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Prognostic Relevance of Who 2016 Chronic Myelomonocytic Leukemia (CMML) Categories – Polish MDS Registry Results (Polish Adult Leukemia Group)
Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
Discussion: In the majority of patients with Hypo-MDS we observe a lower incidence of driver mutations of high risk, lower number of driver clones and lower variant allele frequency. The analysis of molecular pathway by variant, show than mutations in the splicing machinery were less frequent in Hypo-MDS than Hiper-MDS. This data support that Hypo-MDS may be a different clonal architecture with better prognosis. A larger cohort of patients is needed to confirm these data. 249 BONE MARROW FIBROSIS AT DIAGNOSIS IS ASSOCIATED WITH TP53 OVEREXPRESSION AND ADVERSE PROGNOSIS IN LOW-RISK MYELODYSPLASTIC SYNDROME R.P.G. Lemes1, F.B. Duarte2, M.C. Barbosa3, J.P. Vasconcelos2, F.D. Rocha4, T.E.J. Santos3, I. Zalcberg5, D.F. Coutinho5, P.R.L. Vasconcelos4 1 Universidade Federal do Ceara, Research Laboratory in Hemoglobinopathies and Genetics of Hematologic DiseasesPharmacy, Fortaleza, Brazil; 2Walter Cantídio University Hospital, Hematology Service, Fortaleza, Brazil; 3Universidade Federal do Ceara, Research Laboratory in Hemoglobinopathies and Genetics of Hematologic Diseases, Fortaleza, Brazil; 4Department of Surgery, Universidade Federal do Ceara, Fortaleza, Brazil; 5Cellular Therapy Center of Porto Alegre, Center for Experimental Research, Porto Alegre, Brazil Bone-marrow fibrosis is associated with dysplasia in multiple lineages, severe cytopenia, high transfusion dependence and reduced overall survival in patients with myelodysplastic syndrome (MDS). The present study investigated the role of bone marrow fibrosis as an auxiliary prognostic marker in patients with low-risk MDS. Seventy-three low-risk MDS patients participated in the study. Clinical data were obtained from medical records. The degrees of bone marrow fibrosis were established according to the criteria adopted by the European Myelofibrosis Network (EUMNET). TP53 expression analysis was performed by immunohistochemistry. Patients with bone marrow fibrosis at the diagnosis had significantly reduced haemoglobin and haematocrit values. Additionally, there was an association between the presence of bone marrow fibrosis and high TP53 expression. Overall survival analysis showed that patients with bone marrow fibrosis and high TP53 expression at the diagnosis had a shorter survival time. The results suggest that bone marrow fibrosis at the diagnosis, as well as high TP53 expression, may provide important prognostic information for patients with low-risk MDS. 250 IT IS EASIX TO PREDICT MORTALITY OF LOW RISK MDS PATIENTS T. Luft1, A. Hofmann1, U. Germing2, A. Radujkovic1, G. Kobbe2, P. Dreger1 1 Haematology/Rheumatology/Oncology, University Hospital, Heidelberg, Germany; 2Haematology- Oncology, University Hospital Düsseldorf, Düsseldorf, Germany Myelodysplastic Syndromes (MDS) are diseases of elderly patients. Cytogenetic and molecular aberrations help to predict the risk of transformation to acute myeloid leukemia (AML), however, the majority of low risk MDS patients will never progress to AML. Still, mortality is significantly increased in all but the very low risk MDS, and our understanding of this increased mortality is incomplete. Based on recent reports that elderly patients with clonal hematopoiesis mainly succumb to cardiovascular complications, we hypothesized that our recently developed Endothelial Activation and Stress IndeX (EASIX) may predict mortality in low risk MDS.
S143
EASIX is defined as the ratio of LDH*Creatinine/thrombocyte counts and was developed to predict endothelial complications such as transplant-related thrombotic microangiopathy (TMA) after allogeneic stem cell transplantation (alloSCT). The prognostic value of EASIX in the context of alloSCT was validated in three independent cohorts (Blood 2016 128:519). Here we tested EASIX calculated at initial diagnosis of MDS in two independent cohorts patients for predicting overall survival (training n = 142, validation n = 419). EASIX (quartiles) significantly predicted overall survival in 142 MDS patients in multivariable analyses including age, gender, bone marrow blasts, Hb and karyotype, (HR 1.34; 95% CI 1.07–1.69, p = 0.011). This could be validated in 419 independent MDS patients (HR 1.33; 95% CI 1.16–1.5, p < 0.001). Interestingly, subgroup analyses showed that EASIX predicted OS exclusively for low risk MDS patients treated with best supportive care who did not progress into AML (Figure 1).
Fig. 1. Overall survival after initial evaluation of EASIX in the subgroup of low risk MDS patients (BSC, never transformed to AML)
Our data support the hypothesis that comparable to elderly people with clonal hematopoiesis, death of low risk MDS patients may be associated with endothelial cell related complications. 251 PROGNOSTIC RELEVANCE OF WHO 2016 CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) CATEGORIES – POLISH MDS REGISTRY RESULTS (POLISH ADULT LEUKEMIA GROUP) K. Ma˛dry1, A. Waszczuk-Gajda1, J. Drozd-Sokołowska1, K. Lis1, A. Sikorska2, P. Szwedyk3, K. Kapelko-Słowik4, M. Dutka5, A. Jachalska6, A. Kopiń ska7, W. Konopiń ska-Posłuszny8, E. Subocz9, B. Pogłódek10, D. Krochmalczyk11, A. Kopacz12, M. Soroka-Wojtaszko13, A. Wa˛dałowska5, K. Gra˛dzka14, A. Kołkowska-Les´niak2, J. Dwilewicz-Trojaczek1 1 Hematology- Oncology and Internal Diseases, Medical University, Warsaw, Poland; 2Department of Hematology, Institute of Hematology and Transfusiology, Warsaw, Poland; 3Department of Hematology, Voivodal Specialistic Hospital, Kraków, Poland; 4Medical University, Clinic and Hematology- Blood Neoplasms and Bone Marrow Transplantation, Wrocław, Poland; 5Hematology and Bone Marrow Transplantation, Medical University, Gdańsk, Poland; 6Hematology, Medical University, Bydgoszcz, Poland; 7Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland; 8Hematology, SP ZOZ WMCO Oncology Center, Olsztyn, Poland; 9Hematology and Internal Diseases, Military Institute of Medicine, Warszawa, Poland; 10Hematology, Specialistic Hospital, Brzozów, Poland; 11Hematology, Jagiellonian University, Kraków, Poland; 12Hematology, Voivodal Specialistic Hospital, Rzeszów, Poland; 13Hematology, Medical University, Lublin, Poland; 14 Hematology, Medical University, Białystok, Poland Introduction: Three CMML categories were introduced in the 2016 revised classification based on blast marrow and blood percentage.
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Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
In the study we evaluated its prognostic value as well as other laboratory and clinical factors impact on survival. Methods: Between 2009 and 2017 221 CMML patients were registered prospectively in the Polish MDS Registry by PALG-MDSGroup. Data were reported from 20 Polish hematological centers. Epidemiological, clinical and laboratory data were obtained. Both WHO 2008 and 2016 classifications were applied. Results: Median age was 68 (range 23–93), 144 (65.2%) patients were males and 77 (34.8%) females. According to WHO 2016 classification 38% cases belonged to CMML 0 subtype, 33% CMML 1% and 27% CMML 2 and according to WHO 2008 72% cases were CMML 1% and 28% CMML2. Patients with WBC < 13 × 109/L accounted for 41.2% and with WBC ≥ 13 × 109/L 58.8% of patients. Cytogenetics was available in 169 (76.5%) patients. Most of cases showed low risk karyotype by IPSS 82% and by CPSS 81%. The IPSS score was lower risk in 68% and higher in 32%. The low, intermediate-1, intermediate-2 and high risk CPSS subgroups were represented by 21%, 31%, 41% and 7% patients respectively. Median survival in the whole series was 676 days. Univariate analysis showed that hemoglobin <10 g/dL, platelets <50 × 109/L, white blood cell count ≥13 × 109/L, presence of circulating immature myeloid cells, marrow blasts >5%, splenomegaly, RBC and platelet transfusion dependency, elevated LDH activity, hypoalbuminemia, ferritin concentration >1,000 ng/mL, CPSS higher score and CMML 1 and 2 subtypes by WHO 2016 but not CMML 2 subtype by WHO 2008 and higher IPSS were poor prognostic factors ( p < 0.05). In multivariate analysis only platelet transfusion dependency, elevated LDH, splenomegaly and advanced CMML subtypes by WHO 2016 were unfavorable prognostic markers ( p < 0.05). Conclusions: Incorporating CMML 0 in 2016 CMML classification makes more precise prognostication of CMML patients possible. Further studies with implementing new categories are needed and might be useful for earlier access to novel therapies e.g. hypomethylating agents.
252 AN IPSS-R CUTOFF POINT OF 3 STRATIFIED CHRONIC MYELOMONOCYTIC LEUKEMIA PATIENTS INTO TWO RISK GROUPS J. Montoro Gómez1, H. Pomares2, B. Merchan1, A. Molero1, E. Alonso3, M. Fernández1, L. Gallur1, J. Grau4, O. Salamero1, B. Tazón-Vega1, A. Blanco1, M. Ortega1, A. Sureda2, M. Arnán2, D. Valacárcel1 1 Hematology Department, Vall D´hebron University Hospital, Barcelona, Spain; 2Duran i Reynals Hospital- Hematology Department, Institut Català d´Oncologia, Barcelona, Spain; 3 Departmen of Patology, Bellvitge Hospital, Hospitalet, Spain; 4 Departmen of Laboratory Hematology- Hospital Universitari Germans Trias i Pujol, Institut Català d´Oncologia-Josep Carreras Leukemia Research Institute, Barcelona, Spain Introduction: The prognostic stratification of chronic myelomonocytic leukemia (CMML) is commonly based on the International Prognostic Scoring System (IPSS) or the CMML- Prognostic Score System (CPSS). The Revised International Prognostic Scoring System (IPSS-R) has improved the prognostic stratification and includes five risk groups. However, in clinical practice patients are divided into lower- and higher-risk according to the IPSS-R. It is not well defined which is the IPSS-R cutoff point that best divided patients in lower vs. higher risk CMML. The aim of the study is to stratify CMML patients into low vs. high risk patients according to the IPPS-R score and analyze the correlation between this and the CPSS prognostic index. Methods: We included all patients diagnosed with CMML from 2011 to 2016 in the Vall d´Hebron and Duran i Reynals hospitals. A
ROC curve analysis was performed to determine the optimal dichotomization into risk categories (lower-risk vs. higher-risk). Chi square test was used for categorical variables, t-test for continuous variables, Spearman correlation coefficient was used to analyze the association between indices, Akaike information criteria test to stimate the quality of each index and Kaplan-Meier for survival analysis. Statistical analysis was performed by STATA13.1 Results: We included 82 CMML patients. Overall survival (OS) was 31 months (CI95%: 22.8-NA). Forty percent of patients were dead at the time of the analysis. Patient characteristics are detailed in Table 1. The ROC curve analysis showed that the best dichotomization was obtained using an IPSS-R cutoff point of ≤3 vs. >3. According to this cutoff, 71 (87%) and 11 (13%) patients were classified as lower- or higher-risk CMML, with an OS of 31.4 months (CI95%: 25.5–NA) and 15 (CI95%: 3.9–NA) respectively; p = 0.001 (Figure 1). In the univariate analysis laboratory data, WHO classification and cytogenetic categories were statistically significant. Both prognostic indices have a clear correlation between them (rho = 0.52; p < 0.001) and the CPSS have the lowest value in the Akaike information criteria test (231 in CPSS vs. 237 in IPSS-R).
Discussion: In the majority of patients with Hypo-MDS we observe a lower incidence of driver mutations of high risk, lower number of driver clones and lower variant allele frequency. The analysis of molecular pathway by variant, show than mutations in the splicing machinery were less frequent in Hypo-MDS than Hiper-MDS. This data support that Hypo-MDS may be a different clonal architecture with better prognosis. A larger cohort of patients is needed to confirm these data. 249 BONE MARROW FIBROSIS AT DIAGNOSIS IS ASSOCIATED WITH TP53 OVEREXPRESSION AND ADVERSE PROGNOSIS IN LOW-RISK MYELODYSPLASTIC SYNDROME R.P.G. Lemes1, F.B. Duarte2, M.C. Barbosa3, J.P. Vasconcelos2, F.D. Rocha4, T.E.J. Santos3, I. Zalcberg5, D.F. Coutinho5, P.R.L. Vasconcelos4 1 Universidade Federal do Ceara, Research Laboratory in Hemoglobinopathies and Genetics of Hematologic DiseasesPharmacy, Fortaleza, Brazil; 2Walter Cantídio University Hospital, Hematology Service, Fortaleza, Brazil; 3Universidade Federal do Ceara, Research Laboratory in Hemoglobinopathies and Genetics of Hematologic Diseases, Fortaleza, Brazil; 4Department of Surgery, Universidade Federal do Ceara, Fortaleza, Brazil; 5Cellular Therapy Center of Porto Alegre, Center for Experimental Research, Porto Alegre, Brazil Bone-marrow fibrosis is associated with dysplasia in multiple lineages, severe cytopenia, high transfusion dependence and reduced overall survival in patients with myelodysplastic syndrome (MDS). The present study investigated the role of bone marrow fibrosis as an auxiliary prognostic marker in patients with low-risk MDS. Seventy-three low-risk MDS patients participated in the study. Clinical data were obtained from medical records. The degrees of bone marrow fibrosis were established according to the criteria adopted by the European Myelofibrosis Network (EUMNET). TP53 expression analysis was performed by immunohistochemistry. Patients with bone marrow fibrosis at the diagnosis had significantly reduced haemoglobin and haematocrit values. Additionally, there was an association between the presence of bone marrow fibrosis and high TP53 expression. Overall survival analysis showed that patients with bone marrow fibrosis and high TP53 expression at the diagnosis had a shorter survival time. The results suggest that bone marrow fibrosis at the diagnosis, as well as high TP53 expression, may provide important prognostic information for patients with low-risk MDS. 250 IT IS EASIX TO PREDICT MORTALITY OF LOW RISK MDS PATIENTS T. Luft1, A. Hofmann1, U. Germing2, A. Radujkovic1, G. Kobbe2, P. Dreger1 1 Haematology/Rheumatology/Oncology, University Hospital, Heidelberg, Germany; 2Haematology- Oncology, University Hospital Düsseldorf, Düsseldorf, Germany Myelodysplastic Syndromes (MDS) are diseases of elderly patients. Cytogenetic and molecular aberrations help to predict the risk of transformation to acute myeloid leukemia (AML), however, the majority of low risk MDS patients will never progress to AML. Still, mortality is significantly increased in all but the very low risk MDS, and our understanding of this increased mortality is incomplete. Based on recent reports that elderly patients with clonal hematopoiesis mainly succumb to cardiovascular complications, we hypothesized that our recently developed Endothelial Activation and Stress IndeX (EASIX) may predict mortality in low risk MDS.
S143
EASIX is defined as the ratio of LDH*Creatinine/thrombocyte counts and was developed to predict endothelial complications such as transplant-related thrombotic microangiopathy (TMA) after allogeneic stem cell transplantation (alloSCT). The prognostic value of EASIX in the context of alloSCT was validated in three independent cohorts (Blood 2016 128:519). Here we tested EASIX calculated at initial diagnosis of MDS in two independent cohorts patients for predicting overall survival (training n = 142, validation n = 419). EASIX (quartiles) significantly predicted overall survival in 142 MDS patients in multivariable analyses including age, gender, bone marrow blasts, Hb and karyotype, (HR 1.34; 95% CI 1.07–1.69, p = 0.011). This could be validated in 419 independent MDS patients (HR 1.33; 95% CI 1.16–1.5, p < 0.001). Interestingly, subgroup analyses showed that EASIX predicted OS exclusively for low risk MDS patients treated with best supportive care who did not progress into AML (Figure 1).
Fig. 1. Overall survival after initial evaluation of EASIX in the subgroup of low risk MDS patients (BSC, never transformed to AML)
Our data support the hypothesis that comparable to elderly people with clonal hematopoiesis, death of low risk MDS patients may be associated with endothelial cell related complications. 251 PROGNOSTIC RELEVANCE OF WHO 2016 CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) CATEGORIES – POLISH MDS REGISTRY RESULTS (POLISH ADULT LEUKEMIA GROUP) K. Ma˛dry1, A. Waszczuk-Gajda1, J. Drozd-Sokołowska1, K. Lis1, A. Sikorska2, P. Szwedyk3, K. Kapelko-Słowik4, M. Dutka5, A. Jachalska6, A. Kopiń ska7, W. Konopiń ska-Posłuszny8, E. Subocz9, B. Pogłódek10, D. Krochmalczyk11, A. Kopacz12, M. Soroka-Wojtaszko13, A. Wa˛dałowska5, K. Gra˛dzka14, A. Kołkowska-Les´niak2, J. Dwilewicz-Trojaczek1 1 Hematology- Oncology and Internal Diseases, Medical University, Warsaw, Poland; 2Department of Hematology, Institute of Hematology and Transfusiology, Warsaw, Poland; 3Department of Hematology, Voivodal Specialistic Hospital, Kraków, Poland; 4Medical University, Clinic and Hematology- Blood Neoplasms and Bone Marrow Transplantation, Wrocław, Poland; 5Hematology and Bone Marrow Transplantation, Medical University, Gdańsk, Poland; 6Hematology, Medical University, Bydgoszcz, Poland; 7Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland; 8Hematology, SP ZOZ WMCO Oncology Center, Olsztyn, Poland; 9Hematology and Internal Diseases, Military Institute of Medicine, Warszawa, Poland; 10Hematology, Specialistic Hospital, Brzozów, Poland; 11Hematology, Jagiellonian University, Kraków, Poland; 12Hematology, Voivodal Specialistic Hospital, Rzeszów, Poland; 13Hematology, Medical University, Lublin, Poland; 14 Hematology, Medical University, Białystok, Poland Introduction: Three CMML categories were introduced in the 2016 revised classification based on blast marrow and blood percentage.
S144
Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
In the study we evaluated its prognostic value as well as other laboratory and clinical factors impact on survival. Methods: Between 2009 and 2017 221 CMML patients were registered prospectively in the Polish MDS Registry by PALG-MDSGroup. Data were reported from 20 Polish hematological centers. Epidemiological, clinical and laboratory data were obtained. Both WHO 2008 and 2016 classifications were applied. Results: Median age was 68 (range 23–93), 144 (65.2%) patients were males and 77 (34.8%) females. According to WHO 2016 classification 38% cases belonged to CMML 0 subtype, 33% CMML 1% and 27% CMML 2 and according to WHO 2008 72% cases were CMML 1% and 28% CMML2. Patients with WBC < 13 × 109/L accounted for 41.2% and with WBC ≥ 13 × 109/L 58.8% of patients. Cytogenetics was available in 169 (76.5%) patients. Most of cases showed low risk karyotype by IPSS 82% and by CPSS 81%. The IPSS score was lower risk in 68% and higher in 32%. The low, intermediate-1, intermediate-2 and high risk CPSS subgroups were represented by 21%, 31%, 41% and 7% patients respectively. Median survival in the whole series was 676 days. Univariate analysis showed that hemoglobin <10 g/dL, platelets <50 × 109/L, white blood cell count ≥13 × 109/L, presence of circulating immature myeloid cells, marrow blasts >5%, splenomegaly, RBC and platelet transfusion dependency, elevated LDH activity, hypoalbuminemia, ferritin concentration >1,000 ng/mL, CPSS higher score and CMML 1 and 2 subtypes by WHO 2016 but not CMML 2 subtype by WHO 2008 and higher IPSS were poor prognostic factors ( p < 0.05). In multivariate analysis only platelet transfusion dependency, elevated LDH, splenomegaly and advanced CMML subtypes by WHO 2016 were unfavorable prognostic markers ( p < 0.05). Conclusions: Incorporating CMML 0 in 2016 CMML classification makes more precise prognostication of CMML patients possible. Further studies with implementing new categories are needed and might be useful for earlier access to novel therapies e.g. hypomethylating agents.
252 AN IPSS-R CUTOFF POINT OF 3 STRATIFIED CHRONIC MYELOMONOCYTIC LEUKEMIA PATIENTS INTO TWO RISK GROUPS J. Montoro Gómez1, H. Pomares2, B. Merchan1, A. Molero1, E. Alonso3, M. Fernández1, L. Gallur1, J. Grau4, O. Salamero1, B. Tazón-Vega1, A. Blanco1, M. Ortega1, A. Sureda2, M. Arnán2, D. Valacárcel1 1 Hematology Department, Vall D´hebron University Hospital, Barcelona, Spain; 2Duran i Reynals Hospital- Hematology Department, Institut Català d´Oncologia, Barcelona, Spain; 3 Departmen of Patology, Bellvitge Hospital, Hospitalet, Spain; 4 Departmen of Laboratory Hematology- Hospital Universitari Germans Trias i Pujol, Institut Català d´Oncologia-Josep Carreras Leukemia Research Institute, Barcelona, Spain Introduction: The prognostic stratification of chronic myelomonocytic leukemia (CMML) is commonly based on the International Prognostic Scoring System (IPSS) or the CMML- Prognostic Score System (CPSS). The Revised International Prognostic Scoring System (IPSS-R) has improved the prognostic stratification and includes five risk groups. However, in clinical practice patients are divided into lower- and higher-risk according to the IPSS-R. It is not well defined which is the IPSS-R cutoff point that best divided patients in lower vs. higher risk CMML. The aim of the study is to stratify CMML patients into low vs. high risk patients according to the IPPS-R score and analyze the correlation between this and the CPSS prognostic index. Methods: We included all patients diagnosed with CMML from 2011 to 2016 in the Vall d´Hebron and Duran i Reynals hospitals. A
ROC curve analysis was performed to determine the optimal dichotomization into risk categories (lower-risk vs. higher-risk). Chi square test was used for categorical variables, t-test for continuous variables, Spearman correlation coefficient was used to analyze the association between indices, Akaike information criteria test to stimate the quality of each index and Kaplan-Meier for survival analysis. Statistical analysis was performed by STATA13.1 Results: We included 82 CMML patients. Overall survival (OS) was 31 months (CI95%: 22.8-NA). Forty percent of patients were dead at the time of the analysis. Patient characteristics are detailed in Table 1. The ROC curve analysis showed that the best dichotomization was obtained using an IPSS-R cutoff point of ≤3 vs. >3. According to this cutoff, 71 (87%) and 11 (13%) patients were classified as lower- or higher-risk CMML, with an OS of 31.4 months (CI95%: 25.5–NA) and 15 (CI95%: 3.9–NA) respectively; p = 0.001 (Figure 1). In the univariate analysis laboratory data, WHO classification and cytogenetic categories were statistically significant. Both prognostic indices have a clear correlation between them (rho = 0.52; p < 0.001) and the CPSS have the lowest value in the Akaike information criteria test (231 in CPSS vs. 237 in IPSS-R).