclusion: Adding short-term rhTPO can accelerate the early platelet response and decrease platelet transfusion with no obvious side effects. DisclosuresNo relevant conflicts of interest to declare.

Unique Metabolic Vulnerabilities of Myelodysplastic Syndrome Stem Cells

Background: The mechanisms that cause the progression of myelodysplastic syndrome (MDS) are poorly understood. Little is known about major signaling networks and energy metabolism in MDS cells as patients progress from low risk (LR) to high risk (HR) disease and from high risk to secondary acute myelogenous leukemia (sAML). As many as 30% of HR MDS patients progress to sAML and a portion of LR MDS patients progress to HR. The goal of this project is preventing progression by identifying MDS-specific targets for therapy. A deeper understanding of the metabolic properties of leukemia stem cells (LSCs) in AML has shown these cells are uniquely vulnerable to venetoclax and azacitidine (Ven/Aza) (Pollyea et al, Nat. Medicine, 2018) and metabolic changes cause resistance to Ven/Aza (Stevens et al, Nat. Cancer, 2021). Little however is known about the contribution of metabolism to the pathogenesis of MDS. The contributing factors to progression including metabolic properties, transcriptional programs, and immunophenotype are examined in this study.Methods: Bone marrow specimens from MDS patients at various disease stages, including serial samples during progression, were obtained. Single cell techniques including mass cytometry, antibody based single cell RNA sequencing (CITE-Seq) and transcriptional profiling with RNA sequencing were used to elucidate novel mechanisms of progression. Selective targeting of primitive MDS cells was tested using several agents.Results: Our previous work characterizing MDS stem cells (MDSC) showed significant similarities between MDSCs and AML LSCs (Stevens et al, Nat. Communications, 2018). However, little is known about lower risk disease. In order to understand transcriptional changes and their relationship to metabolism across pathogenesis, the transcriptome of blasts from patients with LR, intermediate (INT), or HR IPSS scores was investigated. The first major transcriptional difference identified was enrichment of glycolysis pathway at LR and INT stage. In contrast, HR MDS demonstrated enrichment of oxidative phosphorylation. Furthermore, comparison of intermediate to HR MDS showed increased RNA polymerase and Ribosome pathways at the HR stage. These changes demonstrate the progressive alteration of metabolic properties during MDS pathogenesis with cells first relying on mechanisms associated with normal stem cells (i.e. glycolysis) and later transitioning to a state associated with AML stem cells (i.e. reliance on oxidative phosphorylation).Using serial specimens of patients of who progressed from LR to HR MDS we performed CITE-Seq and mass cytometry. CITE-seq in serial specimens showed up-regulation of protein translation and oxidative phosphorylation in a subset of MDS stem and progenitor cells (CD34+ at transcript and antibody level) present at LR stage and conserved at HR stage (Fig 1A-C). MDSCs also acquired surface antigens including CD99 and CD52 upon progression from LR to HR. Analysis of the mass cytometry data showed significant overlap with CITE-Seq data including increased CD123+ and MCL1 expression in MDS stem cells upon progression.In order to understand therapeutic vulnerabilities as they relate to progression, we investigated ex vivo drug response in LR and HR specimens. MDS samples were challenged with two regimens, Ven/Aza, a regimen known to inhibit OXPHOS; and omacetaxine and azacitidine (Oma/Aza), which inhibits translation. CITE-seq showed that MDSC were selectively sensitive to these agents (Fig 1D). Importantly, addition of either drug regimen caused ablation of MDSC at LR and HR stages and these changes were most profound in cells with LSC properties.Based on preclinical findings, we are investigating MDS patients treated with Ven/Aza or Oma/Aza via CITE-seq and metabolomics for correlation of clinical response with properties of MDSC. Preliminary studies show that patients that respond to Oma/Aza present with a population of MDSC with transcriptional signatures of protein translation and LSCs (Fig. 1E). Studies are underway to investigate overlapping properties of ven/aza resistance in AML to resistance in MDS specifically investigating fatty acid metabolism in MDSC.Conclusions: Analysis of MDS patient bone marrow reveals acquisition of aberrant metabolic properties at both low and high risk stages of disease. These distinct aspects of MDSC biology create unique and targetable features. [Display omitted] DisclosuresPollyea: Genentech: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Syndax: Consultancy; Takeda: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Agios: Consultancy; Glycomimetics: Other.

Low-Density Granulocytes Are Decreased in Acute Myeloid Leukemia and in Myelodysplastic Syndromes with Negative Prognostic Factors

Introduction. Myelodysplastic syndromes (MDS), a group of clonal hematological diseases, are characterized by ineffective hematopoiesis, progressive peripheral blood (PB) cytopenia(s), and increased risk of developing acute myeloid leukemia (AML). Classification and risk stratification are constantly under revision for a better estimation of prognosis in those patients. Investigation of immune biomarkers is needed, because immune dysregulation also plays an important role in dysplastic hemopoiesis and immunological escape of neoplastic clones. Here, we studied frequency of low-density granulocytes (LDGs), a neutrophil subset with immunoregulatory functions, in MDS and AML at diagnosis and during treatments.Methods. A total of 17 patients (M/F, 14/12; median age, 69 years old; range, 21-84 years) and seven healthy subjects were enrolled at the Hematology and Transplant Center, University Hospital “San Giovanni di Dio e Ruggi d'Aragona”, Salerno, Italy, between October 2020 and July 2021. Patients were diagnosed with AML (N = 7), or MDS (N = 10) according to the 2016 World Health Organization criteria. For immunophenotyping, fresh EDTA whole PB was stained with the ollowing antibodies: CD45; HLA-DR; CD15; CD3; CD56; CD19; CD11b; CD33; CD34; CD14; and CD16 (all from Beckman Coulter, Brea, CA). Acquisition was carried out using a Navios EX flow cytometer, and Navios software v1.3 (Beckman Coulter). Post-acquisition compensation and analysis were performed using FlowJo software (v.10.7.1, Becton Dickinson). LDGs were identified as CD3-CD56-CD19-CD11b+CD33+CD14-CD15+ cells, following previously published gating strategies (Rahman S, et al. Ann Rheum Dis. 2019). Data were analyzed using Prism (GraphPad software, La Jolla, CA). A P < 0.05 was considered statistically significant.Results. Frequencies of circulating LDGs were significantly reduced in AML patients at diagnosis compared to controls (P = 0.0018) and MDS (P = 0.0077) and were slightly decreased compared to AML in complete remission (P = 0.1605). MDS patients were then divided based on Revised International Prognostic Scoring System (IPSS-R), and very-low and low-risk MDS patients displayed significantly higher circulating LDG frequencies compared to AML at diagnosis (P = 0.0083), while no differences were described between AML at baseline and intermediate-risk MDS (P = 0.1103). Subsequently, LDGs were correlated with clinical and phenotypic features by correlation analysis showing significant negative correlations between LDGs and blasts identified by flow cytometry (r = -0.5463; P = 0.0057) but not by cytology (P = 0.1346), between LDGs and lymphocytes (r = -0.4407; P = 0.0311) or flow cytometric normalized blast count (NBC; r = -0.5283; P = 0.0096) as previously defined (Giudice V, et al. Biomedicines. 2021). A slight negative correlation was described between LDGs and WT1 expression levels (r = -0.5369; P = 0.0719), particularly evident in MDS patients (r = -0.9980; P = 0.0402), supporting our previous findings of negative prognostic impact of WT1 expression in MDS and AML. Finally, we investigated CD16 expression on LDGs, because CD16 is essential for neutrophil degranulation. Despite no differences were described between percentage of LDG subsets among patients' groups, various correlations were identified by Pearson analysis. In particular, CD16+ LDGs negatively correlated with blasts (P = 0.0229), while positively correlated with lymphocytes (P = 0.0404) detected by flow cytometry. Conversely, CD16int and CD16- LDGs negatively correlated with lymphocytes (P = 0.0109 and P = 0.0021, respectively) and positively correlated with granulocytes identified by flow cytometry (P = 0.0024 and P = 0.0008, respectively). In addition, CD16int LDGs negatively correlated with blasts detected by flow cytometry (r = -0.65; P = 0.0414).Conclusions. Our preliminary results suggested a possible role of LDGs in prognostic definition of AML and MDS patients especially when combined with other biomarkers, such as WT1 expression levels or NBC. Moreover, our data supported the hypothesis of biological heterogeneity of granulocytes, as LDG subsets variously correlated with lymphocytes and leukemic cells suggesting different roles in suppression or activation of immune responses. However, our findings need further validation in larger cohorts and in in vitro studies. DisclosuresNo relevant conflicts of interest to declare.

Characterization of Somatic Mosaicism and Mutational Profiling of Clonal Hematopoiesis Compared to MDS and sAML Depicts Diversities of Clonal Evolution

Background:Clonal hematopoiesis (CH) describes the presence of genetic alterations and expansion of clonal cell populations in the peripheral blood (PB) of individuals without clinical manifestation of a hematologic malignancy. CH is a common, age-related state. However, individuals carrying CH are at greater risk for hematologic cancer. It has been shown that presence of TP53- and other high-risk mutations, variant allele frequency (VAF) >10% or multiple mutations in CH carriers may confer a higher risk of preleukemic development and transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Nevertheless, further insights into the role of CH in clonal evolution towards leukemia and elaborating features that are predictive of leukemic progression are needed.Aims:We have recently shown that CH is common in individuals undergoing hip replacement surgery (Hecker, Hartmann et al., Blood 2021). Here, we compared mutational spectrum in these CH individuals to MDS and secondary AML (sAML) cohorts. Additionally, we analyzed spatial and lineage distribution of CH and longitudinally monitored CH and MDS clones over time.Methods:Samples from individuals without known hematologic disease undergoing hip replacement surgery (n=288 samples from 261 individuals), patients with MDS (n=92) or sAML (n=123) were screened for variants in 68 leukemia-associated genes using a targeted sequencing approach (VAF cut off, 1%). Follow-up (FU) PB samples were available for 21 individuals with CH and 16 untreated low-risk MDS patients, 6-24 months after screening. n=5 CH bone marrow (BM) samples carrying six ASXL1-mutations were sorted for seven different cell fractions.Results:At screening, variants were detected in 127/261 (49%) healthy individuals, 84/92 (91%) MDS and 117/123 (95%) sAML patients, with median VAFs of 2.7% (ranging from 1-44%), 18.8% (1.1-87%) and 37.1% (1-99%), respectively. Individuals with CH had a median number of 1 variant per individual, whereas median detected variants per patient increased with clonal evolution with 3 variants in the MDS and 4 variants per patient in the sAML cohort.CH, MDS and sAML showed entity-specific mutation profiles (Figure 1A). Most variants in CH affected epigenetic modifiers, while mutations in splicing factors, signaling pathways and transcription factors increased with clonal progression.During FU, untreated low-risk MDS patients more frequently gained additional mutations compared to CH individuals (7/16 vs 2/21, respectively; p=0.024). However, we did not observe significant changes in clone sizes over time.In 17 hip replacement individuals both femoral heads were removed simultaneously, allowing paired analysis of two different hematopoietic sites. CH prevalence in this subgroup was 70.6% (12/17). Ten individuals showed identical mutation patterns in BM obtained from the right and left femoral head, with little differences in VAFs (Table 1). In contrast, two other individuals showed significant differences in variant detection comparing one to the other side: ASXL1-mutations were only present in one hip sample, whereas all the other variants were detectable in both sides (p<0.001), indicating possible spatial heterogeneity of CH clones in the BM compartment.To further characterize ASXL1 mosaicism across hematopoietic lineages and differentiation stages, we sorted and sequenced n=5 CH BM samples carrying six ASXL1-mutations for seven different hematopoietic cell fractions. In all cases ASXL1-mutations were identified in CD34 +CD38 -CD90 + hematopoietic stem cells (HSC). VAFs of ASXL1-mutations were differentially distributed (p=0.0049, Kruskal Wallis test): detected VAFs were significantly higher in HSC and common myeloid progenitors (CMP) compared to VAFs in T-cells (p=0.045 and p=0.011, respectively; Dunn´s multiple comparison test; Figure 1B).Conclusions:CH, MDS and sAML show characteristic mutation profiles that remained stable over a 6-24-month period. Gains of additional variants and clonal expansion associated with disease progression. Cellular distribution analysis of ASXL1 CH variants revealed characteristic repartition patterns within the hematopoietic differentiation tree. Additionally, differences in variant detection between cellular BM compartments indicates spatial heterogeneity of CH clones warranting further investigation.J.S.H. and L.H. contributed equally. [Display omitted] DisclosuresPlatzbecker: Geron: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Goetze: BMS/Celgene: Other: Advisory Board, Research Funding; Abbvie: Other: Advisory Board.

Excellent Prognosis of Low-Risk Myelodysplastic Syndromes (MDS) Without Detectable Myeloid-Related Mutations

BackgroundUnexplained cytopenia (UC) and low-risk myelodysplastic syndrome (MDS) are distinguished mainly by morphologic dysplasia, which sometimes shows inter-observer discrepancy. We hypothesized that gene mutations are strong prognostic factors for these low-risk patients. Materials and methodsWe enrolled patients from 4 medical centers with unexplained cytopenia of at least 1 lineage. Diagnosis of low-risk MDS was made according to WHO 2016 classification and a revised international prognostic scoring system (R-IPSS) score of ≤ 3.5. DNA was extracted from bone marrow or blood and sequenced by targeted next generation sequencing (NGS). ResultsOne hundred twenty-one patients were recruited: 25% with UC and 75% with low-risk MDS. Complete blood counts were similar, but low-risk MDS patients carried higher numbers of mutations (1 vs. 0; P = .04) than UC patients. Overall, the most frequent mutated genes were TET2 (14.6%), SF3B1 (12.2%), and ASXL1 (9.7%). Survival rates of low-risk MDS patients versus UC patients were not significantly different. UC patients and low-risk MDS patients without genetic abnormalities showed superior 5-year progression free survival compared to MDS patients with mutations (100% vs. 76.0%; P = .005). Overall, ASXL1 mutations were associated with decreased 4-year overall survival compared to wild-type (59% vs. 31%; P = .01). In a multivariate analysis, ASXL1 and DNMT3A mutations in low-risk MDS patients were associated with a higher risk of disease progression with hazard ratios of 7.88 (95% CI 1.76-35.32, P = .01) and 7.45 (95% CI 1.61-34.46, P = .01), respectively. ConclusionMutation detection is important for proper risk stratification of patients presenting with idiopathic cytopenia.

The anemia-independent impact of myelodysplastic syndromes on health-related quality of life

Myelodysplastic syndromes (MDS) are in the majority of cases characterized by anemia. Both anemia and MDS per se may directly contribute to impairments in health-related quality of life (HRQoL). In this study, we aimed to investigate the anemia-independent impact of MDS on HRQoL. We evaluated participants (≥ 50 years) from the large population-based Lifelines cohort (N = 44,694, mean age 59.0 ± 7.4 years, 43.6% male) and the European MDS Registry (EUMDS) (N = 1538, mean age 73.4 ± 9.0 years, 63.0% male), which comprises a cohort of lower-risk MDS patients. To enable comparison concerning HRQoL, SF-36 scores measured in Lifelines were converted to EQ-5D-3L index (range 0–1) and dimension scores. Lower-risk MDS patients had significantly lower HRQoL than those from the Lifelines cohort, as illustrated in both the index score and in the five different dimensions. Multivariable linear regression analysis demonstrated that MDS had an adjusted total impact on the EQ-5D index score (B = − 0.12, p < 0.001) and an anemia-independent “direct” impact (B = − 0.10, p < 0.001). Multivariable logistic regression analysis revealed an anemia-independent impact of MDS in the dimension mobility, self-care, usual activities, and anxiety/depression (all except pain/discomfort). This study demonstrates that the major part of the negative impact of lower-risk MDS on HRQoL is not mediated via anemia. Thus, the therapeutic focus should include treatment strategies directed at underlying pathogenic mechanisms to improve HRQoL, rather than aiming predominantly at increasing hemoglobin levels.

MDS-223: Response to Erythroid Stimulating Agents (ESA) and Flow Cytometric Characteristics of Bone Marrow Erythroid Precursors in IPSS-R Lower-Risk Myelodysplastic Syndrome Patients

Context: Standard treatment of anemia in lower-risk myelodysplastic syndromes (LR-MDS) is based on erythropoietic-stimulating agents (ESAs), but some patients are primary refractory (PR) or lose response (secondary refractory, SR). High serum erythropoietin (sEPO) is the main negative predictor, and treatment of ESA-resistant anemia is challenging, so more predictors are needed. EPO promotes differentiation of committed erythroid cells (COMe) into erythroid precursors (EP), constituted by early (EEP) and late (LEP) precursors. Flow cytometry (FC) can characterize COMe and EP. RED score is an FC parameter that assesses dyserythropoiesis. Objective: We aimed to correlate COMe, EP, and RED score with response to ESAs, WHO category, and sEPO in 44 anemic LR-MDS patients. Design: We evaluated 10 negative controls, 17 PR patients, 17 SR patients, and 10 long responders (LR, response duration >24 months). Fifty-nine percent had sEPO 500 mU/mL(H-EPO); 23% had single lineage dysplasia (MDS-SLD), 34% multilineage dysplasia (MDS-MLD), 23% ring sideroblasts (MDS-RS), and 20% deletion of 5q (MDS-5q-). FC analysis was performed on bone marrow aspirates for all subgroups at diagnosis and within SR subgroup at loss of response to ESA (SRII). We used anti-CD34, CD36, CD105, CD117, CD33, CD71, and CD45 antibodies to identify COMe, total erythroid cells (TOTe), and EP. Coefficients of variance of CD71 and CD36 were used to calculate RED score. Results: TOTe and COMe were increased in LR-MDS compared to controls (p=0.013 and p=0.04, respectively), with the exception of MDS-5q- cases. In the PR subgroup, LEP were increased and COMe were reduced compared to LR. In the SRII group, COMe were lower than at diagnosis (p=0.039). RED score was higher in PR compared to responders (p=0.011). MDS-5q- cases showed reduced TOTe (p=0.047), while MDS-RS cases had higher LEP and RED score (p=0.008 and p=0.012, respectively). Finally, LEP were increased in the H-EPO group compared to L-EPO (p=0.023). Conclusions: These data suggest that COMe seem to be positively associated with ESA response, whereas higher LEP and RED score are negatively associated and also correlate with MDS-RS and H-EPO. Finally, MDS-5q- cases displayed fewer TOTe and COMe, suggesting premature apoptosis of erythroid precursors.

Poster: MDS-223: Response to Erythroid Stimulating Agents (ESA) and Flow Cytometric Characteristics of Bone Marrow Erythroid Precursors in IPSS-R Lower-Risk Myelodysplastic Syndrome Patients

Poster: MDS-223: Response to Erythroid Stimulating Agents (ESA) and Flow Cytometric Characteristics of Bone Marrow Erythroid Precursors in IPSS-R Lower-Risk Myelodysplastic Syndrome Patients

Profile of patients with Myelodysplastic syndrome: A report from a tertiary care teaching hospital from Eastern India

Objectives: Myelodysplastic syndrome (MDS) is a group of myeloid neoplasms. The clinical manifestations and treatments vary depending on the subtype and risk stratification of the disease. There is a paucity of data on Indian patients with MDS. This study was undertaken to understand MDS with regard to their clinical presentation, pathological, cytogenetic profiles and also to assess their therapeutic outcomes and prognosis from our center in Eastern India. Materials and Methods: This is a prospective observational study conducted in the department of hematology at a tertiary care teaching hospital from eastern part of India. The diagnosis of MDS was made from the peripheral blood examination, bone marrow aspirate examination, cytogenetics, and Fluorescence in situ hybridization results, according to the WHO guidelines. Patients were risk stratified using Revised International Prognostic Scoring System (R-IPSS) and subsequent therapeutic planning was done, with either supportive therapy in the form of recombinant human erythropoiesis stimulating agents, colony stimulating factors, packed red blood cell support as needed for low risk MDS patients. High risk patients were treated with hypomethylating agents such as Azacytidine, Decitabine, or Lenalidomide. Results: The mean duration of follow-up of patients with MDS from the point of diagnosis was 1.8 years (range 4 months–6 years). The median OS was 1.33 years. The median OS in the analysis of our patient cohort with low, intermediate, high, and very high R-IPSS was 1.67 years, 1.33 years, 1.67 years, and 1.67 years, respectively. No patients of very low risk group were identified in our study. Conclusion: Our findings reflect that MDS-MLD with low or intermediate R-IPSS risk groups is the most common types of MDS. Although supportive therapy was used to treat patients irrespective of other therapy given (depending on the risk group of the patient), it was used alone even in higher risk groups due to logistic reasons in some cases. Those patients who received supportive care alone also had a good survival duration. However, a longer follow-up duration is required to firmly establish this outcome. The median age of patients (55 years) was also lower than established studies with a median overall survival of 1.67 years.

Expanding the immune armoury against myelodysplastic syndrome.

Expanding the immune armoury against myelodysplastic syndrome.

Predictors of cardiovascular events and all-cause of death in patients with transfusion-dependent myelodysplastic syndrome.

Cardiovascular disease (CVD) involves the second cause of death in low-risk myelodysplastic syndrome (MDS) population. Prospective study to characterise the CVD and to identify predictors for the combined event (CE) cardiovascular event and/or all-cause mortality in transfusion dependent low-risk MDS patients. Thirty-one patients underwent a cardiac assessment including biomarkers and cardiac magnetic resonance (cMR) with parametric sequences (T1, T2 and T2* mapping) and myocardial deformation by feature tracking (FT) and were analysed for clonal hematopoiesis of indeterminate potential mutations. Cardiac assessment revealed high prevalence of unknown structural heart disease (51% cMR pathological findings). After 2·2 [0·44] years follow-up, 35·5% of patients suffered the CE: 16% death, 29% cardiovascular event. At multivariate analysis elevated NT-proBNP ≥ 486pg/ml (HR 96·7; 95%-CI 1·135-8243; P = 0·044), reduced native T1 time < 983ms (HR 44·8; 95%-CI 1·235-1623; P = 0·038) and higher left ventricular global longitudinal strain (LV-GLS) (HR 0·4; 95%-CI 0·196-0·973; P = 0·043) showed an independent prognostic value. These variables, together with the myocardial T2* time < 20ms, showed an additive prognostic value (Log Rank: 12·4; P = 0·001). In conclusion, low-risk MDS patients frequently suffer CVD. NT-proBNP value, native T1 relaxation time and longitudinal strain by FT are independent predictors of poor cardiovascular prognosis, thus, their determination would identify high-risk patients who could benefit from a cardiac treatment and follow-up.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

Impact of Treatment with Iron Chelation Therapy in Lower-Risk MDS Patients Participating in the European Leukemianet MDS (EUMDS) Registry

BackgroundIron overload/toxicity due to red blood cell transfusions (RBCT) is associated with morbidity and mortality in various patient groups, including patients with lower-risk myelodysplastic syndrome (LR-MDS). Many studies suggested improved overall survival (OS) after iron chelation therapy (ICT), but most studies suffer from methodological problems. In daily practice, many transfused LR-MDS patients receive ICT according to (inter)national guidelines to counteract the effects of RBCT. The value of ICT in LR-MDS remains unproven. The aim of this study is to assess the effect of ICT on OS in LR-MDS patients.MethodsThe EUMDS registry, prospectively collects observational data on LR-MDS patients from 142 centers in 16 countries in Europe and Israel. Three iron chelators are available in Europe for treatment of secondary iron overload, but availability varies between countries. We first assessed the impact of treatment of the three iron chelators on OS. Secondly, we compared the chelated patients with a contemporary control group within the EUMDS registry. The control group consisted of patients who met the eligibility criteria for using ICT (≥15 RBC units, RBCT intensity of ≥1 RBC unit/month during a six-month period between visits, or serum ferritin ≥1000 µg/L), but who did not receive ICT. A Cox proportional hazards model was used, treating receipt of ICT as an time-varying variable. Finally, all transfused chelated and non-chelated patients were compared with a propensity-score matched model (3:1 nearest matching with replacement) in which more confounding factors could be added to Cox model in order to deal with confounding as adequately as possible.ResultsThe EUMDS registry included 2205 patients as of July 2017. At this point, 205 patients received ICT. Table 1 shows the follow-up duration for all patients. Of the chelated patients, 154 received deferasirox as initial chelator, 39 deferoxamine, and 12 deferiprone. Nineteen patients switched from one chelator to another, but usually the treatment period of the 2nd chelator was short compared to the 1st chelator (data not shown). The median time on chelation for all 205 patients was 13 months (range 3-42). Patients receiving ICT were on average younger, had better performance scores and less comorbidities compared to the control group (table 2).Comparison of three iron chelators The OS from the start of ICT for 154 patients treated with deferasirox is not significantly different compared to deferoxamine (n=39; p=0.058). The Hazard Ratio (HR) and 95% confidence intervals (CI) for OS (deferasirox as reference group) adjusted for age, sex, comorbidity, performance status, and cumulative number of RBCT for deferoxamine was 1.95 (0.85-4.50) and for deferiprone 0.38 (0.04-4.06) (Table 2).Comparison with non-chelated control group The control group consisted of 657 non-chelated patients (table 2). The crude HR and 95% CI for OS for all chelated patients was 0.66 (0.52-0.85) (non-chelated group as reference). After adjusting for age, sex, comorbidity, performance status, RBCT intensity, cumulative number of RBCT, and IPSS-R, the HR was 0.75 (0.50-1.15). When the analysis was restricted to the patients treated with deferasirox, the crude HR was 0.61 (0.46-0.81) and the adjusted HR was 0.79 (0.51-1.22).Propensity-matched model The chelated and non-chelated patients were matched for age, RBCT intensity, ferritin level, comorbidity, and performance status. 128 chelated patients and 223 controls could be matched, the overlap of propensity scores in both groups was good (data not shown). The crude HR and 95% CI for OS for the chelated group (non-chelated group as reference) was 0.77 (0.55-1.07). When correcting for age, sex, comorbidity, performance status, RBCT intensity, cumulative RBCT number, and IPSS-R, the HR was 0.62 (0.39-0.98). When we again restricted the analysis to deferasirox, the crude HR was 0.71 (0.48-1.06) and the adjusted HR was 0.58 (0.33-1.01).ConclusionOS of LR-MDS patients treated with ICT, was better compared to a large, control group and significantly better in a propensity-score matched model. In the absence of randomized, controlled trials proving the survival advantage of ICT, our large, prospective, observational study of clinical practice in Europe and Israel provides sound evidence of a beneficial effect of ICT on OS. [Display omitted] DisclosuresFenaux:Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sanz:Gamida Cell: Research Funding. skov-Holm:Celgene: Research Funding. Almeida:Alexion: Honoraria; Bristol Meyer Squibb: Honoraria; Servier: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Itzykson:Janssen: Research Funding; Novartis: Research Funding. Guerci-Bresler:BMS: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau.

A Systematic Review and Meta-Analysis of the Effect of Iron Chelation Therapy on Survival in Patients with Lower Risk Myelodysplastic Syndrome

Background: Anemia is the most common cytopenia among patients with myelodysplastic syndromes (MDS) often necessitating regular red blood cell (RBC) transfusions. As a result, most patients develop iron overload (IO). RBC transfusion dependency and IO have been associated with worse clinical outcomes, including inferior overall survival (OS), in MDS patients. While iron chelation therapy (ICT) is recommended by most clinical guidelines and experts for select MDS patients, the use of ICT remains controversial in the absence of published, randomized controlled trials. To evaluate the impact of ICT on survival among lower risk MDS patients, we performed a systematic review and meta-analysis (SRMA) of the literature.Methods: We conducted an SRMA according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. PubMed and Embase electronic databases were searched through October 2016 with search terms “MDS” OR “myelodysplastic syndrome” AND “iron chelation” OR “iron chelating” OR “iron overload” AND “survival” OR “death” AND “study” OR “trial.” Additionally, the Cochrane Library, the World Health Organization (WHO) International Clinical Trials Registry, and abstracts from recent American Society of Hematology annual meetings (years 2014-2016) were searched. One study, published in 2014, had an updated analysis in 2017 that was used for the current analysis. Information abstracted included data relating to study and patient characteristics, outcome measures (mortality and progression to acute myeloid leukemia [AML]), and measures of effect (calculated odds, hazard ratios [HRs], and confounding variables for adjustment). A Random Effects model was used to compute an adjusted HR (aHR) among the different studies. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies. Study heterogeneity was assessed using the Cochran Q and the I2 statistic. Publication bias was assessed through visual examination of a funnel plot and with the Egger's test for small-study effects.Results: Of the 331 records screened, 23 were assessed for eligibility, and 9 were included (Figure 1). Of these 9 studies, 6 were considered to be of high quality based on the NOS. All 9 were observational studies (4 prospective and 5 retrospective); 8 were identified as including patients with the International Prognostic Scoring System (IPSS)-defined low and intermediate-1 risk MDS. In these 8 studies, ICT was associated with an overall lower risk of mortality (aHR 0.43; 95% confidence interval [CI] 0.30-0.60; p < 0.01) (Figure 2). The pooled estimate of the ratio of median unadjusted survival times was 2.02 (95% CI 1.64-2.49), indicating that the median OS for patients receiving ICT was approximately twice that for patients who did not receive ICT. There was evidence of significant heterogeneity across studies for this outcome measure with I2 = 64% and Cochran's Q statistic = 19.8 (p = 0.006). Although the direction of effects did not change, heterogeneity was significant in prospective studies (I2 = 73%; Cochran's Q statistic = 7.4, p = 0.02), but not in retrospective studies (I2 = 9.8%; Cochran's Q statistic = 4.4, p = 0.35). In the 2 studies that reported on benefits of adequate chelation, any degree of chelation was found to confer a survival benefit, but this was to a lesser degree than the survival benefit accrued by those who received higher adequate doses. ICT seemed to decrease the risk of progression to AML (odds ratio 0.526; 95% CI 0.37-0.74; p < 0.001) in the studies that reported on this outcome (Figure 3); these studies displayed no significant heterogeneity. The impact of ICT on end organ damage could not be assessed due to non-uniform reporting of studies.Conclusions: This SRMA suggests a significant reduction in the adjusted risk of mortality among IPSS low and intermediate-1 risk MDS patients treated with ICT. Furthermore, our analysis suggests that ICT is associated with delayed progression to AML, although the causality of these associations cannot be established based on this study. Randomized controlled studies are needed to confirm these findings. [Display omitted] DisclosuresBallas:Novartis: Honoraria, Speakers Bureau. Zeidan:AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau; Otsuka: Consultancy.

Rigosertib Oral in Transfusion Dependent Lower Risk Myelodysplastic Syndromes (LR-MDS): Optimization of Dose and Rate of Transfusion Independence (TI) or Transfusion Reduction (TR) in a Single-Arm Phase 2 Study

Background:LR-MDS patients have limited treatment options and a large number are transfusion dependent (Raza A, Expert Opinion 2016, 4:9). Erythropoiesis stimulating agents (ESA) are the first line of therapy for LR-MDS patients, but the overall response rate remains low. Thus, novel strategies with the goal of red blood cell (RBC) transfusion reduction (TR) and independence (TI) are required. Rigosertib, a small molecule inhibitor of RAS effector pathways (Athuluri-Divakar SK, Cell 2016;165:643) is under investigation in MDS. The absolute bioavailability of oral rigosertib is about 35% (Komrokji, BJH 2013; 162:517). Here we expand an earlier report (Raza A, ASH 2013 #2745) on rigosertib oral in LR-MDS with updates on dose optimization on the frequency of TI or TR.Methods:Rigosertib oral was tested in this phase 2 study in LR (intermediate-1 or low risk per IPSS classification) transfusion-dependent MDS patients. Fifty-four (65.9%) patients had received ESA. Rigosertib was administered to RBC transfusion-dependent patients; defined as requiring a minimum of 4 packed red blood cell (PRBC) units over 8 weeks, in the cohorts shown in see Table below. Patients were eligible for efficacy analysis if they received a minimum of 8 weeks of rigosertib in their assigned dosing cohort. Erythrocyte stimulating agents (ESAs) were allowed on study. TI is defined as no PRBC transfusions over a period of 8 sequential weeks; TR a reduction in 4 or more RBC units over a period of 8 sequential weeks.Results:Eighty-two patients with a median age of 70 years (range 54-90) were enrolled between May 2012 and February 2015, at 5clinical sites, and received a median of 5.4 months (range 0.1-28.8) of oral rigosertib. Of the 82 enrolled patients, 9 patients were treated with 560 mg BID continuously, 7 patients treated with 560 mg in the AM and 280 mg in the PM continuously, 35 patients treated with 560mg BID intermittently, 31 patients treated with 560mg in the AM and 280mg in the PM intermittently. Sixty patients were treated with ESA and oral rigosertib while on study. An unusual adverse event (AE) (urinary events) was identified as related to dosing. Continuous rigosertib dosing cohorts were closed early due to higher urinary adverse events (AEs) or less efficacy with the lower dose of rigosertib.EfficacyOf the 82 patients, 66 patients received intermittent dosing for at least 8 consecutive weeks; and 20 of 62 evaluable patients (32%) achieved TI lasting 8 to 85+ weeks; with a median of 18 weeks. The highest rate of TI (44%) was observed in the 560 mg BID intermittent cohort: 15 of 34 eligible patients achieved TI lasting 8 to 85+ weeks; with a median of 18 weeks (TABLE). Ninty-three percent (93%) of these 15 patients received rigosertib with continued ESA.SafetyDue to urinary AEs continuous 560 mg BID dosing is no longer being studied. For all intermittent patients (n=66); the most frequent treatment emergent adverse events observed were urinary with pollakiuria (42.4%), fatigue and micturition urgency (33.3%), urinary tract pain (28.8%), hematuria and dysuria (24.2%).In the 560 mg BID intermittent group, 71.4% of all patients experienced urinary AE, the most frequent being pollakiuria (51.4%), micturition urgency (37.1%), and dysuria, hematuria, and urinary tract pain (34.3%); and fatigue (42.9%). Grade 3 or greater hematuria was observed in 11.4% of these patients and dysuria and urinary tract pain in 5.7%. Several strategies were investigated to ameliorate or manage the urinary AEs.Notably, no significant treatment emergent myelosuppression, or other notable AEs were evident in these patients.Conclusions:Oral rigosertib treatment resulted in TR & TI. Patients administered rigosertib for 2 out of 3 weeks at a dose of 560 mg BID (1120 mg over 24 hrs) achieved an impressive TI rate of 44% (15/34). Based on the rate of TI, and the observed urinary AEs, the risk benefit profile of oral intermittent dosing is favorable. Oral rigosertib at a total dose of 1120 mg over 24 hrs administered intermittently in HR-MDS pts in combination with azacitidine is now being studied; with novel strategies employed to continue to minimize the unusual urinary AEs. [Display omitted] DisclosuresRaza:Kura Oncology: Research Funding; Celgene Inc.: Research Funding; Syros Pharmaceuticals: Research Funding; Janssen R&D: Research Funding; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Onconova Therapeutics: Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals: Consultancy; Amgen: Consultancy; Clinipace: Consultancy; Baxalta: Consultancy. Ali:Kura Oncology: Consultancy; Onconova Therapeutics: Consultancy. Fruchtman:Onconova Therapeutics, Inc.: Employment. Petrone:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Heaney:Novartis: Consultancy; Onconova Therapeutics: Research Funding.

Response to Erythropoietin in Different Karyotipic Subsets of Myelodysplastic Syndromes (MDS) and MDS with Sideroblasts: Multicentric Real-Life Experience from the Grom-L Cooperative Group

Background Erythropoietin (EPO) has been widely employed as first-line approach in the treatment of all patients with low-risk Myelodysplastic Syndromes (MDS) and anemia, with response rates ranging from 30 to 60%. Among all low-risk MDS patients, however, there is increasing attention to recognize different subsets characterized by specific karyotipic (del5q-, del20q-), molecular or morphologic (ring sideroblasts) features and, in some cases, by very effective specific treatments (lenalidomide, luspatercept). The role of EPO treatment in these subsets has been very rarely evaluated and is still a matter of debat.Methods To address this issue, the Gruppo Laziale Mielodisplasie (GROM-L) revised retrospectively 316 MDS patients treated with EPO from 1/2002 to 12/2010 by 11 Hematological Centers (5 university hospitals and 6 community-based hospitals) in the metropolitan area of Rome and belonging to 4 different subsets: 82 patients with del5q- isolated or associated to 1 other karyotypic alteration (del5 group), 18 patients with isolated del20q- (del20 group), 41 patients with ring sideroblasts > 15% (RS group) and 175 patients with normal karyotype (NK group) as control group. The main features of these 4 groups are reported in Table 1.Results In Table 2are reported median intervals from diagnosis to EPO start, types of EPO and initial EPO dosages as well as rates of erythroid response (Hb increase > 1.5 g/dl and/or disappearance of transfusion requirement) in the 4 MDS groups. In particular, compared with NK group as control cohort, del5q group had a significant lower rate of erythroid response (p=0.001), while del20q and RS groups showed a similar rate (p=0.431 and p=0.425, respectively). The number of patients with a relapse during EPO treatment was significantly lower in the NK group compared to the other 3 groups, as shown in Table 2 (p=0.005). Median overall survival (OS) from EPO start in the 4 groups is reported in Table 2 while cumulative OS is shown in Figure 1: compared with NK group, only RS group had a better cumulative OS (p=0.026), while both del5q and del20q groups had similar OS (p=0.455 and p=0.367, respectively).Conclusions Our real-life data from a single homogeneous geographic area outline that EPO treatment is effective in all subsets of low-risk MDS considered in this study: the del5q- group had a lower rate of erythroid response, which in any case exceeded 40% of patients. These data, coupled with the excellent toxicity profile of EPO, seem reinforce this treatment as 1st line approach also in those subsets of MDS with specific and very effective (but also quite toxic) new drugs [Display omitted] DisclosuresBreccia:Incyte: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.

Effect of Deferasirox Combined with Erythropoietin Versus Erythropoietin Alone on Erythroid Response in Patients with Low- and Int-1-Risk Myelodysplastic Syndromes: Results of the Phase II Kallisto Trial

Background: Many patients with myelodysplastic syndromes (MDS) have anemia at diagnosis. Erythropoiesis-stimulating agents (ESAs), such as recombinant erythropoietin (EPO), remain the first-choice treatment for anemia in most International Prognostic Scoring System (IPSS) lower-risk MDS patients without del(5q). EPO (~40,000-60,000 U/week) yields ∼60% erythroid responses, as defined by the International Working Group (IWG) 2006 response criteria (Cheson et al. Blood 2006), when baseline EPO is low (<500 U/L) and transfusion requirement is absent/limited. Responses to ESAs occur mostly within 8-12 weeks of treatment. Addition of the oral iron chelator deferasirox (DFX) at low doses could lead to synergism, with elimination of free iron and reduction of toxic reactive oxygen species, improving the bone marrow environment, and enhancing hematopoietic function and response to EPO. Here we present results of a randomized, open-label, Phase II pilot study that evaluated low-dose DFX+EPO compared to EPO alone on erythroid response.Methods: Patients with IPSS Low- or Int-1-risk MDS (not secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases; duration ≥3 months to <3 years), hemoglobin (Hb) ≥8-<10 g/dL, history of <10 RBC transfusions, serum ferritin >300-<1500 ng/mL, and endogenous EPO <500 U/L were enrolled. Patients were randomized 1:1 to DFX (dispersible tablet [DT; 10 mg/kg/day] or, once available, film-coated tablets [FCT; 7 mg/kg/day]) in combination with subcutaneous EPO (40,000 U/week, escalated to 60,000 U/week after 4 weeks if inadequate erythroid improvement) or EPO for 24 weeks (non-responders to EPO after 12 weeks could switch to DFX+EPO for a further 12 weeks). The primary endpoint was the difference in the proportion of patients achieving an erythroid response according to IWG 2006 response criteria (increase from baseline in Hb ≥1.5 g/dL) within 12 weeks. Secondary endpoints included evaluation of hematological responses, tolerability, and safety over 24 weeks.Results: Enrollment was stopped early because of recruitment issues. 23 MDS patients (mean age 72.9 [range 57.7-82.7] years; 43.5% male) were randomized to DFX+EPO (n=11) or EPO (n=12). Eight (34.8%) patients received prior transfusions (n=2 and n=6 in the DFX+EPO and EPO arms, respectively). Baseline serum ferritin was >500 ng/mL in 7 patients in each arm (n=14, 60.9%). After 12 weeks, 5 patients receiving EPO switched to DFX+EPO. Overall, 5 and 4 patients in the DFX+EPO and EPO arms, respectively discontinued; most commonly (n≥1) due to adverse events (AEs; n=4 and n=2). Median EPO exposure was 91 days in patients receiving EPO only (n=7; median dose 270,400 units/week); 77 days in patients receiving DFX DT+EPO (n=10; 295,227 units/week); 100 days in patients receiving DFX FCT+EPO (n=1; 338,800 units/week); and 161 days in patients who switched to DFX+EPO (n=5; 365,833 units/week). Median DFX exposure was 81 days in patients receiving DFX DT+EPO (median dose 10.3 mg/kg/day); 161 days in patients receiving DFX FCT+EPO (3.4 mg/kg/day); and 77 days in patients who switched to DFX+EPO (9.6 mg/kg/day). After 12 weeks, there were 3 (27.3%) erythroid responders in the DFX+EPO arm and 5 (41.7%) in the EPO arm (Table A). Hematologic improvement within 24 weeks was observed in 5 (45.5%) and 12 (100%) patients randomized to DFX+EPO and EPO treatment, respectively (Table B).The most common AEs (n≥3) over 24 weeks were: gastrointestinal disorders (n=5), and infections/infestations (n=3) in the DFX+EPO arm; musculoskeletal and connective tissue disorders (n=3) in the EPO alone arm; infections/infestations (n=4), general disorders, and administration-site conditions (n=3), and musculoskeletal and connective tissue disorders (n=3) in patients who switched to DFX+EPO. No deaths were reported.Conclusions: In this small Phase II, pilot study combining low-dose DFX (10 mg/kg/day) with EPO for the treatment of anemia in Low and Int-1 risk MDS patients, there was no beneficial effect on erythroid response. The combination was well tolerated, with no new or unexpected AEs. As reported by Meunier et al. (ASH 2016), higher erythroid proliferation rates were observed in vitro with lower (3 µM; ~5 mg/kg/day) vs higher (>5 µM) DFX concentrations. It remains of interest to investigate outcomes with lower DFX doses in combination with EPO, as well as the use of DFX after EPO failure. [Display omitted] DisclosuresGattermann:Takeda Pharmaceutical International Co.: Research Funding; Novartis: Honoraria, Other: Travel support; Celgene: Honoraria. DeBonnett:Novartis: Employment. Azmon:Novartis: Employment.

Iron Overload in Lower International Prognostic Scoring System Risk Myelodysplastic Syndromes Patients Receiving Red Blood Cell Transfusions: Relation to Infection and Possible Benefit of Iron Chelation Therapy

Background: Analyses in lower risk myelodysplastic syndromes (MDS) suggest inferior survival in patients (pts) with transfusional iron overload (IOL). Some studies suggest an increased incidence of infections and infection related mortality in transfused MDS pts. Reducing IOL with iron chelation therapy (ICT) appears to give clinical benefit. The literature suggests that IOL can predispose to bacterial, fungal and viral infections, as organisms use iron for metabolism and cell division, and IOL can adversely affect neutrophil function. There are no clinical studies examining infection risk in MDS pts with IOL in the non-stem cell transplant (SCT) setting, and whether this risk can be attenuated with ICT.Methods: We performed a retrospective analysis of pts with a bone marrow biopsy confirmed diagnosis of lower International Prognostic Scoring System (IPSS) risk MDS receiving red blood cell (RBC) transfusions. Pts were identified from the clinical database and charts reviewed. Clinical data extracted included baseline characteristics, serum ferritin level (SF), treatment, and infectious episodes requiring antibiotics, antifungal or antiviral medications. Statistical analyses were performed using SPSS for Windows, version 24.Results: Of 182 transfused MDS pts, 138 were lower IPSS risk. 44 pts were excluded for: not transfused as lower risk, n=19; higher IPSS risk, or received hypomethylating agent or SCT, n=13; and inadequate information, n=12. The median (range) age at first RBC transfusion was 72.5 (31-93) years and 78 (57%) pts were male. 59 pts received ICT: deferasirox (DFX), n=45 (76.3%); deferoxamine (DFO), n=13 (22.0%); and deferiprone, n=1 (1.7%); and 79 did not receive ICT. Median (range) time from 1st RBC transfusion to ICT was 22.5 (1.4-209) months and duration of ICT 13 (1-75) months. Clinical factors differing between ICT and non-ICT pts, respectively, were (median [range]): age at 1st RBC transfusion, 67 (31-88) and 75 (43-93) years; number of RBC units (U) transfused while lower risk, 76 (10-675) and 24 (2-200); number of RBCU/4 weeks, 2.2 (0.5-9.1) and 2.0 (0.1-5.4); SF 914 (49-15608) and 266 (12-5009) ng/mL; and other treatments received, 18 (30.5%) and 5 (6.3%); p</=0.04 for all. Factors not differing between groups were: gender; French American British or World Health Organization MDS diagnosis; marrow blast count; IPSS or IPSSR cytogenetic risk; IPSS or IPSSR risk; neutrophil count at first RBC transfusion or at first infection; and causes of death, p=NS for all. Infections included: bacterial, n=88; viral; fungal; and mycobacterial; n=2 each. In ICT and non-ICT pts, respectively, infections while lower IPSS risk were (number [%]): pts, 23 (40.0%) and 22 (27.8%); episodes (median [range]), 2 (1-6) and 2 (1-5); hospitalizations, 16 (27.1%) and 8 (10.1%); and infectious deaths, 0 (0%) and 1 (1.3%), p=NS for all. In ICT pts, infections occurred pre-ICT in 9 (15.3%); on DFX, n=10 (22.2%), and on DFO, n=4 (30.8%), p<0.0001. Median overall survival (OS) from 1st RBC transfusion while lower IPSS risk was not reached at 105, and 50.1 months for ICT and non-ICT pts, respectively, p=0.01. ICT remained significant for OS in a multivariate analysis (MVA) including: ICT; IPSS cytogenetic risk; and hospitalization for infection; (all p</=0.06 in univariate analysis), p=0.003, hazard ratio (HR) 0.3, 95% confidence intervals (CI) 0.2-0.7, and lost significance when number of RBCU received (p<0.0001) was added to the MVA. However, OS was significantly superior for ICT pts receiving >20 and >50 RBCU (p=0.02, and <0.0001, respectively). Median time to first infection (TTI) was 27 and 7.8 months for ICT and non-ICT pts, respectively, p<0.0001 (Figure 1). ICT remained significant for TTI in an MVA including: age; IPSS cytogenetic risk; marrow blast count; and number of RBCU received (p=0.03, HR 0.3, 95% CI 0.09-0.9). For TTI, marrow blast count was also significant in the MVA (p=0.04). TTI remained significantly longer for ICT pts with blast count <5% (p=0.004).Conclusions: In this retrospective, non-controlled analysis, for lower IPSS risk MDS patients receiving RBC transfusions, receiving iron chelation therapy was associated with superior overall survival. Though number and type of infections were similar between groups and despite similar neutrophil counts, time to first infection was significantly longer in ICT patients. These results should be confirmed in larger, prospective analyses. [Display omitted] DisclosuresLeitch:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exjade: Speakers Bureau; Abbvie: Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.