scholarly journals WT1 mRNA Expression in the Peripheral Blood of Patients with MDS Yields Additional Prognostic Information within the IPSS-R Risk Categories "Very Low", "Low" and "Intermediate"

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1827-1827
Author(s):  
Christina Rautenberg ◽  
Sabrina Pechtel ◽  
Norbert Gattermann ◽  
Rainer Haas ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Peripheral Blood ◽  
Research Funding ◽  
Risk Groups ◽  
Prognostic Information ◽  
Expression Status ◽  
Very High ◽  
Risk Categories ◽  
Who 2008

Abstract Introduction: The revised version of the International Prognostic Scoring System, (IPSS-R), is an accepted standard for assessing the prognosis of patients with MDS. Its usefulness may be further improved by integrating molecular findings. However, such efforts are impeded by limited access to molecular diagnostics, lack of standardized methodology, and a relatively low frequency of individual gene mutations in MDS. The Wilms' Tumor-1 (WT1) gene is overexpressed on mRNA level in the peripheral blood (PB) in about 50% of patients with MDS. The aim of this analysis was to determine whether PB WT1 expression status yields additional prognostic information. Methods: For this purpose, PB WT1 mRNA expression was measured in 91 newly diagnosed patients with MDS (WHO: MDS del5q, n=7; RARS, n=1; RCUD, n=4; RCMD, n=37; RAEB-I, n=16; RAEB-II, n=23; MDS/MPN unclassifiable, n=3 / IPSS-R: very low risk, n=3; low risk, n=28; intermediate risk, n=27; high risk, n=13; very high risk, n=20), using the Ipsogen® WT1 ProfileQuant® Kit. This standardized, commercially available assay uses a validated cut-off level of 50 WT1 copies/104ABL copies for discrimination between normal and overexpression of WT1 in PB. MDS patients in our study cohort were stratified accordingly (normal WT1 expression with <50 WT1 copies versus overexpression with >50 WT1 copies). WT1 expression status was correlated with clinical parameters and outcome. Results: Overall, 53 MDS patients (58%) showed WT1 overexpression, which correlated significantly with WHO 2008 disease category and IPSS-R risk groups, as indicated by both the absolute WT1 levels (correlation with WHO 2008 type, p=0.0028, and IPSS-R, p=0.0075) and the frequency of WT1-overexpressing patients within the respective MDS subgroup (correlation with WHO 2008 type, p=0.0029, and IPSS-R, p=0.0027). Regarding the entire cohort, patients with elevated WT1 expression had a significantly lower progression-free survival (PFS) and overall survival (OS) compared to those with normal WT1 expression (p<0.0001 and p=0.0306). Furthermore, within the IPSS-R risk groups 'very low', 'low' and 'intermediate', PFS differed significantly between patients showing normal vs. elevated WT1 expression status (IPSS-R very low/low: median PFS 30.1 months vs. not reached, for WT1 high vs normal, respectively, p=0.0127; IPSS-R intermediate: median PFS 14.4 months vs. 59.5 months, for WT1 high vs. normal, respectively p=0.0240). These differences in PFS retained their prognostic significance in multivariate analysis after adjusting for IPSS-R (HR 0.306; 95% CI 0,156-0,598, p=0.001). However, they did not translate into a difference in overall survival, which was probably due to a relevant number of patients proceeding to allogeneic stem cell transplantation. Given the large proportion of patients displaying WT1 overexpression in the IPSS-R high and very high risk groups, it was not surprising that no significant prognostic subdivision by WT1 expression level was seen in these risk categories. Conclusion: Our results show that PB WT1 expression offers additional prognostic information in patients belonging to the IPSS-R risk groups 'very low', 'low' and 'intermediate'. Assessment of WT1 expression status at diagnosis is a relatively time and cost efficient method that can be performed without patient discomfort and may help to identify MDS IPSS-R low and intermediate patients at risk for early progression. Disclosures Rautenberg: Celgene: Honoraria. Germing:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kobbe:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Schroeder:Celgene: Consultancy, Honoraria, Research Funding.

The Disease Risk Index Is a Robust Tool for Allogeneic Hematopoietic Stem Cell Transplantation Risk Stratification: An Independent Validation Study on a Large Cohort of the European Society for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 988-988 ◽  
Author(s):  
Roni Shouval ◽  
Joshua Fein ◽  
Myriam Labopin ◽  
Nicolaus Kroger ◽  
Rafael F. Duarte ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Hematological Malignancies ◽  
Disease Risk ◽  
Risk Index ◽  
Risk Groups ◽  
Advisory Committees ◽  
Very High

Abstract Background: Allogeneic stem cell transplantation is a potentially curative procedure to a long list of hematological malignancies, but involves substantial risk of morbidity and mortality. Means for accurately predicting outcome and assessing risk are thus greatly needed. The Disease Risk Index (DRI) is a prognostic tool developed and validated by Armand et al. across a wide range of hematological malignancies (Blood 2012, Blood 2014) on cohorts of American patients. The Index stratifies patients into 4 distinct risk groups (low, intermediate, high, very high) and has yet to be validated in an international cohort. We sought to evaluate the validity of the DRI in a large cohort of European patients. Methods: This was a retrospective validation study on an independent cohort of patients undergoing allogeneic HSCT and reported the European Society for Blood and Marrow Transplantation (EBMT). Patients included had a hematological malignancy and underwent allogeneic transplantation between the years of 2000 and 2015. Risk groups were coded in accordance with the refined DRI (Blood, 2014). Outcomes were evaluated 4 years after the allogeneic HSCT. Overall survival (OS) was calculated with the Kaplan-Meier method. The log-rank test was used for comparisons of Kaplan-Meier curves. Cumulative incidence curves for nonrelapse mortality (NRM) and relapse with or without death were constructed reflecting time to relapse and time to NRM, respectively, as competing risks. The difference between cumulative incidence curves in the presence of a competing risk was tested with the Gray method. The prognostic effect of the DRI strata was estimated using a Cox proportional hazard model for OS and a Fine and Gray model for NRM and relapse. Results: A total of 89,061 patients from 423 transplantation centers were included in the analysis. Median age was 48.3 (IQR 36.2-57.5). The most frequent indication for transplantation was AML (39,530 patients) followed by ALL (16,206) and MDS (9,750); other indications spanned the spectrum of hematological malignancies. The majority of patients were in 1st or 2nd complete remission (54%). The median follow-up period was 3.6 years. Approximately 63% of patients were classified as intermediate risk by DRI, suggesting that this group could be further partitioned. The 4 year overall survival (95% CI) of the low, intermediate, high, and very high risk groups was 60.8% (59.9-61.8), 51.3% (50.8‐51.8), 27.0% (26.1‐27.8), 18.4% (17.1-19.8) (Figure 1). The same groups corresponded with increasing cumulative incidence of relapse; 8.9% (8.3-9.4), 19.3% (18.9-19.7), 39.0% (37.8-39.6), 45.1% (43.4-46.7), respectively. The DRI groups also showed increasing hazard between strata in the overall survival setting; intermediate risk was associated with a hazard ratio of 1.32, high risk 2.67 and very high risk 3.71 relative to low risk. Relapse showed a similar pattern. NRM was less strongly stratified by DRI (Table 1). The DRI groups maintained a similar risk, regardless of whether the transplantation was performed prior or after 2008. DRI was the strongest determinant of overall survival and relapse when introduced to a multivariable model with additional covariates. AUC for the index at 4 years was 62.5 for OS, 58.5 for NRM and 68.2 for relapse. Conclusions: We have validated the Disease Risk Index in a massive European data set. The groupings suggested by the DRI corresponded with distinct risk groups for overall mortality and relapse. Overall, our results indicate the international applicability of this robust prognostic tool. Figure 1. Kaplan-Meyer survival curves for overall survival, stratified by DRI Figure 1. Kaplan-Meyer survival curves for overall survival, stratified by DRI Table 1 Table 1. Disclosures Bader: Medac: Consultancy, Research Funding; Riemser: Research Funding; Neovii Biotech: Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Bonini:Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Dreger:Gilead: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Consultancy; Roche: Consultancy. Kuball:Gadeta B.V,: Membership on an entity's Board of Directors or advisory committees. Montoto:Roche: Honoraria; Gilead: Research Funding.

scholarly journals Prognosis Score System to Predict Survival for COVID-19 Cases: a Korean Nationwide Cohort Study (Preprint)

2020 ◽  
Author(s):  
Sung-Yeon Cho ◽  
Sung-Soo Park ◽  
Min-Kyu Song ◽  
Young Yi Bae ◽  
Dong-Gun Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Rate ◽  
High Risk ◽  
Hospital Stay ◽  
Risk Score ◽  
Validation Cohort ◽  
Length Of Hospital Stay ◽  
Risk Groups ◽  
Prognosis Score ◽  
Very High

BACKGROUND As the COVID-19 pandemic continues, an initial risk-adapted allocation is crucial for managing medical resources and providing intensive care. OBJECTIVE In this study, we aimed to identify factors that predict the overall survival rate for COVID-19 cases and develop a COVID-19 prognosis score (COPS) system based on these factors. In addition, disease severity and the length of hospital stay for patients with COVID-19 were analyzed. METHODS We retrospectively analyzed a nationwide cohort of laboratory-confirmed COVID-19 cases between January and April 2020 in Korea. The cohort was split randomly into a development cohort and a validation cohort with a 2:1 ratio. In the development cohort (n=3729), we tried to identify factors associated with overall survival and develop a scoring system to predict the overall survival rate by using parameters identified by the Cox proportional hazard regression model with bootstrapping methods. In the validation cohort (n=1865), we evaluated the prediction accuracy using the area under the receiver operating characteristic curve. The score of each variable in the COPS system was rounded off following the log-scaled conversion of the adjusted hazard ratio. RESULTS Among the 5594 patients included in this analysis, 234 (4.2%) died after receiving a COVID-19 diagnosis. In the development cohort, six parameters were significantly related to poor overall survival: older age, dementia, chronic renal failure, dyspnea, mental disturbance, and absolute lymphocyte count &lt;1000/mm<sup>3</sup>. The following risk groups were formed: low-risk (score 0-2), intermediate-risk (score 3), high-risk (score 4), and very high-risk (score 5-7) groups. The COPS system yielded an area under the curve value of 0.918 for predicting the 14-day survival rate and 0.896 for predicting the 28-day survival rate in the validation cohort. Using the COPS system, 28-day survival rates were discriminatively estimated at 99.8%, 95.4%, 82.3%, and 55.1% in the low-risk, intermediate-risk, high-risk, and very high-risk groups, respectively, of the total cohort (<i>P</i>&lt;.001). The length of hospital stay and disease severity were directly associated with overall survival (<i>P</i>&lt;.001), and the hospital stay duration was significantly longer among survivors (mean 26.1, SD 10.7 days) than among nonsurvivors (mean 15.6, SD 13.3 days). CONCLUSIONS The newly developed predictive COPS system may assist in making risk-adapted decisions for the allocation of medical resources, including intensive care, during the COVID-19 pandemic.

scholarly journals Overall Survival and Subgroup Analysis from a Randomized Phase III Study of Intravenous Rigosertib Versus Best Supportive Care (BSC) in Patients (pts) with Higher-Risk Myelodysplastic Syndrome (HR-MDS) after Failure of Hypomethylating Agents (HMAs)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 163-163 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Pierre Fenaux ◽  
Aref Al-Kali ◽  
Maria R. Baer ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Phase Iii ◽  
Controlled Study ◽  
Advisory Committees ◽  
Phase Iii Study ◽  
Very High

Abstract Background: No approved treatment options are available to HR-MDS pts after HMA therapy. Study 04-21 (“ONTIME” trial) was a Phase III, randomized, controlled study of the efficacy and safety of rigosertib, a novel small molecule inhibitor of PI3-kinase and PLK pathways, in a heterogeneous population of MDS pts who had relapsed after, failed to respond to, or progressed during administration of HMAs. The study was conducted at 87 sites in the United States and 5 European countries. Methods:From Dec 2010 to Aug 2013, 299 HR-MDS pts [<30% bone marrow blasts (BMBL)] who had progressed on (37% of total enrollment), failed to respond to (25%), or relapsed after (38%) HMA treatment were stratified on BMBL count and randomized 2:1 to receive rigosertib (199 pts) or BSC (100 pts). Rigosertib was administered at 1800 mg/24 hr for 72-hr as a continuous intravenous (CIV) ambulatory infusion, every 2 weeks for the first 16 weeks, and then every 4 weeks. The primary endpoint was overall survival (OS), analyzed on an intention-to-treat (ITT) basis using the Kaplan-Meier method stratified on BMBL (5% to 19% vs. 20% to 30%). The trial had a 95% power to detect a 13-wk increase in median OS from 17 wks on BSC, with a 2-sided alpha = 0.05. The following results are based on 242 deaths: 161 in the rigosertib arm and 81 in the BSC arm. Results : Overall, the 2 arms were balanced in terms of baseline characteristics, with the majority of pts being male (66%), and White (82%). Age ranged from 50-90 yrs in the rigosertib arm and 55-86 years in the BSC arm (median, 74 yrs). The majority of pts (85%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. The median duration of the last HMA therapy was 8.8 months (mo) in the rigosertib arm and 10.3 mo in the BSC arm; 127 (64%) of rigosertib pts and 57% of BSC pts were classified as “primary HMA failure” (ie, they failed to respond to or progressed during HMA therapy, as defined by Prebet et al, J Clin Oncol, 2011). A 2.3-mo improvement in median OS was found in the overall (ITT) population (8.2 mo rigosertib vs. 5.9 mo BSC) (Figure 1). The ITT survival for rigosertib was similar to that noted in Phase I/II studies (35 weeks). The stratified log-rank p-value was 0.33. The stratified hazard ratio was 0.87, which was quite different from the ratio of medians (5.9/8.2 = 0.72), due to the fact that the 2 survival curves converged at 15 mo. Notably, among the 184 patients with primary HMA failure, the median OS was 8.6 mo in the rigosertib arm (N = 127) vs. 5.3 mo in the BSC arm (N = 57), HR= 0.69, p= 0.040 (Figure 2). Multivariate Cox regression, adjusting for pretreatment prognostic factors, showed little change in the treatment effect. The following subgroups were correlated with better OS: pts with failure of/progression on HMA treatment, pts with duration of HMA treatment ≤ 9 mo, pts < 75 years of age, and pts with very high risk per IPSS-R (Figure 3). Rigosertib was well tolerated, with a median dose intensity of 92%. There were no significant compliance or operations issues related to ambulatory continuous infusion. Protocol-defined dose reductions were reported in 5% of pts, with 24% experiencing dose delays of >7 days, mostly due to unrelated adverse events (AEs). No obvious differences between rigosertib and BSC were found in the incidence of AEs (rigosertib, 99%; BSC, 85%) or of ≥ Grade 3 AEs (rigosertib, 79%; BSC, 68%). In the rigosertib arm, AEs reported by ≥ 20% of pts, irrespective of severity or causality, were nausea (35%), diarrhea (33%), constipation (31%), fatigue (30%), fever (27%), anemia (22%), and peripheral edema (21%). Rigosertib had low myelotoxicity, consistent with previous clinical experience. Conclusions:Although the primary endpoint in this Phase III study of rigosertib vs BSC in pts with HR-MDS did not reach statistical significance in the ITT population, encouraging rigosertib treatment-related improvement in OS was noted in several subgroups of MDS pts, including those with “primary HMA failure and in patients in the IPSS-R Very High Risk category. CIV therapy with rigosertib had a favorable safety profile in this orphan population of elderly pts with MDS. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Roboz:Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Wilhelm:Onconova Therapeutics, Inc: Employment. Azarnia:Onconova Therapeutics, Inc: Employment. Maniar:Onconova Therapeutics, Inc: Employment.

scholarly journals Treatment Outcome of Patients with Myelodysplastic Syndromes (MDS) in Regular Care: Incidence of IPSS Risk Groups and Different Therapies in the German Outpatient MDS Registry

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5601-5601 ◽  
Author(s):  
H. Tilman Steinmetz ◽  
Isolde Böttger ◽  
Bernd Lathan ◽  
Annette Sauer ◽  
Enno Moorahrend ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Research Funding ◽  
Risk Groups ◽  
Outpatient Setting ◽  
Observation Time ◽  
Epigenetic Therapy ◽  
International Prognostic Scoring System ◽  
Course Of Disease ◽  
Regular Care

Abstract The international prognostic scoring system (IPSS) for MDS patients (pts) receiving supportive care predicts a median overall survival of 68.4 months (mo), 42 mo, 14.4 mo and 4.8 mo according to the subgroups low, Int-1, Int-2, and high-risk, respectively. In July 2009, we established the German outpatient MDS registry with the aim to describe diagnostic procedures, treatment and course of disease of MDS pts in the community outpatient setting. In this analysis we evaluate the incidence of the IPSS subgroups, the frequencies of different therapies and the outcome, respectively. Methods: Newly diagnosed pts with MDS confirmed by bone marrow biopsy who gave informed consent were registered in an online database (IoStudy®). Baseline characteristics and diagnostics as well as a quarterly update of the course of disease were documented. Results: From July 2009 to March 2014 (56 mo) 1368 pts from 78 institutions were registered. Mean age was 73.5 years (y) (min-max 26.5 - 94.3 y, median 74.5 y) and 41% were women. 1,262 pts (92.3%) were evaluable for follow-up with a mean observation time (OT) of 21.7 mo (median: 19 mo). At diagnosis, IPSS risk classification was available in 898/1,262 (71%) pts. OT, overall survival (OS), number of pts (N) with epigenetic and iron-chelation therapy (ICT) over the entire term and the need of transfusions (tx) per quarter (Q) are given according to risk groups and treatment in the table. The figure shows the estimated Kaplan-Meyer-Plot for the IPSS risk groups. 180/1,315 pts (13.7%) received ICT, whereas 1,035 did not (86.3%). Median OS was 51 (95% confidential interval (CI) 44.7-57.3) and 49 mo (95% CI 43.7-54.3) (p = 0,281) for those with and without ICT, respectively. Conclusion: In the community outpatient setting in Germany, epigenetic therapy is used in a relative high proportion of pts with int-2 risk (57.1%) and high risk MDS (63.5%) at diagnosis, as well as in a substantial minority of patients with low-risk (6.7%) and int-1 risk (28.9%) MDS at progression. In the higher risk groups, transfusion need decreased more than 10% over time and overall survival was substantially longer than predicted by the IPSS. This may be considered as an empirical evidence for the efficacy of the new therapeutic options in regular care. Supported by Celgene, Munich, and Novartis, Erlangen, Germany Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Steinmetz: Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Severin:Novartis: Research Funding; Celgene: Research Funding. Germing:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Schmitz:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Gattermann:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

scholarly journals Outcome of Patients Younger Than 50 Years Old Diagnosed with Myelodysplastic Syndromes (MDS): Single Institution Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5541-5541
Author(s):  
Aref Al-Kali ◽  
Rong He ◽  
Mrinal M Patnaik ◽  
David S Viswanatha ◽  
Patricia T. Greipp ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Older Patients ◽  
Research Funding ◽  
Multivariate Analyses ◽  
Statistical Significance ◽  
Young Patients ◽  
Risk Groups ◽  
World Health ◽  
Very High

Abstract Background: Myelodysplastic syndromes (MDS) are rare hematological neoplasms that are more typically seen in elderly patients. Young patients (< 50 years old) have been reported to comprise between 3-6% in the Surveillance, Epidemiology and End Results (SEER) (Ma X et al, Cancer 2007; Rollison R et al, Blood 2008) with a better overall survival (OS). We hereby report the characteristics of young MDS patients with long survival follow-up. Methods: A total of 1012 MDS patients' data from Oct 1993 to Dec 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our institution. Patients youngers than 50 years old (yMDS) were included as cohort 1, while the rest was included as control group (cohort 2). Prognostic factors were analyzed by univariate and multivariate analyses. Survival estimates were calculated using Kaplan-Meier curves and univariate and multivariate analyses was based on log-rank testing using JMP software version 10. Results: Characteristics: We identified 68 (7%) yMDS patients with a median age of 42 years (range, 18-49). Female gender was more common in yMDS (43% vs 31%, p= 0.05). Upon comparison between cohort 1 and 2, only platelets were significantly lower in yMDS (61 vs 102, p <0.0001), but not white blood cells, hemoglobin or degree of marrow fibrosis. MDS subtyping according to World Health Organization 2016 showed single lineage dysplasia in 15% vs 2%, multilineage dysplasia 24% vs 36% , ring sideroblasts 9% vs 15%, isolated del (5q) 1% vs 3%, excess blasts 44% vs 31%, and unclassifiable in 6% vs 5%. As expected, therapy related MDS (t-MDS) was more frequent in yMDS (33% vs 17%, p= 0.005). Transformation to acute myeloid leukemia (AML) was also more frequent in yMDS (28 % vs 11%, p= 0.0004). Compared to cohort 2, yMDS IPSS-R scores were very high, high, intermediate, low, and very low in 24% vs 13%, 29% vs 16%, 21% vs 20%, 19% vs 35%, and 7% vs 17%, respectively. Allogenic hematopoietic cell transplantation (HCT) was more frequent in yMDS (42% vs 4%, p< 0.0001). Survival outcome: Median OS was longer for cohort 1 vs cohort 2 but did not reach statistical significance (43 vs 21 months, p= 0.1). Median progression free survival (PFS) was shorter for cohort 1 vs cohort 2 but did not reach statistical significance (8 vs 12 months, p= 0.3). Median OS for cohort 1 based on R-IPSS was 44, 105, 40, 18, and 12 months for very low, low, intermediate, high and high risk groups, respectively (p= 0.09). Median OS was shorter in t-MDS vs de novo MDS in cohort 1 (13 vs 47 months, p = 0.04). Young patients who had transformed to AML had a worse median OS (18 vs 93 months, p=0.001). On multivariate analysis neither t-MDS nor R-IPSS had a statistically significant impact on OS. Conclusions: MDS is rarely diagnosed under the age of 50. IPSS-R was less powerful in detecting differences between its risk groups for this patient population, although more than half of the patients with yMDS had either high or very high risk. Among this cohort of yMDS patients, there was a significantly higher proportion with therapy-related myeloid neoplasms compared to older patients (one third of patients), with subsequent higher rates of transformation to AML and higher allogeneic HCT. In our study, we did not find an improved OS for yMDS patients compared to older patients. Disclosures Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

Proposal of A Prognostic Score for Previously Untreated Patients with Chronic Lymphocytic Leukemia Based on An Overall Survival Analysis of Three German CLL Study Group Phase III Trials

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2831-2831
Author(s):  
Jasmin Bahlo ◽  
Natali Pflug ◽  
Thomas Elter ◽  
Kathrin Bauer ◽  
Barbara Eichhorst ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Risk Score ◽  
Research Funding ◽  
Prognostic Score ◽  
Phase Iii ◽  
Mutational Status ◽  
Phase Iii Trials ◽  
Binet Stage ◽  
Very High

Abstract Abstract 2831 Introduction Prognosis and need of treatment in CLL is currently determined by clinical staging systems of Binet and Rai. Recent research has focused on prognostic factors that may predict a poor prognosis independent of the clinical stage. Markers which have shown independent prognostic information are serum parameters and genetic factors (genomic aberrations, IgHV and p53 mutational status). To investigate the relevance of these different factors, we performed a pooled analysis using the data of three multicenter German CLL Study Group phase III trials (CLL1, CLL4 and CLL8). Based on this analysis we propose a prognostic score for previously untreated patients with early and advanced CLL. Material and Methods Patients were recruited between 1997 and 2006 into three phase III trials: 715 in CLL1 (“watch and wait” versus fludarabine (F)), 362 in CLL4 (F versus F and cyclophosphamide (FC)) and 817 patients in the CLL8 trial (FC versus FC and rituximab (FCR)). Serum parameters and genetic factors were centrally analyzed prior to treatment. The main end point of all statistical analyses was overall survival. First, univariate analyses were performed including variables of different groups such as baseline characteristics, stage of disease, laboratory results, molecular cytogenetics, mutational status and serum parameters. Next, multivariate Cox regressions were applied including all parameters that showed a significant association with overall survival in univariate analyses. To create a prognostic score we developed a weighted grading algorithm for independent factors based on ranges of hazard ratios. Finally, a prognostic score was defined as the sum of single ratings of adverse factors. According to this score, four different risk groups for overall survival could be identified. Results In total 1948 patients were eligible for the pooled analysis with a median age of 60 years (range, 30 to 81 years). After a median observation time of 63.4 months 485 deaths were reported. At study entry, 799 patients (42.4%) were at Binet stage A, 717 (38.0%) at Binet stage B and 370 (19.6%) at Binet stage C. Almost all considered variables were significantly associated with outcome and therefore included in the multivariate analysis. Based on the data of 1223 patients for whom all parameters were available, multivariate Cox regressions were performed and identified gender, age, ECOG score, del(17p), del(11q), IgHV mutational status, serum β2-microglobulin and serum thymidine kinase as independent factors for overall survival. Deletion 17p was the strongest adverse factor. Neither the clinical staging (Rai, Binet) nor the treatment modality were independent prognostic factors for overall survival. Similarly, the time interval between first diagnosis and study entry was not an independent prognostic factor. Due to the great differences between hazard ratios of independent factors, we developed a weighted grading system based on a simple algorithm to assign an individual grade to each adverse factor. By using this weighted grading, four different prognostic groups could be separated: low risk (score 0 – 2), intermediate risk (score 3 – 5), high risk (score 6 – 10) and very high risk (score 11 – 14) (figure 1). Overall survival rates were significantly different for these four groups with 95.2%, 86.9%, 67.7% and 18.7% survival after 5 years for the low, intermediate, high and very high risk group, respectively (p<0.0001). Moreover, within the group of patients showing a deletion 17p the score could distinguish patients of a high risk and a very high risk group (p<0.0001). Finally, the score could predict the individual risk for short overall survival independent of and within the different Binet or Rai stages (p<0.0001) (figure 2). Conclusion While Binet and Rai staging systems may remain important for the initial clinical assessment due to their simplicity, our prognostic score using a weighted combination of genetic and serum markers is superior to predict the overall survival of CLL patients. Disclosures: Pflug: Hoffmann-la Roche: Travel grant; Mundipharma: Travel grant. Eichhorst:Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Bergmann:Celgene: Honoraria. Döhner:Hoffmann-la Roche: Research Funding. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fischer:Hoffmann La Roche: Travel Grants. Hallek:Hoffmann-la Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

The Combination of SKY92 and ISS Provides a Powerful Tool to Identify Both High Risk and Low Risk Multiple Myeloma Cases, Validation in Two Independent Cohorts

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2970-2970 ◽  
Author(s):  
Martin van Vliet ◽  
Joske Ubels ◽  
Leonie de Best ◽  
Erik van Beers ◽  
Pieter Sonneveld
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Research Funding ◽  
Prognostic Markers ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Low Risk ◽  
Kaplan Meier ◽  
Standard Risk

Abstract Introduction Multiple Myeloma (MM) is a heterogeneous disease with a strong need for robust markers for prognosis. Frequently occurring chromosomal abnormalities, such as t(4;14), gain(1q), and del(17p) etc. have some prognostic power, but lack robustness across different cohorts. Alternatively, gene expression profiling (GEP) studies have developed specific high risk signatures such as the SKY92 (EMC92, Kuiper et al. Leukemia 2012), which has shown to be a robust prognostic factor across five different clinical datasets. Moreover, studies comparing prognostic markers have indicated that the SKY92 signature outperforms all other markers for identifying high risk patients, both in single and multivariate analyses. Similarly, when assessing the prognostic value of combinations of various prognostic markers, the SKY92 combined with ISS was the top performer, and also enables detection of a low risk group (Kuiper et al. ASH 2014). Here, we present a further validation of the low and high risk groups identified by the SKY92 signature in combination with ISS on two additional cohorts of patients with diverse treatment backgrounds, containing newly diagnosed, previously treated, and relapsed/refractory MM patients. Materials and Methods The SKY92 signature was applied to two independent datasets. Firstly, the dataset from the Total Therapy 6 (TT6) trial, which is a phase 2 trial for symptomatic MM patients who have received 1 or more prior lines of treatment. The TT6 treatment regime consists of VTD-PACE induction, double transplant with Melphalan + VRD-PACE, followed by alternating VRD/VMD maintenance. Affymetrix HG-U133 Plus 2.0 chips were performed at baseline for n=55 patients, and OS was made available previously (Gene Expression Omnibus identifier: GSE57317). However, ISS was not available for this dataset. Secondly, a dataset of patients enrolled at two hospitals in the Czech Republic, and one in Slovakia (Kryukov et al. Leuk&Lymph 2013). Patients of all ages, and from first line up to seventh line of treatment were included (treatments incl Bort, Len, Dex). For n=73 patients Affymetrix Human Gene ST 1.0 array, OS (n=66), and ISS (n=58) was made available previously (ArrayExpress accession number: E-MTAB-1038). Both datasets were processed from .CEL files by MAS5 (TT6), and RMA (Czech), followed by mean variance normalization per probeset across the patients. The SKY92 was applied as previously described (Kuiper et al. Leukemia 2012), and identifies a High Risk and Standard Risk group. In conjunction with ISS, the SKY92 Standard Risk group is then further stratified into low and intermediate risk groups (Kuiper et al. ASH 2014). Kaplan-Meier plots were created, and the Cox proportional hazards model was used to calculate Hazard Ratios (HR), and associated 1-sided p-values that assess whether the SKY92 High Risk group has worse survival than SKY92 Standard Risk group (i.e. HR>1). Results Figure 1 shows the Kaplan Meier plots of the SKY92 High Risk and Standard Risk groups on the TT6 and Czech cohorts. On the TT6 dataset, the SKY92 signature identifies 11 out of 55 patients (20%) as High Risk. In both datasets, the SKY92 High Risk group has significantly worse overall survival, HR=10.3, p=7.4 * 10-6 (TT6), and HR=2.6, p=2.2 * 10-2 (Czech). In addition, the combination of SKY92 with ISS on the Czech dataset identifies a low risk group of 14 out of 61 patients (23%), with a five year overall survival estimate of 100% versus 28.7% in the SKY92 High Risk group (HR=inf). Robustness of the SKY92 signature is further demonstrated by the fact that it validates on both datasets, despite different microarray platforms being used. Conclusions The SKY92 high risk signature has been successfully validated on two independent datasets generated using different microarray platforms. In addition, on the Czech data, the low risk group (SKY92 Standard Risk combined with ISS 1) has been successfully validated. Together, this signifies the robust nature of the SKY92 signature for high and low risk prediction, across treatments, and with applicability in newly diagnosed, treated, and relapsed/refractory MM patients. Figure 1. Kaplan-Meier plots showing a significantly poorer overall survival in patients identified as SKY92 High Risk (red curves), relative to SKY92 Standard Risk, on both the TT6 (left), and Czech (middle) datasets, as well as a low risk group by SKY92 & ISS1 on the Czech dataset (green curve, right). Figure 1. Kaplan-Meier plots showing a significantly poorer overall survival in patients identified as SKY92 High Risk (red curves), relative to SKY92 Standard Risk, on both the TT6 (left), and Czech (middle) datasets, as well as a low risk group by SKY92 & ISS1 on the Czech dataset (green curve, right). Disclosures van Vliet: SkylineDx: Employment. Ubels:SkylineDx: Employment. de Best:SkylineDx: Employment. van Beers:SkylineDx: Employment. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding.

scholarly journals Tumor Mutational Load and Germline Polygenic Risk Score Predicts Time-to-First Treatment in Chronic Lymphocytic Leukemia (CLL) and High-Count Monoclonal B Cell Lymphocytosis (MBL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 852-852
Author(s):  
Geffen Kleinstern ◽  
Daniel R O'Brien ◽  
Brian Kabat ◽  
Kari G Rabe ◽  
Aaron D. Norman ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Weighted Average ◽  
Risk Groups ◽  
Data Safety Monitoring Board ◽  
Polygenic Risk Score ◽  
Intermediate Risk ◽  
Driver Genes ◽  
High Count ◽  
Very High

Background The CLL international prognostic index (CLL-IPI) is a validated staging system for newly diagnosed CLL patients that combines age, clinical stage, serum Beta-2 microglobulin, TP53, and IGHV mutation status into a single score and stratifies CLL patients into four prognostic risk groups with a c-statistic=0.72. Next-generation sequencing identified ~60 putative driver genes recurrently mutated in CLL, and genome-wide association studies (GWAS) identified 41 single nucleotide polymorphisms (SNPs) associated with CLL risk. We previously showed that a polygenic risk score (PRS) of the weighted average of the number of risk alleles among these 41 SNPs is associated with risk of both CLL and MBL. We and others have also shown that the tumor mutational load (TML), i.e., the total number of somatically mutated driver genes, is associated with time to first treatment (TTT). Herein, we examine whether TML and PRS add prognostic value beyond CLL-IPI for disease progression in a cohort of CLL and high-count MBLs. Methods We used the Mayo Clinic CLL resource to identify newly diagnosed (&lt;2 years) previously untreated CLL and high-count MBL patients based on the 2008 International Workshop CLL (IWCLL) criteria . We extracted DNA from CD5+/CD19+ clonal B-cells and sequenced the coding regions of 59 recurrently mutated CLL driver genes using a custom SureSelect panel and Illumina HiSeq 4000. The median coverage depth per sample was 2737X. Somatic mutations were called using MuTect2 in tumor-only mode. Germline variants were eliminated based on minor allele frequencies &gt;0.01%, and by those identified in 1000 Genomes Project, ExAC and/or ESP6500 databases, unless present in known mutation hotspots or COSMIC. After filtering high/moderate impact mutations, we calculated the TML. Peripheral blood DNA was genotyped on Illumina Omni Express array; after extensive quality control metrics, we calculated the germline PRS as the weighted average of the number of risk alleles among the CLL susceptibility SNPs. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) to test for associations with TTT. We analyzed the low/intermediate risk groups and the high/very high risk groups in stratified analyses and tested for interactions between CLL-IPI and TML or PRS. Survival curves are displayed using the Kaplan-Meier method using P-values from the log-rank test; the PRS is displayed by tertile categories. Results Of 166 patients (120 CLL, 46 MBL), 67% were male and the median age at diagnosis was 62 years (range: 28-85). The median follow-up was 5.3 years, and 73 were treated for progressive disease as defined by the 2018 IWCLL criteria. Low risk CLL-IPI comprised 51%, intermediate risk 27%, high risk 18%, and very-high risk 4%. The most commonly somatically mutated genes were TP53 (8%), CHD2 (8%), BIRC3 (8%), SF3B1 (7%), and NOTCH1 (7%). We found that 42%, 32%, and 26% of patients had 0, 1, or 2+ genes with somatic mutations, respectively. The median PRS was 8.3 (range: 6.1-11.3) which is consistent with our prior PRS study on CLL/MBL and higher than 7.53 found in 7983 controls from our prior work. When we modeled TML, PRS, sex, CLL/MBL status and CLL-IPI together with the joint effects of CLL-IPI with TML and PRS, both interactions were significant in the model (P=0.008 for TML*CLL-IPI and P=0.014 for PRS*CLL-IPI), with c-statistic=0.81 (CI:0.77-0.85). When we stratified by CLL-IPI, TML was associated with shorter TTT in the low/intermediate risk (N=129, continuous HR=2.36 per TML category, CI: 1.61-3.47, P=1.3x10-5, Figure 1.A), but there was no evidence of an association in the high/very-high risk (N=37, continuous HR=1.12 per TML category, CI: 0.70-1. 78, P=0.64, Figure 1.B), after adjusting for PRS, sex, and CLL/MBL status. However, the PRS was associated with a shorter TTT in the high/very-high risk (continuous HR=1.77 per SD, CI: 1.00-3.12, P=0.048, Figure 1.D), with no evidence of an association in the low/intermediate risk (continuous HR=0.95 per SD, CI: 0.95-1.29, P=0.74, Figure 1.C), after adjusting for TML, sex, and CLL/MBL status. Conclusions In our study, TML was prognostic among the low/intermediate CLL-IPI risk groups while the PRS was prognostic among the high/very-high CLL-IPI risk groups. Sequencing CLL driver genes and genotyping relevant germline SNPs at time of diagnosis may provide incremental value over the CLL-IPI in predicting TTT among patients with CLL/MBL. Disclosures Parikh: MorphoSys: Research Funding; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Research Funding; Ascentage Pharma: Research Funding; Acerta Pharma: Research Funding. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB.

scholarly journals Myelodysplastic Syndromes with Hypocellular Marrow: Clinical Characteristics and Evaluation of Outcome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1829-1829
Author(s):  
Valeria Santini ◽  
Daniela Maria Gioia ◽  
Elisa Masiera ◽  
Antonella Poloni ◽  
Dario Ferrero ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Lower Risk ◽  
Clinical Characteristics ◽  
Risk Groups ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Very High ◽  
Risk Categories

Abstract Background. MDS may be characterized by hypocellular marrow, irrespective of their WHO classification or molecular characteristics. Their prognostic weight must still be completely evaluated. MDS with hypocellular marrow tend to be considered an aplastic anemia "overlap syndrome" or a pre-aplastic anemia stage. There are no strong specific therapy recommendations, and large studies analyzing the outcome of hypocellular MDS are lacking. While selective sensitivity to immunosuppressive therapy is suggested, evidence in this sense is controversial. Aims. We wanted to evaluate the clinical characteristics, outcome and choice of therapy of patients with hypocellular MDS and compare them with normocellular MDS. Methods. We analyzed 2559 MDS cases with complete clinical annotations and with evaluable bone trephine biopsy, enrolled in our Italian National Registry FISMonlus. In this cohort of patients, 438 had a bone marrow cellularity <= 30% and 2121 cellularity above 30%. We proceeded by comparing these two groups in terms of age, gender, WHO classification, IPSS-R categories, overall survival and first line therapies. As a validation cohort, 874 unselected MDS cases enrolled in Rete Ematologica Lombarda (REL) registry were analyzed. In this population, 108 patients had cellularity <= 30%. Results. In FISM cohort median age was 72.5 yrs in the hypocellular group and 72,3 yrs in the normocellular group; M/F were 53.2%/46.8% for hypocellular MDS vs 62.6%/37.4% in normocellular MDS. IPSS-R risk categories were distributed as follows: Hypocellular MDS Very Low 15.5%, Low 35.1%, Intermediate 30.1%, High 11.3%, Very high 8%; Normocellular MDS Very Low 12.8%, Low 37.2%, intermediate 23.7%, High 15.5%, Very High 11.4%. Global median overall survival (OS) was 77 months for hypocellular MDS and 56 months for normocellular MDS. When OS was evaluated in the different IPSS-R risk groups, Lower risk MDS cases with hypocellular BM had a median OS of 125 mos while normocellular had a median OS of 74 mos (p< .001). Higher risk MDS with hypocellular BM had 19 mos median OS vs 20 mos OS in normocellular MDS. Regarding the first line therapy, the comparison of hypocellular MDS with normocellular ones yielded the following: watch and wait 33.8% vs 31.6% for IPSS-R lower risk, 12.1% vs 16% for higher risk cases; AML like chemotherapy and HSCT were chosen for< 1% of lower risk cases overall, and in 1.7% of higher risk hypocellular MDS, while higher risk MDS with normocellular marrow received it in 6.2% of the cases. Azacitidine was first line treatment for 36.2% of the higher risk MDS patients with hypocellular BM and 25% of normocellular BM. Immunosuppressive treatments were emploied for < 1% and 1.5% respectively in lower risk cases only. Erythroid stimulating agents were administered in 42.6% and 41.2% MDS IPSS-R lower risk, hypo- and normocellular, respectively. We then focused on the validation cohort (REL registry). Median age was 74 yrs in the hypocellular group IPSS-R risk categories were distributed as follows: Very Low risk 9 %, Low 36%, Intermediate 39%, High 17 %, Very high 9%. Global median overall survival (OS) was 79 months for hypocellular MDS and 64 months for normocellular MDS. The difference was significant in very low/low IPSS-R risk groups, cases with hypocellular BM having a median OS of 103 mos vs. 69 mos of normocellular cases (p=.011). No significant differences were present in higher disease risk categories. No significant difference was noticed on first line treatment of choice between hypocellular an normocellular MDS. Immunosuppressive treatments were used in a very low proportion of cases (2% and 3% respectively). Conclusion. Our results are based on an unbiased analysis of "real life" MDS patients with hypocellular BM compared to normocellular ones. Clinical characteristics between the two groups were not significantly different in terms of age, gender, and distribution in the various IPSS-R risk categories. The outcome of the hypocellular marrow-MDS cases was better in comparison with that of normocellular MDS, with significantly longer OS in IPSS-R lower risk cases. The advantage in OS for hypoplastic MDS wasn't present for IPSS-R higher risk cases. Finally, the choice of first line therapy doesn't seem to be influenced by the BM cellularity, with a surprising very low proportion of patients receiving immunosuppressive agents, despite several guideline recommend of this treatment for hypoplastic MDS. Disclosures Santini: Novartis: Honoraria; Otsuka: Consultancy; Celgene: Honoraria, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Finelli:Novartis: Consultancy, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Gaidano:Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Honoraria; Roche: Consultancy, Honoraria. Oliva:Celgene: Consultancy, Other: Royalties, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; La Jolla: Consultancy; Sanofi: Consultancy, Speakers Bureau. Cilloni:celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

The Utility Of Newer Risk Models In Predicting Outcomes Of Patients (pts) With Higher-Risk (HR) Myelodysplastic Syndromes (MDS) Treated With Azactidine (aza)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2771-2771
Author(s):  
Amer M. Zeidan ◽  
Najla H Al Ali ◽  
Mohamed A. Kharfan-Dabaja ◽  
Eric Padron ◽  
Ling Zhang ◽  
...  
Keyword(s):  
High Risk ◽  
Scoring System ◽  
Research Funding ◽  
Goodness Of Fit ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Information Criteria ◽  
Prognostic Groups ◽  
Very High

Abstract Background While aza is the only drug shown to prolong survival in MDS, only half of aza-treated pts achieve objective responses (10-20% complete remission), and 4-6 months might be needed before a response is seen. Therefore the ability to select pts with high and low likelihoods of benefit from aza therapy is a clinical and a research priority. No clinical or laboratory parameter consistently predicts response or survival with aza therapy. A French prognostic scoring system (FPSS) was proposed to predict survival among aza-treated pts with HR-MDS. We sought to compare the relative prognostic discriminatory power of the FPSS with that of the revised IPSS (IPSS-R) and the global MD Anderson prognostic scoring system (MDAPSS) in a large cohort of aza-treated pts with IPSS HR-MDS. Methods The MDS database at Moffitt Cancer Center (MCC) was used to identify patients with HR-MDS (International Prognostic Scoring System [IPSS] intermediate-2 [INT-2] and high-risk) who received aza therapy. Kaplan-Meier curves were used to depict survivals, and the log-rank test was used to compare median overall survival (OS). Akaike information criteria (AIC) were used to assess the relative goodness of fit of the models. Results We identified 259 patients HR-MDS (74.1% with INT-2 and 25.9% with high IPSS) treated with aza at the MCC. The median duration of follow up since diagnosis was 53 months (M) (95% confidence interval [CI], 49-59 M). The median number of aza cycles was 5 (range 1-72), with 75% of pts receiving 4 cycles of therapy or more. The median time from diagnosis to aza initiation was 1.5 M. The median OS for the entire cohort was 19 M (95%CI, 16-22 M), 64% of pts were males, 91% were white, 80% were older than 60 years, and 25% had therapy-related MDS. For the IPSS, the median OS was 23.5 M (CI, 18.4-28.6 M) for INT-2 and 15.9 M (CI, 13.6-18.2 M) for high-risk group (P=0.004). For the FPSS, the median OS was 29.5 M (CI, 14.1-44.9 M) for low risk (LR), 21.1 M (CI, 16.4-26.0 M) for intermediate risk (IR), and 14.1 M (CI, 8.7-19.5 M) for HR (P=0.001). For the MDAPSS the median OS was not reached (NR) for low, 53.5 M (CI, 37.5-69.4 M) for INT-1, 29.5 M (CI, 18.3-40.6 M) for INT-2, and 16.1 M (CI, 14.5-17.7 M) for high risk groups (P<0.0001). For the IPSS-R, the median OS 40.6 M (CI, 22.8-58.4 M) for low, 44.7 M (CI, 25.0-64.4 M) for INT, 23.5 M (CI, 20.3-26.8 M) for high, and 15.2 M (CI, 13.7-16.8 M) for very-high risk groups (P<0.0001). Scores generated using AIC to assess the relative goodness of fit (lower is better) were 1453 (IPSS-R), 1480 (MDAPSS), 1512 (FPSS), and 1522 (IPSS). The IPSS could not refine any of the other models. All three newer models refined IPSS INT-2 but not IPSS high-risk. The IPSS did not refine any of the newer models. The MDAPSS refined the FPSS LR and IR and the IPSS-R high and very-high groups. The FPSS refined IPSS-R very high risk group but not the not the MDAPSS. The R-IPSS did not refine the MDAPSS or the FPSS. Response rates were not statically significantly different within the prognostic groups in any of the scoring systems. Conclusions The IPSS-R, MDAPSS, and the FPSS all functioned well to separate aza-treated pts with IPSS HR-MDS into prognostic groups with different survivals, but the IPSS-R and MDAPSS appear superior to the FPSS. None of the prognostic systems predicted response to aza therapy. HR-MDS patients with poor projected survival with aza therapy might be considered for experimental approaches. Disclosures: Off Label Use: entinostat for MDS. Lancet:Celgene: Research Funding. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau.

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