Number Of Cytopenias Research Articles

Development of a screening score for Hemophagocytic Lymphohistiocytosis among pediatric patients with acute infection of Epstein-Barr virus.

Background and aimsDeciding when to suspect hemophagocytic lymphohistiocytosis (HLH) and perform diagnostic tests in patients with acute infection of Epstein-Barr virus (EBV) is challenging, given the high prevalence of EBV infection, the life-threatening risk of EBV-HLH, the relatively low incidence of EBV-HLH, and the wide spectrum of disease presentations. The aim of this study was to develop an EBV-HLH screening model for pediatric patients diagnosed with acute infection of EBV.MethodsAn inpatient cohort with 3183 pediatric patients who were diagnosed with active infection of EBV was used to construct and validate the EBV-HLH screening score model. The model parameters were selected from common laboratory parameters using the method of Akaike Information Criterion-optimal selection through cross-validation under logistic regression. Performance of the score was evaluated and compared with the performance of screening methods using the number of cytopenias lineages.ResultsThe EBV-HLH screening score has five parameters, including hemoglobin, platelet, neutrophil, albumin, and lactate dehydrogenase. Using a cut-of value of 29, the scoring model had a sensitivity of 89.2% and a specificity of 89.5% in the validation set. The false negative rate, false positive rate, positive predictive value, and negative predictive value in the validation set was 10.8%, 10.5%, 26.8%, and 99.5%, respectively, similar to that of the training set.ConclusionsWith five common laboratory parameters, the EBV-HLH score provides a simple tool to assist the identification of EBV patients who require further evaluation of HLH. Further studies are needed to evaluate the generalizability of the score and optimize the diagnose process for EBV-HLH.

Complex immune deregulation in severe COVID-19: More than a mechanism of pathogenesis.

Complex immune deregulation in severe COVID-19: More than a mechanism of pathogenesis.

Prognostic VALUE of EARLY Drop in the Platelet Counts in Patients with VERY Low, Low and Intermediate Risk IPSS-R Myelodysplastic Syndromes. Results from a Single Center Analysis

Background: Prognosis of very low, low and intermediate risk myelodosplastic syndromes (MDS) is heterogeneous. Recently, the EUMDS (European Leukemia Net Lower-Risk MDS) described that a 20% drop in platelet counts in the first 6 months after diagnosis of patients with lower risk MDS identifies a poor-risk population independently from the IPSS-R. Herein, we present the impact of an early drop in both platelet and neutrophil counts during the first 6 months after diagnosis in a population of patients with lower and intermediate IPSS-R risk MDS.Patients and Methods: A total of 270 consecutive patients diagnosed with MDS (01/2010-12/2016) at the Catalan Institute of Oncology of Barcelona were included in the study. 201 patients were eligible for the study. Reasons for exclusion were: absence of a medical visit at 6 month or later on (n=9), higher-risk MDS patients (n=40) and patients under treatment with hypomethylating agents, lenalidomide or hydroxycarbamide at the follow up visit (n = 20). Patients were classified into two groups according to the presence or not of a 20% drop in neutrophils and platelets at time of or before the landmark time point. Landmark analysis was conducted at 6 months after diagnosis. We analyzed in our series the prognostic impact of early drop in neutrophils and plateletsin both overall survival (OS) and leukemia free survival (LFS).Results: Median age at diagnosis was 75 years and 135 (67.2%) were male. According to the WHO 2008 classification, 3% of the patients were classified as CRDU, 7.5%RA, 48.8% RCMD, 8.5% RAEB‐1, 1%, RAEB‐2, 27.4% CMML, the remaining 4% were MDS‐U and isolated 5q deletion. Hemoglobin, neutrophiland platelet counts were of 11.2 g/dL (5.6-16.9) [median (range)], 2.71 x109/L (0.3-30), 149 x109/L (1-889), respectively; the percentage of bone marrow blast at diagnosis was 2% (0-13). 47% of the patients were diagnosed with a very low IPSS-R, 42% with a low IPSS-R and the remaining 11% with intermediate IPSS-R. At the time of last follow up, 74 (36.3%) patients had died and 17 (8.5%) had progressed to AML.The median time to the landmark blood test was 188 days (1QR: 160-218). Median follow-up from landmark was 31.4 months. Median relative drop in platelets was 2.4%. In univariate analysis male sex, number of cytopenias, IPSS-R, red blood cell transfusion dependency (RBC-TD) and a platelet drop >20% was associated with poorer OS (Figure 1). In multivariate testing, male sex, RBC-TD and a drop of platelets >20% within 6 months were independent significant parameters affecting survival (Table 1). Number of cytopenias, IPSS-R and RBC-TD were associated to an inferior LFS in univariate analysis. IPSS-R was the only independent adverse prognostic factor for LFS in the multivariate analysis. The combination of both RBC-TD and a platelet drop >20% at 6 month after diagnosis enabled us to identify a small subgroup of patients (6%) with a median OS of 20 months.Conclusion: A 20% drop in platelet counts in the first 6 months after diagnosis is able to identify a poor-risk population of patients with MDS within the very low, low and intermediate-risk IPSS-R groups. As therapeutical decisions are based on prognostic risk assessment, the inclusion of this additional parameter may help to better tailor treatment strategies in these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Red Blood Cell Transfusion Intensity on Progression-Free Survival in Lower-Risk MDS Patients Included in the European Leukemianet MDS Registry

Abstract Background Progression-free survival (PFS) of lower-risk (LR) MDS patients treated with red blood cell transfusions (RBCT) is usually reduced, but whether the RBCT intensity is important for prognosis is unknown. The EUMDS Registry contains data on 2,192 newly diagnosed LR-MDS patients from 16 European countries and Israel, collected at diagnosis and at 6 months intervals.The aim of this analysis is to assess the effect of RBCT intensity on PFS of patients with LR-MDS in a prospective, observational setting. MethodsData on the number of RBCT units received during each visit-interval were analyzed using proportional hazards regression with time-varying co-variates. The cumulative dose received at the end of each interval was divided by the time since the beginning of the interval in which the first RBCT was received rather than for each visit-interval, to give an overall dose density. Dose density rises over time when RBCT intensity increases over time, but declines when patient becomes RBCT independent after treatment. In Cox regression with time-varying covariates, PFS was adjusted by relevant confounders, including age, gender, patient condition (proxied by EQ-5D index), and number of cytopenias at diagnosis. We analyzed a cohort of 1,509 patients with at least 3 visit reports available. Within this group 476 patients have died and 118 patients have progressed to higher-risk MDS or AML, which were defined as events. ResultsPatients with ring sideroblastic MDS (RS-MDS) received more frequently RBCT after diagnosis compared to non-RS-MDS (60% vs 54%). Very low-risk patients according to IPSS-R received RBCT less often compared to intermediate risk patients (35% vs 69%). Age, gender, presence of co-morbidities, and countries influenced RBCT dependency and RBCT rate. The transfused patients were subdivided in 3 groups according to the maximum RBCT rate over time: low rate ( 2 units/month) in order to analyse the impact of the RBCT rate in more detail (figure A). Unadjusted overall PFS stratified this way, is shown in figure B. Univariate analysis of the 404 patients transfused at a high rate showed a strong association of age (p ConclusionThe negative effect of RBCT treatment on PFS already occurs at low RBCT densities below 2 units/month and before 25 units of RBCT have been transfused. This indicates that the RBCT dependency, even at relatively low intensities, may be considered as an indicator of poor prognosis for survival. Download : Download high-res image (93KB) Download : Download full-size image Figure . Disclosures Fenaux: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sanz: Gamida Cell: Research Funding. Germing: Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Almeida: Servier: Consultancy; Alexion: Honoraria; Novartis: Consultancy; Celgene: Consultancy; Bristol Meyer Squibb: Honoraria. Itzykson: Janssen: Research Funding; Novartis: Research Funding. Park: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira/Pfizer: Research Funding; Celgene: Research Funding. de Witte: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen Cilag: Research Funding.

Sequential Stratification Prognostic Score for Patients with Intermediate-Risk Myelodysplastic Syndrome

Background: The International Prognostic Scoring System-Revised (IPSS-R) is one gold standard for myelodysplastic syndrome (MDS) risk stratification. An accurate estimate of prognosis allows clinicians to make appropriate management decisions. The IPSS-R intermediate-risk (int-risk) group however, shows marked heterogeneity with respect to disease outcomes, and contributes to uncertainty about patient management. A more refined yet simple sequential scoring model is therefore proposed to improve the classification of int-risk patients to allow for appropriate therapeutic decisions.Methods: A retrospective patient-centered analysis was conducted at MD Anderson Cancer Center on patients diagnosed with primary MDS between 2000 and 2015. All patients were scored according to the IPSS-R criteria and int-risk patients were included. The primary outcome was overall survival (OS), and covariate characteristics included: hemoglobin, ferritin, white blood cell (WBC) count, platelet count, absolute neutrophil count (ANC), percentage of peripheral blood (PB) and bone marrow (BM) blasts at diagnosis, number of cytopenias, performance status, RBC and platelet transfusion history, and type of treatment received. Survival differences between groups were compared and univariate Cox proportional hazards regressionwas used to evaluate association between each covariate and OS. Classification and regression tree (CART) analysis was used to find the best cut-off points to differentiate OS for some continuous variables. CART analysis for failure time data used the Martingale residuals of a Cox model to approximate chi-square values for all possible cut points. A multivariate Cox proportional hazards model was then fitted for OS by including all statistically significant covariates from univariate Cox models. A backward stepwise selection was performed using a threshold significance of 0.05 for covariates to stay in the final model. Internal validation testing of the final stratification score was performed using the bootstrap method, and external validation was performed using an independent external cohort from Cleveland Clinic.Results: Out of 3167 patients, a total of 298 were identified with IPSS-R int-risk MDS and retrospectively analyzed in this study. Age of 66 years or greater (2 points), peripheral blood blasts of 2% or more (1 point), and history of RBC transfusion (1 point) were significantly associated with inferior survivaland were included in the final OS prognostic model. The score divided MDS patients who have IPSS-R intermediate-risk into two prognostic risk groups: an int-favorable group with a score of 0-1, and an int-adverse group with a score of 2-4. Overall survival was significantly different between the two risk groups of patients, with median survival of approximately 6 and 2 years for int-favorable and int-adverse, respectively (p <0.001, Figure 1A). Transfusions per patient year were significantly higher in int-adverse patients for both red blood cells and platelets (p<0.001, Figure 1B). The stratification prognostic score was robust in the classification of patients with IPSS-R intermediate-risk myelodysplastic syndrome by internal validation, and analysis of 111 IPSS-R int-risk MDS patients from a separate institution demonstrated significantly different OS between int-favorable and int-adverse patients, with median survival of approximately 4 and 2 years respectively (p=0.04).Conclusions: Sequential prognostication provides a clinically practical framework to aid clinicians in determining appropriate treatment approaches for the heterogeneous group of int-risk MDS patients. [Display omitted] DisclosuresJabbour:Bristol-Myers Squibb: Consultancy. Komrokji:Celgene: Honoraria; Novartis: Honoraria, Speakers Bureau. Steensma:Pfizer: Consultancy; Incyte: Equity Ownership; Janssen: Consultancy, Research Funding; H3 Biosciences: Consultancy; Celgene: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Onconova: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz:Cellectis: Research Funding; AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; Novartis: Research Funding.

Bone Marrow Levels of PARP1 mRNA Predict Response to Treatment with 5-Azacytidine in Patients with Myelodysplastic Syndrome

IntroductionPoly [ADP-ribose] polymerase 1 (PARP1) is the major member of a family of nuclear enzymes that participate in DNA repair and gene transcription, by recruiting various proteins involved in DNA repair to sites of DNA damage. PARP1 overexpression has been correlated to poor treatment response in children with acute lymphoblastic leukemia, while PARP1-driven apoptosis is important in patients with chronic lymphocytic leukemia. Moreover, PARP1 inhibitors have been tested in vitro in lymphoid malignancies, acute myeloid leukemia, myelodysplastic syndrome (MDS) and acute promyelocytic leukemia.We have recently shown that bone marrow PARP1 mRNA levels correlate to the prognosis of patients with MDS (Diamantopoulos et al. Blood Cancer 2017). Moreover, PARP1 has been related to hypermethylation through DNA methyltransferase-1 (DNMT1) gene upregulation and protein activation (Zampieri et al. PLoS One. 2009). This correlation with DNA methylation is very important, since hypermethylation is a major event in the pathogenesis of high risk MDS, and hypomethylating agents, such as 5-azacytidine, are the most effective available treatment option for patients with higher risk MDS.AimBased on the relation of PARP1 with hypermethylation, we investigated the correlation of bone marrow PARP1 mRNA levels of patients with MDS with treatment response to 5-azacytidine.MethodsBone marrow samples were collected from patients with MDS at diagnosis. Only samples from patients that were eventually treated with 5-azacytidine were selected for analysis. RNA extraction and reverse transcription were performed using standard protocols. Primers for PARP1 and beta-actin were designed using the primer3 software (University of Massachusetts, USA) and a SYBR green based real-time PCR was performed on a CFX96 RT-PCR system (Bio-Rad Laboratories, Hercules, CA, USA). PARP1 mRNA levels were expressed as a PARP1/beta-actin ratio. IBM SPSS statistics, version 23.0 (IBM Corporation, North Castle, NY, USA) was used for the analysis of the results.ResultsSixty-seven patients diagnosed with MDS per the WHO 2008 classification and treated with 5-azacytdine were included in the study. The basic characteristics of the patients are shown in Table 1. The median follow-up of the patients was 25.8 (2.6-117.0) months. Response to treatment with 5-azacytidine per the International Working Group (IWG) criteria is shown in Table 1. The median PARP1 mRNA level was 0.0793 (range (0.0000424 - 3.43). Response to treatment differed between patients with high and low PARP1 mRNA levels (Independent samples Kruskal-Wallis test, 2-sided p=0.009). More precisely, the median level of PARP1 mRNA was 4 times higher in responders (partial response, complete response, hematologic improvement) than in non-responders (failure and stable disease), Independent samples Mann-Whitney U test, 2-sided p=0.006. We found no correlation of any other of the studied factors (MDS type, IPSS, IPSS-R, WPSS, karyotype risk, number of cytopenias, marrow blast percentage, hemoglobin level, neutrophil and platelet count, dose reduction of 5-azacytidine) to response to treatment in this cohort of patients. Although there was no correlation of PARP1 mRNA levels with overall survival, survival of patients after 5-azacytidine treatment tended to be longer in patients with higher PARP1 mRNA levels (38.7 versus 19.8 months, log rank test, p=0.136).DiscussionWe found that patients with MDS and high PARP1 mRNA levels have a better response to treatment with 5-azacytidine. This correlation has a theoretical basis, since upregulation of PARP1 is correlated to DNA hypermethylation, and hypomethylating agents may be more effective in cells with higher methylation levels. Moreover, in our cohort of patients, PARP1 level was the only factor affecting treatment response, although this response was not translated into a survival benefit.PAPR1 is the only biological factor and one of very few identified factors to predict response to treatment with hypomethylating agents - low hemoglobin and platelet count were found to be an independent factor of poor response to hypomethylating agents (Jung et al. Oncotarget 2016), and absence of aberrant myeloid progenitor cells were found to predict response to treatment (Alhan et al. Cytometry B Clin Cytom 2014). A possible synergy between PARP1 inhibitors and hypomethylating agents in MDS should be further investigated. [Display omitted] DisclosuresVassilakopoulos:Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene/GenesisPharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Analysis of Expansion Mesenchymal Stromal Cells in patients with low risk myelodysplastic syndrome

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoiet­ic disorders characterized by ineffective hematopoiesis, cytopenias and dysplasia and one or more lineages. The stratification of MDS is made based on the percentage of bone marrow blasts, number of cytopenias and karyotype at diagnosis. Somatic mutations in the p53 tu­mor suppressor gene are found in approximately 50% of all human tumors, making it the most commonly mutated gene. The expression of p53 protein and the study of mutations is especially needed in the prognosis of MDS. In this context, the study aims to evaluate the expansion of mesenchymal stromal cells (MSCs) and the expression of p53 protein in pa­tients with SMD, low risk, according to the International Prognostic System (IPSS), in order to demonstrate the importance of these evaluations also diagnostics. This is a cross-sectional analytical study with review 3 adult patients of both sexes, the diagnosis of low-risk MDS receiving outpatient treatment at the University Hospital Walter Cantídio (HUWC). MSCs were characterized by immunophenotyping and screening of mutation of the p53 gene by Real Time PCR System (Applied Biosystems). For data analysis, the statistical software was used GraphPadPrism 5.0. Statistical differences between groups were checked by Student t or Mann-Whitney’s test significance level was p &lt; 0.05 for all analyzes. The results showed a smaller expansion of MSCs in the bone marrow of patients with MDS compared with a control group. A survey of mutation of the p53 gene was negative in all patients. The results demonstrate an impairment in the growth of MSCs in patients with MDS, collaborating with the hypothesis that medullary microenvironment in MDS may be compromised contributing greater understanding of disease mechanisms. However studies with larger sample should be conducted in order to establish the best results.

The Prognostic Significance of Monocytopenia in Patients with Myelodysplastic Syndrome

The Prognostic Significance of Monocytopenia in Patients with Myelodysplastic Syndrome

Bone Marrow Ribonucleotide Reductase mRNA Levels and Methylation Status As a Prognostic Factor in Patients with Myelodysplastic Syndrome Treated with 5-Azacytidine

Bone Marrow Ribonucleotide Reductase mRNA Levels and Methylation Status As a Prognostic Factor in Patients with Myelodysplastic Syndrome Treated with 5-Azacytidine

Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes.

Progression-free survival (PFS) of patients with lower-risk myelodysplastic syndromes (MDS) treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals from newly diagnosed lower-risk myelodysplastic syndromes patients in 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk MDS/acute myeloid leukemia as events. Of the 1,267 patients included in the analyses, 317 died without progression; in 162 patients the disease had progressed. PFS was significantly associated with age, EQ-5D index, baseline World Health Organization classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with PFS (P<1×10−4): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoiesis-stimulating agents, lenalidomide and/or iron chelators. In conclusion, the negative effect of transfusion treatment on PFS already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior PFS. This trial was registered at www.clinicaltrials.gov as #NCT00600860.

CIRCULATING microRNA EXPRESSION IN MYELODYSPLASTIC SYNDROME

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and cytopenia in peripheral blood, where about a third of patients may develop acute myeloid leukemia (AML). The diagnosis of MDS requires the analysis of peripheral blood and bone marrow. Depending on the percentage of blasts in the bone marrow, the number of cytopenias and cytogenetic abnormalities, determination of the prognostic indices is possible (IPSS – „International Prognostic Scoring System“, R-IPSS-„Revised International Prognostic Scoring System“, WPSS – „WHO Prognostic Scoring System“). Until today, numerous studies have been conducted on the molecular mechanisms and epigenetic pathways in myelodysplastic syndrome, and their prognostic and therapeutic importance, but there are few studies analyzing the importance of microRNAs (miRNAs) in MDS. In the last few years, there have been numerous results on the impact of aberrant miRNA expression in malignant disorders where the miRNA represent tumor suppressor genes or oncogenes. Several miRNAs have been recognized as diagnostic and prognostic parameters and possible therapeutic targets. In this paper, we present the overview of recent results on the role of miRNA in MDS.

Characteristics of Long-Term Survival of Patients with MDS Treated with 5-Azacytidine. Results from the Hellenic 5-Azacytidine Registry

IntroductionThe prognosis of patients with myelodysplastic syndromes (MDS) depends on several disease characteristics such as the cytopenias, the percentage of bone marrow blasts, and the cytogenetic profile of the patients. The use of hypomethylating agents (HMAs) has altered the prognosis of patients with higher risk MDS offering a median survival of around 24 months. Nevertheless, the range of survival is wide, with some patients achieving long remissions and high survival rates irrespective of their initial prognostic characteristics. Long-term survivors after 5-azacytidine administration constitute a large group of patients with potentially special characteristics and needs.AimWe analyzed data from a large cohort of patients with MDS treated with 5-azacytidine to describe the hematologic and prognostic characteristics of long-term survivors and compare them to those of patients with shorter survival.Patients and MethodsWe retrospectively recorded through the Hellenic 5-azacytidine registry the main demographic, hematologic and treatment characteristics of adult patients with MDS treated with 5-azacytidine monotherapy. Patient data from 28 centers meeting the 2008/2016 WHO diagnostic criteria for MDS were recorded during a 7-month period.We defined two groups of long-term survivors based on their survival after initiation of treatment with 5-azacytidine (OST). The first group comprised patients with OST above the third quartile (Q3 or 75th percentile) of the whole group (Q3 group) and the second patients with OST above the 90th percentile of the whole group (P90 group). Correlations were made between long- and short-term survivors for both groups.IBM SPSS statistics, version 23.0 (IBM Corporation, North Castle, NY, USA) was used for the statistical analysis of the results.ResultsData from 626 patients was recorded. The Q3 group comprised 157 patients with an OST longer than 24.5 months (median, 43.3 months) and the P90 group 63 patients with an OST longer than 36.4 months (median, 65.7 months). The detailed characteristics of the two groups along with comparisons with the remaining patients with OST below Q3 and P90 respectively are shown in Table 1. Data analysis revealed that the sex, the age, the type of MDS at diagnosis per the 2008/2016 WHO classification, the presence of excess (≥5%) marrow blasts, the number of cytopenias, the hemoglobin, neutrophil and platelet count, and the transfusion needs were not predictive of long-term survival in neither of the groups. On the other hand, the presence of peripheral blood blasts, the karyotype risk, the IPSS, IPSS-R and WPSS classification and response to treatment were predictive of long term survival in both groups (Table 1). Multivariate analysis revealed that response to 5-azacytidine was the strongest determinant of long-term survival (Kaplan Meier, Log Rank, p<0.0001) in a model comprising IPSS, IPSS-R, WPSS and response to treatment. Nevertheless, patients with stable disease were almost equally distributed in the groups of long- and short-term survivors (p=0.795 for the Q3 group and p=0.310 for the P90 group).DiscussionThe use of HMAs in MDS has increased survival rates, hence long-term survival is now a feasible target when managing such patients. One fourth of the patients of this registry achieved an OST over 24.5 months and 10% over 36.4 months. IPSS, IPSS-R and WPSS are powerful prognostic tools for patients with MDS. Among the prognostic components of IPSS and IPSS-R at diagnosis (cytopenias, bone marrow blast count, karyotype risk), the karyotype risk seems to be the stronger determinant of survival. Nevertheless, among long-term survivors there are patients with adverse prognostic characteristics at diagnosis, whose prognosis is altered by the administration of HMAs. Failure to respond to 5-azacytidine is a major determinant of OST, but stable disease was not correlated to survival in this cohort. This result highlights the importance of continuing treatment with hypomethylating agents in patients not achieving an optimal response (PR, CR, HI), since a significant proportion of them may achieve long survival rates. Further search for new clinical and/or molecular prognostic markers is warranted to identify the prognosis of patients with MDS and define those who would benefit from the use of HMAs or other upcoming treatment choices. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Azacitidine in Lower-Risk Myelodysplastic Syndromes: A Meta-Analysis of Data from Prospective Studies.

After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients with lower-risk myelodysplastic syndromes (LR-MDS). Optimal choice of these agents as front-line therapy in non-del(5q) LR-MDS is unclear. Because azacitidine clinical data mainly describe experience in higher-risk MDS, we performed a meta-analysis of patient-level data to evaluate azacitidine in patients with red blood cell (RBC) transfusion-dependent LR-MDS. We searched English-language articles for prospective phase II and III azacitidine clinical trials and patient registries published between 2000 and 2015, and Embase abstracts from 2015 conferences. Patient-level data from identified relevant studies were provided by investigators. Meta-analyses followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Efficacy endpoints were RBC transfusion independence (TI) and Clinical Benefit (RBC-TI, erythroid response, and complete or partial remission, per International Working Group 2006 criteria for MDS). Data for 233 patients from 6 clinical studies and 1 registry study met criteria for inclusion in analyses. Overall, 90.3% of patients had non-del(5q) LR-MDS. Pooled estimates from random-effects models of RBC-TI and Clinical Benefit were 38.9% and 81.1%, respectively; for the ESA-refractory subgroup, they were 40.5% and 77.3%; and for patients with isolated anemia, they were 41.9% and 82.5%. In multivariate analyses, planned use of ≥6 azacitidine treatment cycles was significantly predictive of response. Azacitidine effects in these patients, most with non-del(5q) LR-MDS, were promising and generally similar to those reported for lenalidomide in similar patients. The choice of initial therapy is important because most patients eventually stop responding to front-line therapy and alternatives are limited. Lower-risk myelodysplastic syndromes (LR-MDS) are primarily characterized by anemia. After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients. This meta-analysis of 233 azacitidine-treated red blood cell (RBC) transfusion-dependent patients with LR-MDS (92.3% non-del[5q]) from 7 studies showed 38.9% became RBC transfusion-independent. There is no clear guidance regarding the optimal choice of lenalidomide or hypomethylating agents for patients with non-del(5q) LR-MDS following ESA failure. Clinical presentation (e.g., number of cytopenias) and potential outcomes after hypomethylating agent failure are factors to consider when making initial treatment decisions for LR-MDS patients.

Telomere length is an independent prognostic marker in MDS but not in de novo AML.

Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P<0·0001) where telomere length was also significantly shorter in younger AML patients (age <60years) (P=0·02) and in FLT3 internal tandem duplication-mutated AML patients (P=0·03). Using a previously determined telomere length threshold for telomere dysfunction (3·81kb) did not provide prognostic resolution in AML [Hazard ratio (HR)=0·68, P=0·2]. In contrast, the same length threshold was highly prognostic for overall survival in the MDS cohort (HR=5·0, P<0·0001). Furthermore, this telomere length threshold was an independent parameter in multivariate analysis when adjusted for age, gender, cytogenetic risk group, number of cytopenias and International Prognostic Scoring System (IPSS) score (HR=2·27, P<0·0001). Therefore, telomere length should be assessed in a larger prospective study to confirm its prognostic role in MDS with a view to integrating this variable into a revised IPSS.

Azacitidine Use in the Real World Does Not Replicate AZA-001 Results in Higher Risk MDS/Low Blast Count AML: An Audit of 1101 Patients in the Cancer Care Ontario Registry

▪Background: In the AZA-001 trial, azacitidine (AZA) altered the natural history of patients with higher-risk MDS (Fenaux et al., Lancet 2009) by significantly improving overall survival compared to conventional care regimens (24.5 months versus 15.0 months). Once approved for drug reimbursement by the provincial health ministry, Cancer Care Ontario (CCO) mandated that all eligible patients be enrolled in a prospective registry to ensure compliance with eligibility criteria and schedules of drug administration. Baseline characteristics were recorded and treatment response were to be submitted every 6 cycles of treatment. Our objectives were to audit this clinical program for results after 6 years and identify the prognostic markers for survival in a homogenous higher-risk MDS/low blast count AML patient population.Methods: Only higher-risk MDS patients (intermediate-2, high) as defined by the International Prognostic Scoring System (IPSS) and low blast count AML (20-30% blasts) treated with AZA in Ontario, Canada from June 1, 2010 to March 2, 2016 were eligible and included. Our primary outcome was overall survival (OS) from date of first AZA treatment. Our secondary outcomes were overall response rates and the predictors of OS including administration schedules, centre size or type (regional cancer versus community). Univariate and multivariable Cox proportional hazard model were used to determine the predictors of OS. Hazard ratios and generalized R2 (higher the R2, stronger association with OS) were also calculated.Results: 825 higher-risk MDS and 276 low blast count AML were included (n = 1101 total). Median age was 74 years (range 19 to 99), 65.2% were male and the IPSS scores were intermediate-2 (64.3%) and high-risk (35.7%). Sixty-six percent of patients were transfusion dependent (TD) at time of AZA initiation and 15.5% had received previous chemotherapy. By dosing schedule, 24.7% received AZA for 7 consecutive days (7d), 12.4% for 6 consecutive days (6d) and 62.9% by the 5-2-2 schedule. Overall, the median number of cycles received was 6 (range 1 to 67) and 8 (range 6 to 14) when restricted to the 692 (63%) patients who received at least 4 cycles of treatment. Dose reductions were seen in 33.3% of patients (mean 11.1 mg/m2 in those with reductions) and were more common over time (negative slope 0.178; p < .0001). Of those with repeat bone marrow (n = 293) best response was complete response (CR) in 16.7% and partial response (PR) in 10.6%. Of those without CR/PR/progressive disease on bone marrow (n = 814), 20.4% experienced hematologic improvement including those with marrow CR and marrow stable disease. The actuarial median survival was 11.6 months (95% CI 10.7- 12.4) with a significantly longer OS for MDS compared with low blast count AML (12.4 months vs. 9.6 months; p = .0002) and 16.7 months (95% CI 15.2-18.1) for those receiving at least 4 cycles. There was no difference in OS between the 3 dosing schedules (11.7 months (7d) vs. 10.2 months (6d) vs. 12.0 months (5-2-2); p = .87; figure 1A), regional cancer centre vs. community (11.3 months vs. 11.7 months; p = .19; figure 1B) or by centre volume (11.4 months < 50 patients vs. 11.6 months > 50 patients; p = .38; figure 1C). On univariate analysis, the following were predictive of OS: blast percentage, number of cytopenias, karyotype, IPSS, WHO classification, TD, greater transfusion burden and secondary MDS. The multivariate model with the highest R2 (13.5%) included blast percentage (p < .0001), karyotype (p < .0001), cytopenias (p = .038), TD (p < .0001) and secondary MDS (p = .0006) as summarized in the table below.Conclusions: In our large real world evaluation of AZA use in higher-risk MDS/low blast count AML, we validated the expected overall response rates to AZA but demonstrated a lower than expected OS compared to the AZA-001 trial. Reassuringly, survival did not differ by dosing schedules, centre volumes or center type (regional cancer vs. community). OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realized. This represents the largest real world evaluation of AZA in higher-risk MDS/low blast count AML and additional analyses are underway. [Display omitted] [Display omitted] DisclosuresMozessohn:Celgene: Honoraria. Buckstein:Celgene: Honoraria, Research Funding; Novartis: Honoraria.

An International Data Set for the Study of Chronic Myelomonocytic Leukemia (CMML) Validates Modern Prognostic Scoring Systems and Demonstrates a Critical Need for Novel Prognostication Strategies

Introduction: CMML is a heterogeneous malignancy characterized by peripheral monocytosis and a propensity for AML transformation. Given the low incidence of CMML and its broad range complexity, a large disease-specific data set is necessary to discern independent co-variates predictive of disease behavior. Several prognostic models derived from smaller data sets have been developed to stratify CMML patients into distinct groups that are predictive for OS. However, the validity of these models in a large international data set has never been investigated. Here, we present the largest International CMML data base established to date and report key baseline characteristics predictive for disease outcome. We externally validate and perform a detailed statistical comparison between the International Prognostic Scoring System (IPSS), Revised (R)-IPSS, Global MD Anderson Scoring System (MDASC), MD Anderson Prognostic Score (MDAPS), Dusseldorf Score (DS), Mayo, and Spanish Scoring Systems (CPSS).Methods: Data were abstracted by each contributing institution and deposited for central data review at the Moffitt Cancer Center. Manual review of cases was performed to ensure data quality prior to analysis. Only WHO defined CMML was included. The primary objective of this study was to establish an international CMML data set and validate the above models calculated at the time of presentation to each center. All prognostic models were calculated as previously described. The Kaplan–Meier (KM) method was used to estimate median OS and the log rank test was used to compare KM survival estimates with SPSS version 21.0. Random Forest Survival (RSF) and ROC analysis was done with R.Results: Between July 1981 and June 2014, 1832 CMML patients were captured in the International CMML database. Median age at diagnosis was 70 (16-93) years with a male (67%) predominance. By the WHO classification, the majority of patients had CMML-1 (79.9% vs. 20.1%) and most patients were evenly subcategorized as MPN-CMML (49.8%) versus MDS-CMML (50.2%) by FAB criteria. Splenomegaly was demonstrable in 25%. Most patients had favorable cytogenetics by both IPSS (70%) and CPSS (67.6%) classification schemas. Mean BM blast % was 5.6 and mean monocyte count was 4.85x103/dL. Median OS of the entire data set was 31.6 months. All tested prognostic models were valid and able to predict OS (p<0.0001). To compare relative model performance, 1013 complete cases with sufficient data to calculate all risk models were compared using time dependent receiver operator characteristic (ROC) curves and their area under the curves (AUC). ROC curves were calculated for OS at 36 months. The R-IPSS model had the highest AUC (0.694) while the DS model had the lowest (0.635). The difference in AUC between the R-IPSS and DS models was statistically significant (p = 0.003) whereas there was no significant difference from other models tested. To determine which models were most vulnerable to reclassification from low-risk to higher risk, we calculated a vulnerability score defined by the number of models able to up-stage low-risk disease in more than 15% of cases. Using this metric, the Mayo and MDASC scores were least vulnerable to up-staging by other models. Lastly, we used an orthogonal method for determination of variable importance (RSF for OS at 36 months). RSF is an ensemble method of classification and regression tree methodology. Ranking of variables by their weighted importance determined by this procedure identified the top five variables were hemoglobin, circulating blasts, platelet count, number of cytopenias, and karyotype. A new risk model was developed using the results of the RSF with an AUC of 0.720, which was comparable but not significantly different than other modern scoring systems.Conclusions: This represents the largest international CMML-specific data set derived from eight unique centers of excellence. All modern prognostic models were valid and performed comparably. Despite novel strategies for variable importance discovery, an improved model could not be constructed. This data suggest that the power of clinical variables has reached an asymptote and highlights the need for incorporation of molecular and other novel biological features. This data set is currently being populated with molecular data and is being leveraged to test published CMML molecular prognostic models which will be disclosed at the time of presentation. DisclosuresGarcia-Manero:Epizyme, Inc: Research Funding. Fenaux:Celgene, Janssenm, Novartis: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Sekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen Corp: Membership on an entity’s Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity’s Board of Directors or advisory committees.

Hypocellular Myelodysplastic Syndrome in the Hypomethylating Agent Era

ABSTRACT Aim: Hypocellular myelodysplastic syndrome (MDS) represents 10 ∼ 15% of total MDS cases. Several studies reported that hypocellular MDS had some different clinical and pathologic features as compared to those of normo/hypercellular MDS. However, the treatment strategy and prognosis of hypocellular MDS has not been well-defined, especially in the epigenetic therapy era. In this study, we evaluated the clinical characteristics of hypocellular MDS and responses to the hypomethylating agent compared with normo/hypercellular MDS. Methods: Total 51 patients who diagnosed as de novo MDS, and treated with hypomethylating agent between 2006 and 2012 were enrolled. Clinical parameters including laboratory findings at diagnosis and during treatment with hypomethylating agents, treatment response and survivals were analyzed retrospectively. Hypocellular MDS was defined as bone marrow cellularity less than 30% in patients younger than 70 years, or less than 20% in patients older than 70 years. Clinical characteristics and treatment outcomes between hypocellular MDS and normo/hypercellular MDS were compared. Results: Patients with hypocellular MDS showed a lower white blood cell count (2.08 x 103/µL vs. 2.88 x 103/µL, p = 0.036) and a higher erythropoietin level (1353 mIU/mL vs. 110 mIU/mL, p = 0.005) than normo/hypercellular MDS. The age, gender, absolute neutrophil count, hemoglobin level, platelet count, number of cytopenia, IPSS cytogenetics and IPSS risk groups were not significantly different between the groups. The overall response rate (14% vs. 23%, P = 0.334) and hematologic improvement rate (20% vs. 36%, P = 0.196) were slightly lower in hypocellular MDS, but did not show any statistical significance. Overall survival, progression free survival, and leukemia free survival after the initiation of the hypomethylating agent in hypocellular MDS were not significantly different from those of normo/hypercellular MDS. Conclusions: Patient with hypocellular MDS treated with the hypomethylating agents showed comparable response rates and survival rates with those with normo/hypercellular MDS. The hypomethylating agents seem to be one of feasible treatment options in hypocellular MDS, as well as in normo/hypercellular MDS. Disclosure: All authors have declared no conflicts of interest.

Specific scoring systems to predict survival of patients with high-risk myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) after intensive antileukemic treatment based on results of the EORTC-GIMEMA AML-10 and intergroup CRIANT studies.

High-risk myelodysplastic syndrome (MDS) patients have usually a less favorable outcome after intensive treatment compared with de novo acute myeloid leukemia (AML) patients. This may reflect different disease-related and patient-related factors. The purpose of this analysis is to identify disease-specific prognostic factors and to develop prognostic scores for both patient groups. A total of 692 patients in the EORTC/GIMEMA AML-10 study and 289 patients in the CRIANT study received identical remission-induction and consolidation treatment. Estimated 5-year survival rate was 34% in the AML-10 versus 27% in the CRIANT study, and estimated disease-free survival was 40% versus 28%, respectively. In multivariate analysis, cytogenetic characteristics, white blood count, and age appeared prognostic for survival in both studies. French-American-British (FAB) subtype and performance status were prognostic in the AML-10 study only, whereas number of cytopenias and duration of antecedent hematologic disorder >6months were prognostic in the CRIANT study only. The prognostic scores distinguish three groups with a 5-year survival rate of 54, 38, and 19% in the AML-10 study versus 69, 37, and 5% in the CRIANT study. The prognostic value of these scores has been validated on two external series. The new scoring systems form a practical tool to predict the outcome of individual MDS and AML patients treated with intensive antileukemic therapy.

The Revised IPSS (IPSS-R) Predicts Response To Erythropoietic Stimulating agents (ESA) In Pts With Classical IPSS Low Or Intermediate-1 (int 1)- MDS: A Joint Retrospective Study Of The GFM, Düsseldorf Registry and Fism

▪ IntroductionThe “classical” IPSS, based on cytogenetics, marrow blast percentage, and number of cytopenias, has played a major role in prognosis assessment in MDS. The recently published revised IPSS (IPSS-R), refines the original IPSS prognostic value (Greenberg et al, Blood 2012). However, its prognostic value for response to ESA has not been assessed. We analyzed it retrospectively in 456 IPSS Low-/Int-1-risk MDS patients (pts) treated with ESA in France, Germany and Italy. ResultsThose 456 pts had serum EPO < 500mU/ml and Hb≤10g/dl, and had received ESA (EPO alfa or beta 40000-60000 IU/week, or darbepoietin 150 - 300µg/week) for at least 12 weeks. In addition to IPSS-R parameters, age, sex, serum EPO level, serum ferritin (SF), and RBC transfusion requirement before ESA onset were assessed for response to ESA (based on IWG 2006 criteria), and overall survival (OS) from ESA onset. Characteristics of the 456 pts at ESA onset are listed in Table 1. 71% of the pts had never received RBC transfusions, with a median Hb level of 9.3g/dl (range 7.0-10) , and 29% pts had received at least 4 RBC concentrates/8wks before ESA onset (with a maximum of 12). Median SF was 357ng/ml and serum EPO 60mU/ml (range 6-483). IPSS was low in 55% and intermediate-1 in 45% pts. IPSS-R was very low in 15%, low in 61%, intermediate in 19% and high in 4% of the pts.Table 1Baseline patient characteristics. * 109/L.Univariate and multivariate analyses for response (IWG 2006 criteria).n=456% of ptsErythroid response ( IWG 2006 criteria)Univariate analysis pMultivariate analysis pHb g/dl<85211%338-1029264%66=1011225%78<0.0001ANC<0.8429%55≥0.841491%660.16Platelet *<50173%3750-1005813%57>10038184%670.01Marrow blasts, %≤223852%72<2-<511826%615-1010022%530.0052IPSS-R karyotypevery good215%71good37983%65intermediate4510%75poor-very poor112%200.008IPSSlow25655%72Int-121045%520.001IPSS-Rvery low6915%85low28161%68intermediate8719%48high194%31<0.00010.008Sexmale25055%62female20645%680.14Age≤60296%55>6042794%660.23EPO, mU/ml≤20039386%75>2006313%31<0.0001<0.0001SF, ng/ml≤35022449%72>35023251%580.0010.01Previous RBC transfusionsno32371%73yes13329%550.00050.001WHORA11024%73RAEB-16915%50RARS11425%70RARS-T20.3%100RCMD12427%62MDS WITH DEL 5q215%62MDS-U164%550.030.71303 (61%) pts had an erythroid response (ER), including 72% and 52% of low and int-1 risk pts respectively (p=0.001). Using IPSS-R, 85%, 68%, 48% and 31% of pts had ER in the very low, low, intermediate and high risk group respectively (p<0.0001).Other prognostic factors of ER, in univariate analysis, included individual IPSS-R parameters analyzed according to IPSS-R thresholds (Hb level, platelet count, ANC, marrow blast %, cytogenetics) serum EPO level, SF (variables tested as continuous variables) and previous RBC-transfusions. In multivariate analysis, IPSS-R, serum EPO, and SF remained significantly associated with ER (p<0.0001, p=0.002 and p<0.0001 respectively).Applying 1 point to each of the following unfavorable variables of ER: serum EPO >200mU/ml (=1), SF >350 ng/ml (=1), IPSS-R (very low=0, low=1, intermediate=2 and high=3), yielded a score ranging from 0 to 4, with ER rates of 85%, 80%, 64%, 40% and 20% respectively. As expected, IPSS-R also had strong prognostic value for OS (not shown). ConclusionIn this patient cohort with overall favorable prognostic factors of response to ESA according to the Nordic score (ie serum EPO <500 mU/ml and no or limited transfusion dependence, Hellstrom-Lindberg et al BJH 2003), IPSS-R alone, and even better, a score >=3 (using IPSS-R, serum EPO and SF) proved useful to identify pts with low response to ESA, who also have worse OS and may require alternative treatments (Kelaidi et al, Leukemia 2013). Disclosures:No relevant conflicts of interest to declare.

P-168 Familial myelodysplastic syndrome/acute leukemia in adult setting – Experience from a single Brazilian center

Introduction: Myelodysplastic syndromes (MDS) are a group of heterogenous clonal stem cell disorders characterized by inefficient haematopoiesis with one or more cytopenias and increased risk of transformation to acute leukemia. Purpose: The current diagnosis includes peripheral blood morphology, bone marrow biopsy and cytogenetic exam. Clonal cytogenetic abnormalities are described in 40-60% of cases. In 1997, the established System of International Prognostic Score was based on the number of cytopenias on the peripheral blood, precentage bone marrow blasts and karyotype abnomalities. In this system are described a limited number of cytogenetic abnormalities and the importance of their forecast is underestimated. This score classify patients into four risk groups, allow overall survival and estimate the risk of progression to acute leukemia. Materials and Methods: In September 2012 the Revised International Prognostic Scoring System (R-IPSS) was developed in the framework of a project of the International Working Group for Prognosis in MDS (IWG-PM) peak. For scoring according to IPSS-R, it was taken into account: severity of cytopenias (Hb level, the number of platelets, the absolute number of neutrophils), the percentage of bone marrow blasts and cytogenetic exam. It was found that this system prognostic allows a better classification of patients with MDS into risk groups. We analyzed 25 patients diagnosed with MDS, according to theWHO classification 2001, with low risk and intermediate-1 during the period 2008-2012. These patients have been hospitalized in three centers of Hematology Departments from Romania. Results: The lot of patients was evaluated according to R-IPSS (2012) and it was found that the new system allows a better prognosis estimation and more accurate patient risk group classification. Conclusions: Although according to IPSS (1997), all patients included in this studywere low risk (0-1) but applying the new scoring system has allowed a better classification of patients, six of them were with intermediate and high risk (3,5-6).