WHO Prognostic Scoring Research Articles

MDS-420 Low Risk Myelodysplastic Syndromes in Morocco

Myelodysplastic syndromes (MDS) are a diverse group of clonal hematopoietic malignancies, characterized by ineffective hematopoiesis, progressive bone marrow failure, cytogenetic and molecular abnormalities, and variable risk of progression to acute myeloid leukemia (AML). Clinically, MDS patients often present with symptoms related to peripheral cytopenia (tiredness, pallor, infections, bruising, bleeding), although they may also be asymptomatic with abnormal blood counts found on routine evaluation. The most commonly used scores are the WHO Prognostic Scoring System (WPSS), International Prognostic Scoring System (IPSS), and more recently, the Revised International Prognostic Scoring System (RIPSS). In addition to the factors that make up these scores, other independent prognostic factors have been identified such as age, the Eastern Cooperative Oncology Group (ECOG) score, ferritin level, beta 2 microglobulin and lactic dehydrogenase (LDH). Our study includes all patients diagnosed with MDS between January 2004 and December 2018, over an age range of 5 months to 95 years, encompassing 272 patients. Data were collected from the patients' files. According to the prognostic score, we found 73 patients with a low risk, 165 patients with intermediate I risk; based on this score, 88% of the myelodysplasias in our series were of low risk. According to the IPSS-R, we found that 67 patients had a very low risk, 126 patients were at low risk, 36 patients were at intermediate risk. According to the IPSS and IPSS-R, low risk patients are children and adolescents, with a stable evolution. Abstinence from therapy was recommended as the treatment choice in 20% of patients with low-risk MDS. In our series, 74% of cases received symptomatic treatment including: 67% of cases were transfused with packed red blood cells, 22% were transfused with platelet units, 6% received iron chelators, 4% were treated with erythropoietin, 24% were treated with antibiotic therapy. Our results are consistent with published studies regarding the epidemiology, the clinic, and prognosis. Our study confirms the prognostic value of bone marrow karyotype and validates the WPSS IPSS and RIPSS scores in predicting overall survival of Moroccan patients with myelodysplastic syndromes.

The prognostic significance of pretransplantation evaluation of IPSS-R and WPSS in patients with myelodysplastic syndrome undergoing allogeneic hematopoietic stem cell transplantation

目的探究不同时间进行修订版国际预后积分系统（IPSS-R）及WHO预后积分系统（WPSS）评分对异基因造血干细胞移植（allo-HSCT）治疗骨髓增生异常综合征（MDS）患者的预后评估价值。方法回顾性分析2016年7月至2019年6月于苏州大学附属第一医院行allo-HSCT的184例MDS患者临床资料，在初诊及移植前两个时间点进行IPSS-R及WPSS评分，比较两者预后评估价值，分析影响移植预后的危险因素。结果中位随访21.9（0.5～47.5）个月，移植后2年总体生存（OS）、无进展生存（PFS）率分别为（75.1±3.4）％、（71.6±3.6）％，2年复发（RR）率和无复发死亡率（NRM）分别为（11.9±0.1）％、（16.5±0.1）％。初诊时IPSS-R≤3.5分与>3.5分组OS、PFS差异无统计学意义（P＝0.409；P＝0.724），WPSS≤2分与>2分组OS、PFS差异无统计学意义（P＝0.462；P＝0.726）。移植前除外10例患者转化为急性髓系白血病（AML），174例患者可进行IPSS-R及WPSS评估，其中IPSS-R≤3.5分组OS、PFS率显著优于>3.5分组［OS：（88.6±4.1）％对（65.8±5.3）％，P＝0.003；PFS：（87.6±4.2）％对（60.5±5.8）％，P＝0.002］，WPSS≤2分与>2分组间OS、PFS差异无统计学意义（P＝0.584；P＝0.565）。此外，移植前IPSS-R较初诊时相比改善组OS、PFS率显著优于未改善组［OS：（83.8±4.6）％对（69.3±5.8）％，P＝0.027；PFS：（82.8±4.4）％对（64.0±7.2）％，P＝0.006］，多因素分析发现移植前TP53突变（P＝0.047，HR＝2.460，95％ CI 1.014～5.971）和移植前IPSS-R>3.5分（P＝0.021，HR＝2.510，95％ CI 1.151～5.476）是影响OS的独立不良预后因素，移植前细胞遗传学差及极差（P＝0.008，HR＝2.765，95％ CI 1.305～5.856）和移植前IPSS-R>3.5分（P＝0.017，HR＝2.457，95％ CI 1.175～5.141）是影响PFS的独立不良预后因素。结论移植前进行IPSS-R评分对行allo-HSCT的MDS患者的预后评估有重要价值，移植前IPSS-R较初诊时改善的患者有着更好的预后。

BMT for Myelodysplastic Syndrome: When and Where and How.

Myelodysplastic syndromes (MDS) are a diverse group of hematological malignancies distinguished by a combination of dysplasia in the bone marrow, cytopenias and the risk of leukemic transformation. The hallmark of MDS is bone marrow failure which occurs due to selective growth of somatically mutated clonal hematopoietic stem cells. Multiple prognostic models have been developed to help predict survival and leukemic transformation, including the international prognostic scoring system (IPSS), revised international prognostic scoring system (IPSS-R), WHO prognostic scoring system (WPSS) and MD Anderson prognostic scoring system (MDAPSS). This risk stratification informs management as low risk (LR)-MDS treatment focuses on improving quality of life and cytopenias, while the treatment of high risk (HR)-MDS focuses on delaying disease progression and improving survival. While therapies such as erythropoiesis stimulating agents (ESAs), erythroid maturation agents (EMAs), immunomodulatory imide drugs (IMIDs), and hypomethylating agents (HMAs) may provide benefit, allogeneic blood or marrow transplant (alloBMT) is the only treatment that can offer cure for MDS. However, this therapy is marred, historically, by high rates of toxicity and transplant related mortality (TRM). Because of this, alloBMT is considered in a minority of MDS patients. With modern techniques, alloBMT has become a suitable option even for patients of advanced age or with significant comorbidities, many of whom who would not have been considered for transplant in prior years. Hence, a formal transplant evaluation to weigh the complex balance of patient and disease related factors and determine the potential benefit of transplant should be considered early in the disease course for most MDS patients. Once alloBMT is recommended, timing is a crucial consideration since delaying transplant can lead to disease progression and development of other comorbidities that may preclude transplant. Despite the success of alloBMT, relapse remains a major barrier to success and novel approaches are necessary to mitigate this risk and improve long term cure rates. This review describes various factors that should be considered when choosing patients with MDS who should pursue transplant, approaches and timing of transplant, and future directions of the field.

A Personalized Prediction Model to Risk Stratify Patients with Myelodysplastic Syndromes (MDS)

BackgroundPatients (pts) with myelodysplastic syndromes (MDS) have widely variable outcomes, ranging from months to more than a decade. Although several prognostic scoring systems have been developed to stratify MDS pts, survival significance varies even within discrete categories. This heterogeneity may contribute to over-treating or under-treating some pts classified within the same risk category.Here, we explore how incorporation of genomic-clinical data using machine learning algorithms can create a personalized (precision) prediction model that can outperform other commonly used models in MDS.MethodClinical and mutational data from MDS pts diagnosed according to 2008 WHO criteria were analyzed. The model was developed in a cohort from our institution and validated in a separate cohort from other MDS Clinical Research Consortium sites. Next generation targeted deep sequencing of 60 gene mutations commonly mutated in myeloid malignancies was included. pts who underwent hematopoietic cell transplant (HCT) were censored at the time of transplant. OS was measured from the time of diagnosis to death or last follow up. Leukemia-free survival was calculated from the time of diagnosis to time of acute myeloid leukemia (AML) progression or last follow up. A random survival forest (RSF) algorithm was used to build the model, in which clinical and molecular variables are randomly selected for inclusion in determining survival, thereby avoiding the shortcomings of traditional Cox step-wise regression in accounting for variable interactions. Survival prediction is thus specific to each pt's particular clinical and molecular characteristics. The accuracy of the proposed model compared to other models was assessed by concordance (c-) index.Results:Of the 975 pts included, 527 were in the training cohort and 448 in the validation cohort. In the training cohort, the median age was 67 years (range, 19-99), pts received a median of 2 lines of therapies (range, 0-7) and 15% underwent HCT. First line therapies included: supportive care (22%), growth factors (22%), azacitidine +/- combinations (30%), decitabine+/- combinations (6%), lenalidomide (5%), induction chemotherapy (3%), immunosuppressive therapy (3%), and other therapies/clinical trials (9%). A total of 105 pts (20%) progressed to AML. Risk stratification by IPSS: 148 (28%) low, 235 (45%) intermediate-1, 106 (20%) intermediate-2, 38 (7%) high and by IPSS-R: 78 (15%) very low, 200 (38%) low, 95 (18%) intermediate, 98 (19%) high, and 56 (10%) very high. Cytogenetic analysis by IPSS-R criteria: 15 (3%) very good, 331 (62%) good, 87 (17%) intermediate, 37 (7%) poor, and 57 (11%) very poor. The most commonly mutated genes were: SF3B1 (14%), ASXL1 (13%), TET2 (12%), SRSF2 (11%), DNMT3A (11%), STAG2 (9%), TP53 (8%), and RUNX1 (8%). All clinical variables and mutations present in >/= 5 pts were included in the RSF algorithm. Variable importance analysis (the most important variables that contributed to the outcome) and multiple backward elimination analysis (identifying the least number of variables that can provide the least error rate) identified the following variables (ranked from the most important to the least important) that impacted OS: cytogenetics categories by IPSS-R, bone marrow blasts %, 2008 WHO criteria, platelets, WBC, hemoglobin, TP53, RUNX1, ANC, STAG2, SRSF2, NPM1, secondary vs. de novo MDS, age, PHF6, IDH1, EZH2, and SF3B1 . The clinical and mutational variables can be entered into a web application that can run the trained model and provide OS and AML transformation estimates as an output, Figure 1.The C-index for the new model was 0.71 for OS and 0.76 for AML transformation. The new model outperformed all commonly used models for OS and AML transformation including IPSS (c-index 0.65, 0.72), IPSS-R (0.67, 0.73), WHO prognostic scoring system (WPSS) (0.65, 0.73) and MD Anderson prognostic model (MDAPSS) (0.65, 0.7), respectively. When applying the new model to the validation cohort, the c-index for OS and AML transformation were 0.7, 0.75, respectively.ConclusionA personalized (precision) prediction model based on clinical and genomic data outperforms all commonly used prognostic models to refine survival and AML transformation estimates that are unique for a given pt. The web application that can ease the translation of this model into the clinic is being developed. [Display omitted] DisclosuresKomrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria. Padron:Incyte: Honoraria, Research Funding. Steensma:Takeda: Consultancy; Pfizer: Consultancy; Onconova: Consultancy; Incyte: Equity Ownership; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; H3 Biosciences: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: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; Cellectis: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Outcomes in the management of high-risk gestational trophoblastic neoplasia in trophoblastic disease centers in South America

BackgroundSouth America has a higher incidence of gestational trophoblastic disease than North America or Europe, but whether this impacts chemotherapy outcomes is unclear. The purpose of this study was to...

Single or two drug combination therapy as initial treatment for low risk, gestational trophoblastic neoplasia. A Canadian analysis

IntroductionLow risk gestational trophoblastic neoplasia, WHO prognostic score of 0 to 6, is highly curable. There is no consensus on the optimal chemotherapy. Common regimens are q2wk actinomycin-D (ACT-D), weekly intramuscular methotrexate (MTX) or multi-day MTX. Combination MTX/ACT-D is rarely used. MethodsA four centre, retrospective cohort study was carried out comparing commonly used regimens: weekly MTX, q2weekly ACT-D and q2 weekly MTX and ACT-D. Results412 patients - 196 MTX/ACT-D, 107 MTX, 109 ACT-D - were treated between October 1994 and January 2019. Initial regimen failure (secondary to resistance or toxicity) occurred in 37% (MTX), 21% (ACT-D) and 5% (MTX/ACT-D). Relapse after completion of primary therapy (initial plus switch to another therapy if needed) was rare (0–5%). All eventually were cured. Mean number of cycles required to achieve remission were 10.1 (MTX), 7 (ACT-D) and 5.6 (MTX/ACT-D) with corresponding mean treatment durations of 3.12, 2.9 and 2.26 months. Dosage reductions occurred in 3% (MTX), 0% (ACT-D) and 29% (MTX/ACT-D). Higher failure rates occurred with WHO prognostic scores of 5 to 6 and HCG levels ≥10,000. SummaryInitial regimen failure ie the need to switch to an alternative treatment was more common with MTX. ACT-D and MTX/ACT-D were similar within prognostic score 0–4 or HCG < 10,000. ACT-D then appears the better initial choice with its superior convenience. Above these levels primary failure rates are less with MTX/ACT-D, making it a better choice.

Evaluation of different scoring systems and gene mutations for the prognosis of myelodysplastic syndrome (MDS) in Chinese population.

MDS is a heterogeneous disease with diverse clinical manifestations, and an effective prognostic evaluation tool for MDS patients is needed. To achieve more accurate prognosis assessment for Chinese MDS patients, here we examined several scoring systems and explored the implications of gene mutations. The prognostic conditions were stratified against three different score systems (International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS), and Revised International Prognostic Scoring System (IPSS-R)) were retrospectively applied to 110 de novo MDS patients in study cohort in our hospital and the prognostic conditions were stratified respectively. IPSS-R out-performed the others, since it had less overlaps in survival curve, especially in the relatively low-risk group. Furthermore, genetic mutations were identified in 84 out of 110 patients and their association with overall survival (OS) were determined. Among them, sixty-three percent patients had at least one-point mutation, including thirty-five patients with normal karyotypes. The presence of TP53 mutations, but not TET2, DNMT3A or ASXL1 mutations was significantly correlated with shorter OS. A new model incorporating IPSS-R and TP53 mutations into survival analysis was proposed, and the prognostic value of this model was validated to be predominant in a 190-primary MDS patient independent cohort. Our data suggested that IPSS-R was more suitable for Chinese population. Attentions should be paid to the unfavourable mutations that might exert impact on the survival, especially in patients with relatively low risk.

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.

Factors Predicting Early Mortality in Newly Diagnosed Myelodysplastic Syndrome (MDS): A Population Based Study

Myelodysplastic syndromes (MDS) are a heterogeneous collection of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis, dysplasia, and risk of progression to secondary acute myeloid leukemia (AML). Despite the development of numerous prognostic scoring systems (MDS Comorbidity Index (MDS-CI),International Prognostic Scoring System (IPSS) and IPSS-R, updated WHO classifications, and WHO prognostic scoring system (WPSS)), little prospective data regarding the influence of these and other factors on patient outcomes is available. To better elucidate the features of early mortality in MDS we compare characteristics of patients dying within one year of MDS diagnosis with those surviving longer in our Adults in Minnesota with MDS (AIMMS) population based case-control study.The AIMMS study is a statewide prospective population-based case-control study (R01 CA142714) conducted by the University of Minnesota (UMN), Mayo Clinic, and the Minnesota Department of Health. Adults (age 20-85 years) with a new diagnosis of MDS between April 2010 and October 2014 were recruited through the Minnesota Cancer Surveillance System. Patients completed a comprehensive questionnaire to capture retrospective epidemiologic data. All cases went through central medical review including pathology review by two independent hematopathologists, cytogenetic analyses, and oncologist medical record review with assignment of IPSS, IPSS-R, WPSS 1.2 noting past medical history, exposures, and treatment history and response. Annual clinical review of all patient cases for four years after initial enrollment is ongoing in a batched, non-real time manner.Three hundred and ninety-nine patients with a confirmed diagnosis of MDS based on central review and one year of clinical follow-up review were included in the analysis. For the entire group, we observed early mortality in those with abnormal cytogenetics, three or greater cytogenetic abnormalities, treatment at a community medical center only (versus academic), and with 2-3 concurrent medical comorbidities (Table 1). Treatment with hypomethylating agents also correlated with early mortality but when adjusted for WPSS and IPSS-R, this association was no longer significant.To investigate varied impact of disease and patient characteristics within different groups of MDS patients, we did multivariable regression analysis within the following categories: High/Very High Risk IPSS-R; Very low/Low/Intermediate Risk IPSS-R; Treated Patients; Supportive Care Only Patients. In patients with high or very high risk IPSS-R, the presence of 3 or more cytogenetic abnormalities was the only significant predictor early mortality in a multivariable adjusted model (OR: 3.66, 95% CI: 1.57-8.53). Similarly, in those with very low, low, or intermediate IPSS-R, abnormal cytogenetics was the only significant predictor of early mortality in an adjusted model (OR: 3.71, 95% CI 1.49-9.26).In patients receiving supportive care only, early mortality was seen in those who had diabetes (OR: 3.06, 95% CI 1.11-8.42), had complex cytogenetics (OR for ≥ 3 abnormalities: 4.94, 95% CI 1.25-19.46), and had very high or high IPSS-R (OR: 4.20, 95% CI 1.43-12.34). Likewise, complex cytogenetics remained the sole significant predictor of early mortality in treated patients (OR: 4.84, 95% CI 1.43-16.37).Complex cytogenetics and prognostic risk category (either by WPSS or IPSS-R) have previously been associated with higher risk disease and early mortality without intervention. Our data confirm this association in a large prospectively followed MDS cohort and highlight the significance of cytogenetic abnormalities and complexity regardless of IPSS-R risk categorization or treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Determination of Clinical Process and Response Rate to Treatment in Patients with Gestational Trophoblastic Neoplasia (GTN) with Low and High Risk and Evaluation of Their First Pregnancy Outcome

Background: The present study was conducted to determine the response to treatment in patients with GTN, the survival rate and to investigate the outcomes of first pregnancy after chemotherapy. Materials and Methods: The treatment protocol was based on the FIGO Staging of GTN and the Modified WHO Prognostic Scoring. Results: Complete remission was achieved with MTX in 100% of the low-risk patients and with combination therapy in 91% of the high-risk cases. Out of 27 low-risk patients, 21 had no metastasis 6 had lung metastasis, 18 preserved their fertility and conceived in the first year following the chemotherapy. Out of 3 patients who had developed invasive moles, 1 got pregnant after chemotherapy. Four of the patients with choriocarcinoma conceived in the first year following the chemotherapy. In the patient with placental site trophoblastic tumors, there was no pregnancy due to hysterectomy. Conclusion: GTN was found to be a chemosensitive condition, but more effective therapeutic protocols are therefore required.

Verification of Survival Predictors in Elderly Patients with Myelodysplastic Syndrome from Outpatient Clinical Practice

Summary Background Myelodysplastic syndrome (MDS) is a clonal disorder affecting older persons. We aimed to analyze the effectiveness of the scoring systems and of the number of received red blood cell (RBC) units in predicting survival. Methods The study included an unselected group of 73 patients with MDS who were diagnosed and treated in a single hospital over a period of 12 years. International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), WHO-Prognostic Scoring System (WPSS), Charlson Age-Comorbidity Index (CACI), and impact of performance status (PS) on overall survival (OS) and event free survival (EFS) were tested. The follow-up of received RBC units was conducted. Results The median age at diagnosis was 69.5 years, the median CACI was 3.0. The median survival times of the group were 7.04 and 2.78 years for OS and EFS, respectively. The concordance values of the IPSS, IPSS-R and WPSS are 0.812, 0.892 and 0.889 for OS; 0.785, 0.847 and 0.827 for EFS. The comorbidity index and PS were the only auxiliary criteria when determining the risk and selecting the therapeutic approach in MDS patients. In transfusion-dependent unchelated patients, both OS and EFS were negatively influenced by both higher ferritin levels and the numbers of RBC units; however, the risk does not continue to increase after more than 20 RBC units are administered. Conclusions IPSS-R is best suited as a predictor of survival. CACI and PS present auxiliary criteria for determining the risk. Number of received RBC units was detected as a significant predictor of survival.

WHO Prognostic Scoring Scale in Acute Bacterial Meningitis of Children: A Prospective Study

Background: Acute Bacterial Meningitis (ABM) is one of the most severe infectious diseases in childhood. The global burden of the disease is high. Various factors that determine the outcome of the diseases are age, early diagnosis, early treatment, duration of treatment and type of microorganism. This study aimed to describe clinical and bacteriological profile of ABM and to correlate the WHO prognostic scoring scale and outcome of children with ABM. Methods: A hospital based prospective study was carried out in Pediatric Medical Units of Mandalay Children’s Hospital during February 2009 to February 2010. Total of 62 children (3 months to 12 years) with confirmed ABM were included in the study. Results: Among 62 cases of ABM, most cases occur in three months to one year age group. The most common presenting features were fever, seizures, lethargy and altered consciousness. Meningeal irritation signs including neck stiffness, positive Kernig and Brudinzski signs were detected in 27.41% to 38.7%. Gram positive and gram negative organisms were detected in 15 cases by CSF gram stain and organisms were isolated in 4 cases by CSF culture. WHO prognostic scoring scale 9 and the patient expired.

Validation of the Revised International Prognostic Scoring System in 2582 Patients with Myelodysplastic Syndrome: A Multicenter Study By the Hellenic MDS Study Group

▪Introduction - Aims: Several prognostic scoring systems have been developed for patients with myelodysplastic syndromes (MDS), including the International Prognostic System (IPSS), the WHO Prognostic Scoring System (WPSS) and the Revised IPSS (IPSS-R). We evaluated the prognostic value of the IPSS-R on an independent group of 2,582 Greek patients with MDS, registered in the Hellenic National MDS Registry. The aim of this multicenter study was to validate the IPSS-R as a predictor for leukemia-free survival (LFS) and overall survival (OS), in newly-diagnosed MDS patients and to compare its prognostic significance with that of IPSS and WPSS. Moreover, to investigate the predictive value of IPSS-R in association with other recognized prognostic variables, such as patient's age, baseline serum lactate dehydrogenase (LDH), and ferritin concentrations, IPSS, WPSS, Eastern Cooperative Oncology Group (ECOG) performance status, transfusion dependency, and response to first-line treatment.Methods: Clinicopathological data from 2,582 MDS patients, diagnosed between 1/2000 - 1/2015 and registered in the Hellenic National MDS Registry were analyzed. Patients with MDS/MPN were excluded. Data included age, gender, date of diagnosis, clinical characteristics, WHO-2008 classification, laboratory parameters, transfusion dependency, bone marrow aspirate and biopsy morphology, cytogenetic findings, and type of treatment. LFS was calculated from the date of initial diagnosis of MDS until bone marrow blast increased to ≥20% [transformation to acute myeloid leukemia (AML), according to the WHO classification], or last contact. OS was defined as the time from MDS diagnosis to death, or last contact. Patients alive and not having developed AML until last follow-up were censored for OS and LFS, respectively. Kaplan-Meier survival analysis and Cox regression analysis were performed with regard to LFS and OS. Differences between Kaplan-Meier curves were evaluated using the Mantel-Cox (log-rank) test. All significant variables identified by univariate Cox regression analysis and clinical factors important for MDS were used to build the multivariate Cox regression models. Multivariate Cox regression analysis included only those patients for whom the status of all variables was known, and comprised age, serum LDH, and ferritin levels, transfusion dependency, response to first-line treatment, IPSS, WPSS, and IPSS-R. Confidence intervals (CI) were estimated at the 95% level; all tests were two-sided, accepting p<0.05 as indicative of a statistically significant difference. All statistical analyses were performed with the statistical software SPSS (version 21).Results: 1,623 male (62.9%) and 959 female MDS patients with a median age of 74 years at diagnosis were included in the current study. Complete follow-up information was available for 2,376 patients. The estimated median OS was 58 months (95% CI = 52.9 - 63.1 months). For 1,974 patients, data used in the calculation of all three scoring systems were complete, thus allowing risk score calculation and comparison of the three risk assessment systems. Median OS was significantly different in patient subgroups classified according to IPSS, WPSS, and IPSS-R, as shown by the Kaplan-Meier survival analysis (p<0.001). Fig. 1 shows Kaplan-Meier OS curves of MDS patients stratified according to IPSS-R (p<0.001). Moreover, the comparison of the prognostic value of the IPSS, WPSS, and IPSS-R revealed that the IPSS-R was significantly superior to both, WPSS and IPSS (p<0.001 in all cases). Multivariate Cox regression analysis demonstrated that the high prognostic value of IPSS-R, in terms of LFS and OS, was independent of patient’s age, serum LDH, and ferritin concentration, ECOG performance status, and transfusion dependency (p<0.001). Interestingly, besides IPSS-R, patient age and transfusion dependency retain their small - yet significant - prognostic impact in the multiparametric models, thus implying that these two parameters could add prognostic value to the IPSS-R.Conclusions: Our data support the notion that all three prognostic scores are very useful predictors for both, LFS and OS in MDS, yet IPSS-R is superior to IPSS and WPSS as a prognostic tool, with regard to OS. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical implications of the quantitative detection of ID4 gene methylation in myelodysplastic syndrome.

BackgroundMyelodysplastic syndrome (MDS) eventually transforms into acute leukemia (AL) in about 30% of patients. Hypermethylation of the inhibitor of DNA binding 4 (ID4) gene may play an important role in the initiation and development of MDS and AL. The aim of this study was to quantitatively assess ID4 gene methylation in MDS and to establish if it could be an effective method of evaluating MDS disease progression.MethodsWe examined 142 bone marrow samples from MDS patients, healthy donors and MDS-AL patients using bisulfite sequencing PCR and quantitative real-time methylation-specific PCR. The ID4 methylation rates and levels were assessed.ResultsID4 methylation occurred in 27 patients (27/100). ID4 gene methylation was more frequent and at higher levels in patients with advanced disease stages and in high-risk subgroups according to WHO (P < 0.001, P < 0.001, respectively) and International Prognostic Scoring System (IPSS) (P = 0.002, P = 0.007, respectively) classifications. ID4 methylation levels changed during disease progression. Both methylation rates and methylation levels were significantly different between healthy donor, MDS patients and patients with MDS-AL (P < 0.001, P < 0.001, respectively). Multivariate analysis indicated that the level of ID4 methylation was an independent factor influencing overall survival. Patients with MDS showed decreased survival time with increased ID4 methylation levels (P = 0.011, hazard ratio (HR) = 2.371). Patients with ID4 methylation had shorter survival time than those without ID4 methylation (P = 0.008).ConclusionsOur findings suggest that ID4 gene methylation might be a new biomarker for MDS monitoring and the detection of minimal residual disease.

In MDS Del(5q), Factors Other Than Age and Sex Distribution Contribute to the Prognostic Advantage, Which Diminishes over Time

IntroductionThe WHO classification of myelodysplastic syndromes defines several subtypes. Prognosis of MDS del(5q) is considered favourable, which is reflected in the WHO prognostic scoring system (WPSS). Compared to other subtypes like refractory cytopenia with unilineage dysplasia (RCUD), refractory cytopenia with multilineage dysplasia (RCMD) and refractory anaemia with ringed sideroblasts (RARS), MDS del(5q) patients are however younger and the percentage of female patients is higher.Thus, the aim of this work was to determine to which extent the prognostic advantage of MDS del(5q) over other MDS subtypes is due to the more favourable age and sex distribution in this group.Patients and MethodsBetween 1982 and 2013, 5383 patients were included in the Duesseldorf MDS registry. We identified 2011 patients who had no more than 5% blasts in the bone marrow and were classified either as RCUD, RCMD, RARS or MDS del(5q).Besides WHO type and blast count, sex, age at diagnosis as well as the classification into primary and secondary MDS were regarded. 99 patients were omitted from the analysis due to missing values. Thus, the final data set contained 1912 patients, of whom 1576 patients had received best supportive care only as well as 336 patients who had received one or more therapies during the observation period, the most frequent being lenalidomide.Kaplan-Meier curves and Cox proportional hazards models were estimated for mortality. Interaction effects between WHO type and sex were tested. Models were compared using the Akaike information criterion (AIC). Additionally “progression to AML” was analysed with the competing event “death without progression”.ResultsAccording to the WHO criteria, 125 (7%) were classified as MDS del(5q), 265 patients (14%) as RCUD, 206 (11%) as RARS and 1316 (69%) as RCMD. Median age was 68 years (range: 32-89) for MDS del(5q), 70 years (17-91, RCUD), 73 years (18-88, RARS) and 71 years (18-93, RCMD). In our sample 911 patients (48%) were women, but with considerable differences between the different WHO subtypes (MDS del(5q):67%, RCMD: 44%). The median observation time was 9.1 years (range: 0.01-31 years). During this period, 1312 deaths were observed, 194 patients progressed to AML.Median survival was 6.17 years (95%-CI: [5.07-8.09]) for MDS del(5q) patients, 5.20 years (95%-CI: [4.41-5.98]) for those with RARS, 4.48 years (95%-CI: [3.70-5.49]) for RCUD patients and 2.96 years (95%-CI: [2.64-3.22]) for those with RCMD. Survival curves gave strong hints of non-proportionality.Thus we had to incorporate a time-dependent effect for the WHO type in the multivariate cox model considering all covariates mentioned above, Best results were achieved with an effect of the type β1+β2*log(time). Among blasts and type of MDS (primary vs. secondary), age (hazard ratio (HR): 1.040, 95%-confidence interval (CI): [1.035-1.046]) and sex (HR: 0.856, 95%-CI: [0.766-0.956] for women vs. men) remained in the model as well. No interactions between age, sex and WHO type were found.According to this model, at diagnosis HRs were 1.812 (95%-CI: [1.199-2.740], RCUD vs MDS del(5q)), 1.167 (95%-CI: [0.742-1.837], RARS vs MDS del(5q)) and 2.284 (95%-CI: [1.550-3.366], RCMD vs MDS del(5q)). Interestingly this advantage of MDS del(5q) disappeared over time, the hazard ratio became 1 after about 3.5 years for RCUD, 7.2 years for RCMD.Regarding progression to AML no time-dependent coefficients were needed and we did not find any significant differences concerning the WHO subtypes. Age and sex did not seem to play a major role. The risk of progression to AML was mainly determined by the blast count and the type of MDS (primary vs. secondary).ConclusionsOur analyses indicate that the higher survival probabilities are not only due to the different age and sex distributions. However, we found strong hints that the survival advantage of MDS del(5q) is vanishing over time, especially in comparison to RCUD and RCMD. For the next revision of the WPSS it should be discussed to introduce a time-dependent component at least for the different WHO subtypes, since it seems likely that the hazard ratios are not constant over time. DisclosuresNo relevant conflicts of interest to declare.

Increased CD34+CD38 -CD123 + cells in myelodysplastic syndrome displaying malignant features similar to those in AML.

Leukocyte interleukin-3 receptor α (CD123) is regarded as a marker of leukemia stem cells. We previously found that CD123 was also highly expressed on CD34(+)CD38(-) cells in myelodysplastic syndrome (MDS) patients, but it is unclear whether the level and the characteristics of CD34(+)CD38(-)CD123(+) cells in MDS are similar to those in acute myeloid leukemia (AML). Based on previous research by our team, we further enlarged the specimens and found that the mean proportion and the mean MFI of CD34(+)CD38(-)CD123(+) cells in low-grade MDS were lower than that in AML, and those in high-grade MDS were similar to those in AML. CD34(+)CD38(-)CD123(+) cells expressed lower granulocyte stimulating factor receptor, CD11b, and apoptosis molecule (Annexin V), meanwhile, these cells showed upregulation of transcription factors (GATA-1, GATA-2) and transferrin receptor (CD71) in MDS and AML. Furthermore, an increase in CD34(+)CD38(-)CD123(+) cells was closely related to the number of cytopenias involving hematopoietic lineages, anemia, blast count in bone marrow smear, fluorescence in situ hybridization analysis and WHO prognostic scoring system score. Thus, increases in CD34(+)CD38(-)CD123(+) cells may reflect malignant clonal cells with aberrant differentiation, overproliferation, and decreased apoptosis in MDS, which were similar to AML. CD123 may thus be a promising indicator for identifying malignant clonal cells in MDS and a candidate for targeted therapy.

Combined overexpression of WT1 and BAALC genes May Predict AML evolution in MDS Patients

Background and aimsMyelodisplastic syndromes (MDS) are a group of hemopoietic disorder characterized by an impaired blood cell production, morphologic dysplasia and peripheral cytopenias; they are the most common hematologic neoplastic disorder and its diagnosis relays on morphologic evaluation, associated to a karyotypic assay.In order to predict the outcome of patients affected from these disorders, knowing that the order of survival can be extremely variable, several prognostic index were developed such as International Prognostic Score Sistem (IPSS) or the most usefull WHO-Prognostic Score Sistem (WPSS).On the contrary of acute leukemia, these disorders have not a biomolecular profile evalutation of intrinsic markers able to stratify patients in different prognostic risk groups.The aim of our study is to assess the risk of leukemic evolution, in MDS patients, on the basis of the levels expression of WT1 and BAALC at disease diagnosis, and to evaluate the leukemia free survival (LFS) at 6-12-24-36 months of follow up, among the different risk category according to IPSS and irrespectively of treatment. Materials and methodIn five years we analized 102 patients with a diagnosis of MDS divided according to the WHO classification such as follows: 38 AR, 1 AR with del(q5), 21 aREB-1, 23 AREB-2, 3 chronic myelomonocitic leukemia, 1 RARS, 1 MDS, 11 RCMD, 1 5q- syndrome, 2 suspected MDS.According to IPSS 58 belonged to the low risk category, 21 to the intermediate-1, 23 to the intermediate-2/high risk.Cytogenetic assay showed 20 people with an abnormal karyotype, 8 of them fallen into the high risk class and 12 into the intemediate risk.Low risk and intermediate-1 patients were treated only with supportive care; high risk patients were treated with hypomethylating agents. Iron chelation were used when necessary. Lenalidomide was used in the only case of 5 q- syndromeSamples of bone marrow were analized with Real-Time quantitave PCR and levels of WT1 and BAALC expression were determinated.Molecular datas were analized with X-square Test and a significant association was recorded between overexpression of the genes evaluated (WT1 higher than 100 copy numbers and BAALC higher than 1000 copy numbers) and the probability of develop acute myeloid leukemia ( AML ). ResultsNine out of 102 patients showed an isolated WT1 hyperexpression (3 of them developed an AML ), in 15 cases we reported an isolated BAALC overexpression (3 of them developed an AML ), while 13 out 18 patients ( 72% ) with combined WT1 and BAALC overexpression developed AML within an average time of 6 months; instead only 5% of patients, which expressed low levels of WT1 and BAALC, developed AML within the interval of observation.In particulary a combined high expression of WT1 and BAALC were strongly associated with an high risk to develop leukemia and a short LFS, especially in INT-1 subset.After that we calculated the LFS, divided for the risk category at 6-12-24-36 months of follow up.Patients with combined overexpression of WT1 and BAALC showed a LFS of 40% at 6 months of follow up and 0% at 24 months. ConclusionMDS have a great variable survival, and the current approach to these diseases relays on morphological evaluation, karyotypic assay and need of transfusional support; gene expression could be a promising system to predict the prognosis in these patients.Analysis of gene expression, which belong to AML evaluation, allows to divide patients in several risk groups; furthermore is not the single gene evaluation that is more predictable but a combined assay.With this method, which seems to be more realiable than IPSS, we could find that a great percentage of patients with levels of WT1>100 and BAALC >1000, indipendently from karyotypic status and treatment, developed AML and have a shorter LFS than the population with WT1 <100 and BAALC < 1000. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Validation of the revised International Prognostic Scoring System (IPSS-R) in patients with myelodysplastic syndrome: A multicenter study

The revised IPSS (IPSS-R) was developed aiming at a better prognostication, taking into account patients treated with best supportive care. We herein validated this model on the basis of data from 1314 patients who received BSC only as well as patients who underwent induction chemotherapy (n=214) or allogeneic transplantation (n=167). We could demonstrate a clear distinction of the IPSS-R risk categories with regard to survival and risk of AML evolution in all patient cohorts. When comparing IPSS-R, IPSS, WHO prognostic scoring system (WPSS) and Duesseldorf score, the best results regarding the ability to predict survival were obtained by the IPSS-R.

Revised International Prognostic Scoring System (IPSS) Predicts Survival and Leukemic Evolution of Myelodysplastic Syndromes Significantly Better Than IPSS and WHO Prognostic Scoring System: Validation by the Gruppo Romano Mielodisplasie Italian Regional Database

The definition of disease-specific prognostic scores plays a fundamental role in the treatment decision-making process in myelodysplastic syndrome (MDS), a group of myeloid disorders characterized by a heterogeneous clinical behavior. We applied the recently published Revised International Prognostic Scoring System (IPSS-R) to 380 patients with MDS, registered in an Italian regional database, recruiting patients from the city of Rome (Gruppo Romano Mielodisplasie). Patients were selected based on the availability of IPSS-R prognostic factors, including complete peripheral-blood and bone marrow counts, informative cytogenetics, and follow-up data. We validated the IPSS-R score as a significant predictor of overall survival (OS) and leukemia-free survival (LFS) in MDS (P < .001 for both). When comparing the prognostic value of the International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS), and IPSS-R, using the Cox regression model and the likelihood ratio test, a significantly higher predictive power for LFS and OS became evident for the IPSS-R, compared with the IPSS and WPSS (P < .001 for both). The multivariate analysis, including IPSS, WPSS, age, lactate dehydrogenase, ferritin concentration, Eastern Cooperative Oncology Group performance status, transfusion dependency, and type of therapy, confirmed the significant prognostic value of IPSS-R subgroups for LFS and OS. Treatment with lenalidomide and erythropoiesis-stimulating agents was shown to be an independent predictor of survival in the multivariate analysis. Our data confirm that the IPSS-R is an excellent prognostic tool in MDS in the era of disease-modifying treatments. The early recognition of patients at high risk of progression to aggressive disease may optimize treatment timing in MDS.

Magnetic Resonance Imaging (MRI) Detection of Iron Overload In Patients with Myelodysplastic Syndrome (MDS)

AbstractAbstract 4960 Introduction:Transfusion dependent anemia and iron overload are associated with reduced survival in patients with MDS. Increased iron absorption at the gastrointestinal tract may also contribute to iron overload. Serum ferritin is the most common method of assessing body iron content, but it can be elevated in patients with inflammatory conditions, and may not correlate with iron overload in specific organs such as the heart. T2* MRI is a non-invasive method for detecting iron overload in patients with transfusion-dependent anemia, and its efficacy has been validated in patients with thalassemia major. There are few studies reporting on the efficacy of T2* MRI for detection of iron overload in patients with MDS. Objective:To evaluate the efficacy of T2* MRI in detection of iron overload in patients with MDS, the prevalence of iron overload in this disease and correlate MRI findings with iron indexes (ferritin, transferrin and non-transferrin bound iron [NTBI]). Methods:Patients with MDS or chronic myelomonocytic leukemia (CMML), independent of transfusion requirements, were recruited into a prospective, single center trial to assess the efficacy of T2* MRI for detection of iron overload in this scenario. Patients receiving iron chelation therapy were excluded. Iron indexes were measured at the time of T2* MRI evaluation. Hepatic iron overload was considered in patients with a hepatic iron concentration (HIC) ≥ 2 g/mg. Cardiac iron overload was considered in patients with a T2* value < 20 milliseconds. Mann-Whitney and Fischer exact tests were used to compare baseline continuous and categorical variables among patients with and without iron overload as assessed by HIC. Correlation between HIC and iron indexes was assessed with Spearman correlation. Results:A total of 37 patients with MDS and one patient with CMML were recruited. Three patients were not evaluated by MRI due to claustrophoby, so 35 patients remain for the analysis. Median age was 68 years (range 18–84). MDS subtypes by the WHO classification include refractory anemia (N=3), refractory anemia with ring sideroblasts (N=5), 5q- syndrome (N=3), refractory cytopenias with multilineage dysplasia (N=13), refractory anemia with excess blasts-I (N=6) and –II (N=3) and unclassifiable MDS (N=1). Information about transfusion requirement was available for 28 patients, and 14 (50%) were transfusion dependent. Twenty-two patients could be classified by the WHO Prognostic Score System (WPSS) and were categorized as very low-risk (N=6), low-risk (N=3), intermediate risk (N=6) and high risk (N=7). Median ferritin, transferrin saturation and NTBI values were 1079.6 ng/mL (range 21.8–12738 ng/mL), 63% (range 6–100%) and 0.34 microM (range 0–12.93 microM), respectively. Median cardiac T2* value was 45.3 ms (range 19.7–70.1 ms), and only one patient had a T2* value indicative of cardiac iron overload. Median HIC value was 3.31 g/mg (range 0.2–9.97 g/mg), and 66% of patients had hepatic iron overload. Patients with hepatic iron overload had higher ferritin levels (1181 ng/mL vs. 131 ng/mL, p=0.007) and transferrin saturation (64% vs. 39%, p=0.02), but no differences in NTBI (0.29 microM vs. 0.22 microM, p=0.42). Patients with elevated HIC had a higher prevalence of transfusion dependency but the difference was not significant (50% vs. 33%, p=0.67). Ferritin levels and transferrin saturation correlated with HIC (r = 0.552, p=0.001 [ferritin]; r = 0.609, p=0.001 [transferrin saturation]). Conclusion:T2* MRI can detect iron overload in patients with MDS. Iron overload in MDS cannot be solely explained by transfusion dependent anemia. The study is currently ongoing and updated results will be presented at the meeting. Disclosures:No relevant conflicts of interest to declare.