Incidence and Prevalence of Patients with Myelodysplastic Syndromes (MDS) in Düsseldorf 1996-2005.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1774-1774 ◽  
Author(s):  
Judith Neukirchen ◽  
W. Marieke Schoonen ◽  
Carlo Aul ◽  
Rainer Haas ◽  
Norbert Gattermann ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Population Based ◽  
Low Risk ◽  
High Risk Disease ◽  
Population Counts ◽  
Incident Cases ◽  
The Town ◽  
Age And Sex

Abstract Abstract 1774 Poster Board I-800 Background Population-based data on myelodysplastic syndromes (MDS) are scarce. Since its inception in 1982, the Düsseldorf MDS Registry has captured 3598 patients with MDS, of whom 21 % live in the town district of Düsseldorf. Between 1996-2005 we are confident that all MDS patients residing in the town district of Düsseldorf were entered and followed in the registry through regular follow-ups. As yearly age- and sex-specific population counts are also available for Düsseldorf, the Registry provides a unique opportunity to estimate MDS disease frequency. Here we aim to quantify the incidence and prevalence of MDS disease subtypes. Methods Patients were identified from the MDS Registry. Age- and sex-specific yearly population counts were obtained from the Statistical Office of North-Rhine Westphalia. The number of residents in Düsseldorf minimally increased during the study period from 1996 to 2005 (mean: 571,000 residents). The number of patients with a first-time MDS diagnosis in a given calendar year (incident cases) was divided by the total Düsseldorf population in that year to estimate incidence. Prevalence was estimated by dividing the number of existing plus incident MDS patients in a given year by the total population of Düsseldorf that year. Incidence (per 100,000 person-years (PY) and prevalence per 100,000 persons are presented with corresponding 95% confidence intervals (CI) calculated using the delta and Wilson methods, respectively. Low-risk MDS was defined as WHO subtypes RA, RCMD or MDS with del(5q). High-risk included subtypes RAEB-I and RAEB-II. Results 344 MDS patients were included in our analyses (279 incident patients). Incidence and prevalence of low-risk MDS was 2.87 (95%CI 2.46–3.35) per 100,000PY and 12.4 (95%CI 11.5–13.4) per 100,000 persons, respectively, with no difference between men and women (Table). High-risk disease was less common. The incidence of high-risk disease in men appeared to be higher (1.22 (95%CI 0.87–1.72) per 100,000PY) than in women (0.63 (95%CI 0.40–0.99) per 100,000PY). Prevalence of high-risk disease among men was statistically significantly higher in men compared to women (2.93 (95%CI 2.35 – 3.65) per 100,000 persons) and 1.56 (95%CI 1.17 – 2.08) per 100,000 persons), respectively (Table). Conclusion In this population-based study we found that MDS more common in men than in women. The majority of MDS cases had low-risk disease. Incidence and prevalence of high risk disease (but not low risk) is higher in men compared to women. Financial disclosures: This study was supported by Amgen Inc. Disclosures Neukirchen: Amgen Inc.: Research Funding. Schoonen:Amgen Inc.: Research Funding. Aul:Amgen Inc.: Research Funding. Haas:Amgen Inc.: Research Funding. Gattermann:Amgen Inc., Celgene, Novartis: Honoraria, Research Funding. Germing:Amgen Inc., Celgene, Novartis: Honoraria, Research Funding.

Outcome Of Patients (pts) With Low and Intermediate-1 Risk Myelodysplastic Syndrome (MDS) After Hypomethylating Agent (HMA) Failure

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 388-388 ◽  
Author(s):  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
Lianchun Xiao ◽  
Al Ali Najla ◽  
Asmita Mishra ◽  
...  
Keyword(s):  
High Risk ◽  
Scoring System ◽  
Lower Risk ◽  
Research Funding ◽  
Complete Response ◽  
Low Risk ◽  
International Prognostic Scoring System ◽  
Cancer Center ◽  
Primary Resistance ◽  
High Risk Disease

Abstract Background HMA are standard of care in pts with high-risk MDS and commonly used in pts with lower risk. Pts with high-risk disease post HMA failure have a poor prognosis with a median survival of 4-6 months. The prognosis of pts with low and intermediate-1 risk MDS by the International Prognostic Scoring System (IPSS) after HMA failure is not known. Aims To assess outcome of pts with low and intermediate-1 risk disease post HMA failure that might benefit from specific strategies or investigational agents. Methods Data from 423 pts with low (n= 141, 33%) and intermediate-1 risk disease (n=282, 67%) by IPSS score treated with HMA at MD Anderson Cancer Center (MDACC; n=144) and Moffitt Cancer Center (MCC; n=279) between 2000 and 2011 were analyzed. Results Median age was 69 years. 294 (69%) pts had a diploid cytogenetic analysis. 63 (15%) pts had therapy-related MDS. 282 (67%) pts received azacitidine, 87 (21%) decitabine, and 54 (12%) both. Median number of cycles of HMA administered was 6 (range, 1-64) for a median duration of therapy of 7 months (range, 1- 74). Best response to HMA was complete response (CR) in 39 (9%) pts, partial response (PR) in 13 (3%), a bone marrow CR in 6 (1%), and hematologic improvement (HI) in 90 (21%) pts. Pts had discontinued HMA because of primary resistance in 198 (47%) pts, loss of response in 141 pts (33%), intolerance in 13 pts (3%) and other reasons in 71 pts (17%). At the time of HMA failure, 81 (19%) pts transformed into acute myeloid leukemia (AML). Of the 302 remaining pts evaluable by IPSS, 67 (22%) pts were of low-risk, 158 (53%) of intermediate-1 risk, 48 (16%) of intermediate-2 risk, and 29 (9%) of high-risk disease. By the revised IPSS (R-IPSS), the percentage of pts with low, very low, intermediate, high, and very high risk disease were 11%, 29%, 30%, 20%, and 10%, respectively. By the MDACC global prognostic scoring system (MDGPSS) 18%, 35%, 29%, and 18%, of the pts were of low-risk, intermediate-1, intermediate-2, and high-risk disease, respectively. After a median follow-up of 16 months from HMA failure, 117 (28%) pts remained alive. The median overall survival (OS) was 15 months (95% CI: 12-18) with estimated 1- and 3-year OS rates of 55% and 27%, respectively. Both, the R-IPSS and the MDGPSS were predictive of survival post HMA failure (Table 1 ). Conclusion In the largest cohort of lower risk MDS pts treated with HMA, the outcome after HMA failure is poor. Treatment of those patients remains an unmet medical need. OS is a reasonable primary endpoint for clinical studies targeting this population. Disclosures: Lancet: Celgene: Research Funding. Sekeres:Celgene: Consultancy; Amgen: Consultancy. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau.

scholarly journals A Novel Prognostic Model That Is Superior to FLIPI-1 and FLIPI-2 and Integrates Clinical and Treatment Factors to Predict Progression-Free Survival and Early Treatment Failure in Patients with Follicular Lymphoma in the GALLIUM Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2872-2872 ◽  
Author(s):  
Farheen Mir ◽  
Andrew Grigg ◽  
Michael Herold ◽  
Wolfgang Hiddemann ◽  
Robert Marcus ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Model ◽  
Low Risk ◽  
Prognostic Variables ◽  
Advisory Committees ◽  
High Risk Disease ◽  
Risk Patients ◽  
Equity Ownership

Abstract Introduction: Progression of disease within 24 months of initial therapy (POD24) is associated with poor survival in patients with follicular lymphoma (FL). Existing prognostic models, such as FLIPI-1 and FLIPI-2, show poor sensitivity for POD24, and are derived from cohorts lacking bendamustine-treated patients. More accurate predictive models based on current standard therapies are needed to identify patients with high-risk disease. The Phase III GALLIUM trial (NCT01332968) compared the safety and efficacy of standard chemotherapy regimens plus rituximab (R) or obinutuzumab (G) in patients with previously untreated FL. Using GALLIUM data, we developed a novel risk stratification model to predict both PFS and POD24 in FL patients after first-line immunochemotherapy. Methods: Enrolled patients were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulk), and ECOG PS ≤2, and required treatment by GELF criteria. Patients were randomized to receive either G- or R-based immunochemotherapy, followed by maintenance with the same antibody in responders. The chemotherapy arm (CHOP, CVP, or bendamustine) was selected by each study center. POD24 was defined as progressive disease or death due to disease within 24 months of randomization (noPOD24 = no progression or lymphoma-related death in that period). The most strongly prognostic variables, based on PFS hazard ratios, were estimated using penalized multivariate Cox regression methodology via an Elastic Net model. Selected variables were given equal weights, and a clinical score was formed by summating the number of risk factors for each patient. Low- and high-risk categories were determined using a cut-off that provided the best balance between true- and false-positives for PFS. PFS correlation and sensitivity to predict POD24 were assessed. The data used are from an updated GALLIUM efficacy analysis (data cut-off: April 2018; median follow-up: 57 months). Results: 1202 FL patients were enrolled. Based on data availability and biological plausibility (i.e. could reasonably be linked with high-risk disease), 25 potential clinical and treatment-related prognostic variables were entered into the Elastic Net model (Table). A model containing 11 factors was retained by the methodology and chosen as the best model (Table). Patients were categorized as 'low risk' if they scored between 0 and 3 (n=521/1000 patients with complete data) and as 'high risk' if they scored between 4 and 11 (n=479/1000 patients). At 2 years, the PFS rate was 84.5% in the whole FL population. Using our model, 2-year PFS for high-risk patients was 77% compared with 79.9% for FLIPI-1 and FLIPI-2. In low-risk patients, 2-year PFS was 92% compared with 87.9% for FLIPI-1 and 87.6% for FLIPI-2 (low-intermediate-risk patients). Our model increased the inter-group difference in 2-year PFS rate from 8% (FLIPI-1) and 7.7% (FLIPI-2) to 15%. At 3 years, the inter-group difference increased from 6.9% (FLIPI-1) and 9% (FLIPI-2) to 17% (Figure). Sensitivity for a high-risk score to predict POD24 was 73% using our model compared with 55% for FLIPI-1 and 52% for FLIPI-2 (based on 127 POD24 and 873 noPOD24 patients with complete data). Excluding patients who received CVP, which is now rarely used, resulted in an inter-group difference in PFS of 15% at 2 years and 16.8% at 3 years. A sensitivity analysis showed that inclusion of the 9 clinical factors only (i.e. removal of CVP and R treatment as variables) formed a more basic scoring system (low-risk patients, 1-3; high-risk patients, 4-9); the inter-group difference in PFS was 16.5% at 2 years and 17.6% at 3 years. However, sensitivity for POD24 decreased to 56%. Conclusion: Our clinical prognostic model was more accurate at discriminating patients likely to have poor PFS than either FLIPI-1 or FLIPI-2, and its prognostic value was sustained over time. Our model also identified the FL population at risk of POD24 with greater sensitivity. Variables such as age and bone marrow involvement were not retained by our model, and thus may not have a major impact in the current era of therapy. Factors such as sum of the products of lesion diameters were included, as this captures tumor burden more accurately than presence of bulk disease. Future studies will aim to improve the accuracy of the model by considering gene expression-based prognostic markers and DNA sequencing to form a combined clinico-genomic model. Disclosures Mir: F. Hoffmann-La Roche: Employment. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy. Seymour:Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bolen:Roche: Other: Ownership interests PLC*. Knapp:Roche: Employment. Launonen:Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Roche: Employment, Other: Travel, accommodation, expenses. Mattiello:Roche: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Casulo:Gilead: Honoraria; Celgene: Research Funding.

Reduced TET2 expression in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2822-2822
Author(s):  
Renata Scopim-Ribeiro ◽  
Joao Machado-Neto ◽  
Paula de Melo Campos ◽  
Patricia Favaro ◽  
Adriana S. S. Duarte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Erythroid Differentiation ◽  
Low Risk ◽  
High Risk Disease ◽  
Cd34 Cells ◽  
Acute Myeloid

Abstract Abstract 2822 Introduction: Acquired mutations in TET2 and DNMT3A have been found in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and may predict a worse survival in these diseases. TET2 mutations are considered to be a loss-of-function mutation and results in decreased 5-hydroxymethylcitosine (5-hmc) levels. In normal CD34+ cells, TET2 silencing skews progenitor differentiation towards the granulomonocytic lineage at the expense of lymphoid and erythroid lineages. Dnmt3a participates in the epigenetic silencing of hematopoietic stem cell regulatory genes, enabling efficient differentiation. Here, we attempted to evaluate the expression of TET2 and DNMT3A in total bone marrow cells from normal donors, patients with MDS and AML, and in CD34+ cells from MDS and normal controls during erythroid differentiation. Materials and Methods: The study included normal donors (n = 21), patients with MDS (n = 43) and AML (n = 42) at diagnosis. All normal donors and patients provided informed written consent and the study was approved by the ethics committee of the Institution. MDS patients were stratified into low and high-risk according to WHO classification (RCUD/RCMD/RARS=31 and RAEB1/RAEB2=12). TET2 and DNMT3A mRNA expression was assessed by quantitative PCR. CD34+ cells from normal donors (n = 9) and low-risk MDS patients (n = 7) were submitted to erythroid differentiation. Cells were collected and submitted to immunophenotyping for GPA and CD71 (days 6 and 12) and q-PCR for TET2 and DNMT3A expression (days 6, 8 and 12). Results of gene expression in normal donors and patients are presented as median, minimum-maximum, and were compared using Mann-Whitney test. Student t test was used for comparison of gene expression during CD34+ erythroid diferentiation. Overall survival was defined from the time of sampling to the date of death or last seen. Univariate analysis for overall survival was conducted with the Cox proportional hazards model. Results: TET2 expression was significantly reduced in both AML (0.62; 0.01–32.69) and MDS (1.46; 0.17–21.30) compared to normal donors (2.72; 0.43–31.49); P<0.0001 and P=0.01, respectively. TET2 expression was also significantly reduced in AML compared to MDS (P=0.0007). MDS patients were stratified into low and high-risk disease, and we still observed a significant reduction in TET2 expression in high-risk (0.73, 0.17–7.25) when compared to low-risk (1.58; 0.48–21.30; P=0.02) patients, but no difference was noted between normal donors vs. low-risk MDS, and high-risk MDS vs. AML. In MDS cohort, the median overall survival was 14 months (range 1–83), increased TET2 expression was associated with a longer survival (HR, 0.44; 95% CI, 0.21–0.91, P=0.03), and, as expected, WHO high-risk disease was associated with a shorter survival (HR, 10.16; 95% CI, 3.06–33.72, P<0.001), even though the confidence interval (CI) was large. TET2 expression did not impact survival in our cohort of AML patients. The erythroid differentiation was effective in cells from normal donors and MDS patients, as demonstrated by the flow cytometry analyses of GPA and CD71. TET2 expression was significantly increased on day 12 of erythroid differentiation, P<0.05. On the other hand, DNMT3A expression was similar between normal donors (0.74; 0.22–1.53), MDS (0.78; 0.26–3.46) and AML (0.95, 0.15–6.46), and during erythroid differentiation, with no impact on survival. Conclusion: These data suggest that decreased TET2 expression may participate in leukemogenesis, and supports the participation of TET2 in the erythroid differentiation of MDS. DNMT3A was not differentially expressed in AML and MDS, indicating that the presence of mutations in this gene may be the predominant mechanism of changes in protein function. We thus suggest that decreased TET2 expression may explain the reduced levels of 5-hmc found in TET2 wild type patients, and may become a predictive marker for outcomes in MDS and other myeloid diseases. Further studies would be necessary to better elucidate the clinical relevance and biologic significance of our findings, and whether the decreased TET2 expression results in hypermethylation in these diseases. Disclosures: Maciejewski: NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding.

scholarly journals REVEAL: Characteristics of Patients with Polycythemia Vera Who Were Diagnosed within 6 Months of Enrollment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5370-5370
Author(s):  
Aaron T. Gerds ◽  
Ivy Altomare ◽  
Philomena Colucci ◽  
Dilan Paranagama ◽  
John M Burke
Keyword(s):  
High Risk ◽  
Polycythemia Vera ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Prospective Observational Study ◽  
Low Risk ◽  
Early Satiety ◽  
High Risk Disease ◽  
History Of ◽  
Equity Ownership

Background Polycythemia vera (PV), characterized by erythrocytosis and JAK2 mutations, is associated with increased morbidity and mortality. Patients (pts) are at risk for thrombotic events and experience symptoms (sxs) that may impact quality of life. Data describing the clinical characteristics of pts with PV at the time of diagnosis (dx) are limited. The Prospective Observational Study of Patients with Polycythemia Vera in US Clinical Practices (REVEAL) is a multicenter, prospective, observational study designed to collect data on disease burden, clinical management, and pt-reported outcomes (PROs) of adult pts (aged ≥18) with PV. This analysis describes pt demographic and clinical characteristics, treatment patterns, and sxs of newly dxed pts with PV. Methods Pts enrolled in REVEAL who were dxed ≤6 months prior to enrollment were included in this analysis. Descriptive statistics were used to summarize pt demographic and clinical characteristics, tests at dx, and management patterns at dx. Sxs were assessed with a validated PRO instrument: the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). Mean and standard deviation for individual sx scores and total sx score (TSS) at enrollment are reported. Results Of the 2510 pts enrolled in REVEAL, 321 dxed within 6 months of enrollment were included in this analysis. Median age at enrollment was 67.0 (range, 23.0-94.0) years, 54.8% were male, and most (74.5%) had high-risk disease (aged ≥60 years and/or history of thrombosis). The most common physician-reported symptoms at the time of presentation included fatigue (24.6%), pruritus (17.1%), insomnia (10.3%), and muscle aches/bone pain (9.7%). Of those pts reported to have undergone mutation testing at dx (n=201), 99.5% were JAK2V617F positive. A history of thrombosis was reported for 15.9% of pts (arterial, 8.1%; venous, 8.7%), and the most common relevant comorbidities were hypertension (58.6%), obesity (19.6%), and diabetes mellitus (15.9%). Of 188 pts with lab values within 1 month before dx, 95.2% had elevated (≥45%) hematocrit and 59.6% had elevated (>10 × 109/L) white blood cell counts. Most high-risk and low-risk pts were reported to have received phlebotomies within 6 months after dx (71.7% and 78.4%, respectively). A higher proportion of pts with high-risk disease initiated a pharmacologic therapy for PV compared with those who had low-risk disease (60.5% vs 23.9%); hydroxyurea (HU) was the most common cytoreductive therapy (n=151 [93.2%]). Most of these pts (n=137 [90.7%]) were still receiving HU 2 years after dx. Of those who initiated HU within 6 months of dx, 5.3% (n=8) received an alternative cytoreductive therapy following HU. A total of 287 pts provided PRO data at enrollment (Table 1). The most common pt-reported sxs were fatigue (77.2%), early satiety (61.1%), and inactivity (58.0%); the mean (SD) MPN-SAF TSS was 18.5 (15.6). The sxs with the highest reported mean (SD) scores were fatigue (3.4 [2.7]), inactivity (2.6 [2.9]), and early satiety (2.5 [2.6]) and were largely similar between low-risk and high-risk pts. Conclusions Compared with all 2510 pts enrolled in REVEAL (Clin Lymphoma Myeloma Leuk 2018[18]12:788-95), this subgroup of 321 pts dxed within 6 months of enrollment was similar with respect to age and sex. However, in the newly dxed subgroup, a slightly lower proportion of pts (74.5%) had high-risk disease (77.3% of the full cohort). In the newly dxed subgroup, a higher proportion of pts (62.6%) underwent mutation testing (49.2% of all enrolled pts). The HU discontinuation rate early in the treatment course was approximately 9.3%, which is similar to the rate (6.3%) of HU discontinuation due to toxicity in patients with PV in a large, multicenter, MPN cohort (Am JHematol 2012[87]5:552-4). Sx burden in pts who completed the MPN-SAF TSS at enrollment was similar in the newly dxed pts (mean TSS, 18.5) and all pts enrolled in REVEAL (18.8; Clin Lymphoma Myeloma Leuk 2018[18]9:590-6); the most frequent pt-reported sxs (fatigue, early satiety, and inactivity) in this smaller pt subgroup were the same as those observed in the larger pt cohort. Overall, near the time of dx, a greater proportion of pts had low-risk disease. Despite this difference, the sx constellation and severity tends to be very similar to the larger cohort. It also appears that only a very small proportion of pts are unable to tolerate HU early on in the course of the disease. Disclosures Gerds: Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Pfizer: Consultancy; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding. Altomare:Novartis: Consultancy; Amgen: Consultancy; Incyte: Consultancy, Speakers Bureau; Rigel: Consultancy. Colucci:Incyte: Employment, Equity Ownership. Paranagama:Incyte: Employment, Equity Ownership. Burke:Roche/Genentech: Consultancy; Celgene: Consultancy; Gilead: Consultancy.

scholarly journals Transplantation Outcome By Disease Risk and Donor Type over Time: An Analysis of 100,000 Allogeneic Stem Cell Transplantation on Behalf of the Acute Leukemia Working Party of the EBMT

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 668-668
Author(s):  
Roni Shouval ◽  
Joshua Fein ◽  
Myriam Labopin ◽  
Nicolaus Kröger ◽  
Rafael F Duarte ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Disease Risk ◽  
Disease Status ◽  
Low Risk ◽  
Allogeneic Hsct ◽  
High Risk Disease ◽  
Donor Type ◽  
Unrelated Donors ◽  
Matched Sibling

Abstract Background: Donor type is a key modifiable determinant of outcome following allogeneic hematopoietic stem cell transplantation (HSCT). Utilizing a dataset of more than 100,000 allogeneic transplantations registered with the European Society for Blood and Marrow Transplantation (EBMT), we sought to characterize the evolution of outcomes in transplantation with different donor types across levels of disease-associated risk. Methods: This retrospective study included adult patients treated for hematologic malignancies who underwent first allogeneic HSCT between 2000 and 2015 in EBMT centers. Cord-blood transplantations were excluded, as were patients for whom diagnosis, disease status, or donor relationship were unknown. Missing values were accounted for by multiple imputations. A three-level disease-risk scheme (low, intermediate, and high), was defined by introducing combinations of diagnosis and disease status into a Cox multivariate model for overall survival (OS), similar to the method employed in creating the Disease Risk Index (Armand et al., Blood, 2014). Additional covariates included in the model were reflective of patient, disease, transplant, and center related features. Patients were classified according to a combination of disease risk, donor type, and HSCT year (2000-2005, 2006-2010, 2011-2015). A variable capturing the grouping was introduced into a Cox multivariate analysis adjusted for major transplantation parameters, with the reference category being a matched sibling donor in low-risk disease transplanted between 2011 and 2015. OS was estimated using the Kaplan-Meier method. Competing risk analysis was used to calculate cumulative incidence of non-relapse mortality (NRM) and relapse. Results: A total of 106,086 patients were included in the analysis, with a median age of 48 years (IQR 36-58); Twenty five percent of patients were transplanted between 2000 - 2005, 33% between 2006 and 2010 and 42% between 2011 and 2015. The leading indications for HSCT were acute leukemia (58%), myeloproliferative neoplasms (11%) and non-Hodgkin's lymphomas (10%). Recipients had either HLA matched sibling donors (MSD) (46%), unrelated donors (overall 50%; HLA matched 10/10 (MUD) [20%], mismatched HLA 9/10 (MMUD) [6%], mismatched HLA&lt;9/10 [2%], imputed HLA match [21%]) or haploidentical (Haplo) (4%) donors. Graft source was primarily peripheral blood (81%). Myeloablative conditioning was used in 53% of cases. The median follow-up was 3.6 years (95% CI 3.5-3.6). The risk of overall mortality varied depending on the combination of donor type, disease risk and transplantation year (figure A). In low and intermediate risk disease, a matched sibling donor had the most favorable outcome across year-periods. However, in high-risk disease, overlapping hazard ratios (HRs) were observed between MSD and MUD in 2011-2015 (2.8 [2.6-3.0] versus 3.0 [2.8-3.2], respectively). The cumulative incidence for NRM for MSD vs. MUD in high-risk disease transplanted from 2011-2015 was 26.1% (23.8-28.6) vs. 35.3% (32.6-38.3, p &lt; 0.0001), respectively. Similarly, relapse incidence was 50.7% (48.0-53.6) vs. 41.0% (38.3-44.0, p &lt; 0.0001). In high disease risk, the risk for mortality has decreased over the years for MSD and MUD, and even more so for transplantations from Haplo donors (2000-2005 HR 5.11 [4.3-6.1]; 2011-2015 HR 3.9 [3.5-4.3]). In the low-risk setting, transplantations from Haplo donors had a comparable risk to MSD and MUD (2011-2015 Low risk: MSD reference, MUD 1.2 [1.1-1.3], Haplo 1.3 [1.2-1.5]). A representative example is seen in Figure B: the probability of 2-year overall survival between 2011-2015, low risk in MSD was 66.5% (95% CI 65.0-68.0), MUD 63.4% (61.7-65.1), and Haplo 60.4 (56.9-64.1). Conclusion: Survival has improved following allogeneic HSCT over the past two decades. This improvement is especially clear in the case of haploidentical donors, though MSD and MUD are still associated with better outcomes. In high-risk disease, the risk of mortality is equivalent between matched sibling and matched unrelated donors. Notably, the probability for NRM is higher with MUD, but relapse incidence is lower, emphasizing the importance of graft-versus-tumor effect in the high-risk setting and the ongoing need for NRM reduction strategies. Disclosures Kröger: Janssen Global Services, LLC: Speakers Bureau; Amgen Inc.: Speakers Bureau; Novartis AG: Research Funding; RIEMSER Pharma: Research Funding; Neovii Pharmaceuticals AG: Speakers Bureau; Novartis AG: Speakers Bureau; Sanofi: Speakers Bureau. Bader: Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding. Kuball: Miltenyi: Research Funding; Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gdT cells and receptors and isolation strategies , Research Funding. Snowden: Sanofi: Honoraria. Mohty: Sanofi: Honoraria, Speakers Bureau.

scholarly journals Very similar cardiometabolic profile in the moderate and high cardiovascular risk classes: a population-based study

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
M Chlabicz ◽  
J Jamolkowski ◽  
W Laguna ◽  
P Sowa ◽  
M Paniczko ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Cardiovascular Risk ◽  
High Risk ◽  
Population Based ◽  
Low Risk ◽  
Public Institution ◽  
Population Based Study ◽  
The Metabolic Syndrome ◽  
Cardiometabolic Profile

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Medical University of Bialystok, Poland Background Cardiovascular disease (CVD) is a major, worldwide problem and remain the dominant cause of premature mortality in the word. Simultaneously the metabolic syndrome is a growing problem. The aim of this study was to investigate the cardiometabolic profile among cardiovascular risk classes, and to estimate CV risk using various calculators. Methods The longitudinal, population-based study, was conducted in 2017-2020. A total of 931 individuals aged 20-79 were included. Anthropometric and biochemical profiles were measured according to a standardized protocols. The study population was divided into CV risk classes according to the latest recommendation. Comparisons variables between subgroups were conducted using Dwass-Steele-Critchlow-Fligner test. To estimate CV risk were used: the  Systematic Coronary Risk Estimation system, Framingham Risk Score and LIFEtime-perspective model for individualizing CardioVascular Disease prevention strategies in apparently healthy people (LIFE-CVD). Results The mean age was 49.1± 15.5 years, 43.2% were male. Percentages of low-risk, moderate-risk, high-risk and very-high CV risk were 46.1%, 22.8%, 13.5%, 17.6%, respectively. Most of the analyzed anthropometric, body composition and laboratory parameters did not differ between the moderate and high CV risk participants, whereas the low risk group differed significantly. In the moderate and high-risk groups, abdominal distribution of adipose tissue dominated with significantly elevated parameters of insulin resistance. Interestingly, estimating lifetime risk of myocardial infarction, stroke or CV death using LIFE-CVD calculator yielded similar results in moderate and high CV risk classes. Conclusion The participants belonging to moderate and high CV risk classes have a very similar unfavorable cardiometabolic profile which may result in the similar lifetime CV risk. This may imply the need for more aggressive pharmacological and non-pharmacological management of CV risk factors in the moderate CV risk population. It would be advisable to consider combining the moderate and high risk classes into one high CV risk class, or it may be worth adding one of the parameters of abdominal fat distribution to the CV risk calculators as an expression of increased insulin resistance. Abstract Figure 1.

Real-World Experience with Minimal Residual Disease Testing with Next Generation Flow Cytometry and Functional Imaging in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
David Böckle ◽  
Paula Tabares Gaviria ◽  
Xiang Zhou ◽  
Janin Messerschmidt ◽  
Lukas Scheller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
High Risk ◽  
Functional Imaging ◽  
Real World ◽  
Research Funding ◽  
Residual Disease ◽  
Focal Lesions ◽  
High Risk Disease ◽  
Minimal Residual

Background: Minimal residual disease (MRD) diagnostics in multiple myeloma (MM) are gaining increasing importance to determine response depth beyond complete remission (CR) since novel agents have shown to induce high rates of deep clinical responses. Moreover, recent reports indicated combining functional imaging with next generation flow cytometry (NGF) could be beneficial in predicting clinical outcome. This applies in particular to the subset of patients suffering from relapsed/refractory multiple myeloma (RRMM) who tend to show a higher incidence of residual focal lesions despite serological response. Here, we report our institutions experience with implementing both functional imaging and NGF-guided MRD diagnostics in clinical practice. Methods: Our study included patients with newly diagnosed multiple myeloma (NDMM) and RRMM achieving VGPR, CR or sCR. Bone marrow aspirates were obtained for MRD-testing according to IMWG 2016 criteria. Samples were collected between July 2019 and July 2020 and analyzed with NGF (according to EuroFlowTM guidelines) at a sensitivity level of 10-5. Results were compared to functional imaging obtained with positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI). High-risk disease was defined as presence of deletion 17p, translocation (14;16) or (4;14). Results: We included 66 patients with NDMM (n=39) and RRMM (n=27) who achieved VGPR or better. In patients with RRMM the median number of treatment lines was 2 (range 2-11). Fifteen patients suffered from high-risk disease. Median age at NGF diagnostics was 64 years (range 31-83). Among patients achieving VGPR (n=27), CR (n=10) and sCR (n=29) seventeen (26%) were MRD-negative by NGF testing. CR or better was significantly associated NGF MRD-negativity (p=0.04). Notably, rates of NGF MRD-negativity were similar among patients with NDMM (28%) and RRMM (26%). Even some heavily pretreated patients who underwent ≥ 4 lines of therapy achieved MRD-negativity on NGF (2 of 9). Functional imaging was performed in 46 (70%) patients with DW-MRI (n=22) and PET (n=26). Median time between NGF and imaging assessment was 2 days (range 0-147). Combining results from imaging and NGF, 12 out of 46 (26%) patients were MRD-negative with both methods (neg/neg). Three patients displayed disease activity as measured with both, imaging and NGF (pos/pos). Twenty-nine of the remaining patients were MRD-positive only according to NGF (pos/neg), while two patients were positive on imaging only (neg/pos). More patients demonstrated combined MRD-negativity on NGF and imaging (neg/neg) in the NDMM setting than in RRMM (32% versus 19%). We also observed that 30% of the patients with high-risk genetics showed MRD-negativity on both imaging and NGF. Of note, none of the patients with very advanced disease (≥4 previous lines) was MRD-negative on both techniques. Conclusion In the clinical routine, MRD diagnostics could be used to tailor maintenance and consolidation approaches for patients achieving deep responses by traditional IMWG criteria. Our real-world experience highlights that MRD-negativity can be achieved in patients suffering from high-risk disease and also in late treatment lines, supporting its value as endpoint for clinical trials. However, our data also support MRD diagnostics to be combined with functional imaging at least in the RRMM setting to rule out residual focal lesions. Future studies using MRD for clinical decision-making are highly warranted. Disclosures Einsele: Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rasche:Celgene/BMS: Honoraria; GlaxoSmithKline: Honoraria; Oncopeptides: Honoraria; Skyline Dx: Research Funding; Janssen: Honoraria; Sanofi: Honoraria.

P0894OBESITY IMPAIRS THE ACUTE RESPONSE TO AN ORAL PHOSPHATE CHALLENGE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Mandy Turner ◽  
Christine White ◽  
Patrick Norman ◽  
Corinne Babiolakis ◽  
Michael Adams ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Risk ◽  
Kidney Function ◽  
Area Under The Curve ◽  
Fractional Excretion ◽  
Low Risk ◽  
Normal Kidney ◽  
Phosphate Excretion ◽  
Fractional Excretion Of Phosphate ◽  
Age And Sex

Abstract Background and Aims T Obesity is an increasing health problem world-wide. People who are overweight or obese are at greater risk of developing chronic diseases including cardiovascular disease (CVD). Factors associated with dysregulated phosphate metabolism have been linked to the presence of vascular calcification in people with type 2 diabetes (T2D) with normal kidney function. Insulin resistance and abdominal obesity are associated with increased circulating levels of phosphaturic hormones including fibroblast growth factor 23 (FGF-23) and parathyroid hormone (PTH). Abnormalities in phosphate regulation may not be reflected in single circulating measurements of serum phosphate, but can be revealed by the acute circulating and mineral response to an oral challenge of phosphate. The aim of this study was to determine if obesity and insulin resistance impact the acute capacity to excrete an oral phosphate challenge. Method Community-dwelling people (N=78) free of T2D and symptomatic CVD (∼10 males and ∼10 females from each decade between 40 and 80 years) with normal kidney function were recruited from Kingston, Ontario, Canada. Following a 12-hour fast, participants consumed a 1250 mg phosphate drink (sodium phosphate) where blood and urine were collected at baseline, 1, 2 and 3 hours following the oral challenge. Participants with a high-risk metabolic profile characterized by an elevated waist-to-height ratio (WHtR) (&gt; 0.58) were matched by age and sex to participants with a low risk WHtR (&lt;0.5). Results The results reveal a significant impact of obesity on phosphate excretion in response to an oral phosphate challenge. There was an association between WHtR ratio and the level of iFGF-23 (R=-0.34 p&lt;0.01) but not PTH. After adjustment for age and sex, WHtR ratio was inversely correlated with urinary phosphate excretion in response to the phosphate challenge (R=-0.29, p=0.02) and the change in fractional excretion of phosphate (r=-0.34, p=0.007). From the larger cohort, an age- and sex- matched subset was selected for 12 high risk and 12 low risk metabolic profiles with WHtR of 0.66±0.02 and 0.46±0.01, respectively. Kidney function was the same between the two groups (eGFR 92.3±13.1 versus 95.8±13.6 ml/min/1.73m2 respectively) but high risk participants had significantly higher homeostatic model assessment of insulin resistance (HOMA-IR) (1.61±0.81 versus 0.68±0.3, p&lt;0.01). Participants with a high risk metabolic profile had a greater increase in serum phosphate from baseline (29% increase in the area under the curve, p=0.04) and a significantly blunted increase in the fractional excretion of phosphate in response to the oral phosphate challenge (35% reduction in area under the curve [AUC], p=0.03) compared to the matched low risk profile participants. Conclusion Overweight/obese individuals demonstrate impaired response to an oral phosphate challenge, whereby phosphate excretion was impaired and there was increased exposure to new circulating phosphate. An impaired acute phosphate response may contribute to the initiation or propagation of vascular calcification. Dysregulated phosphate homeostasis may be an under-recognized cardiovascular risk factor in obese people that could be modified by diet and weight loss. Whether insulin enhances renal phosphate reabsorption requires further study.

MDM2 SNP309 and TP53 SNPArg72Pro Polymorphisms in Myelodysplastic Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1745-1745
Author(s):  
João Agostinho Machado Neto ◽  
Fabiola Traina ◽  
Paula Melo Campos ◽  
Marilisia Andreoli ◽  
Irene Lorand Metze ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Low Risk ◽  
Healthy Controls ◽  
Mdm2 Snp309 ◽  
P53 Pathway ◽  
Hematopoietic Stem ◽  
High Risk Disease

Abstract Abstract 1745 Poster Board I-771 Introduction Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress towards acute myeloid leukemia (AML). The progression of the disease may be associated with genetic or epigenetic alterations and a possible change in protein function. MDM2/P53 pathway plays an important role in the control of apoptotic and proliferation mechanisms. Single nucleotide polymorphisms (SNPs) were identified in the TP53 and MDM2 genes. MDM2 SNP309 results in higher levels of MDM2 and attenuates p53 pathway. The SNP in codon 72 of the TP53 gene results in either a C or G nucleotide and leads to either Proline (Pro) or Arginine (Arg), respectively. The Arg variant has been shown to be more potent in apoptosis induction and the Pro variant has been shown to be better in inducing cell-cycle arrest and to have a greater ability to repair damaged-DNA. The aim of the present study was to investigate the incidence of MDM2 and TP53 polymorphisms in MDS patients and to correlate the frequency of these SNPs with age, neutrophis and platelets at diagnosis, low risk versus high risk disease according to FAB (RA and RARS versus AREB and AREBt) and IPSS (Low and Int-1 versus Int-2 and high), cytogenetic risk (low versus intermediate and high risk), disease progression and overall survival. Patients and Methods We studied 103 healthy controls and 63 patients with MDS. According to FAB, patients were distributed as follows: 43 RA, 10 RARS, 7 RAEB, 1 RAEBt and 2 CMML. The median follow-up time was 40 months (range 2 – 159 months). Samples were obtained from peripheral blood or bone marrow and were screened for the presence of polymorphisms MDM2 SNP309 and TP53 SNPArg72Pro, by PCR analysis with specific primers and appropriate restriction enzyme. Appropriate statistical analyses were used for each test. Results The frequencies of genotypes for MDM2 SNP309 and TP53Pro7Arg were similar between MDS and healthy controls; MDM2 SNP309: 51% vs 53%, for TT, 38% vs 32% for TG, and 11% vs 15% for GG, TP53Pro7Arg: 47.5% vs 44%, for Arg/Arg, 47,5% vs 42% for Pro/Arg, and 5% vs 14% for Pro/Pro. No differences were observed between MDS patients with presence or absence of the polymorphisms in relation to age, neutrophis and platelets at diagnosis, low risk versus high risk disease according to FAB, IPSS and cytogenetic risk, disease progression and overall survival. Conclusions MDM2 and TP53 polymorphisms have been described to affect the risk for cancer, onset age and overall survival in solid tumors and leukemias. This was the first study to report these SNPs in MDS and leads to believe that these polymorphisms are not associated with risk for the disease and with clinical data. Keywords: MDM2, p53, myelodysplasia, polymorphisms Disclosures No relevant conflicts of interest to declare.

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