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3. Topic: AS01-Diagnosis/AS01a-Cytomorphology: ARTIFICIAL INTELLIGENCE MAY HELP THE HEMATOPATHOLOGIST IN EVALUATION OF BONE MASS AND CELLULARITY IN BONE MARROW SPECIMENS OF PATIENTS WITH MDS

Author

Kolomansky, A., primary, Karlik, E. Cohen, additional, Malka, R., additional, Rahamim, M., additional, Kislev, S., additional, Ben-Ezra, J., additional, Shahar, S., additional, Globerson, A., additional, Neumann, D., additional, Mittelman, M., additional, and Oster, H., additional

Published
2023
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5. Topic: AS03-Health Economics & Outcome Research/AS03a-Cost of care: ARE WE READY TO PERFORM NGS FOR ALL MDS PATIENTS ?

Author

Santini, V., primary, Bejar, R., additional, Belli, C., additional, Buckstein, R., additional, Campelo, M., additional, Dezern, A., additional, Fontenay, M., additional, Griffiths, E., additional, Grille, S., additional, Haferlach, T., additional, Iastrebner, M., additional, Kosmider, O., additional, Magalhaes, S., additional, Mittelman, M., additional, Platzbecker, U., additional, Wei, A., additional, and Zeidan, A., additional

Published
2023
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6. Cause of death and excess mortality in patients with lower-risk myelodysplastic syndromes (MDS): A report from the European MDS registry.

Author

Mądry, K., Lis, K., Fenaux, P., Bowen, D., Symeonidis, A., Mittelman, M., Stauder, R., Čermák, J., Sanz, G., Hellström-Lindberg, E., Langemeijer, S.M.C., Malcovati, L., Germing, U., Holm, M.S., Guerci-Bresler, A., Culligan, D., Sanhes, L., Kotsianidis, I., Marrewijk, C. van, Crouch, S., Witte, T.J. de, Smith, A, Mądry, K., Lis, K., Fenaux, P., Bowen, D., Symeonidis, A., Mittelman, M., Stauder, R., Čermák, J., Sanz, G., Hellström-Lindberg, E., Langemeijer, S.M.C., Malcovati, L., Germing, U., Holm, M.S., Guerci-Bresler, A., Culligan, D., Sanhes, L., Kotsianidis, I., Marrewijk, C. van, Crouch, S., Witte, T.J. de, and Smith, A

Abstract

01 februari 2023, Item does not contain fulltext, Information on causes of death (CoDs) and the impact of myelodysplastic syndromes (MDS) on survival in patients with lower-risk MDS (LR-MDS) is limited. A better understanding of the relationship between disease characteristics, clinical interventions and CoDs may improve outcomes of patients with LR-MDS. We prospectively collected data on patients with LR-MDS in the European MDS registry from 2008 to 2019. Clinical, laboratory and CoDs data were obtained. To examine MDS-specific survival, relative survival (RS) was estimated using national life tables. Of 2396 evaluated subjects, 900 died (median overall survival [OS]: 4.7 years; median follow-up: 3.5 years). The most common CoDs were acute myeloid leukaemia/MDS (20.1%), infection (17.8%) and cardiovascular disease (CVD; 9.8%). Patients with isolated del(5q) and with red cell transfusion needed during the disease course, had a higher risk of fatal CVD. The 5-year OS was 47.3% and the 5-year RS was 59.6%, indicating that most patients died due to their underlying MDS. Older patients (aged >80 years) and the lowest-risk patients were more likely to die from competing causes. This study shows that MDS and its related complications play crucial role in the outcome of patients with LR-MDS.

Published
2023

7. Raising the standards of patient-centered outcomes research in myelodysplastic syndromes: Clinical utility and validation of the subscales of the QUALMS from the MDS-RIGHT project.

Author

Efficace, F., Koinig, K., Cottone, F., Bowen, D., Mittelman, M., Sommer, K., Langemeijer, S.M., Culligan, D., Filanovsky, K., Storck, M., Smith, A, Marrewijk, C. van, Dugas, M., Stojkov, I., Siebert, U., Witte, T.J. de, Stauder, R., Efficace, F., Koinig, K., Cottone, F., Bowen, D., Mittelman, M., Sommer, K., Langemeijer, S.M., Culligan, D., Filanovsky, K., Storck, M., Smith, A, Marrewijk, C. van, Dugas, M., Stojkov, I., Siebert, U., Witte, T.J. de, and Stauder, R.

Abstract

Item does not contain fulltext, BACKGROUND: Clinical decision-making for patients with myelodysplastic syndromes (MDS) is challenging, and both disease and treatment effects heavily impact health-related quality of life (HRQoL) of these patients. Therefore, disease-specific HRQoL measures can be critical to harness the patient voice in MDS research. METHODS: We report a prospective international validation study of the Quality of Life in Myelodysplasia Scale (QUALMS) with a main focus on providing information on the psychometric characteristics of its three subscales: physical burden (QUALMS-P), emotional burden (QUALMS-E), and benefit finding (QUALMS-BF). The analysis is based on patients enrolled from three European countries and Israel, participating to the MDS-RIGHT Project. The scale structure and psychometric properties of the QUALMS were assessed. RESULTS: Overall, 270 patients with a median age of 74 years were analyzed and the majority of them (60.3%) had a low MDS-Comorbidity Index score. Results of the confirmatory factor analysis supported the underlying scale structure of the QUALMS, which, in addition to a total score, includes three subscales: QUALMS-P, QUALMS-E, and the QUALMS-BF. The QUALMS-P exhibited the highest Cronbach's alpha coefficients. Discriminant validity analysis indicated good results with the QUALMS-P and QUALMS-E distinguishing between patients with different performance status, comorbidity, anemia, and transfusion dependency status. No floor and ceiling effects were observed. Responsiveness to change analysis supported the validity of the measure. Patients with a hemoglobin (Hb) level of <11 g/dL at study entry, who subsequently showed an improvement in their Hb levels, also reported a mean score change of 9 and 8 points (scales ranging between 0 and 100) in the expected direction of the QUALMS-E and QUALMS-P, respectively. CONCLUSIONS: Our study provides additional validation data on the QUALMS from the international MDS-RIGHT Project. The use of this disease-spec

Published
2023

8. Determinants of low health-related quality of life in patients with myelodysplastic syndromes: EUMDS registry study

Author

Stojkov, I., Conrads-Frank, A., Rochau, U., Arvandi, M., Koinig, K.A., Schomaker, M., Mittelman, M., Fenaux, P., Bowen, D., Sanz, G.F., Malcovati, L., Langemeijer, S.M.C., Germing, U., Madry, K., Guerci-Bresler, A., Culligan, D.J., Kotsianidis, I., Sanhes, L., Mills, J., Puntscher, S., Schmid, D., Marrewijk, C.J. van, Smith, A, Efficace, F., Witte, T.J. de, Stauder, R., and Siebert, U.

Subjects
Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2], All institutes and research themes of the Radboud University Medical Center, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2]
Abstract

Item does not contain fulltext Patients with myelodysplastic syndromes (MDS) frequently experience a significant symptom burden, which reduces health-related quality of life (HRQoL). We aimed to identify determinants of low HRQoL in patients recently diagnosed with MDS, for guiding early intervention strategies. We evaluated longitudinal data in 2205 patients with MDS during their first year after diagnosis. Median values of EQ-5D 3-level (EQ-5D-3L) index (0.78) and visual analog scale (VAS) score (0.70) were used as thresholds for low HRQoL. In addition, the 5 dimensions of EQ-5D-3L were analyzed for impairments (any level vs "no problem" category). After multiple imputation of missing values, we used generalized estimating equations (GEE) to estimate odds ratios (OR) for univariable determinant screening (P < .15), and to subsequently derive multivariable models for low HRQoL with 95% confidence intervals (CI). Multivariable GEE analysis showed the following independent determinants (OR, 95% CI) for low EQ-5D index: increased age (60-75 years: 1.33, 1.01-1.75; >75: 1.84, 1.39-2.45), female sex (1.70, 1.43-2.03), high serum ferritin level (≥1000 vs ≤300 μg/L: 1.41, 1.06-1.87), comorbidity burden (per unit: 1.11, 1.02-1.20), and reduced Karnofsky performance status (KPS, per 10 units: 0.62, 0.58-0.67). For low VAS score, additional determinants were transfusion dependence (1.53, 1.03-2.29), low hemoglobin

Published
2022

13. Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.

Author

Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L.R., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Campelo M.D., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., Mittelman M., Fianchi L., Torre I.L., Zhong J., Laille E., De Menezes D.L., Skikne B., Beach C.L., Giagounidis A., Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L.R., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Campelo M.D., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., Mittelman M., Fianchi L., Torre I.L., Zhong J., Laille E., De Menezes D.L., Skikne B., Beach C.L., and Giagounidis A.

Abstract

PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n 5 107) or placebo (n 5 109). The median age was 74 years, median platelet count was 25 3 109/L, and absolute neutrophil count was 1.3 3 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P5.0002), with median durations of 11.1 and 5.0 months. Reductions of $ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had $ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC- 486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P 5 .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC- 486, n 5 16; placebo, n 5 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 3 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of

Published
2022

14. Erythropoiesis‐stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower‐risk myelodysplastic syndrome

Author

Garelius, H. K. G., Johnston, W. T., Smith, A. G., Park, S., de Swart, L., Fenaux, P., Symeonidis, A., Sanz, G., Čermák, J., Stauder, R., Malcovati, L., Mittelman, M., van de Loosdrecht, A. A., van Marrewijk, C. J., Bowen, D., Crouch, S., de Witte, T. J. M., and Hellström‐Lindberg, E.

Published
2017
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20. O08 - Topic: AS06-Prognosis/AS06a-Prognostic factors of outcome and risk assessment: LYMPHOPENIA IS HIGHLY PREVALENT IN MDS AND PROVIDES ADDITIONAL PROGNOSTIC INFORMATION FOR IPSS-R VERY-LOW AND LOW-RISK PATIENTS. AN ANALYSIS FROM THE EU-MDS REGISTRY

Author

Silzle, T., Taylor, A., De Witte, T., Malcovati, L., Fenaux, P., Bowen, D., Symeonidis, A., Mittelman, M., Stauder, R., Cermak, J., Sanz, G., Hellström-Lindberg, E., Langemeijer, S., Holm, M. Skov, Madry, K., Tatic, A., Almeida, A. Medina, Savic, A., Rogulj, I. Mandac, Germing, U., and Smith, A.

Published
2021
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21. Toxic iron species in lower-risk myelodysplastic syndrome patients : course of disease and effects on outcome

Author

Hoeks, Marlijn, Bagguley, Tim, van Marrewijk, Corine, Smith, Alex, Bowen, David, Culligan, Dominic, Kolade, Seye, Symeonidis, Argiris, Garelius, Hege, Spanoudakis, Michail, Langemeijer, Saskia, Roelofs, Rian, Wiegerinck, Erwin, Tatic, Aurelia, Killick, Sally, Panagiotidis, Panagiotis, Stanca, Oana, Hellström-Lindberg, Eva, Cermak, Jaroslav, van der Klauw, Melanie, Wouters, Hanneke, van Kraaij, Marian, Blijlevens, Nicole, Swinkels, Dorine W., de Witte, Theo, Stauder, R., Walder, A., Pfeilstöcker, M., Schoenmetzler-Makrai, A., Burgstaller, S., Thaler, J., Mandac Rogulj, I., Krejci, M., Voglova, J., Rohon, P., Jonasova, A., Cermak, J., Mikulenkova, D., Hochova, I., Jensen, P. D., Holm, M. S., Kjeldsen, L., Dufva, I. H., Vestergaard, H., Re, D., Slama, B., Fenaux, P., Choufi, B., Cheze, S., Klepping, D., Salles, B., de Renzis, B., Willems, L., De Prost, D., Gutnecht, J., Courby, S., Siguret, V., Tertian, G., Pascal, L., Chaury, M., Wattel, E., Guerci, A., Legros, L., Itzykson, R., Ades, L., Isnard, F., Sanhes, L., Benramdane, R., Stamatoullas, A., Amé, S., Beyne-Rauzy, O., Gyan, E., Platzbecker, U., Badrakan, C., Germing, U., Lübbert, M., Schlenk, R., Kotsianidis, I., Tsatalas, C., Pappa, V., Galanopoulos, A., Michali, E., Panagiotidis, P., Viniou, N., Katsigiannis, A., Roussou, P., Terpos, E., Kostourou, A., Kartasis, Z., Pouli, A., Palla, K., Briasoulis, V., Hatzimichael, E., Vassilopoulos, G., Symeonidis, A., Kourakli, A., Zikos, P., Anagnostopoulos, A., Kotsopoulou, M., Megalakaki, K., Protopapa, M., Vlachaki, E., Konstantinidou, P., Stemer, G., Nemetz, A., Gotwin, U., Cohen, O., Koren, M., Levy, E., Greenbaum, U., Gino-Moor, S., Price, M., Ofran, Y., Winder, A., Goldshmidt, N., Elias, S., Sabag, R., Hellman, I., Ellis, M., Braester, A., Rosenbaum, H., Berdichevsky, S., Itzhaki, G., Wolaj, O., Yeganeh, S., Katz, O., Filanovsky, K., Dali, N., Mittelman, M., Malcovati, L., Fianchi, L., vd Loosdrecht, A., Matthijssen, V., Herbers, A., Pruijt, H., Aboosy, N., de Vries, F., Velders, G., Jacobs, E., Langemeijer, S., MacKenzie, M., Lensen, C., Kuijper, P., Madry, K., Camara, M., Almeida, A., Vulkan, G., Stanca Ciocan, O., Tatic, A., Savic, A., Pedro, C., Xicoy, B., Leiva, P., Munoz, J., Betes, V., Benavente, C., Lozano, M., Martinez, M., Iniesta, P., Bernal, T., Diez Campelo, M., Tormo, D., Andreu Lapiedra, R., Sanz, G., Hesse Sundin, E., Garelius, H., Karlsson, C., Antunovic, P., Jönsson, A., Brandefors, L., Nilsson, L., Kozlowski, P., Hellstrom-Lindberg, E., Grövdal, M., Larsson, K., Wallvik, J., Lorenz, F., Ejerblad, E., Culligan, D., Craddock, C., Kolade, S., Cahalin, P., Killick, S., Ackroyd, S., Wong, C., Warren, A., Drummond, M., Hall, C., Rothwell, K., Green, S., Ali, S., Bowen, D., Karakantza, M., Dennis, M., Jones, G., Parker, J., Bowen, A., Radia, R., Das-Gupta, E., Vyas, P., Nga, E., Creagh, D., Ashcroft, J., Mills, J., Bond, L., Life Course Epidemiology (LCE), and VU University medical center

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Iron Overload, Iron, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Ferroportin, Lower risk, Gastroenterology, Article, Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2], 03 medical and health sciences, 0302 clinical medicine, Hepcidin, Internal medicine, Humans, Medicine, Blood Transfusion, Prospective Studies, Aged, Soluble transferrin receptor, biology, business.industry, Transferrin saturation, Hematology, Middle Aged, Erythroferrone, Prognosis, 3. Good health, Survival Rate, Ferritin, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Oncology, Myelodysplastic Syndromes, 030220 oncology & carcinogenesis, biology.protein, Erythropoiesis, Female, business, Myelodysplastic syndrome, Follow-Up Studies, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Red blood cell transfusions (RBCT) remain the cornerstone of supportive care in lower-risk myelodysplastic syndrome (LRMDS) [1]. Transfusion dependency in LRMDS patients is associated with inferior outcomes, mainly attributed to severe bone marrow failure [2]. However, iron toxicity, due to frequent RBCT or ineffective erythropoiesis, may be an additional negative prognostic factor [3,4,5,6]. Recently, much progress has been made in unraveling the iron metabolism. The peptide hormone hepcidin is the key regulator by inhibiting iron uptake through degradation of ferroportin, a cellular iron exporter [7]. Erythroferrone and GDF15, produced by erythroblasts, inhibit hepcidin production, which leads to increased uptake and cellular release of iron for the purpose of erythropoiesis [8]. The pathophysiology of iron metabolism in MDS is still not completely understood. Exceedingly high reactive oxygen species (ROS) levels are associated with iron toxicity, disease development, and progression in MDS patients [9,10,11,12]. Malondialdehyde (MDA), resulting from lipid peroxidation of polyunsaturated fatty acids, is a biomarker of oxidative stress [10, 12]. Currently, little is known about the prognostic impact of ROS in MDS patients. The aim of this study is twofold: (1) describe iron and oxidative stress parameters over time in LRMDS patients and (2) to assess their effect on overall and progression-free survival. The EUMDS registry prospectively collects observational data on newly diagnosed LRMDS patients from 148 centers in 16 countries in Europe and Israel as of January 2008. All patients provided informed consent. Clinical data were collected at baseline and at each six-monthly follow-up visit. Serum samples were collected prospectively at each visit from 256 patients included in six participating countries. Conventional iron parameters were measured with routine assays. We additionally analyzed hepcidin, growth differentiation factor 15 (GDF15), soluble transferrin receptor (sTfR), non-transferrin bound iron (NTBI), labile plasma iron (LPI), and MDA. Subjects were prospectively followed until death, loss to follow-up, or withdrawal of consent. All iron parameters were measured centrally at the department of Laboratory Medicine of the Radboudumc, Nijmegen, The Netherlands. Serum samples were collected just prior to transfusion in transfusion-dependent patients and stored at −80 °C. Details on the assays and reference ranges of hepcidin, GDF15, sTfR, NTBI, LPI, and MDA are provided in the supplement. The Spearman rank test was used to evaluate correlations between iron parameters. We stratified the results by transfusion dependency per visit and the presence of ring sideroblasts. When evaluating temporal changes in iron parameters, with linear quantile mixed models, we excluded patients from the timepoint they received iron chelation therapy. Overall survival (OS) was defined as the time from MDS diagnosis to death or, in case of progression-free survival, to date of progression or death; patients still alive at the end of follow-up were censored. Time-dependent Kaplan–Meier curves and cox proportional hazards models were used. In total, 256 consecutive patients, were included in this study. Over five six-monthly visits, 1040 samples were collected. Table 1 describes the patient characteristics. Most patients without ring sideroblasts were transfusion-independent at diagnosis (nonRS-TI; 55.9%), 18.8% with ring sideroblasts were transfusion-independent (RS-TI), 18.4% without ring sideroblasts were transfusion-dependent (nonRS-TD), and 7% with ring sideroblasts were transfusion-dependent patients (RS-TD). The median follow-up time was 6.6 years (95% CI 5.9–7.0). LPI was positively correlated with transferrin saturation (TSAT) (r = 0.15, p < 0.001, Fig. S1). LPI values increased exponentially at TSAT values above 80%. This effect was most pronounced in the transfusion-dependent groups, but also observed in the RS-TI group. MDA was weakly correlated with NTBI (r = 0.09, p = 0.069) and negatively correlated with hemoglobin level (r = −0.1, p = 0.033). GDF15 and hepcidin were negatively correlated in the RS-TI and nonRS-TD group and significantly negatively correlated in the RS-TD group (r = −0.34, p = 0.007, Fig. S2). Serum ferritin levels were elevated in all subgroups with a mean value of 858 µg/L at visit 5. The highest serum ferritin levels were observed in the RS-TD group (mean value at visit 5: 2092 µg/L, Table S1). Serum ferritin increased significantly per visit in the RS-TD group (beta 454.46 µg/L; 95% CI 334.65–574.27), but not in the other groups (Table S2). All subgroups, except for the nonRS-TI, had elevated TSAT levels. TSAT levels were most markedly increased in the RS-TD group with a mean TSAT of 88% at visit 5 (Table S1). In both transfusion-dependent groups the median increase per visit was significant (Table S2). LPI was elevated in the RS-TD group exclusively with a mean value of 0.59 µmol/L at visit 5 (Table S1). NTBI was elevated in all subgroups, with the highest values in the RS-TD group (Table S1). The increase in median NTBI level was significant in both transfusion-dependent groups (Table S2). Hepcidin levels were markedly elevated in the nonRS-TD group. Interestingly, hepcidin levels were lower in the RS-TD group, probably reflecting ineffective erythropoiesis, likewise supported by lower hepcidin/ferritin ratios in RS groups (Table S1). Median hepcidin levels increased over time in the transfusion-dependent subgroups only (Table S2). GDF15 levels, analyzed in the light of its potential role in hepcidin suppression, were increased in all subgroups (Table S1). The RS subgroups had higher GDF15 levels compared to the nonRS groups, reflecting increased erythropoiesis. Mean sTfR levels were within the reference range in all subgroups except for the RS-TI group, which showed elevated levels, reflecting...

Published
2021
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23. Topic: AS06-Prognosis/AS06a-Prognostic factors of outcome and risk assessment

Author

Silzle, T., primary, Taylor, A., additional, De Witte, T., additional, Malcovati, L., additional, Fenaux, P., additional, Bowen, D., additional, Symeonidis, A., additional, Mittelman, M., additional, Stauder, R., additional, Cermak, J., additional, Sanz, G., additional, Hellström-Lindberg, E., additional, Langemeijer, S., additional, Holm, M. Skov, additional, Madry, K., additional, Tatic, A., additional, Almeida, A. Medina, additional, Savic, A., additional, Rogulj, I. Mandac, additional, Germing, U., additional, and Smith, A., additional

Published
2021
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27. Toxic iron species in lower-risk myelodysplastic syndrome patients: course of disease and effects on outcome

Author

Hoeks, M. Bagguley, T. van Marrewijk, C. Smith, A. Bowen, D. Culligan, D. Kolade, S. Symeonidis, A. Garelius, H. Spanoudakis, M. Langemeijer, S. Roelofs, R. Wiegerinck, E. Tatic, A. Killick, S. Panagiotidis, P. Stanca, O. Hellström-Lindberg, E. Cermak, J. van der Klauw, M. Wouters, H. van Kraaij, M. Blijlevens, N. Swinkels, D.W. de Witte, T. Stauder, R. Walder, A. Pfeilstöcker, M. Schoenmetzler-Makrai, A. Burgstaller, S. Thaler, J. Mandac Rogulj, I. Krejci, M. Voglova, J. Rohon, P. Jonasova, A. Cermak, J. Mikulenkova, D. Hochova, I. Jensen, P.D. Holm, M.S. Kjeldsen, L. Dufva, I.H. Vestergaard, H. Re, D. Slama, B. Fenaux, P. Choufi, B. Cheze, S. Klepping, D. Salles, B. de Renzis, B. Willems, L. De Prost, D. Gutnecht, J. Courby, S. Siguret, V. Tertian, G. Pascal, L. Chaury, M. Wattel, E. Guerci, A. Legros, L. Itzykson, R. Ades, L. Isnard, F. Sanhes, L. Benramdane, R. Stamatoullas, A. Amé, S. Beyne-Rauzy, O. Gyan, E. Platzbecker, U. Badrakan, C. Germing, U. Lübbert, M. Schlenk, R. Kotsianidis, I. Tsatalas, C. Pappa, V. Galanopoulos, A. Michali, E. Panagiotidis, P. Viniou, N. Katsigiannis, A. Roussou, P. Terpos, E. Kostourou, A. Kartasis, Z. Pouli, A. Palla, K. Briasoulis, V. Hatzimichael, E. Vassilopoulos, G. Symeonidis, A. Kourakli, A. Zikos, P. Anagnostopoulos, A. Kotsopoulou, M. Megalakaki, K. Protopapa, M. Vlachaki, E. Konstantinidou, P. Stemer, G. Nemetz, A. Gotwin, U. Cohen, O. Koren, M. Levy, E. Greenbaum, U. Gino-Moor, S. Price, M. Ofran, Y. Winder, A. Goldshmidt, N. Elias, S. Sabag, R. Hellman, I. Ellis, M. Braester, A. Rosenbaum, H. Berdichevsky, S. Itzhaki, G. Wolaj, O. Yeganeh, S. Katz, O. Filanovsky, K. Dali, N. Mittelman, M. Malcovati, L. Fianchi, L. vd Loosdrecht, A. Matthijssen, V. Herbers, A. Pruijt, H. Aboosy, N. de Vries, F. Velders, G. Jacobs, E. Langemeijer, S. MacKenzie, M. Lensen, C. Kuijper, P. Madry, K. Camara, M. Almeida, A. Vulkan, G. Stanca Ciocan, O. Tatic, A. Savic, A. Pedro, C. Xicoy, B. Leiva, P. Munoz, J. Betes, V. Benavente, C. Lozano, M. Martinez, M. Iniesta, P. Bernal, T. Diez Campelo, M. Tormo, D. Andreu Lapiedra, R. Sanz, G. Hesse Sundin, E. Garelius, H. Karlsson, C. Antunovic, P. Jönsson, A. Brandefors, L. Nilsson, L. Kozlowski, P. Hellstrom-Lindberg, E. Grövdal, M. Larsson, K. Wallvik, J. Lorenz, F. Ejerblad, E. Culligan, D. Craddock, C. Kolade, S. Cahalin, P. Killick, S. Ackroyd, S. Wong, C. Warren, A. Drummond, M. Hall, C. Rothwell, K. Green, S. Ali, S. Karakantza, M. Dennis, M. Jones, G. Parker, J. Bowen, A. Radia, R. Das-Gupta, E. Vyas, P. Nga, E. Creagh, D. Ashcroft, J. Mills, J. Bond, L. the EUMDS Registry Participants

Published
2021

28. A predictive algorithm using clinical and laboratory parameters may assist in ruling out and in diagnosing MDS

Author

Oster, H.S., Crouch, S., Smith, A, Yu, G., Shrkihe, B. Abu, Baruch, S., Kolomansky, A., Ben-Ezra, J., Naor, S., Fenaux, P., Symeonidis, A., Stauder, R., Cermak, J., Sanz, G., Hellström-Lindberg, E., Malcovati, L., Langemeijer, S.M., Germing, U., Holm, M.S., Madry, K., Guerci-Bresler, A., Culligan, D., Sanhes, L., Mills, J., Kotsianidis, I., Marrewijk, C.J. van, Bowen, D., Witte, T.J. de, Mittelman, M., Oster, H.S., Crouch, S., Smith, A, Yu, G., Shrkihe, B. Abu, Baruch, S., Kolomansky, A., Ben-Ezra, J., Naor, S., Fenaux, P., Symeonidis, A., Stauder, R., Cermak, J., Sanz, G., Hellström-Lindberg, E., Malcovati, L., Langemeijer, S.M., Germing, U., Holm, M.S., Madry, K., Guerci-Bresler, A., Culligan, D., Sanhes, L., Mills, J., Kotsianidis, I., Marrewijk, C.J. van, Bowen, D., Witte, T.J. de, and Mittelman, M.

Abstract

Contains fulltext : 237720.pdf (Publisher’s version ) (Open Access), We present a noninvasive Web-based app to help exclude or diagnose myelodysplastic syndrome (MDS), a bone marrow (BM) disorder with cytopenias and leukemic risk, diagnosed by BM examination. A sample of 502 MDS patients from the European MDS (EUMDS) registry (n > 2600) was combined with 502 controls (all BM proven). Gradient-boosted models (GBMs) were used to predict/exclude MDS using demographic, clinical, and laboratory variables. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to evaluate the models, and performance was validated using 100 times fivefold cross-validation. Model stability was assessed by repeating its fit using different randomly chosen groups of 502 EUMDS cases. AUC was 0.96 (95% confidence interval, 0.95-0.97). MDS is predicted/excluded accurately in 86% of patients with unexplained anemia. A GBM score (range, 0-1) of less than 0.68 (GBM < 0.68) resulted in a negative predictive value of 0.94, that is, MDS was excluded. GBM ≥ 0.82 provided a positive predictive value of 0.88, that is, MDS. The diagnosis of the remaining patients (0.68 ≤ GBM < 0.82) is indeterminate. The discriminating variables: age, sex, hemoglobin, white blood cells, platelets, mean corpuscular volume, neutrophils, monocytes, glucose, and creatinine. A Web-based app was developed; physicians could use it to exclude or predict MDS noninvasively in most patients without a BM examination. Future work will add peripheral blood cytogenetics/genetics, EUMDS-based prospective validation, and prognostication.

Published
2021

29. Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.

Author

Skikne B., Lopes de Menezes D., Beach C.L., Giagounidis A., Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L.R., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Diez Campelo M., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., Mittelman M., Fianchi L., La Torre I., Zhong J., Laille E., Skikne B., Lopes de Menezes D., Beach C.L., Giagounidis A., Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L.R., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Diez Campelo M., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., Mittelman M., Fianchi L., La Torre I., Zhong J., and Laille E.

Abstract

PURPOSE: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia. METHOD(S): Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULT(S): Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 x 109/L, and absolute neutrophil count was 1.3 x 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P = .0002), with median durations of 11.1 and 5.0 months. Reductions of >= 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had >= 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 x 109/L. CONCLUSION(S): CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further e

Published
2021

30. Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes

Author

Garcia-Manero, G, Santini, V, Almeida, A, Platzbecker, U, Jonasova, A, Silverman, LR, Falantes, J, Reda, G, Buccisano, F, Fenaux, P, Buckstein, R, Campelo, MD, Larsen, S, Valcarcel, D, Vyas, P, Giai, V, Oliva, EN, Shortt, J, Niederwieser, D, Mittelman, M, Fianchi, L, La Torre, I, Zhong, J, Laille, E, de Menezes, DL, Skikne, B, Beach, CL, Giagounidis, A, Garcia-Manero, G, Santini, V, Almeida, A, Platzbecker, U, Jonasova, A, Silverman, LR, Falantes, J, Reda, G, Buccisano, F, Fenaux, P, Buckstein, R, Campelo, MD, Larsen, S, Valcarcel, D, Vyas, P, Giai, V, Oliva, EN, Shortt, J, Niederwieser, D, Mittelman, M, Fianchi, L, La Torre, I, Zhong, J, Laille, E, de Menezes, DL, Skikne, B, Beach, CL, and Giagounidis, A

Abstract

PURPOSE: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia. METHODS: Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS: Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION: CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation

Published
2021

31. Impact of red blood cell transfusion dose density on progression-free survival in lower-risk myelodysplastic syndromes patients

Author

de Swart L, Crouch S, Hoeks M, Smith A, Langemeijer S, Fenaux P, Symeonidis A, Cermák J, Hellström-Lindberg E, Stauder R, Sanz G, Mittelman M, Holm MS, Malcovati L, Madry K, Germing U, Tatic A, Savic A, Almeida AM, Gredelj-Šimec N, Guerci-Bresler A, Beyne-Rauzy O, Culligan D, Kotsianidis I, Itzykson R, van Marrewijk C, Blijlevens N, Bowen D, de Witte T, and EUMDS Registry Participants

Subjects
Myelodysplastic Syndromes, lower-risk, progression-free survival, red blood cell transfusions, transfusion dose density
Abstract

Progression-free survival of lower-risk myelodysplastic syndromes patients treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals of newly diagnosed lower-risk myelodysplastic syndromes patients from 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk myelodysplastic syndromes /acute myeloid leukemia as events. Of the 1267 patients included in the analyses, 317 patients died without progression, in 162 patients the disease had progressed. Progression-free survival was significantly associated with age, EQ-5D index, baseline WHO classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with progression-free survival (p1x10-4): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoietin agents, lenalidomide and/or iron chelators. Conclusion: the negative effect of transfusion treatment on progression-free survival already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior progression-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00600860.

Published
2020

32. Novel dynamic outcome indicators and clinical endpoints in myelodysplastic syndrome; the European LeukemiaNet MDS Registry and MDS-RIGHT project perspective

Author

Witte, T.J.M. de, Malcovati, Luca, Fenaux, P., Bowen, D., Symeonidis, A., Mittelman, M., Langemeijer, S.M.C., Hoeks, M.P.A., Marrewijk, C.J. van, Crouch, S., Smith, A., Witte, T.J.M. de, Malcovati, Luca, Fenaux, P., Bowen, D., Symeonidis, A., Mittelman, M., Langemeijer, S.M.C., Hoeks, M.P.A., Marrewijk, C.J. van, Crouch, S., and Smith, A.

Abstract

Contains fulltext : 228715.pdf (publisher's version ) (Open Access)

Published
2020

33. A phase iii placebo-controlled trial of CC-486 in patients with red blood cell transfusiondependent (RBC-TD) anemia and thrombocytopenia due to IPSS lower-risk myelodysplastic syndromes (LR-MDS).

Author

Laille E., Fianchi L., Zhong J., La Torre I., Giagounidis A., Beach C., Skikne B., Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Diez Campelo M., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., Mittelman M., Laille E., Fianchi L., Zhong J., La Torre I., Giagounidis A., Beach C., Skikne B., Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Diez Campelo M., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., and Mittelman M.

Abstract

Background: MDS is characterized by bone marrow dysplasia and peripheral cytopenias of variable severity. Treatment (Tx) options are limited for LR-MDS patients (pts) with low blast counts but high-risk disease features (eg, RBC-TD anemia and thrombocytopenia). The phase III placebo (PBO)-controlled QUAZAR Lower-risk MDS trial (NCT01566695) assessed CC-486, an oral hypomethylating agent, in pts who were RBC-TD and thrombocytopenic at study entry. Aim(s): Describe clinical outcomes from the QUAZAR Lower-risk MDS trial. Method(s): Eligible pts were age >=18 yrs, with IPSS LR-MDS, average RBC transfusion requirement of >=2 units (U)/28 days (d) for 56d, and 2 platelet (PLT) counts <=75 x 109/L taken >=21d apart. Pts were randomized 1:1 to CC-486 300 mg or PBO QD for 21d per 28d Tx cycle (C). The primary endpoint was RBC transfusion independence (TI) lasting >=56d (IWG 2006). Key secondary endpoints were overall survival (OS), >=84d RBC-TI, and hematologic improvement in erythroid and PLT lineages (HI-E, HI-P). Planned enrollment was 386 pts. An imbalance of early deaths in the CC-486 arm led to a decision to close enrollment; the final sample size (N = 216) allowed comparison of RBC-TI between Tx arms with ~99% power. Result(s): At data cutoff all pts (CC-486 n = 107; PBO n = 109) completed >=12 mo of Tx or discontinued before 12 mo. Baseline (BL) characteristics were similar between Tx arms. Median age was 74 yrs (30-89), Hgb 8.1 g/dL (5.4-10.9), PLT count 25x109/L (5-73), ANC 1.3x109/L (0.1-25), and transfusion requirement 6.7 U/56d. All pts had IPSS INT-1 MDS. Significantly more pts in the CC-486 arm achieved RBC-TI for >=56d (31%, vs. 11% with PBO; P = 0.0002) (Table 1). Median RBC-TI durations in the CC-486 and PBO arms were 11.1 and 5.0 mo, respectively (P = 0.42). In the CC-486 and PBO arms, 42% and 31%, respectively, had RBC transfusion reductions of >=4 U from BL, sustained for a median of 10.0 and 2.3 mo (P = 0.0001). While HI-E rates were comparable (P = 0.1

Published
2020

34. Contributors

Author

Aalen, Reidunn B., primary, Abdel-Wahab, Yasser H.A., additional, Adams, Michael E., additional, Adan, Roger A.H., additional, Ahima, Rexford S., additional, Ahmed, Naima, additional, Al-Massadi, Omar, additional, Altstein, Miriam, additional, Anouar, Youssef, additional, Anselmi, Laura, additional, Ansorge, Siegfried, additional, Antcheva, Nikolinka, additional, Antonova-Koch, Yevgeniya, additional, Appel, Jon R., additional, Arik, Anam J., additional, Arter, Alison L., additional, Arvan, Peter, additional, Ashkenazi, Avraham, additional, Baas, P.W., additional, Bado, André, additional, Baird, Andrew, additional, Baiula, Monica, additional, Bakaletz, Lauren O., additional, Bakken, Earl E., additional, Balaskó, Márta, additional, Baldwin, Graham S., additional, Banks, William A., additional, Barra, Donatella, additional, Barson, Jessica R., additional, Basille, Magali, additional, Bauer, Natalie N., additional, Bedini, Andrea, additional, Beeton, Christine, additional, Begley, David J., additional, Beinfeld, Margery C., additional, Bendena, William G., additional, Benoit, Stephen C., additional, Bentov, Itay, additional, Bern, Howard, additional, Bierbaum, Gabriele, additional, Billington, Charles J., additional, Blasiak, Anna, additional, Block, Norman L., additional, Bloom, Stephen. R., additional, Bonney, Iwona, additional, Bowie, John H., additional, Boyd, Sunny K., additional, Brain, Susan D., additional, Brede, Dag A., additional, Broeck, Jozef Vanden, additional, Brown, Kelly L., additional, Brown, Mark R., additional, Bugni, James M., additional, Bundgaard, Jens R., additional, Burel, Delphine, additional, Butenko, Melinka A., additional, Call, Melissa J., additional, Calò, Girolamo, additional, Campbell, Duncan John, additional, Carlsson, Anna, additional, Carr, Daniel B., additional, Carraway, Robert E., additional, Carreira, Marcos C., additional, Casanueva, Felipe F., additional, Cassella, Sarah N., additional, Casson, Stuart A., additional, Castaño, Justo P., additional, Cebrat, Marek, additional, Chappe, Valerie, additional, Chatenet, David, additional, Chen, Keqiang, additional, Chen, Chen, additional, Chen, Longchuan, additional, Chen, Duan, additional, Cheng, Carrie Y.Y., additional, Cho, Sung Ki, additional, Chow, Billy K.C., additional, Christopoulos, Arthur, additional, Chu, Shijian, additional, Clarke, Iain J., additional, Coast, Geoffrey M., additional, Compere, Vincent, additional, Concepcion, Gisela P., additional, Cone, Roger D., additional, Conlon, J. Michael, additional, Cornélissen, Germaine, additional, Courel, Maité, additional, Couture, Réjean, additional, Cramer, W.A., additional, Croft, Nathan P., additional, Crujeiras, Ana B., additional, Cuttitta, Frank, additional, Cynis, Holger, additional, D’Acquisto, F., additional, Davis, Jon F., additional, Davis, Thomas P., additional, de La Serre, Claire Barbier, additional, de Lartigue, Guillaume, additional, de Lecea, Luis, additional, de Oliveira Santos, Marcelo, additional, De Waard, Michel, additional, Bolette Hartmann, Carolyn F. Deacon, additional, Delestre, Charlène, additional, Delgado, Mario, additional, Demuth, Hans-Ulrich, additional, Deng, Xiaoming, additional, Dharmawardhana, Palitha, additional, Di Cosmo, Anna, additional, Dias, Simoni Campos, additional, Dickerson, Jonathan W., additional, Diep, Dzung B., additional, Dircksen, H., additional, Dischinger, Jasmin, additional, do Rego, Jean-Claude, additional, Dobner, Paul R., additional, Dockray, Graham J., additional, Dores, Robert M., additional, Ducroc, Robert, additional, Dudek, Nadine L., additional, Dumont, Yvan, additional, Duraffourd, Celine, additional, Duterte-Boucher, Dominique, additional, Eberlé, Alex N., additional, Egleton, Richard D., additional, Eipper, Betty A., additional, Engel, Jorg B., additional, Englander, Ella W., additional, Epelbaum, Jacques, additional, Erlanson-Albertsson, Charlotte, additional, Evangelista, S., additional, Fagan, Karen A., additional, Farber, Joshua M., additional, Farkasfalvi, Klára, additional, Fekete, Csaba, additional, Flatt, Peter R., additional, Flower, R.J., additional, Forssmann, Wolf-Georg, additional, Fournier, Alain, additional, Foy, Kevin Chu, additional, Franco, Octávio Luiz, additional, Frenkel, Dan, additional, Fricker, Lloyd D., additional, de la Fuente-Núñez, César, additional, Fukuda, Hiroo, additional, Gäde, Gerd, additional, Galas, Ludovic, additional, Gallagher, Patricia E., additional, Gandolfo, Pierrick, additional, Garcia-Espinosa, Maria A., additional, García-Sanmartín, Josune, additional, Geary, Nori, additional, Geng, Hua, additional, Germano, Patrizia M., additional, Goetze, Jens P., additional, Gonzalez, Alexis A., additional, Gonzalez, Ana, additional, Gosnell, Blake A., additional, Goto, Katsutoshi, additional, Gourcerol, Guillaume, additional, Gozes, I., additional, Gracia-Navarro, Francisco, additional, Grayson, Bernadette E., additional, Greeley, George H., additional, Greenwald-Yarnell, Megan, additional, Gressens, Pierre, additional, Grider, John R., additional, Grünewald, Jan, additional, Guerreiro, Juliano R., additional, Guerrini, Remo, additional, Guida, Filomena, additional, Guilhaudis, Laure, additional, Guilmeau, Sandra, additional, Gundlach, Andrew L., additional, Gutkowska, Jolanta, additional, Hackbarth, Clifton, additional, Haim Ohana, Y., additional, Halberg, Franz, additional, Hallberg, Mathias, additional, Hamidi, Sayyed A., additional, Han, Song, additional, Han, Ji-Sheng, additional, Hancock, Robert E.W., additional, Haque, Samer-ul, additional, Hara-Nishimura, Ikuko, additional, Hariton, Aliza, additional, Hartsock, Wendy J., additional, Harvey, Alan L., additional, Hasunuma, Itaru, additional, Henning, Robert J., additional, Heppner, Kristy M., additional, Hertweck, Kate L., additional, Herzog, Herbert, additional, Higashiyama, Tetsuya, additional, Hinuma, Shuji, additional, Hippenstiel, Stefan, additional, Hirakawa, Yuki, additional, Hirose, Shuichi, additional, Hirsch, Jochen R., additional, Hocke, Andreas C., additional, Hodges, Robert S., additional, Hoffmann, Werner, additional, Hökfelt, Tomas, additional, Holst, Jens Juul, additional, Holzer, Peter, additional, Horodyski, Frank M., additional, Hosoda, Hiroshi, additional, Hou, Xiaowen, additional, Huffaker, Alisa, additional, Iijima, Norio, additional, Ikeuchi, Momoko, additional, Imperial, Julita S., additional, Improta, Giovanna, additional, Inui, Akio, additional, Irwin, Nigel, additional, Ishii, Munehiro, additional, Iturrioz, Xavier, additional, Ivanisevic, Ljubica, additional, Iwao, Hiroshi, additional, Iwata, Takeo, additional, Izumi, Yasukatsu, additional, Izumiyama, Hajime, additional, Jankowski, Marek, additional, Janssen, Tom, additional, Jégou, Sylvie, additional, Jensen, Robert T., additional, Jethwa, Preeti H., additional, Johannessen, Helene, additional, Johanson, Conrad, additional, Judkowski, Valeria, additional, Kaczmarek, Przemyslaw, additional, Kageyama, Haruaki, additional, Kakimoto, Tatsuo, additional, Kang, Ki Sung, additional, Kangawa, Kenji, additional, Kastin, Abba J., additional, Kato, Johji, additional, Kaumaya, Pravin T.P., additional, Keep, Richard F., additional, Kem, William R., additional, Khomenko, Tetyana, additional, Kikuyama, Sakae, additional, Kim, Young-Joon, additional, Kimura, Sadao, additional, King, Ross, additional, Kiptoo, Paul, additional, Kishimoto, Ichiro, additional, Kitamura, Kazuo, additional, Kluczyk, Alicja, additional, Kobori, Hiroyuki, additional, Kodama, Yosuke, additional, Kojima, Masayasu, additional, Kondo, Yuki, additional, Körner, Meike, additional, Kosson, Piotr, additional, Kotz, Catherine M., additional, Krishnan, Bhavani, additional, Kulseng, Bård, additional, Kumpf, Robert, additional, Laburthe, Marc, additional, Lacaille, Hélène, additional, Ladenheim, Ellen E., additional, Ladram, Ali, additional, Laksitorini, Marlyn D., additional, Lambert, David G., additional, Lange, Angela B., additional, Langhans, Wolfgang, additional, Larauche, Muriel, additional, Larhammar, Dan, additional, Larráyoz, Ignacio M., additional, Lattanzi, Roberta, additional, Lechan, Ronald M., additional, Lefranc, Benjamin, additional, Leibowitz, Sarah F., additional, Lelièvre, Vincent, additional, Leprince, Jérôme, additional, Levine, Allen S., additional, Li, Qun, additional, Lifshitz, Veronica, additional, Lihrmann, Isabelle, additional, Chi-Jen Lin, James, additional, Lindberg, Iris, additional, Lindsey, Keith, additional, Lipkowski, Andrzej W., additional, Liron, T., additional, Liu, Junli, additional, Liu, Ying, additional, Liu, Min, additional, Llorens-Cortes, Catherine, additional, Loizidou, Marilena, additional, Lopez, C., additional, Lovejoy, David A., additional, Luca, Vincenzo, additional, Lutz, Thomas A., additional, Ma, Sherie, additional, Mains, Richard E., additional, Malagon, Maria M., additional, Malendowicz, Ludwik K., additional, Wan, Jennifer Man-Fan, additional, Mangoni, Maria Luisa, additional, Manigrasso, Michaele B, additional, Marahiel, Mohamed A., additional, Marco, Heather G., additional, Maric-Bilkan, Christine, additional, Marks, Nikki J., additional, Martin, Roland, additional, Martinez, Vicente, additional, Martínez, Alfredo, additional, Martinez-Fuentes, Antonio J., additional, Masler, Edward P., additional, Matsubayashi, Yoshikatsu, additional, Mattu, Harman S., additional, Maule, Aaron G., additional, McLaughlin, Patricia J., additional, McMurtry, Ivan F., additional, Meelkop, Ellen, additional, Mehdi, Saher, additional, Melchiorri, Pietro, additional, Millar, R.P., additional, Miller, Laurence J., additional, Miller, Miles, additional, Million, Mulugeta, additional, Minamino, Naoto, additional, Mittelman, M., additional, Miyauchi, Takashi, additional, Miyazato, Mikiya, additional, Mizoguchi, Hirokazu, additional, Mohme, Malte, additional, Montero-Hadjadje, Maité, additional, Moody, Terry W., additional, Mookherjee, Neeloffer, additional, Moran, Timothy H., additional, Morganstern, Irene, additional, Mori, Masatomo, additional, Morin, Fabrice, additional, Morris, John F., additional, Moura, Daniel S., additional, Mudge, Anna J., additional, Mul, Joram D., additional, Murthy, Karnam S., additional, Myers, Martin G., additional, Nachman, Ronald J., additional, Nahon, Jean-Louis, additional, Naithani, Sushma, additional, Nakada, Tomoaki, additional, Nakamachi, Tomoya, additional, Nakamura, Yuki, additional, Nalivaeva, Natalia N., additional, Nasrallah, June B., additional, Nässel, Dick R., additional, Navar, L. Gabriel, additional, Neelakantan, Pratap, additional, Negri, Lucia, additional, Nes, Ingolf F., additional, Neumann, D., additional, Neveu, Cindy, additional, Ng, Tzi Bun, additional, Ng, Stephanie Y.L., additional, Nicholson, Graham M., additional, Nicolas, Pierre, additional, Nishikimi, Toshio, additional, Nishiyama, Mariko, additional, Nogueiras, Rubén, additional, Norton, Raymond S., additional, Novotny, Laura A., additional, Nowak, Krzysztof W., additional, Nyberg, Fred, additional, Ochoa-Callejero, Laura, additional, Ove Ögren, Sven, additional, Ohgusu, Hideko, additional, Oh-I, Shinsuke, additional, Ojo, Opeolu O., additional, Olivera, Baldomero M., additional, Olucha-Bordonau, Francisco E., additional, Oppenheim, Joost J., additional, Orchard, Ian, additional, Ouellette, André J., additional, Pacheco-López, Gustavo, additional, Page, Nigel M., additional, Palma, Mario Sergio, additional, Pan, Weihong, additional, Park, Yoonseong, additional, Parmentier, Marc, additional, Passemard, Sandrine, additional, Patterson, Michael, additional, Paunovic, Brankica, additional, Pearce, Gregory, additional, Pedersen, Jens, additional, Peeters, Theo L., additional, Eugene Pekary, A., additional, Pelletier, Georges, additional, Perboni, Simona, additional, Pérez-Tilve, Diego, additional, Perjés, Ábel, additional, Perretti, M., additional, Pétervári, Erika, additional, Pinilla, Clemencia, additional, Pinskim, Jacek, additional, Pisegna, Joseph R., additional, Plankensteiner, Kristof, additional, Podvin, Sonia, additional, Poitras, Pierre, additional, Polese, Gianluca, additional, Pollock, David M., additional, Porto, William Farias, additional, Possani, Lourival D., additional, Pothoulakis, Charalabos, additional, Presse, Françoise, additional, Prieto, Minolfa C., additional, Prutchi-Sagiv, S., additional, Purcell, Anthony W., additional, Purtell, Louise, additional, Quirion, Rémi, additional, Rabat, Catalina Abad, additional, Rademaker, Miriam, additional, Rajpal, Gautam, additional, Randeva, Harpal S., additional, Rebuffat, Sylvie, additional, Reeve, Joseph R., additional, Rehfeld, Jens F., additional, Reinhold, Dirk, additional, Reinscheid, Rainer K., additional, Reubi, Jean Claude, additional, Rezvani, Katayoun, additional, Ribeiro, Suzana Meira, additional, Richard, D., additional, Richards, Mark, additional, Riehle, Michael A., additional, Rinaldi, Andrea C., additional, Rode, Bernd M., additional, de la Vega, Ricardo C. 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Published
2013
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35. Erythropoietin

Author

Ohana, Y. Haim, primary, Liron, T., additional, Prutchi-Sagiv, S., additional, Mittelman, M., additional, Souroujon, M.C., additional, and Neumann, D., additional

Published
2013
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43. Prognostic impact of a suboptimal number of analyzed metaphases in normal karyotype lower-risk MDS

Author

Swart, L. de, Smith, A., Haase, D., Fenaux, P., Symeonidis, A., Cermak, J., Sanz, G., Stauder, R., Mittelman, M., Hellstrom-Lindberg, E., Malcovati, L., Langemeijer, S.M., Skov-Holm, M., Madry, K., Germing, U., Almeida, A.M., Tatic, A., Savic, A., Simec, N.G., Marrewijk, C.J. van, Guerci-Bresler, A., Sanhes, L., Luno, E., Culligan, D., Beyne-Rauzy, O., Burgstaller, S., Blijlevens, N.M., Bowen, D., Witte, T.J. de, Swart, L. de, Smith, A., Haase, D., Fenaux, P., Symeonidis, A., Cermak, J., Sanz, G., Stauder, R., Mittelman, M., Hellstrom-Lindberg, E., Malcovati, L., Langemeijer, S.M., Skov-Holm, M., Madry, K., Germing, U., Almeida, A.M., Tatic, A., Savic, A., Simec, N.G., Marrewijk, C.J. van, Guerci-Bresler, A., Sanhes, L., Luno, E., Culligan, D., Beyne-Rauzy, O., Burgstaller, S., Blijlevens, N.M., Bowen, D., and Witte, T.J. de

Abstract

Contains fulltext : 190736.pdf (publisher's version ) (Open Access), Conventional karyotype is one of the most relevant prognostic factors in MDS. However, about 50% of patients with MDS have a normal karyotype. Usually, 20-25 normal metaphases (nMP) are considered to be optimal to exclude small abnormal clones which might be associated with poor prognosis. This study evaluated the impact of examining a suboptimal number of metaphases in patients recruited to the EUMDS Registry with low and intermediate-1 risk according to IPSS. Only 179/1049 (17%) of patients with a normal karyotype had a suboptimal number of nMP, defined as less than 20 metaphases analyzed. The outcome (overall survival and progression-free survival) of patients with suboptimal nMP was not inferior to those with higher numbers of analyzed MP both in univariate and multivariate analyses. For patients with an abnormal karyotype, 224/649 (35%) had a suboptimal number of MP assessed, but this did not impact on outcome. For patients with a normal karyotype and suboptimal numbers of analyzable metaphases standard evaluation might be acceptable for general practice, but we recommend additional FISH-analyses or molecular techniques, especially in candidates for intensive interventions.

Published
2018

47. Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome

Author

Garelius, H.K., Johnston, W.T., Smith, A.G., Park, S., Swart, L. de, Fenaux, P., Symeonidis, A., Sanz, G., Cermak, J., Stauder, R., Malcovati, L., Mittelman, M., Loosdrecht, A.A. van de, Marrewijk, C.J. van, Bowen, D., Crouch, S., Witte, T.J.M. de, Hellstrom-Lindberg, E., Garelius, H.K., Johnston, W.T., Smith, A.G., Park, S., Swart, L. de, Fenaux, P., Symeonidis, A., Sanz, G., Cermak, J., Stauder, R., Malcovati, L., Mittelman, M., Loosdrecht, A.A. van de, Marrewijk, C.J. van, Bowen, D., Crouch, S., Witte, T.J.M. de, and Hellstrom-Lindberg, E.

Abstract

Contains fulltext : 169659.pdf (publisher's version ) (Open Access), BACKGROUND: The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower-risk myelodysplastic syndrome (MDS) from 17 European countries from both university hospitals and smaller regional hospitals. OBJECTIVE: The aim of this study was to describe the usage and clinical impact of erythropoiesis-stimulating agents (ESAs) in 1696 patients enrolled between 2008 and 2014. METHODS: The effects of ESAs on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. RESULTS: ESA treatment (median duration of 27.5 months, range 0-77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit (HR 0.82, 95% CI: 0.65-1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions (P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post-ESA treatment transfusion was 6.1 months (IQR: 4.3-15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0-47.8 months) in patients without prior transfusions (HR 2.4, 95% CI: 1.7-3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death (HR 0.65, 95% CI: 0.45-0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia (HR 0.71, 95% CI: 0.39-1.29, P = 0.27). CONCLUSION: Appropriate use of ESAs can significantly delay the onset of a regular transfusion need in patients with lower-risk MDS.

Published
2017

48. Clinical characteristics and outcomes according to age in lenalidomide-treated patients with RBC transfusion-dependent lower-risk MDS and del(5q)

Author

Fenaux, P., Giagounidis, A., Selleslag, D., Beyne-Rauzy, O., Mittelman, M., Muus, P., Nimer, S.D., Hellstrom-Lindberg, E., Powell, B.L., Guerci-Bresler, A., Sekeres, M.A., Deeg, H.J., Canizo, C. Del, Greenberg, P.L., Shammo, J.M., Skikne, B., Yu, X., List, A.F., Fenaux, P., Giagounidis, A., Selleslag, D., Beyne-Rauzy, O., Mittelman, M., Muus, P., Nimer, S.D., Hellstrom-Lindberg, E., Powell, B.L., Guerci-Bresler, A., Sekeres, M.A., Deeg, H.J., Canizo, C. Del, Greenberg, P.L., Shammo, J.M., Skikne, B., Yu, X., and List, A.F.

Abstract

Contains fulltext : 175140.pdf (publisher's version ) (Open Access), BACKGROUND: Particularly since the advent of lenalidomide, lower-risk myelodysplastic syndromes (MDS) patients with del(5q) have been the focus of many studies; however, the impact of age on disease characteristics and response to lenalidomide has not been analyzed. METHODS: We assessed the effect of age on clinical characteristics and outcomes in 286 lenalidomide-treated MDS patients with del(5q) from two multicenter trials. RESULTS: A total of 33.9, 34.3, and 31.8% patients were aged <65 years, >/=65 to <75 years, and >/=75 years, respectively. Age <65 years was associated with less favorable International Prognostic Scoring System (IPSS) risk and additional cytopenias at baseline versus older age groups, significantly lower cytogenetic response rates (p = 0.022 vs. >/=65 to <75 years; p = 0.047 vs. >/=75 years), and higher rates of acute myeloid leukemia (AML) progression (Gray's test, p = 0.013). Lenalidomide was equally well tolerated across age groups, producing consistently high rates of red blood cell transfusion independence >/=26 weeks. CONCLUSIONS: Baseline disease characteristics and AML progression appear to be more severe in younger lower-risk MDS patients with del(5q), whereas older age does not seem to compromise the response to lenalidomide. TRIAL REGISTRATION: ClinicalTrials.gov NCT00065156 and NCT00179621.

Published
2017

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