Time Of Myelodysplastic Syndromes Diagnosis Research Articles

Cutaneous manifestations of myelodysplastic syndrome: A systematic review.

Myelodysplastic syndrome (MDS) may present with specific skin lesions, such as leukaemia cutis, which is a well known poor prognostic marker of leukaemia with a high risk of acute leukaemic transformation. However, less is known regarding non-specific cutaneous manifestations of MDS including the prevalence, types and their prognostic and therapeutic significance, which we aimed to determine through this systematic review. We searched electronic databases (PubMed, Medline and EMBASE) from inception up to 26 January 2023 for studies reporting cutaneous manifestations of MDS. Eighty eight articles (case reports n=67, case series n=21), consisting of 134 patients were identified. We identified 6 common cutaneous manifestations: neutrophilic dermatoses (n=64), vasculitis (n=21), granulomatous (n=8), connective tissue disease (CTD) (n=7; composed of dermatomyositis (n=5), cutaneous lupus erythematosus (n=1), and systemic sclerosis (n=1)), panniculitis (n=4), immunobullous (n=1), and other (n=29). Cutaneous features either occurred at time of MDS diagnosis in 25.3%, preceding the diagnosis in 34.7% (range 0.5-216months), or after diagnosis in 40.0% (range 1-132months). Prognosis was poor (40.2% death) with 34.1% progressing to acute myeloid leukaemia (AML). 50% of those with MDS who progressed to AML had neutrophilic dermatoses (p=0.21). Myelodysplastic syndrome was fatal in 39.2% of neutrophilic dermatoses (median time from onset of cutaneous manifestation: 12months), 50% of vasculitis (7.5months), 62.5% of granulomatous (15.5months) and 14.3% of CTD (7months). Recognition of patterns of cutaneous features in MDS will improve early diagnosis and risk stratification according to subtype and associated prognosis.

Higher Prevalence of Chronic Kidney Disease in Myelodysplastic Syndromes Patients Compared to Age- Adjusted General Population - Results from the Polish Adult Leukemia Group (PALG) Registry

Introduction Chronic comorbidities that are common in the elderly population can have a significant impact on the clinical course, the choice of treatment, and survival of myelodysplastic syndromes (MDS) patients. No studies have focused on the coexistence of two diseases that are common in the elderly population, chronic kidney disease (CKD) and MDS, so the epidemiological data and clinical implications of both diseases occurring together are unknown. Aims Primary objective: to assess the prevalence of CKD in patients with MDS in comparison to the age-adjusted general population. Secondary objective: to evaluate the impact of CKD on clinical course in MDS patients. Methods This was a prospective analysis using clinical and laboratory data from MDS patients who were registered in the Polish Adult Leukemia Group (PALG) Registry from 2010 to 2023. Data have been provided by 28 hematologic centers. CKD was defined as an eGFR < 60 mL/min/1.73m², disregarding albuminuria since urinalysis results were not recorded in the database. The stages of CKD were classified based on eGFR according to the NKF KDOQI National Kidney Foundation Kidney Disease Outcome Quality Initiative guidelines, and eGFR was calculated using CKD-EPI equation. For comparison of the prevalence of CKD in MDS subjects aged ≥60 years to the general population, we used data from the PolSenior 2 study (covering the years 2018-2019). Data were age and sex standardized using demographic tables from Statistics Poland (https:// demografia.stat.gov.pl/bazademografia/Tables.aspx). Median survival time was calculated using Kaplan-Meier estimator. Multivariate analysis was performed using Cox regression. Results Overall, data (including eGFR) were available for 1813 MDS patients. Median age at diagnosis was 71 years [IQR 64 - 78]. and 55.3% patients were male. Sixty percent of the patients were diagnosed as IPPS lower risk. At the time of MDS diagnosis, CKD was detected in 479 patients (26.4%). Among patients aged ≥ 60, the crude rate of CKD was 30.3%. The standardized rate of CKD in the general population aged ≥ 60 years was significantly lower than in the similarly aged MDS group, with rates of 13.2% [CI 12.3-14.1] and 25.5% [CI 22.9-28.4]; p<0.001, respectively. (Figure 1) Patients with CKD were significantly older (median 78 yo) than those without CKD (median 68 yo; p<0.001), and more likely to have diabetes (33.2% vs 19.7%; p<0.001), and to have coincidence of another malignancy (21.6%) than those without CKD (14.9%; p=0.001). Median hemoglobin concentration was significantly lower in the CKD group (8.9 g/dL) than in the non-CKD group (9.4 g/dL; p < 0.05). Subjects with decreased eGFR were more likely to be dependent on RBC transfusion (56.5%) than subjects with eGFR ≥ 60 ml/min per 1.73m 2 (48.9%; p=0.0008). Median survival of patients with eGFR ≥ 60 ml/min per 1.73m 2 was 2.5 y [CI 1.0-6.1] vs 1.4 y [CI 0.6-4.2] for CKD. In multivariate analysis we found that CKD stage, age ≥ 65, higher IPSS score, high-risk IPSS cytogenetics and ECOG >1 were independent predictors of shorter survival. (Figure 2). Conclusions Myelodysplastic syndrome (MDS) subjects are more likely to have chronic kidney disease (CKD) than the general population. The presence of CKD in MDS patients is associated with worse overall survival and higher RBC transfusion requirement.

Metabolic Syndrome Among Patients with Myelodysplastic Syndrome: A Population Analysis

Introduction: Metabolic syndrome (MS) comprises a cluster of cardiovascular risk factors, including central obesity, dysglycemia, elevated blood pressure (BP), increased triglyceride levels (HyperTG), and low HDL cholesterol levels. Epidemiologic and clinical data suggest that MS may be an important etiologic factor in the progression of certain cancer types. These studies have excluded patients with myelodysplastic syndromes (MDS), but MS may be relevant in these patients owing to the link between cardiovascular disease and MDS derived from clonal hematopoiesis. We conducted a population-based analysis to define the prevalence of MS and its components among patients with MDS and explore the effect of MS on MDS outcomes. Methods: We identified patients aged 66 and older diagnosed with MDS between 2007 and 2017 using the SEER-Medicare database. Preexisting MS was identified using ICD-9/10 codes in claims from at least 12 months before MDS diagnosis. MS was defined as the presence of 3 or more of the 5 MS components. MDS histologic risk was defined based on ICD-O-3 morphology codes. Transfusion dependence, defined as 2 or more transfusions within 8 weeks of MDS diagnosis date, and therapy with hypomethylating agents (HMA), lenalidomide and erythropoietin stimulating agents (ESA) were defined from HCPCS codes and prescription records. Other variables defined included age, sex, race/ethnicity, rurality (using RUCC codes), marital status, and socioeconomic status [SES] (using the Yost index). Descriptive statistics were used to define the frequency of MS and its components. MDS outcomes of interest were transformation to acute myeloid leukemia (AML), defined from ICD-9/10 codes for AML, and overall survival (OS), defined as the time between MDS diagnosis and death from any cause. Cox proportional hazards regression was used to determine the association between MS and AML transformation and OS, through adjusted hazard ratios (HR). Results: A total of 15,227 cases diagnosed with MDS between 2007 and 2017 were analyzed, including 3,402 (22.3%) with baseline MS. High BP was present in 72.2%, HyperTG in 47.8%, dysglycemia in 35.5%, central obesity in 4.6% and 0.5% had low HDL cholesterol. The prevalence of MS and the distribution of its components did not significantly differ based on MDS histologic risk (Table 1). The prevalence of hyperTG was notably higher in patients with MDS, especially in the high histologic risk category (50.4%). Compared to other MDS patients, those with preexisting MS were predominantly male (55.5% vs 53.3%, p=0.03) of non-White race (6.7% vs 4.8% non-Hispanic Black, p<0.01, and 2.1% vs 1.5% Hispanic, p<0.01), from urban/metropolitan areas (87.7% vs 86%, p=0.01) and lower SES quintiles 1 and 2 (34.2% vs 31.5%, p<0.01). In a model adjusting for age, sex, race/ethnicity, rurality, marital status, SES, MDS risk, transfusion dependence and MDS therapies (HMA, lenalidomide and ESA), baseline MS at the time of MDS diagnosis was not associated with a significant effect on the risk of AML transformation (HR=1.0, 95%CI 0.9-1.2) or the risk of death from any cause (HR=1.0, 95%CI 0.9-1.1) (Table 2). In models assessing the effect of MS subcomponents on MDS outcomes, high BP (HR=1.0, 95CI% 1.0-1.1) and obesity (HR=1.1, 95CI% 1.0-1.2) were associated with an increased risk of mortality. Obesity was also associated with an increased risk of transformation to AML (HR=1.3, 95CI% 1.0-1.6). Conclusions: The overall prevalence of MS among patients with MDS appears similar to that reported in the general population and does not differ based on the histologic risk category. The observed prevalence of HyperTG was higher than expected, particularly in high-risk MDS patients. Older males of non-White race from urban/metropolitan areas of lower SES are more likely affected across all groups. Though preexisting MS is present in an important proportion of MDS patients, it was not significantly associated with an increased risk of mortality or AML transformation after adjusting for confounders. Obesity was associated with higher mortality and linked to increased transformation to AML. Given recent data suggesting that statins may improve survival and decrease AML transformation in MDS, future studies should investigate the potential association between other metabolic parameters and MDS outcomes.

Impact of Hypomethylating Agents on Cardiovascular Disease Risk Among Patients with Myelodysplastic Syndromes

Introduction: The association between clonal hematopoiesis (CH) and cardiovascular disease (CVD) risk has drawn attention to cardiovascular outcomes in myelodysplastic syndromes (MDS). CVD accounts for 25% of deaths in MDS, potentially via CH-mediated accelerated atherosclerosis from inflammatory vascular responses. We previously demonstrated that MDS was independently associated with increased risk of CVD in older adults from SEER-Medicare. We subsequently hypothesized that treatment with hypomethylating agents (HMA) could reduce CVD risk by ameliorating CH clones and reducing the inflammation. In this study, we aimed to define the impact of HMA on incident cardiovascular events among older adults with MDS. Methods: We identified subjects ≥66 years diagnosed with MDS from 2007 to 2017 in SEER-Medicare. Exclusion criteria including lacking continuous Medicare parts A, B, and D, enrolled in HMO, or incomplete follow-up. Demographics included age, sex, race, rurality, socioeconomic quintile, marital status, and geographic region. Baseline CVD risk factors, defined from ICD-9/10 codes, included hypertension, hyperlipidemia, diabetes, atrial fibrillation, pre-existing cardiac disease, obesity, and smoking. MDS factors, defined using HCPCS codes, ICD-O-3 codes and prescription records, included MDS subtype and histologic risk stratification, transfusion dependence and treatment with hypomethylating agents (HMA), lenalidomide, or erythropoietin-stimulating agents (ESA) as time-varying variables. Incident CVD was defined as new myocardial infarction (MI) and/or ischemic stroke occurring after MDS diagnosis, using published ICD-9/10 algorithms. We controlled for confounding using 2 complementary analytic approaches. First, we assessed the association between HMA use and CVD using propensity score adjusted cause-specific competing risk Cox hazard models with death as competing risk, Second, we used a case-crossover design with conditional logistic regression, in which subjects with CVD served as their own controls, using a 3-month HMA treatment window and a control period 6 months prior to the incident event. Results: We identified a cohort of 15,227 eligible patients with MDS. Of these, 1,125 patients had an MI and/or ischemic stroke within 1 year before MDS diagnoses and were excluded. We analyzed 14,102 MDS patients, with median age 82 years (IQR 77 - 86), who were predominantly male (53.8%), non-Hispanic white (88.6%), and from urban/suburban areas (86.2%). MDS was of low, intermediate, and high histologic risk in 14.7%, 72.8%, and 12.5%, respectively, and 28.6% were transfusion dependent. Pre-existing CVD risk factors at time of MDS diagnosis were present in 12,538 patients, with baseline cardiovascular risk defined as low, intermediate, and high in 11.1%, 32.3%, and 56.6% of the cohort. The cumulative incidences of MI, ischemic stroke and composite CVD events were 11.3%, 10.6% and 20.4%, respectively. The propensity score (PS) conditional probability for being treated with HMA included demographic variables, CVD risk factors, MDS histology and transfusion dependence. Our PS model adequately predicted HMA treatment propensity (AUC 0.76). Cause-specific regression with death as competing risk, adjusted for PS and other MDS-specific treatments (ESA and lenalidomide), showed no significant effect of HMA on the risk of composite CVD events, MI, or ischemic stroke (Table 1). Conditional logistic regression in the case-crossover analysis of 1,907 patients with composite CVD events showed no significant effect of HMA. Results were similar for analysis of patients with MI and ischemic stroke (Table 2). Conclusions: No study has previously investigated the effect of HMA therapy on cardiovascular outcomes in patients with MDS. We demonstrate that HMA therapy is not associated with a significant risk reduction in cardiovascular events among patients with MDS patients from the SEER-Medicare database. These results show that HMA therapy is unlikely to reduce cardiovascular mortality and underscore the need for alternative therapeutic strategies targeting cardiovascular health patients with MDS.

High Serum ST2 Level Predicts Progression and Poor Prognosis of Denovomyelodysplastic Syndrome

Background: Myelodysplastic syndromes (MDS) are heterogeneous hematological stem cell malignancies with a complex pathophysiology involving immune, genetic, and epigenetic changes induced by aging, oxidative stress, and genotoxicity. Dysregulated immune responses and aberrant inflammatory signaling have been identified as critical drivers of MDS development. Recent research has highlighted the significant association of the IL-33/ST2 signaling axis with tumorigenicity and tumor immunity in various cancers. Soluble ST2 (sST2), a transmembrane-free receptor induced by IL-33, negatively regulates the IL-33/ST2 signaling pathway, and elevated levels of sST2 have been reported to correlate with poor prognosis in malignant tumors. However, the specific level of soluble ST2 and the precise role of the IL-33/ST2 signaling axis in the context of MDS remain uncertain and require further investigation. Method: This prospective study enrolled 89 newly diagnosed, untreated outpatient individuals with MDS to assess their clinical prognostic risk using the International Prognostic Scoring System-Revised (IPSS-R) and the International Prognostic Scoring System-Molecular (IPSS-M). A control group of 45 healthy donors (HD) was also included. The levels of various cytokines (sST2, IL-33, IL-2Rα, IL-6, IL-15) were measured using ELISA. Result: Our study revealed that sST2 levels in MDS patients were significantly higher compared to HD (22.18 vs. 12.43 ng/ml, p = 0.0313), with no significant difference between low and high-risk groups. The Receiver Operating Characteristic (ROC) curve analysis showed an Area Under the Curve (AUC) of 0.6140 for sST2 (p = 0.0315, 95%CI 0.5199-0.7081). Using the maximum Youden index, the optimal cut-off value for sST2 (>14.71 ng/ml) was determined with a sensitivity and specificity of 51.69% and 73.33%, respectively. Progressive events include conversion to leukemia(n=8), transfusion-dependent occurrence(n=1) and death (n=29). Patients with higher sST2 levels in both high and low-risk groups demonstrated poorer Event-Free Survival (EFS) (p = 0.0193) and Overall Survival (OS) (p = 0.0130) (Figure 1). Further, multivariate analysis identified cytokine sST2(HR = 0.337, 95%CI 0.163-0.696, P=0.003), blast percentage(HR = 0.472, 95%CI 0.237-0.940, P = 0.033), and transfusion dependence(HR = 0.367, 95%CI 0.179-0.753, P = 0.006) as independent risk factors, indicating sST2's potential in predicting prognosis and adverse event risk in MDS patients. Furthermore, sST2 exhibited a significant correlation with other inflammatory cytokines (IL-2Rα, r = 0.4152, p = 0.0005; IL-6, r = 0.4897, p = 0.0013; IL-15, r = 0.3535, p = 0.0253). This suggests that sST2 plays an active role in immune system activation and chronic inflammation. Multiple attempts to detect IL-33 expression in the serum of MDS patients were unsuccessful, indicating the need for a more sensitive and specific assay. In our study, no statistically significant difference was observed in the level of sST2 between bone marrow and peripheral blood (P=0.2197), as well as before treatment and after chemotherapy (P=0.3965). These findings indicate that sST2 is an easily detectable and relatively stable indicator. Conclusions: sST2 emerges as a significant, independent negative prognostic factor at the time of MDS diagnosis, offering valuable predictive insights into disease progression and a poor prognosis.

Chronic neutrophilic leukemia preceded by myelodysplastic syndromes.

Chronic neutrophilic leukemia (CNL) is primarily diagnosed by excluding myelodysplastic syndromes (MDS). We report the case of a patient who developed secondary CNL 3years after hypoplastic MDS. We used droplet digital polymerase chain reaction mutation detection assay to analyze genomic alterations during the progression from MDS to CNL. At the time of MDS diagnosis, U2AF1 Q157P and SETBP1 D868N were dominant and additional mutation of ASXL1 1934_insG was observed. CSF3R T618I and SETBP1 D868N were increasing at the time of CNL diagnosis. We revealed the accumulation of multiple gene mutations during CNL development from MDS. This suggests that CNL was clonally developed from the founding clone of MDS and CSF3R mutation contributes to the development of CNL in the present case. These findings provide insights into the pathology of CNL.

P92 Cutaneous manifestations of myelodysplastic syndrome: a systematic review

Abstract A variety of associations between cutaneous manifestations and myelodysplastic syndrome (MDS) have been described, but the frequency is unknown. The presence of cutaneous manifestations may have therapeutic and prognostic significance, as the presence thereof has been reported to be associated with poor prognosis or acute myeloid leukaemia (AML) progression, or may precede the diagnosis of MDS [Farah C, Bulai Livideanu C, Jegu J et al. Prevalence and prognostic value of cutaneous manifestations in patients with myelodysplastic syndrome. J Eur Acad Dermatol Venereol 2010; 24:1171–5; Ghoufi L, Ortonne N, Ingen-Housz-Oro S et al. Histiocytoid Sweet syndrome is more frequently associated with myelodysplastic syndromes than the classical neutrophilic variant: a comparative series of 62 patients. Medicine (Baltimore) 2016; 95:e3033]. We aimed to determine the types and prevalence of cutaneous manifestations in MDS, treatment options and prognosis associated with specific cutaneous manifestations and MDS subtypes. PubMed, MEDLINE and Embase were searched from inception up to 26 January 2023 for studies reporting cutaneous manifestations of MDS in adults aged ≥ 18 years, as per the World Health Organization classification. Case reports and case series were included. The review was registered with PROSPERO (CRD42021293140). In total, 92 studies were included (case reports n = 71, case series n = 21), consisting of 140 patients [98 male, mean age 61.0 (SD 15.4)]. We identified six common cutaneous manifestations: neutrophilic, e.g. Sweet syndrome and pyoderma gangrenosum (n = 66); vasculitis, e.g. leucocytoclastic vasculitis and Behçet disease (n = 21); granulomatous, e.g. granuloma annulare and interstitial granulomatous dermatitis (n = 8); connective tissue disease (CTD), e.g. dermatomyositis (n = 7); panniculitis (n = 4); immunobullous (n = 2); and other (n = 30). Sweet syndrome (81.8%) and pyoderma gangrenosum (18.2%) were the commonest presentations of neutrophilic dermatosis. Cutaneous features either occurred at time of MDS diagnosis in 24.7%, preceded the diagnosis in 36.1% (mean 17 months; range 0.5–216), or after diagnosis in 39.2% (mean 20.6 msonths; range 1–132). Prognosis was poor (40.2% death) with 34.1% progressing to acute myeloid leukaemia (AML), 50% of which had neutrophilic dermatosis. Death occurred in 38.5% of neutrophilic dermatoses (median time from onset of cutaneous manifestation: 12 months), 50% of vasculitis (7.5 months), 62.5% of granulomatous (15.5 months), 14.3% of CTD (7 months), and none reported in immunobullous and panniculitis. Granulomatous skin lesions had the poorest prognosis, 60% of which had progressed to AML. This systematic review highlights the range of cutaneous manifestations associated with myelodysplastic syndrome. Of note, we found that the majority of cases progressing to AML were associated with neutrophilic dermatoses overall; however, granulomatous skin lesions had the poorest prognosis with the highest proportion progressing to AML. We speculate that these manifestations may confer an increase in risk of transformation, compared with other cutaneous changes.

MDS-431 Outcomes of Transformation to Acute Myeloid Leukemia after Hypomethylating Agent Therapy in Patients With Myelodysplastic Syndromes

Most patients with myelodysplastic syndrome (MDS) have progression of disease after hypomethylating agent (HMA) failure, including transformation to acute myeloid leukemia (AML). We aimed to understand the clinical characteristics and outcomes of AML transformation after HMA failure in MDS. We conducted a retrospective review of 147 patients with newly-diagnosed MDS from 2017-2021 who later developed HMA failure, focusing on AML transformation. With a median follow-up time of 19.5 months, 71 patients (48%) developed AML after HMA failure. Patients with eventual transformation were more likely to be younger, have higher bone marrow or peripheral blasts, and lower platelet counts at the time of MDS diagnosis. Moreover, these transformed patients had higher-risk MDS by IPSS-R, more adverse cytogenetics (CG), and more frequent TP53 mutations and less frequent SF3B1 mutations at MDS diagnosis. Patients with AML transformation had a shorter time from diagnosis to HMA failure (7.5 vs. 15.0 months, p<0.001) and overall survival (OS) from HMA failure (4.2 vs. 8.4 months, p=0.003). Age <65 years old, higher-risk IPSS-R, and HMA response was associated with AML transformation by multivariate analysis. In patients with AML transformation, the median overall survival (OS) after AML diagnosis was 4.0 months. After transformation, the median number of treatment lines was 1 with 17% not receiving AML-directed therapy. 52% patients continued HMA-based therapy, and 51% received venetoclax. Out of 44 patients with evaluable responses, 6 achieved complete remission (CR) and 17 attained CR with incomplete hematologic recovery, with an overall response rate of 52%. However, most patients died of refractory disease (73%) and/or complications from pancytopenia (19%). The 60-day and 180-day mortality were high at 33% and 69%, respectively. The type or intensity of treatment was not associated with survival. Therapy-related disease, ELN adverse risk, higher risk CG, and TP53 and KRAS mutations were associated with worse survival. Four of 5 patients who underwent allogeneic stem cell transplantation achieved survival over 1 year (17.7-39.6 months). The outcomes of AML transformation after HMA failure MDS remain extremely poor. Further understanding of the biology and disease characteristics of this patient population is warranted for better treatment approaches.

P770: A COMPARATIVE STUDY OF LEUKEMIC TRANSFORMATION IN THERAPY-RELATED AND DE NOVO MYELODYSPLASTIC SYNDROME AFTER HYPOMETHYLATING AGENT FAILURE

Background: Therapy-related myelodysplastic syndrome (t-MDS) is subset of myelodysplastic syndrome (MDS), known for having dismal survival outcomes. The majority of patients (pts) with t-MDS have similar clinical courses with de novo MDS patients after hypomethylating agent failure (HMA-F) that often results in transformation to acute myeloid leukemia (AML). Aims: We conducted a study to identify unique clinicopathologic features of t-AML from t-MDS compared to secondary AML (sAML) from de novo MDS after HMA-F. Methods: We identified sAML patients after HMA-F from all untreated MDS pts in a tertiary cancer center registry from 2017-2021. Clinical characteristics and pathologic data including cytogenetic (CG) and next generation sequencing (NGS) information were collected at the time of MDS diagnosis (dx), HMA-F, and AML dx. Results: 71 (48%) MDS pts with AML transformation after HMA-F were included in the study with a median follow-up time of 15.4 months (mo). At the time of MDS dx, 31 (43%) pts had t-MDS: 97%, 58% and 29% had a history of chemotherapy, radiation, and prior stem cell transplant (SCT), respectively. t-MDS patients were more likely to present with age<65 (48% vs. 28%, p=0.070) and thrombocytopenia (33,000 vs. 75,500, p=0.004) when compared to de novo MDS pts. The majority of t-MDS pts had very high risk disease by IPSS-R (67% vs. 39%, p=0.031), while de novo MDS pts frequently had high risk disease (50% vs. 20%, p=0.013). 90% of t-MDS pts had adverse CG (IPSS-R CG score 3-4) at MDS dx, compared to 46% in de novo MDS pts (p=0.004). NGS at MDS dx showed more frequent TP53 mutations in t-MDS than in de novo MDS (73% vs 36%, p=0.003). Interestingly, ASXL1 (36% vs. 1%, p=0.001), RUNX1 (9% vs. 0%, p=0.004), STAG2 (21% vs. 0%, p=0.013), TET2 (13% vs. 0%, p<0.001), and SRSF2 (18% vs. 0%, p=0.027) were more frequently found in de novo MDS (Table). t-MDS had worse overall survival (OS) from MDS dx (HR 1.82, p=0.026). The median OS from MDS dx was 19.4 mo and 14.3 mo in de novo MDS and t-MDS, respectively. The number of HMA cycles received before HMA-F was 6 (range: 1-13) in t-MDS and 5 (range: 1-23) in de novo MDS. At the time of HMA-F, t-MDS pts presented with more anemia (p=0.005) and thrombocytopenia (p=0.064). The number of CG clones were similar, but the number of CG abnormalities were higher in t-MDS pts (p=0.025). Among pts with subsequent AML transformation after HMA-F, the median time from HMA-F to AML was 1.5 mo in t-MDS to AML, compared to 4.6 mo in de novo MDS to AML. At time of AML dx, 48 (68%) pts had mutation panels available. All TP53 mutation status stayed the same in t-MDS pts at the time of MDS and AML dx. Other changes in mutations were shown in Table. Though the median OS from AML transformation was short in all pts, t-MDS pts had inferior outcomes (2.4 mo vs. 5.0 mo, HR 1.70, p=0.043). The initial response rate to salvage therapy was comparable between t-MDS and de novo MDS after AML transformation (50% and 56%, p=0.761), but more pts underwent SCT with de novo MDS compared to t-MDS (10% vs. 3%, p=0.383). Image:Summary/Conclusion: Transformation to AML after HMA-F results in poor outcomes, but pts with t-MDS have worse survival with distinct CG and mutation profiles. Further understanding of the pathogenesis of AML transformation in both t-MDS and de novo MDS after HMA-F is warranted with improved therapy options an area of unmet need.

Statins reduce mortality of patients with myelodysplastic syndromes.

e19063 Background: Statins can inhibit cholesterol synthesis through inhibition of mevalonic acid synthesis, and reduce prenylation of proteins involved in tumor growth. Their anti-neoplastic potential has been explored for many malignancies (e.g., multiple myeloma) with improvement in progression free- and overall- survival. Preclinical data support anti-neoplastic activity of statins for myeloid malignancies. In this study, we examined the effect of statins on mortality of patients with myelodysplastic syndromes (MDS) in this nationwide retrospective cohort study. Methods: We identified patients diagnosed with MDS through ICD-O-03 codes in the SEER-Medicare database between 2007 and 2017. Statins users were required to have at least one claim for a statin prescription within 6 months prior to MDS diagnosis. Propensity score matching was done to identify non-statin users with a similar cardiovascular risk profile. We analyzed the effect of statins on mortality (from any cause) in a Cox proportional hazards model that adjusted for demographics, SEER-Medicare MDS Risk Score ( SMMRS comprises of age, comorbidities, MDS histological subtype, cytopenias, transfusion-dependence and hospital admissions), treatments for lower risk MDS (growth factors or lenalidomide), and higher risk MDS (hypomethylating agents/stem cell transplant). Results: Our cohort of 6878 MDS patients (3439 statin users and 3439 non-statin users) had a median age of 80 years at diagnosis, and most were Caucasians. Non-statin users were more likely to have higher risk MDS (by SMMRS) at diagnosis. Statins users had a 33% {95% Confidence Interval (CI) 25%-40%; p &lt;.001} lower risk of death than non-statin users. The beneficial effect of statins on mortality diminished over time (Table). Sub-group analysis (data not shown) showed a significant reduction in mortality with statin use in both patients with lower risk {low or intermediate-1 risk: Adjusted hazards ratio (aHR) 0.72; 95% CI 0.58-0.90; p = 0.003)} and higher risk {intermediate-2 or high-risk: aHR 0.67; 95% CI 0.59-0.76; p &lt; 0.001)} MDS (categorized by SMMRS). Conclusions: Use of statins at time of MDS diagnosis is associated with reduced mortality among these patients. The beneficial effect of statins on death from cardiovascular events and myeloid malignancy should be further explored in clinical trials enrolling MDS patients.[Table: see text]

Reduced Plasmacytoid Dendritic Cell Output Is Associated With High Risk in Low-grade Myelodysplastic Syndrome.

Reduced Plasmacytoid Dendritic Cell Output Is Associated With High Risk in Low-grade Myelodysplastic Syndrome.

Model Heterogeneity in Predicting Outcomes of Patients with Myelodysplastic Syndromes (MDS)

BackgroundThe outcome of MDS patients (pts) is heterogeneous, with some pts living for years, while others die within a few months of diagnosis. Several prognostic models have been developed to risk stratify pts with MDS including: the International Prognostic Scoring System (IPSS), Revised IPSS (IPSS-R), World Health Organization classification-based Prognostic Scoring System (WPSS), and MD Anderson Prognostic Scoring System (MDPSS). When applying these models to clinical practice, considerable heterogeneity in their prediction of outcomes is observed. Understanding such heterogeneity can impact disease expectations and treatment recommendations, as these can differ considerably based on the model used.MethodsClinical data from pts who were diagnosed with MDS according to 2008 WHO criteria and treated at our institution between 1/2000 and 1/2017 were analyzed. All prognostic models were calculated at the time of MDS diagnosis. Overall survival (OS) was calculated from the time of diagnosis to time of last follow up or death. Descriptive statistics were used to study the changes in risk categories across models.ResultsOf 687 pts included in the final analysis, the median age at diagnosis was 68 (11-99) years with a male (63%) predominance. Cytogenetic analysis per IPSS-R: very good 19 (3%), good 441(64%), intermediate (INT) 117 (17%), poor 47 (7%), and very poor 63 (9%). Risk categories by IPSS included: 204 (30%) with low risk, 319 (46%) intermediate-1 (INT-1), 124 (18%) intermediate-2 (INT-2), and 40 (6%) high risk. Risk categories by IPSS-R included: 114 pts (17%) with very low risk, 264 (38%) low, 128 (19%) intermediate, 118 (17%) high, and 63 (9%) very high.Significant heterogeneity was observed when comparing all models to IPSS-R risk categories. Among 378 pts with lower-risk disease (Very Low / Low) per IPSS-R, 3 pts (1%) were re-classified INT-2 per IPSS, 73 (19%) as INT and 28 (7%) as high/very high per WPSS, and 11 (29%) as higher-risk per MDAPSS, Table 1. Among 128 pts with intermediate risk by IPSS-R, 102 (20%) were reclassified as lower-risk per IPSS, 44 (34%) as lower-risk and 47 (37%) as higher-risk per WPSS, and 65 (50%) as lower-risk per MDAPSS, Table 1. Among 181 pts with high/very high-risk by IPSS-R, 44 (25%) were reclassified as lower-risk by IPSS, 54 (30%) per WPSS, and 58 (32%) per MDAPSS, Table1. Among 523 pts with lower-risk (low / INT-1) by IPSS, 102 (20%) were reclassified as INT risk and 46 (9%) as higher-risk per IPSS-R, 113 (22%) as INT and 62 (12%) as higher-risk per WPSS, and 186 (36%) as higher risk per MDAPSS, Table 2. Among 164 pts with higher-risk (INT-2/High) per IPSS, 26 (16%) were reclassified as INT per IPSS-R, 24 (15%) per WPSS, and 53 (32%) per MDAPSS, Table 2.The predicted OS per IPSS-R was overestimated when compared to the actual OS (evaluable in 429 pts) for pts in lower-risk categories. The difference between the median predicted IPSS-R OS and median actual OS was 70.6 months (m) for very low risk, 54 m for low, 9.5 m for INT, 6.7 m for high, and -2.4 m for very high risk (pts lived longer than their predicted OS). The IPSS, on the other hand, underestimated the OS, as the difference between the median predicted OS and median actual OS was -23.3 m for low risk, -16.5 m for INT1, -11.8 m for INT2, and -11.1 m for high risk.ConclusionsSignificant intra-patient (difference of outcome in the same pt based on the model used) and intra-group (difference in outcome among pts who have similar risk category by a given model) variability is observed when applying commonly used models in MDS. More importantly, IPSS-R overestimate OS for lower-risk disease and IPSS underestimate OS across all risk categories. This heterogeneity can impact survival expectations, treatment strategies, and clinical trial eligibility criteria based on the model used. A personalized prediction model that can precisely forecast the actual outcome of a pt is needed. [Display omitted] DisclosuresGerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Advani:Pfizer: Consultancy; Takeda/ Millenium: Research Funding. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Apellis Pharmaceuticals: Consultancy; Ra Pharma: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Comorbidities and malignancies negatively affect survival in myelodysplastic syndromes: a population-based study

AbstractPopulation-based studies that contain detailed clinical data on patients with myelodysplastic syndrome (MDS) are scarce. This study focused on the real-world overall survival (OS) of MDS patients in association with comorbidities, specifically malignancies. An observational population-based study using the HemoBase registry was performed, including all patients with MDS diagnosed between 2005 and 2017 in Friesland, a Dutch province. Detailed information about diagnosis, patient characteristics, previous treatment of malignancies, and comorbidities according to the Charlson Comorbidity Index (CCI) was collected from electronic health records. Patients were followed up until June 2019. Kaplan-Meier plots and Cox regression analyses were used to study survival differences. In the 291 patients diagnosed with MDS, the median OS was 25.3 months (95% confidence interval [CI], 20.3-30.2). OS was significantly better for patients with CCI score <4, age <65 years, female sex, and low-risk MDS. Fifty-seven patients (20%) had encountered a prior malignancy (excluding nonmelanoma skin cancer), and a majority (38 patients; 67%) were therapy related. Both therapy-related and secondary MDSs were associated with worse OS (hazard ratio, 1.51; 95% CI, 1.02-2.23 and 1.58; 95% CI, 0.95-2.65, respectively), as compared with de novo MDS patients (P = .04). Patients in remission at time of MDS diagnosis had a similar median OS compared with patients with de novo MDS (25.5 vs 28.3 months). This population-based study involving all newly diagnosed MDS patients over a 13-year period in Friesland showed that multiple comorbidities, including previous malignancies, are associated with shorter OS. OS was not related to the use of radiotherapy or chemotherapy.

Detection of Abnormal Pretransplant Clones in Progenitor Cells of Patients Who Developed Myelodysplasia After Autologous Transplantation

AbstractSecondary myelodysplastic syndromes (MDS) have been reported after autologous transplantation. It is not known whether the MDS results from the pretransplant conventional-dose chemotherapy or from the high-dose chemotherapy (HDC) used for the transplant procedure. We performed a multicenter, retrospective analysis of morphologically normal pretransplant marrow or stem cell specimens from 12 patients who subsequently developed myelodysplasia after HDC. To determine if the abnormal clone was present before HDC, we used fluorescence in situ hybridization (FISH) to detect the cytogenetic markers observed at the onset of posttransplant MDS. Cryopreserved, pretransplant bone marrow, peripheral blood stem cell specimens, obtained at the time of harvest, or archival smears were used. Standard cytogenetic analysis had been performed pretransplant in four patients, showing a normal karyotype. In 9 of 12 cases, the same cytogenetic abnormality observed at the time of MDS diagnosis was detected by FISH in the pre-HDC specimens. Our findings support the hypothesis that, in many cases of posttransplant MDS, the stem cell damage results from prior conventional-dose chemotherapy and may be unrelated to HDC or the transplantation process itself.

Burden of Cardiovascular Events and Bleeding Is High in Myelodysplastic Syndromes

Background: Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) patients are older and suffer with cardiovascular (CV) diseases. Management of these patients with antiplatelet and anticoagulation therapy is challenging as thrombocytopenia can increase the risk of bleeding. Aim: To assess burden and CV disease related mortality, review of anticoagulant /antiplatelet therapy and bleeding complications in MDS and oligoblastic AML patients. Methods: Electronic medical records of 910 MDS and oligoblastic AML patients enrolled in the South Australian MDS (SA-MDS) registry were reviewed. CV risk factors, CV and bleeding events requiring or occurring during hospitalisation, anticoagulation and/or antiplatelet therapy information were collected. Platelet counts of &amp;lt;100, &amp;lt;50 and &amp;lt;20 (x109/L) were defined as mild, moderate and severe thrombocytopenia respectively. Severity of bleeding events was classified using modified International Society of Thrombosis and Hemostasis (ISTH) classification. MDS patients require regular RBC transfusion, hence fall in hemoglobin ≥20 gm/L or ≥2 units of RBC transfusion were not used for defining major bleeding. Results: At the time of MDS diagnosis, 72% (658/910) and 42% (386/910) patients had ≥1 and ≥2 CV risk factors. Twenty-five percent patients required hospitalization for CV events prior to the MDS diagnosis and their median OS was significantly poor compared to patients who did not have CV events (Figure 1A). During median follow up of 28 months after MDS diagnosis, 27.5% (251/910) patients were admitted with or developed CV events during hospitalization. In a Cox-regression analysis age, absolute monocyte count, CV risk factors and prior CV events were independent predictors of CV events following MDS diagnosis (Figure 1B). The most frequent CV events were arrhythmia (137/399; 34%), congestive cardiac failure (129/399; 32%), and ischemic heart disease (94/399; 23%). Atrial fibrillation (AF) contributed towards 78% (108/137) of all arrhythmias. 39% of AF occurred in the setting of infections and 12% patients died during the same hospitalization or were palliated. 89% of AF patients had a CHADS2VASc2 score ≥2, however only 30% (20/65) and 24% (16/65) events with available information were treated with anticoagulation and antiplatelet therapy respectively. While 60% (39/65) AF events did not receive antiplatelet or anticoagulation therapies. Four AF patients developed ischemic stroke following MDS diagnosis and five patients had stroke before MDS diagnosis and were subsequently diagnosed with AF. Importantly, 36% (34/94) AF patients developed 45 bleeding events. The frequency of bleeding events was not significantly different between patients treated with anticoagulation/antiplatelet therapy versus who were not treated (13.8% vs. 13.6%). Although, cumulative incidence of bleeding and CV events was similar at 29% and 28% at five-years (Figure 1C-D), only some patients had both events. Of the 387 patients, 39% (n= 152) and 39% (n=153) patients required hospitalization only for CV or bleeding events, while only 21% (82/387) required hospitalization for both bleeding and CV events. Identifying these three groups early is crucial to optimize their outcome. Of the 387 bleeding events, 88 (24%) were major and 296 (76%) were clinically relevant minor bleeding. Notably, 127, 47 and 15 bleeding events were gastrointestinal, intracranial and intraocular respectively. While 50% bleeding events occurred in the setting of moderate to severe thrombocytopenia, 19% and 31% of bleeding events occurred at platelet counts of &amp;gt;50-100 and &amp;gt;100x109/L respectively (Figure 1E). Details of anticoagulation/antiplatelet therapy were available for 66% (161/243) of bleeding events. Importantly, 76% of bleeding events occurred without anticoagulation and antiplatelet therapy, while 10% and 13% bleeding occurred while on anticoagulation therapy and antiplatelet therapy respectively. Conclusions: Our analysis demonstrates a significant burden of CV and bleeding in MDS. Only 23% of all bleeding events occurred while on anticoagulation therapy and some patients with recurrent CV events did not require hospitalization for bleeding. However, large numbers of CV events are sub-optimally managed due to perceived excess risk of bleeding. Therefore, guidelines for anticoagulation and/or antiplatelet therapy are required for MDS patients. Disclosures Hiwase: Novartis Australia: Research Funding.

The Prognostic Significance of Blast Aberrancies By Flow Cytometry in Low/Int Risk MDS

Background: The myelodysplastic syndromes (MDS) represent heterogeneous disorders with varied clinical courses. The major prognostic tool in MDS is the IPSS-R, which helps estimate survival outcome and estimate risk for AML transformation. In low or intermediate risk pts, the IPSS-R has shortcomings; in these pts, the development of transfusion dependent anemia is the major disease associated complication, and this is not addressed by IPSS-R stratification. Previous studies have indicated that aberrancies detected by flow cytometry can risk stratify pts with MDS. The purpose of this study was to determine whether detection of neoplastic-specific blast aberrancies in pts diagnosed with low or intermediate risk MDS can identify pts at higher risk for transfusion dependent anemia after MDS diagnosis. Methods: We performed a retrospective chart review on MDS patients initially diagnosed at our institution between 1/2010 and 12/31/2017. Patients with low/intermediate risk by IPSS-R were identified. Flow cytometry findings on initial diagnostic BM biopsies performed at our institution only were reviewed. Flow cytometry (4- and 8-color) was performed on bone marrow aspirates for the following antigens: CD3, CD7, CD11b, CD13, CD14, CD15, CD19, CD20, CD33, CD34, CD36, CD38, CD45, CD56, CD64, CD117, and HLA-DR using FACS Calibur or FACSCanto II flow cytometers. Myeloblasts were identified by cluster analysis, as previously described (Am J Clin Pathol. 2010 Nov; 134(5):749-61), and compared to 20 control cases. Blast aberrancies were defined as an immunophenotypic difference of &gt; ¼ log compared to the blasts in the controls. Neoplasia-specific blast aberrancies were defined as: expression of CD7, CD11b, CD15, and/or CD56 and/or under expression of CD38 and CD45. We estimated probability of transfusion dependent anemia using Kaplan Meier product limit method and compared survival curves using log-rank test. Analyses were performed using Stata v12.0. Results: A total of 63 patients were identified, with median age of 68 years (range 31-89 years). Median hemoglobin (Hg) at diagnosis was 9.8 (range 5.2-15.3). Cytogenetic risk categories were very good, good, intermediate and poor in 3%, 71% 16%, and 10% respectively. IPSS-R category was very low or low in 70% (44 pts), and intermediate in 30% (19 pts). The presence of blast aberrancies was similar in proportion among low risk patients (61%, n=27) compared to intermediate risk patients (68%, n=13). Overall, the presence of only one blast aberrancy, whether neoplasia-specific or not, did not significantly segregate patients at greater risk for transfusion dependence. However, the presence of 2 or more aberrancies statistically defined two populations. Those possessing 0-1 blast aberrancy did not reach a median time to transfusion dependence, whereas those possessing 2+ aberrancies had a median time to transfusion dependence of 1.2 years (p=0.02). Additionally, when looking at neoplasia-specific blast aberrancies, pts with 0-1 aberrancy had a median time to transfusion of 4.7 years, compared to 2+ aberrancies, at 0.8 years (p=0.02). Figure 1 illustrates this finding. Conclusion: The determination of blast aberrancies by flow at time of MDS diagnosis may provide prognostic information in low/intermediate risk MDS patient and could help predict risk for early red blood cell transfusion dependence. Upfront risk stratification would be valuable information to plan follow-up for these patients, as well as treatment decision making including early initiation of ESAs. Disclosures Michaelis: Novartis: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; BMS: Research Funding; Bioline: Research Funding; ASTEX: Research Funding; Janssen: Research Funding; Millenium: Research Funding; Macrogeneics: Research Funding; Pfizer: Equity Ownership, Research Funding; Incyte: Consultancy, Research Funding. Runaas:Agios: Honoraria; Blueprint Medicine: Honoraria. Atallah:Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Helsinn: Consultancy. Abedin:Actinium Pharmaceuticals: Research Funding; Pfizer Inc: Research Funding; Helsinn Healthcare: Research Funding; Agios: Honoraria; Jazz Pharmaceuticals: Honoraria.

Prognostic Significance of Reduced BCAS4 expression in Bone Marrow Cells of Patients with Myelodysplastic Syndromes

Deletion of long arm of chromosome 20 (del(20q)) is commonly observed in myelodysplastic syndromes (MDS). Reduced expression of genes located within the common deleted region (CDR) of del(20q) due to haploinsufficiency may play a role in molecular pathogenesis of MDS. In the previous study, we examined expression of genes located within the CDR which we determined using array-CGH, in bone marrow mononuclear cells in MDS patients with or without del(20q), indicating that BCAS4 expression was significantly reduced in bone marrow cells in MDS patients with or without del(20q). The BCAS4 gene, which was identified as a fusion transcript expressed in MCF7 cells, encodes 23kD protein. Although function of BCAS4 protein remains unclear, it could be a member of "cappuccino" family, which belong to lysosome-related organelles. Abnormality of genes encoding lysosome-related organelles cause variety of congenital disorders, including the Hermansky-Pudlak syndromes, which is characterized by oculocutaneous albinism and bleeding tendency due to platelet dysfunction as a result of lysosome abnormalities. In the present study we investigated clinical implication of BCAS4 expression level in MDS patients. Mononuclear cells separated from bone marrow samples taken at the time of MDS diagnosis were used for analysis. Written informed consent was obtained from patients before study. To analyze BCAS4 expression, quantitative RT-PCR was performed using cDNA from mononuclear cells as template by the TaqMan probe method (Applied Biosystems) with co-amplification of the endogenous control gene, human GAPDH (Applied Biosystems). Samples from 103 MDS patients, 64 males and 39 females with median age of 67 years (range: 20-91 years), with (n=14) or without (n=89) del(20q), were examined in the present study. Patients were classified as RCUD (n=12), RCMD (n=55), RARS (n=9), RAEB-1 (n=10), and RAEB-2 (n=13), according to WHO 2008 classification, and in RAEB-T (n=4) according to FAB classification. They also were categorized in four IPSS risk groups, low risk (n=30), intermediate-1 risk (n=46), intermediate-2 risk (n=18), and high risk (n=9). There was no significant difference in relative BCAS4 expression level between patients with del(20q) and those without del(20q), and among WHO subtypes. Higher IPSS risk groups (INT-2 and High) showed trend in association with reduced BCAS4 expression compared with lower IPSS risk groups (Low and INT-1) (P=0.104). We analyzed impact of BCAS4 expression on overall survival (OS). Based on BCAS4 expression level, 103 patients were divided into four groups, highest (Q1), intermediate (Q2, Q3), and lowest (Q4) quartiles. The Kaplan-Meier analysis demonstrated that Q4 showed significantly worse OS compared with remaining quartiles (Q1-Q3) (log-rank test, P=0.0031). The estimated 2-year OS rates in Q1-3 group and Q4 group were 75.1% and 48.9%, respectively. According to the COX proportional hazards model, univariate analysis showed lower BCAS4 expression (Q4 vs Q1-Q3) was associated with worse OS (hazard ratio 3.43, 95%CI 1.89-6.11, P=0.0001) as well as older age (65 years or older vs less than 65 years), and higher IPSS risk groups (INT-2 and High vs Low and INT-1). Multivariate analysis indicated that lower BCAS4 expression showed trend for association with worse OS (hazard ratio 1.90, 95%CI 0.96-3.64, P=0.0651) by analyzing with two variables (older age and higher IPSS groups). Next, we investigated whether OS is predicted by combination of three variables, BCAS4 expression level, IPSS risk groups, and age at diagnosis. We defined lower BCAS4 expression (Q4), higher IPSS (INT-2 and High), and older age (65 years or older), as risk factors. The Kaplan-Meier analysis showed that survival curves were well separated according to number of risk factors (0, 1, and 2 or more) (P&lt;0.0001). The estimated 1-year, 2-year, and 5-year survival rates were 100%, 100%, and 86.5% in patients without risk factor, 75%, 70.2%, and 51.7% in patients with one risk factor, and 54%, 34.3%, and 11.4% in patients with two or more risk factors. The present study demonstrated that reduced BCAS4 expression is associated with inferior clinical outcome, indicating that BCAS4 expression level could be a useful prognostic marker in MDS, especially by combination with IPSS risk and patients age at diagnosis. Disclosures Tanaka: Bristol-Myers Squibb: Research Funding.

Improving Revised International Prognostic Scoring System Pre-Allogeneic Stem Cell Transplantation Does Not Translate Into Better Post-Transplantation Outcomes for Patients with Myelodysplastic Syndromes: A Single-Center Experience

The natural history of patients with myelodysplastic syndromes (MDS) is variable. The Revised International Prognostic Score (IPSS-R) is commonly used in practice to predict outcomes in patients with MDS at both diagnosis and before hematopoietic stem cell transplantation (HSCT). However, the effect of change in the IPSS-R before allogeneic HSCT with chemotherapy or hypomethylating agents on post-transplantation outcomes is currently unknown. We assessed whether improvement in IPSS-R prognostic score pre-HSCT would result in improvement in clinical outcomes post-HSCT. Secondary goals included studying the effect of prognostic factors on post-transplantation survival. All patients with MDS who underwent allogeneic HSCT at the Leukemia/BMT Program of British Columbia between February 1997 and April 2013 were included. Pertinent information was reviewed from the program database. IPSS-R was calculated based on data from the time of MDS diagnosis and before HSCT. Outcomes of patients who had improved IPSS-R pre-HSCT were compared with those with stable or worse IPSS-R. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method, with P values determined using the log-rank test. Hazard ratios were calculated using multivariable Cox proportional hazards regression models to study the effects of the prognostic variables on OS and EFS. A total of 138 consecutive patients were included. IPSS-R improved in 62 of these patients (45%), worsened in 23 (17%), remained stable in 41 (30%), and was unknown in 12 (9%). OS was not statistically different across the improved, worsened, and stable groups (30% versus 22% versus 40%, respectively; P = .63). The cumulative incidences of relapse and nonrelapse mortality at 5 years were 28.4% (95% confidence interval [CI], 21.1 to 36.1) and 31.6% (95% CI, 23.8 to 39.7), respectively. The rate of relapse was 23% in patients with <5% blasts at the time of HSCT, 69% in those with 5% to 20% blasts, and 66% in those with >20% blasts (P = .0004). In the entire cohort OS was 34% and EFS was 33%. There was no significant difference in outcomes between patients who received myeloablative conditioning and those who received nonmyeloablative conditioning before HSCT (OS, 34% and 39%, respectively; P = .63 and EFS, 34% and 32%, respectively; P = .86). OS was not statistically different among patients with improved, worsened, or stable IPSS-R. On multivariate analysis, only 3 factors were associated with OS: cytogenetic risk group at diagnosis, blast count at transplantation, and the presence or absence of chronic graft-versus-host disease. Improving IPSS-R before HSCT does not translate into better survival outcomes. Blast count pretransplantation was highly predictive of post-transplantation outcomes.

Certain Autoimmune Manifestations Are Associated With Distinctive Karyotypes and Outcomes in Patients With Myelodysplastic Syndrome: A Retrospective Cohort Study.

Autoimmune manifestations (AIMs) are common in patients with myelodysplastic syndrome (MDS). This study aimed to investigate whether AIMs are associated with a specific cytogenetic abnormalities and worse survival in patients with MDS.A total of 67 MDS patients with AIMs and 134 age- and sex-matched MDS patients without AIMs, all of whom received medical care at Seoul National University Hospital from January 2000 through July 2014, were enrolled. The clinical features, chromosomal abnormalities, and outcomes were examined. The effect of AIMs on mortality was estimated after adjusting for age, sex, and the International Prognostic Scoring System.The mean age (±SD) at the time of MDS diagnosis was 54.5 ± 17.1 years, and 44.8% of patients were male. Neutrophilic dermatosis (ND; Sweet syndrome and pyoderma gangrenosum) was the most prevalent AIM (n = 24 36%]), followed by Behcet disease (10 [15%]), rheumatoid arthritis (9 [13%]), vasculitis (8 [12%]), myositis (3 [4%]), spondyloarthropathy (3 [4%]), and systemic lupus erythematous (2 [3%]). ND and vasculitis occurred at the time of MDS diagnosis, whereas other AIMs occurred years after MDS diagnosis. Deletion of 5q was associated with ND (P = 0.001), whereas trisomy 8 was associated with Behcet disease (P = 0.015). Strikingly, ND was associated with a 1.8-fold increase in mortality (95% CI 1.033–3.093; P = 0.038).Certain AIMs in MDS patients are associated with distinctive karyotypes and worse survival. A larger study is needed to confirm whether the presence of AIMs influences disease outcome in MDS.

Prophylactic Rh and Kell Antigen Matching Significantly Decreases Rates of Alloimmunization in Transfusion Dependent MDS Patients

Background: 40-80 % of patients with myelodysplastic syndrome (MDS) become transfusion dependent during their disease course and are at risk for the development of alloimmunization. Red blood cell (RBC) alloantibodies can make finding compatible blood for transfusion more difficult, expensive and time consuming. Allommunization rates of approximately 30-47% have been reported in patients with sickle cell disease and the transfusion of RBCs prophylactically matched for Rh antigens E and C, and K antigens reduced the rate of alloimmunization from 3% to 0.5% per unit (Vichinsky et al, 2001). In 2007, our hospital instituted a policy of transfusing prophylactic Rh and K matched blood to MDS patients. The objectives of this study were to compare the rates of alloimmunization in MDS patients who received prophylactic Rh and K matched blood compared to those that did not and identify potential risk factors for alloimmunization. Methods: 193 Transfusion dependent MDS patients were identified out of 387 patients registered and prospectively followed in a local MDS registry. Transfusion dependence was defined as the receipt of at least 1 unit of PRBC every 8 weeks for a minimum of 16 weeks. Records of transfusions received up to May 1, 2014 were collected from blood bank databases of the hospitals at which patients were transfused. Patients were classified according to whether phenotyping had been performed, the location of transfusions (transfused only at our institution, transfused only at an outside institution or transfused at both sites) and whether prophylactic Rh (E, C antigens) and K matched blood was transfused. Data were descriptively analyzed and we conducted univariate and multivariate logistic regression using p< 0.05 as statistically significant to identify risk factors for alloimmunization.Results: 176 MDS patients with complete transfusion records are included, 73 transfused at Sunnybrook, 92 transfused in community hospitals and 11 at both. The median age was 72 yrs (range 22-89), 60% were male, and 8%, 43% and 27% had very low, low and intermediate risk R-IPSS scores respectively. Median follow up was 2.9 years (IQR 1.6-5) 3.49 SD). Blood groups O, A, B, AB and O were 45%, 38%, 15% and 2% respectively, while 85% were RhD+. The median time from diagnosis until first transfusion was 4 months (IQR: 0.2-14), with 51 patients having received at least 1 transfusion prior to diagnosis at a median time of 0.9 months. 4.5% had a pre-existing allo-antibody at time of MDS diagnosis. With a median follow up from diagnosis of 3 years (IQR:1.6-5)), the median number of RBC units transfused was 38 (IQR: 15-98)) and 36 (20%) patients developed new alloantibodies (median 2 (IQR (1-2.5) alloantibodies). The median number of RBC units until first allo antibody was 13.5 units (range 0-121) and 1.25 years from diagnosis (95% CI:0.4-2.1). The majority of the alloantibodies were in the Rh (n=28) and K (n=14) groups (80%) and co-existed 27% of the time. More patients transfused at our hospital received prophylactic Rh K matched blood sometimes or always (60% versus 26%) and rates of allo-immunization were decreased by 65% (absolute rate of alloimmunization 10% versus 29%). By multivariate analysis analysis, number of rbc transfused (p<.0001), receiving prophylactic phenotype matched blood (p=.0008) and location of transfusions (Sunnybrook versus elsewhere (p=.03)) were independent risk factors for alloimmunization.Conclusions: 20-30% of RBC transfusion dependent MDS patients will become allo-immunized to clinically significant blood group antigens, the majority being Rh and K antigens. The practice of phenotyping at baseline and prophylactically transfusing Rh and Kell matched blood decreases rates of alloimmunization up to 65% and should be strongly considered for routine transfusion practice in centres that treat MDS.Table 1All Patients (n=176)Sunnybrook (n=73)Community(n=92)Ever phenotyped45%64%28%Phenotyped before 1st transfusion20%38%8%Developed allo-antibodies20%10%29%Received prophylactic Rh K matched blood(developed alloantibodies)NeverSometimesAlways58% (16%)24% (42%)18% (6%)40% (3%)23% (23%)37% (7%)74% (22%)22% (60%)4% (0%) [Display omitted] DisclosuresWells:Celgene: Honoraria, Other, Research Funding; Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Buckstein:Celgene: Research Funding.