Validation of a Prognostic Model and the Impact of SF3B1, DNMT3A, and Other Mutations in 289 Genetically Characterized Lower Risk MDS Patient Samples

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 969-969 ◽  
Author(s):  
Rafael Bejar ◽  
Kristen Stevenson ◽  
Bennett Caughey ◽  
Omar Abdel-Wahab ◽  
Naomi Galili ◽  
...  
Keyword(s):  
Scoring System ◽  
Lower Risk ◽  
Prognostic Model ◽  
Point Mutations ◽  
Gene Mutations ◽  
Risk Groups ◽  
Appropriate Therapy ◽  
Md Anderson ◽  
Risk Categories ◽  
Independent Cohort

Abstract Abstract 969 Selection of the appropriate therapy for patients with myelodysplastic syndromes (MDS) depends heavily on the predicted prognosis of each afflicted individual. Prognostic scoring systems help stratify patients into risk groups, but outcomes can be highly variable even within these groups. Of particular concern are patients predicted to have lower risk disease that go on to progress more rapidly than expected. Such patients may not be offered risk-appropriate therapy at a time when it might be of greatest benefit. A prognostic model that better predicts survival in patients believed to have lower risk disease has been proposed by investigators at the MD Anderson Cancer Center, but not yet validated in an independent cohort. Acquired genetic mutations can also identify patients with higher-than-predicted disease risk. We have previously demonstrated that mutations in any of five genes (TP53, EZH2, ETV6, RUNX1, and ASXL1) predict a poorer prognosis independently of the International Prognostic Scoring System (IPSS). In this study, we examined 289 MDS patients with Low or Intermediate-1 IPSS risk for mutations in 21 genes, including two genes that have recently been reported to be frequently mutated in MDS: DNMT3A and SF3B1. We validate the ability of the Lower-Risk MD Anderson Prognostic Scoring System (LR-PSS) to more finely risk-stratify patients using an independent cohort and identify gene mutations independently associated with clinical features and overall survival. Patients were stratified into one of three risk categories using the LR-PSS shown in the Table. The 58 patients (20%) assigned to Category 1 had a median survival of 5.19 years (95% confidence interval in years [CI] 3.05–10.34), compared to 2.65 years (CI 2.18–3.30) for the 160 patients (55%) in Category 2, and 1.11 (CI 0.82–1.51) for the 71 patients (25%) in Category 3. Differences in survival were significant between all three categories (p < 0.001 for all comparisons). Point mutations were identified in 63% of samples, including 64% of those with a normal karyotype. The 10 most frequently mutated genes were TET2 (23% of cases), SF3B1 (21%), ASXL1 (15%), DNMT3A (14%), RUNX1 (9%), EZH2 (8%), JAK2 (3%), NRAS (3%), TP53 (2%), and ETV6 (2%). Mutations of SF3B1 were highly enriched in cases of refractory anemia with ring sideroblasts (RARS; 32 out of 43, 74%), associated with normal blast percentages (p = 0.04) and neutrophil counts (p = 0.002), and more likely to be present in cases with platelet counts greater than 450,000/μl (p < 0.001). We extended our analysis of SF3B1 mutations by adding a separate cohort of 98 RARS patients with Low or Intermediate-1 IPSS risk for a total of 141 cases. In this extended RARS set, SF3B1 mutations were associated with improved survival even after adjustment for IPSS risk group or LR-PSS category (hazard ratio [HR]=0.49; CI 0.29–0.81, HR=0.35; CI 0.21–0.58, respectively). SF3B1 is the first gene mutation independently associated with a favorable prognosis in non-CMML MDS. In contrast, DNMT3A mutations were not associated with differences in overall survival in the 289 patients with lower IPSS risk MDS. In a model generated from stepwise Cox regression analysis that considered LR-PSS risk categories and the mutation status of the 13 most frequently mutated genes as candidates, only EZH2 mutations emerged as a LR-PSS-independent risk factor associated with a poor prognosis (HR=2.90; CI 1.86–4.53). In a similar model using IPSS risk groups, EZH2 (HR=2.85; CI 1.78–4.57), NRAS (HR=2.78; CI 1.35–5.72), and ASXL1 (HR=1.60; CI 1.09–2.34) were significant IPSS-independent risk factors. Mutations in genes such as ASXL1, RUNX1, NRAS, and ETV6, which are associated with poor survival in unselected MDS patients, were most common in patients assigned to the LR-PSS risk Category 3, indicating that this prognostic model may capture more clinically relevant information associated with adverse gene mutations. In conclusion, this study validates the LR-PSS 's ability to identify higher risk MDS patients among those with lower IPSS risk and demonstrates that point mutations are common in this cohort, associate with specific clinical features, and independently provide both favorable and adverse prognostic information.Table:Table:. The Lower-Risk MD Anderson Prognostic Scoring System (LR-PSS) Disclosures: No relevant conflicts of interest to declare.

A Comparison of Prognostic Models for Chronic Myelomonocytic Leukemia (CMML) in the Era of Hypomethylating Agents

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1695-1695 ◽  
Author(s):  
Eric Padron ◽  
Najla H Al Ali ◽  
Deniz Peker ◽  
Jeffrey E Lancet ◽  
Pearlie K Epling-Burnette ◽  
...  
Keyword(s):  
Overall Survival ◽  
Scoring System ◽  
Prognostic Model ◽  
Median Overall Survival ◽  
Prognostic Score ◽  
Risk Groups ◽  
Prognostic Models ◽  
Rank Test ◽  
Log Rank Test ◽  
Md Anderson

Abstract Abstract 1695 Introduction: CMML is a genetically and clinically heterogeneous malignancy characterized by peripheral monocytosis, cytopenias, and a propensity for AML transformation. Several prognostic models attempt to stratify patients into subcategories that are predictive for overall survival (OS), six models of which are specific to CMML. However, these models have either never been externally validated in the context of CMML or were externally validated prior to the use of hypomethylating agents. We externally validate and perform a detailed statistical comparison between the International Prognostic Scoring System (IPSS), MD Anderson Scoring System (MDASC), MD Anderson Prognostic Score (MDAPS), Dusseldorf Score (DS), and Spanish Scoring Systems (SS) in a large, single institution cohort. Methods: Data were collected retrospectively from the Moffitt Cancer Center (MCC) CMML database and charts were reviewed of patients that satisfied the WHO criteria for the diagnosis of CMML. The primary objective of the study was to validate the above prognostic models calculated at the time of initial presentation to MCC. All prognostic models were calculated as previously published. All analyses were conducted using SPSS version 15.0 (SPSS Inc, Chicago, IL). The Kaplan–Meier (KM) method was used to estimate median overall survival and the log rank test was used to compare KM survival estimates between two groups. Results: Between January 2000 and February 2012, 123 patients were captured by the MCC CMML database. The median age at diagnosis was 69 (30–90) years and the majority of patients were male (69%). By the WHO classification, the majority of patients had CMML-1 (84% vs. 16%) and most patients were subcategorized as MPN-CMML (59%) versus MDS-CMML (39%) by the FAB CMML criteria. The median overall survival of the entire cohort was 30 months and the rate of AML transformation was 44% (54). Twenty-two patients (18%) were treated with decitabine and 66 (54%) patients were treated with 5-azacitidine. Risk group stratification according to specific prognostic model is summarized in Table 1. The IPSS, MDASC, DS, and SS all predicted OS (p<0.05) while the MDASP could not be validated (p=0.924). When only patients who were treated with 5-azacitadine were considered, the MDASC, DS, and SS continued to predict OS (p<0.05) while the IPSS (p=0.15) and MDASP (p=0.239) did not. Previous reports have demonstrated that the MDASC provides further discrimination to refine stratification by the IPSS in Myelodysplastic Syndromes (MDS). Except for the low-risk DS patients, we grouped patients in our CMML cohort into lower and higher risk disease with each prognostic score and attempted to further stratify patients by the MDASC using KM and the log rank test. The MDASC was able to further risk stratify patients in each group for all prognostic models except those in the higher risk groups by the SS (p=0.07) and DS (P=0.45). When a similar statistical analysis was applied to each prognostic scoring system, only the MDASC was consistently able to further stratify the majority of risk groups as described in Table 2. The Dusseldorf scoring system was able to further stratify all lower risk groups regardless of model but was not able to do so in higher risk disease. Conclusions: This represents the first external validation of existing CMML prognostic models in the era of hypomethylating agent therapy. Except for the MDASP, we were able to validate the prognostic value all models tested. The MDASC represents the most robust model as it consistently refined the stratification of other models tested and remained predictive of OS in 5-azacitidine treated patients. Multi-institution collaboration is needed to construct a robust CMML specific prognostic model. Comparison to the IPSS-R is in progress. Disclosures: No relevant conflicts of interest to declare.

Transfusion Dependency Is Associated With Inferior Survival Even In Very Low and Low Risk IPSS-R Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1518-1518 ◽  
Author(s):  
Devendra K. Hiwase ◽  
Monika M Kutyna ◽  
Rakchha Chhetri ◽  
Stuart Howell ◽  
Peter B Harrison ◽  
...  
Keyword(s):  
Scoring System ◽  
Lower Risk ◽  
Risk Group ◽  
Risk Groups ◽  
Low Risk ◽  
Transfusion Dependency ◽  
The Impact ◽  
Very High ◽  
Rbc Transfusion ◽  
Independent Cohort

Abstract Background The International Prognostic Scoring System (IPSS) is commonly used for predicting the outcome of myelodysplastic syndrome (MDS) patients. Recently, a Revised IPSS (IPSS-R) has been developed to address the limitations of IPSS. IPSS-R identifies five different categories and stratifies patients better than IPSS. Although transfusion dependency is associated with inferior survival outcome, it has not been included in the risk stratification of IPSS-R mainly due to limited availability of transfusion data on patients used for deriving the IPSS-R. Aim To evaluate the impact of RBC transfusion on survival outcome in IPSS-R subgroups and assess the validity of IPSS-R in an independent cohort of patients. Materials and Methods To match the patient selection criteria used for generating the IPSS-R scoring system, primary MDS patients who were not treated with disease modifying agents or stem cell transplantation were included for this analysis. The impact of RBC transfusion on overall survival (OS) was assessed in IPSS-R subgroups. RBC transfusion dependency was defined as transfusion of at least 1 unit/8 weeks for at least 4 months. Results A total of 182 patients were included in this analysis. Their median age was 73 years (21 to 91 years) and 66% patients were male. 106 patients were in the Very Low or Low risk groups (termed ‘lower risk'). The median OS of IPSS-R Very Low, Low, Intermediate, High and Very High risk groups was 87.1, 63.9, 24.5, 17.2 and 7.8 months, respectively (Fig.1. p<0.0001), consistent with previously published results (Greenberg et al, Blood 2012). Of the 182 patients, 115 (63%) patients were RBC transfusion dependent. RBC transfusion dependency was more frequent in Very High (18/18, 100%), High (25/28, 89%) and Intermediate (21/31, 68%) risk groups as compared to lower risk IPSS-R groups: Low (35/67, 52%) and Very Low (17/39, 43%). The mean pre-transfusion Hb was 79.1 ±12.3 gm/L, and the trigger for transfusion was Hb ≤90, >90 to ≤100 and >100 gm/L in 83%, 11% and 6% of episodes, respectively. In a multivariate analysis, RBC-transfusion dependency (HR 3.18; P<0.0001) was associated with poor survival, independent of the IPSS-R category and age at diagnosis (Table 2). The median OS of transfusion-dependent patients (n=115) was significantly lower (23.8 vs. 117.8 months; p<0.0001) than that of transfusion-independent patients (n=67). As the majority of IPSS-R higher risk patients were transfusion dependent, we restricted further assessment to IPSS-R lower risk groups. The median OS between Low and Very Low risk group was not significantly different (87.1 vs Low 63.2 months; p=0.1), hence they were grouped together. The median OS of transfusion-dependent lower risk IPSS-R patients (n=52) was significantly shorter than that of transfusion-independent (n=54) patients (52.7 vs 122.5 months; p=0.001). Conclusions We have demonstrated that transfusion dependency is associated with inferior survival even in Very Low and Low risk IPSS-R group patients. This warrants further refinement of IPSS-R scoring system specifically for lower risk group patients. IPSS-R scoring system is validated in our independent cohort of patients. Disclosures: Hiwase: Novartis Australia: Research Funding; Celgene Australia: Research Funding.

scholarly journals Clinical Validation of the Myelofibrosis Transplant Scoring System in an Independent Series of Myelofibrosis Patients Undergoing Allogeneic Hematopoietic Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5733-5733 ◽  
Author(s):  
Juan-Gonzalo Correa ◽  
Rosalía de la Puerta ◽  
Ana Benzaquen ◽  
Jorge Mora ◽  
Ana A. Martín ◽  
...  
Keyword(s):  
High Risk ◽  
Survival Probability ◽  
Cumulative Incidence ◽  
Scoring System ◽  
Prognostic Model ◽  
Univariate Analysis ◽  
Risk Groups ◽  
Independent Series ◽  
Standard Risk ◽  
Risk Categories

Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) constitutes the only curative treatment for myelofibrosis (MF), but its associated toxicity remains high. Prognostic risk models are widely used in clinical practice to select those MF patients who are more likely to benefit from transplantation. Recently, a new prognostic model, the Myelofibrosis Transplant Scoring System (MTSS), has been developed to predict the outcome of MF patients undergoing allo-HCT (Gagelmann N et al, Blood 2019). We aimed to evaluate the performance of such model in an independent series of patients. Methods: This is a retrospective study that included all adult patients who underwent first allo-HCT for MF between January 2005 and May 2019 in 8 Spanish hospitals. Patients transplanted after leukemic transformation were excluded. Survival probability from the time of HCT was estimated by the method of Kaplan-Meier and compared by the log-rank test. Each parameter of the MTSS was tested for its potential association with survival in univariate analysis. Cumulative incidence functions were used to estimate incidence of Graft-versus-Host-Disease (GVHD), Relapse Incidence (RI), and Non-Relapse Mortality (NRM) within a competing risk setting. Statistical analyses were performed with SPSS 19 (SPSS Inc./IBM, Armonk, NY) and R. Results: Demographics and transplant characteristics of the overall series of 107 MF patients are shown in Table 1. After a median follow-up from allo-HCT of 5.3 years, 49 patients (46%) had died. The survival probability at 1, 3, and 5-years was 64.5%, 52%, and 50%, respectively. Transplantation outcome improved over the years. Thus, the survival probability at 3-years was 35% (95% CI: 12-58), 50% (95% CI: 33-67), and 65% (95% CI: 50-80) during the time periods 2005-2009 (n=17), 2010-2014 (n=34), and 2015-2019 (n=56), respectively (P=0.038). The cumulative incidence of grade II-IV acute GVHD at day 100 was 45%. The cumulative incidence of relapse at 1, 3, and 5-years was 16%, 19.5%, and 19.5%, respectively. NRM probability at 1, 3, and 5-years was 24%, 29%, and 31%, respectively. In univariate analysis, the only parameter included in the MTSS that was significantly associated with survival was the Karnofsky performance status < 90% (HR: 1.9, 95% CI: 1.1-3.4; P=0.031). Neither age > 57 years (P=0.68), platelets <150 x 109/L (P=0.79), leukocytes >25 x 109/L (P=0.38), ASXL1 mutations (P=0.34), non-CALR/MPL driver mutation (P=0.57) nor HLA-mismatched unrelated donor (P=0.22) correlated with survival. Among other classical risk factors for transplant outcome, only a comorbidity index >= 3 was significantly associated with shorter survival (HR: 2.1, 95% CI: 1.1-4; P=0.017). A total of 64 cases had all required clinical and molecular data to calculate the MTSS. Figure 1 shows the survival curves of the different risk groups as defined by the MTSS. As can be seen, the prognostic model was not able to discriminate four risk groups. We then pooled together patients assigned to the low (n=26) and intermediate risk (n=23) groups, and those within the high (n=9) and very high risk (n=6) groups. On this basis, two-categories could be identified: standard risk (n=49 [77% of patients]) and high risk (n=15 [23%]). The 3-year overall survival was 65% (95% CI: 51-79) in the standard risk and 17% (95% CI: 0-46) in the high risk categories (P=0.060)(Figure 2). Conclusions: the MTSS did not discriminate four different risk categories in our series. Both, the limited number of cases and the differences in patients and transplant characteristics in our series as compared to those of the original MTSS cohort might account for this finding. Nevertheless, the MTSS was able to identify a subset of patients with a very poor prognosis after transplantation. Such information could be useful to assist on transplant decision-making. Disclosures Sanchez-Guijo: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria. Hernandez Boluda:Incyte: Other: Travel expenses paid.

scholarly journals Validation of a Prognostic Model and the Impact of Mutations in Patients With Lower-Risk Myelodysplastic Syndromes

2012 ◽  
Vol 30 (27) ◽  
pp. 3376-3382 ◽  
Author(s):  
Rafael Bejar ◽  
Kristen E. Stevenson ◽  
Bennett A. Caughey ◽  
Omar Abdel-Wahab ◽  
David P. Steensma ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndromes ◽  
Scoring System ◽  
Lower Risk ◽  
Prognostic Model ◽  
Prognostic Significance ◽  
International Prognostic Scoring System ◽  
Disease Modifying Therapy ◽  
Md Anderson ◽  
The Impact

Purpose A subset of patients with myelodysplastic syndromes (MDS) who are predicted to have lower-risk disease as defined by the International Prognostic Scoring System (IPSS) demonstrate more aggressive disease and shorter overall survival than expected. The identification of patients with greater-than-predicted prognostic risk could influence the selection of therapy and improve the care of patients with lower-risk MDS. Patients and Methods We performed an independent validation of the MD Anderson Lower-Risk Prognostic Scoring System (LR-PSS) in a cohort of 288 patients with low- or intermediate-1 IPSS risk MDS and examined bone marrow samples from these patients for mutations in 22 genes, including SF3B1, SRSF2, U2AF1, and DNMT3A. Results The LR-PSS successfully stratified patients with lower-risk MDS into three risk categories with significant differences in overall survival (20% in category 1 with median of 5.19 years [95% CI, 3.01 to 10.34 years], 56% in category 2 with median of 2.65 years [95% CI, 2.18 to 3.30 years], and 25% in category 3 with median of 1.11 years [95% CI, 0.82 to 1.51 years]), thus validating this prognostic model. Mutations were identified in 71% of all samples, and mutations associated with a poor prognosis were enriched in the highest-risk LR-PSS category. Mutations of EZH2, RUNX1, TP53, and ASXL1 were associated with shorter overall survival independent of the LR-PSS. Only EZH2 mutations retained prognostic significance in a multivariable model that included LR-PSS and other mutations (hazard ratio, 2.90; 95% CI, 1.85 to 4.52). Conclusion Combining the LR-PSS and EZH2 mutation status identifies 29% of patients with lower-risk MDS with a worse-than-expected prognosis. These patients may benefit from earlier initiation of disease-modifying therapy.

scholarly journals Impact of Driver Mutations in Patients with Lower-Risk Myelodysplastic Syndromes Classified By the MD Anderson Lower-Risk Prognostic Scoring System

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4317-4317
Author(s):  
Guillermo Montalban-Bravo ◽  
Koichi Takahashi ◽  
Ana Alfonso Pierola ◽  
Feng Wang ◽  
Song Xingzhi ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Scoring System ◽  
Lower Risk ◽  
Research Funding ◽  
Prognostic Model ◽  
Advisory Board ◽  
Driver Mutations ◽  
New Model ◽  
Mutation Data ◽  
Md Anderson

Abstract INTRODUCTION: Patients with lower-risk myelodysplastic syndromes (MDS) as defined by the International Prognostic Scoring System (IPSS) are generally considered to have favorable prognosis. The MD Anderson Lower-risk Prognostic Scoring system (MDA LR-PSS) is a validated prognostic model that defines a subset of patients with shorter than expected survival. Presence of EZH2mutations has been reported to independently impact survival of these patients. Further evaluation and validation of the addition of mutation data to this prognostic model is needed. METHODS: We conducted whole exome sequencing of 74 previously untreated patients with Low or Int-1 IPSS. Exome capture hybrid was performed using Agilent SureSelect All Exon V4. Sequencing was performed with Illumina HiSeq 2000 and aligned to the hg19 human genome reference. Common virtual normal in house pool was used for somatic variant calling. Generalized linear models were used to study association of overall response (OR), complete response (CR) and risk factors. Response was defined following 2006 IWG criteria. The Kaplan-Meier produce limit method was used to estimate the median overall survival (OS) and leukemia-free survival (LFS). RESULTS: Patient characteristics are summarized in Table 1. Seventeen (23%) patients had CMML and 57 (77%) had MDS. Seventy (95%) patients had evaluable cytogenetics. A total of 46 (66%) patients had normal karyotype with 4 (6%) patients having complex karyotype. Twenty-three (31%) patients were classified as Low risk by IPSS and 51 (69%) as Int-1. Twelve (16%) patients were classified as Category 1 by the MDA LR-PSS, 38 (51%) as Category 2 and 24 (32%) as Category 3. A total of 148 driver mutations in 27 genes were detected. Median number of driver mutations per patient was 2 (range 0-5). Mutations in TET2, SRSF2, ASXL1, SF3B1 and ZRSR2 were the most frequently detected mutations present in >10% cases. Frequency of identified mutations is shown in Figure 1A. The median follow up was 26.5 months (range 3-102 months). Median OS was 43.2months (95% CI 35.04-50.46). Survival by MDA LR-PSS category is shown in Figure 1B. A total of 6 patients had transformation to acute myeloid leukemia with a median time to transformation of 22.4 months (95% CI 0.00-45.28). By univariate analysis, mutations in BCOR (HR 5.49, 9% CI 1.24-24.29, p=0.011), RUNX1 (HR 2.8, 95% CI 1.11-7.09, p=0.023) and STAG2 (HR 3.32, 95% CI 1.12-9.82, p=0.022) predicted for shorter OS. When analyzing for LFS, mutations in EZH2 (HR 18.61, 95% CI 2.99-115.92, p<0.001) and U2AF1 (HR 5.08, 95% CI 0.92-28.06, p=0.038) predicted for shorter LFS. By multivariate analysis combining the identified driver mutations with prognostic relevance and the MDA LR-PSS category, presence of MDA LR-PSS Category 3 (HR 5.98, 95%CI 1.28-28, p=0.023), RUNX1 mutation (HR 4.18, 95%CI 1.36-12.81, p=0.012) and STAG2 mutation (HR 3.7, 95%CI 1.02-13.47, p=0.047) retained there prognostic significance. Based on these results we designed a new model with scoring being based on HR for each given variable: MDA LR-PSS Category 3 2 points, RUNX1mut 1 point and STAG2mut 1 point. Patients were classified into three categories: Low, High or Very high with significantly different survival outcomes (Figure 1C). Based on this new model, patients with Category 2 MDA LR-PSS with either STAG2 or RUNX1 mutations had similar outcomes to those with Category 3 and no mutations (p=0.747). Patients with either Category 1 or Category 2 by MDA LR-PSS without STAG2 or RUNX1 mutations had similar OS (p=0.306) and represented the population with most favorable outcomes (p<0.001). Finally, patients with Category 3 with STAG2 or RUNX1 mutations had the worse outcomes in terms of survival (p<0.001). CONCLUSION: Similar to previous studies, our data suggests integration of mutation data into the MDA LR-PSS can improve our ability to predict outcomes of patients with lower-risk MDS. Mutations in STAG2 and RUNX1 can help identify a subset of patients with worse than expected outcomes as predicted by the MDA LR-PSS. Table 1 Table 1. Figure 1 Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Daver:Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; Ariad: Research Funding; BMS: Research Funding; Sunesis: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Validation of the Lower Risk MD Anderson Prognostic Scoring System for Patients with Myelodysplastic Syndromes (MDS)

2015 ◽  
Vol 15 ◽  
pp. S232-S233
Author(s):  
Hanadi Ramadan ◽  
Maria Corrales-Yepez ◽  
Najla Ali ◽  
Ling Zhang ◽  
Eric Padron ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Scoring System ◽  
Lower Risk ◽  
Md Anderson

scholarly journals Characterization of Myelodysplastic Syndromes (MDS) with T-Cell Large Granular Lymphocyte Proliferations (LGL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 113-113 ◽  
Author(s):  
Christa Roe ◽  
Najla Alali ◽  
Eric Padron ◽  
Pearlie K Burnette ◽  
Kendra L. Sweet ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cell ◽  
Peripheral Blood ◽  
Scoring System ◽  
Lower Risk ◽  
Research Funding ◽  
Somatic Mutations ◽  
Gene Mutations ◽  
Significant Difference ◽  
Somatic Gene

Abstract Introduction: MDS include a spectrum of hematopoietic stem cell malignancies characterized by bone marrow failure and dysplastic morphology. LGL is a clonal proliferation of cytotoxic T cells, which manifest as neutropenia, anemia, and thrombocytopenia and is associated with autoimmune disorders. LGL in association with MDS has been previously reported. However, clinicopathological features, prognostic, and predictive factors in those patients diagnosed with both LGL and MDS is not well studied. Methods: We identified patients at Moffitt Cancer Center (MCC) diagnosed with MDS who were previously tested for the presence of LGL clonal populations by peripheral blood flow cytometry at time of first visit. An LGL population was defined by the standard flow cytometry immunophenotype and clonality confirmed by T-cell receptor gamma and beta gene rearrangement.. Next Generation sequencing data was available for 151 patients. Recurrent somatic gene mutations were compared between patients with an LGL clone and those without. Results: Of the 675 patients with MDS tested for LGL in the database, 206 (30.5%) had an LGL clonal population. The mean LGL absolute cell count in the peripheral blood was 335/µL. Table-1 summarizes the baseline characteristics of the two groups. There was no difference in response to azacitidine therapy. Among 50 patients with LGL clone who received azacitidine with available data on response, the rate of hematological improvement or better (HI+) was 38%. The (HI+) was 28% among 105 patients evaluable for response without LGL clone. P .14 The median overall survival (OS) was for patients with no LGL clone was 65 months (mo) compared to 46 mo (p .024). The median OS for lower risk MDS patients (low/int-1 by International Prognostic Scoring System [IPSS]) was 68 mo versus 97 mo for those with or without LGL proliferation, respectively (P .005). In higher risk MDS, there was no difference in median OS between those with or without LGL expansion, respectively (20 mo versus 16 mo, p .7). The median OS for patients with very low/ low Revised-Internatinal Prognostic Scoring System (R-IPSS) was 96 mo if LGL proliferation was detected compared to 128 mo if it was not, (p value .016). For intermediate R-IPSS the median OS was 65 mo and 41 mo with or without LGL proliferation (p .16). Finally, for high/very high R-IPSS the median OS was 18 and 16 mo with or without LGL proliferation, (p .84) In cox regression analysis the presence of an LGL clone was independently prognostic for OS after adjusting for age and R-IPSS, Hazard ratio 1.3, p = .05. Somatic gene mutation data were available for 151 patients; there was no statistically significant difference in the distribution of any mutation except IDH-2 (Table-2). The most common somatic mutations observed among patients with LGL clone were SF3B1 19%, TET-2 16%, U2AF1 13%, IDH-2 13%, RUNX-1 13%, and ASXL-1 10%. In patients without an LGL clone the most common somatic mutations were TET-2 26%, ASXL-1 20%, DNMT3A 16%, TP53 13%, SF3B1 12%. Conclusion: An LGL clone is demonstrable in approximately 30% of patients with MDS in association with advancing age. The presence of LGL proliferation was associated with worse OS in lower risk MDS pts. Although the spectrum of somatic gene mutations were similar, the presence of IDH-2 mutation and absence of DNMT3A or TP53 gene mutationscharacterized LGL+ cases. Table 1. Table 1. Table 2. Table 2. Disclosures Roe: Celgene: Speakers Bureau; Alexion: Speakers Bureau; Seattle Genetics: Speakers Bureau. Sweet:Pfizer: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding; Karyopharm: Honoraria, Research Funding. Sokol:Seattle Genetics: Consultancy; Spectrum: Consultancy. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy.

Validation of Alternative Chronic Myelomonocytic Leukemia (CMML)-Specific Prognostic Scoring (CPSS) System in UT MD Anderson Cancer Center Cohort

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3278-3278
Author(s):  
Priyanka Priyanka ◽  
Janhavi Raut ◽  
Patricia S Fox ◽  
Francesco Stingo ◽  
Tariq Muzzafar
Keyword(s):  
Overall Survival ◽  
Scoring System ◽  
Risk Groups ◽  
Risk Classification ◽  
Chronic Myelomonocytic Leukemia ◽  
Cancer Center ◽  
Newly Diagnosed ◽  
Md Anderson ◽  
Myelomonocytic Leukemia

Abstract INTRODUCTION: Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm that belongs to the category of myelodysplastic syndrome / myeloproliferative neoplasms (MDS / MPN). The International Prognostic Scoring System for Myelodysplastic Syndromes (IPSS) classification and its revised version (IPSS-R) addressed patients with newly diagnosed, untreated MDS and excluded CMML. While numerous investigators have attempted to devise a prognostic risk scoring system for CMML, no system has been generally accepted for this entity. A CMML-specific prognostic scoring (CPSS) system proposed by Such, et al [Blood. 2013; 11;121(15):3005-15] defines 4 different prognostic risk categories for estimating both overall survival (OS) and risk for AML transformation; the alternative version replaces RBC transfusion dependency with hemoglobin levels. AIM: The aim of the study is to validate the alternative CPSS scoring system on the CMML patient cohort at UT MD Anderson Cancer Center (UTMDACC). METHODS: The databases of the Department of Hematopathology at UTMDACC were searched for patients diagnosed with CMML presenting from 2005 to 2012. Cases were classified by WHO 2008 criteria. Inclusion criteria were: confirmed diagnosis of CMML, age > 18 years, persistent absolute monocyte count >1 × 109/L, marrow blasts < 20%, peripheral blood blasts < 20%. The alternative CPSS score was calculated as a function of WHO subtype, FAB subtype, CMML-specific cytogenetic risk classification, and hemoglobin score. Cox proportional hazards regression was used to model overall survival and time to AML progression from date of diagnosis. For time to AML progression, patients who did not experience AML progression were censored at their date of death or last follow-up. Kaplan-Meier curves were used to estimate survival and the log-rank test was used to test for significant differences by CPSS score. All statistical analyses were performed using SAS 9.3 for Windows. RESULTS: Two hundred and three patients with newly diagnosed, untreated CMML were identified in the clinical databases. These included 132 males and 71 females; median age was 70 (range 55-80) years. 149 had CMML-1 and 54 had CMML-2. A total of 107 deaths and 38 progressions were observed. The median (range) follow-up time for all patients was 1.9 (2 days-10.8) years. The variables that compose the alternative CPSS (WHO subtype, FAB subtype, CMML-specific cytogenetic risk classification, hemoglobin) as well as a description of how the score is calculated are given in Tables 1-2. In univariate Cox models, the alternative CPSS score was a significant predictor of both OS and time to AML progression (Type III p-values <.0001 and 0.0037, respectively). Median survival times for OS were 4.07, 3.32, 2.14, and 1.23 years in the low, intermediate-1, intermediate-2, and high risk groups, respectively. Since less than half the patients progressed, the median time to AML progression could not be estimated for all groups but was 6.40 and 1.60 in the intermediate-2 and high risk groups, respectively. Overall, the alternative CPSS score was highly predictive of both OS and progression free survival (PFS) and clearly delineated the patient risk groups in this sample. CONCLUSIONS: These data reinforce the validity of the alternative CPSS and serve as an additional validation cohort. Table 1. Alternative CMML-specific prognostic scoring system (CPSS) score criteria Variable Each level assigned the following value(sum to get the composite CPSS score): 0 1 2 WHO subtype CMML-1 blasts (including promonocytes) <5% in the PB and <10% in the BM CMML-2 blasts (including promonocytes) from 5% to 19% in the PB and from 10% to 19% in the BM, or when Auer rods are present irrespective of blast count — FAB subtype CMML-MD (WBC <13 × 109/L) CMML-MP (WBC ≥13 × 109/L) — CMML-specific cytogenetic risk classification* Low Intermediate High Hemoglobin ≥10 g/dL <10/dL WBC: white blood cell * CMML-specific cytogenetic risk classification; low: normal and isolated –Y; intermediate: other abnormalities; and high: trisomy 8, complex karyotype (≥3 abnormalities), chromosome 7 abnormalities Table 2. Alternative CPSS: scores used for predicting likelihood of survival and leukemic evolution in individual patient with CMML Risk group Overall CPSS score Low 0 Intermediate-1 1 Intermediate-2 2-3 High 4-5 Figure 1 Overall Survival by alternative CPSS Score Figure 1. Overall Survival by alternative CPSS Score Figure 2 Time to AML Progression by alternative CPSS Score Figure 2. Time to AML Progression by alternative CPSS Score Disclosures No relevant conflicts of interest to declare.

scholarly journals Association of Comorbidities With Overall Survival in Myelodysplastic Syndrome: Development of a Prognostic Model

2011 ◽  
Vol 29 (16) ◽  
pp. 2240-2246 ◽  
Author(s):  
Kiran Naqvi ◽  
Guillermo Garcia-Manero ◽  
Sagar Sardesai ◽  
Jeong Oh ◽  
Carlos E. Vigil ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Median Survival ◽  
Prognostic Model ◽  
Cox Regression ◽  
Risk Groups ◽  
International Prognostic Scoring System ◽  
Cancer Center ◽  
Kaplan Meier ◽  
Severe Comorbidity ◽  
Md Anderson

Purpose Patients with cancer often experience comorbidities that may affect their prognosis and outcome. The objective of this study was to determine the effect of comorbidities on the survival of patients with myelodysplastic syndrome (MDS). Patients and Methods We conducted a retrospective cohort study of 600 consecutive patients with MDS who presented to MD Anderson Cancer Center from January 2002 to December 2004. The Adult Comorbidity Evaluation-27 (ACE-27) scale was used to assess comorbidities. Data on demographics, International Prognostic Scoring System (IPSS), treatment, and outcome (leukemic transformation and survival) were collected. Kaplan-Meier methods and Cox regression were used to assess survival. A prognostic model incorporating baseline comorbidities with age and IPSS was developed to predict survival. Results Overall median survival was 18.6 months. According to the ACE-27 categories, median survival was 31.8, 16.8, 15.2, and 9.7 months for those with none, mild, moderate, and severe comorbidities, respectively (P < .001). Adjusted hazard ratios were 1.3, 1.6, and 2.3 for mild, moderate, and severe comorbidities, respectively, compared with no comorbidities (P < .001). A final pognostic model including age, IPSS, and comorbidity score predicted median survival of 43.0, 23.0, and 9.0 months for lower-, intermediate-, and high-risk groups, respectively (P < .001). Conclusion Comorbidities have a significant impact on the survival of patients with MDS. Patients with severe comorbidity had a 50% decrease in survival, independent of age and IPSS risk group. A comprehensive assessment of the severity of comorbidities helps predict survival in patients with MDS.

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.

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