Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 5561-5561

Abstract: Background Since 2012, the Study Alliance Leukemia (SAL), a group of over 50 clinical trial and research centers (university hospitals, community hospitals, private practice), is establishing a systematic assessment of MPN patients in a German-wide registry, partly supported by Novartis. The main goal of this registry is the evaluation of the epidemiological distribution of clinical characteristics and outcome parameters, to enhance the understanding of MPN disease pathogenesis and disease progression. An important characteristic of our registry is that in addition to large centers, also small institutions are included which allows the collection of real-life data in MPN, due to the fact that these diseases are frequently treated outside large clinical centers in Germany. Methods The registry is a non-interventional, prospective and multi-centered epidemiological study. Inclusion criteria was the diagnosis of MPN according to WHO criteria (2008). Furthermore a minimum age of 18 and a written informed consent were conditions for entering the registry, independently of therapy regime and comorbidities. In addition to prospective collection of patients, data of patients who died or were lost to follow-up was evaluated once, covered by the central ethics approval. Epidemiological data and clinical characteristics were assessed at date of enrollment and every 12 months for an unlimited period of time. For this analysis only initial data was included. For statistical analysis, descriptive methods were used to describe the data with mean and median including standard deviations, range and/or 95%-confidence intervals. Results So far, 506 patients have been registered, comprising 243 evaluable patients with a mean age of 55 years (range 21-85). An updated analysis will be presented at the meeting. The proportion of male patients was 52%. The distribution of sex within the entities and other critical parameters are given in Table 1. 62% of all patients were JAK2V617F positive. As expected, complications like thrombosis and thromboembolism were mostly associated with PV and ET (38% and 29%). In 22 % of MPN patients, life-threatening thrombotic or thromboembolic events occurred during the clinical history. Similarly severe bleedings, as defined by a hemoglobin-level decrease 〉 2 mg/dl, were common in MPN; including 11 % of patients suffering from acute bleeding, most frequently from the upper gastrointestinal tract (56% of all hemorrhages). Acute bleedings occurred most common in PV, followed by PMF patients. Hydroxyurea was the most frequently administered substance (42%) followed by watch and wait strategies (22%). Other drugs were applied in 36% of all patients. Conclusions MPN are still associated with life-threatening events, such as thrombosis or severe bleeding. 33% of patients experiencing such an event had already been diagnosed with MPN and thus were already under medical surveillance. Novel strategies to pre-define risk factors and optimal therapeutic strategies are required to improve prevention strategies with the ultimate goal to avoid thromboembolic complications and improve survival and quality of life in MPN. Abstract 5561. Table 1 Clinical and laboratory results for PV, ET, PMF and Post PV/ET-MF Variable, mean (SD) All Patients PV ET PMF Post PV/ET- MF Age n = 132 56 (15) 56 (16) 49 (14) 58 (12) 65 (11) Male (%) n = 243 52 65 40 76 48 Leukocytes (/nl) n = 206 12.02 (8.0) 11.17 (6.7) 11.8 (6.0) 12.07 (8.3) 10.57 (6.0) Hemoglobin (g/dl) n = 206 13.4 (8.9) 13.3 (2.9) 12.94 (3.0) 11.69 (2,7) 13.17 (3.0) Platelets (/nl) n = 205 521.7 (404) 558.8 (390) 550.1 (423) 477.6 (372) 497.7 (415) LDH (U/l) n = 195 482.0 (377.8) 417.2 (258.7) 394,9 (256,1) 573.7 (413.7) 444.0 (295.6) Spleen Length (cm) n = 106 17.0 (6.6) 16.6 (5.9) 17.5 (8.9) 18.3 (7.5) 18.9 (7.1) Thromboembolism (%) n = 202 21.8 38.5 29.3 22.9 15.8 Severe Bleeding (%) n = 197 10.5 23.1 7.3 14.3 5.3 Therapy regime n = 203 Watch and wait (%) 21.7 27.8 29.7 26.9 28.6 Hydroxyurea (%) 42.4 44.4 48.7 34.6 42.9 Other Substances (%) 36.0 27.8 21.6 38.5 28.6 Disclosures Wolf: Novartis: Consultancy, Honoraria, Research Funding, Travel and Accommodation Other. Gattermann:Novartis: Honoraria, Research Funding. Lang:Novartis: Research Funding, Travel, Accommodation Other. Bennemann:Novartis: Consultancy, Honoraria. Bruemmendorf:Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding. Koschmieder:Novartis: Consultancy, Honoraria, Research Funding, Travel, Accommodation Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.5561.5561

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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detail.hit.zdb_id: 80069-7

In: Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 95, No. 20 ( 2016-05), p. e3355-

Type of Medium: Online Resource

ISSN: 0025-7974

URL: Article

DOI: 10.1097/MD.0000000000003355

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2016

detail.hit.zdb_id: 2049818-4

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1501-1503

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-169324

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Cancers, MDPI AG, Vol. 13, No. 16 ( 2021-08-13), p. 4086-

Abstract: Inflammation-induced thrombosis represents a severe complication in patients with myeloproliferative neoplasms (MPN) and in those with kidney dysfunction. Overlapping disease-specific attributes suggest common mechanisms involved in MPN pathogenesis, kidney dysfunction, and thrombosis. Data from 1420 patients with essential thrombocythemia (ET, 33.7%), polycythemia vera (PV, 38.5%), and myelofibrosis (MF, 27.9%) were extracted from the bioregistry of the German Study Group for MPN. The total cohort was subdivided according to the calculated estimated glomerular filtration rate (eGFR, (mL/min/1.73 m2)) into eGFR1 (≥90, 21%), eGFR2 (60–89, 56%), and eGFR3 ( 〈 60, 22%). A total of 29% of the patients had a history of thrombosis. A higher rate of thrombosis and longer MPN duration was observed in eGFR3 than in eGFR2 and eGFR1. Kidney dysfunction occurred earlier in ET than in PV or MF. Multiple logistic regression analysis identified arterial hypertension, MPN treatment, increased uric acid, and lactate dehydrogenase levels as risk factors for kidney dysfunction in MPN patients. Risk factors for thrombosis included arterial hypertension, non-excessive platelet counts, and antithrombotic therapy. The risk factors for kidney dysfunction and thrombosis varied between MPN subtypes. Physicians should be aware of the increased risk for kidney disease in MPN patients, which warrants closer monitoring and, possibly, early thromboprophylaxis.

Type of Medium: Online Resource

ISSN: 2072-6694

URL: Article

DOI: 10.3390/cancers13164086

Language: English

Publisher: MDPI AG

Publication Date: 2021

detail.hit.zdb_id: 2527080-1

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4637-4637

Abstract: Introduction: Mutations (muts) in JAK2, MPL, and CALR are genetic hallmarks in myeloproliferative neoplasms such as myelofibrosis (MF). Prognostication in MF is predominantly based on clinical parameters according to the Dynamic International Prognostic Scoring System (DIPSS). However, gene mutations become increasingly important allowing for a more precised assessment of prognosis. For instance, CALR mutated MF is associated with favorable prognosis, while mutations in distinct high molecular-risk (HMR) genes are considered adverse. Our multicenter phase-Ib/II MPNSG-0212 trial (NCT01644110) investigating ruxolitinib plus pomalidomide in a total cohort of 92 patients with advanced MF and anemia provides an ideal basis for investigating the genomic landscape and molecular risk in a well-defined study population. Aims & Methods: To assess the genomic landscape in MF patients treated within the MPNSG-0212 trial and to correlate the results with clinical parameters and overall survival (OS). So far, targeted next generation sequencing (NGS) of 269 candidate genes was performed in peripheral blood or bone marrow from 81/92 patients using libraries prepared with SureSelectXT HS (Agilent, Santa Clara, USA). NGS was carried out on a NextSeq550 (Illumina, San Diego, USA). Results: At study entry, median age of the 81 patients was 71 years (range 52-86), median Hb 8.6 g/dL (range 5.4-11.7 g/dl); 30% of patients were RBC transfusion-dependent; 67% had primary MF (PMF) and 33% secondary MF (SMF), respectively. According to DIPSS, the vast majority of the patients were categorized as intermediate-2 (63%) or high-risk (26%) MF; 11% were low- and intermediate-1 risk patients. Overall, 315 muts were identified in 80/81 (99%) patients with a median of 3 muts/patient (range 0-9). Recurrent muts (≥5%) were identified in JAK2 (60%), ASXL1 (30%), SRSF2 (21%), CALR (20%; type-1: 75% [n=12], type-2 and non-type-1/2: 12.5% [n=2] each), MPL (19%), SF3B1 (19%), TET2 (16%), U2AF1 (15%), CBL and EZH2 (10% each), IDH2 and DNMT3A (7% each), PHF6, ZRSR2, and CUX1 (5% each). The majority of the patients (95%) was characterized by the presence of a driver mut in JAK2, CALR, or MPL; 4/81 patients (5%) were triple negative (Figure 1). JAK2mut was associated with TET2mut (p=.047), whereas muts in CALR and TET2 were mutually exclusive (p=.05). CALRmut patients had less co-muts than patients with JAK2/MPL muts (mean 2.5 vs. 4.1, p=.007) and were mutually exclusive with muts in the spliceosome regulating genes SRSF2, SF3B1, U2AF1, and ZRSR2 (p=.009). Compared to MF with mutated JAK2 or MPL, MF patients with mutated CALR had a longer median OS (not reached vs. 3.1 years; p=.04). With regard to high molecular risk (HMR) muts, n=56 were detected in 38 patients (47%), with 40% (15/38) of the patients harboring ≥2 HMR muts. The most commonly mutated HMR genes were ASXL1 (43%; 24/56), followed by SRSF2 (30%), EZH2 (14%), IDH2 (11%), and IDH1 (2%). MPLmut but not JAK2mut or CALRmut were significantly associated with HMR mut (p=.023). HMR mut patients harbored more co-muts than HMR wt patients (median 5 vs. 3; p & lt;.0001). There were no significant differences in the variables age, sex, WBC, Hb, PLT, or LDH level between patients with HMR mut and HMR wt MF. In univariate analysis, patients with HMR mut MF had shorter median OS (2.3 vs 3.7 years, p=.007). In multivariate analysis (HMR mut, age, DIPSS-category, SMF vs. PMF) a higher DIPSS-score (HR, 3.2; 95% CI, 1.5-7.0; p=.004) and muts in HMR genes (HR, 3.5; 95% CI, 1.5-8.1; p=.003) were significant adverse prognostic factors for OS. Conclusions: Our NGS data underline the genomic complexity of advanced MF. CALR mutations were only found in 20% of the patients that were characterized by less co-mutations, mutual exclusivity with spliceosome mutations, and with more favorable outcome suggesting a distinct disease biology. Almost 50% of patients showed mutations in HMR genes which were associated with an inferior OS in univariate and multivariate analyses. §Frank Stegelmann and Konstanze Döhner contributed equally to this work. Figure 1 Figure 1. Disclosures Koschmieder: Shire: Honoraria, Other; Alexion: Other: Travel support; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Abbvie: Other: Travel support; CTI: Membership on an entity's Board of Directors or advisory committees, Other; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Image Biosciences: Other: Travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karthos: Other: Travel support. Heidel: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hebart: AbbVie: Honoraria; AstraZeneca: Honoraria; BMS: Honoraria; Janssen: Honoraria; Roche: Honoraria. Isfort: Alexion: Other: Travel reimbursement; Roche: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Mundipharma: Other: Travel reimbursement; Hexal: Other: Travel reimbursement; BMS: Honoraria; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement. Reiter: AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding. Waller: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Mylan: Consultancy; Alvotech: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Lilly: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Chugai: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Amgen: Membership on an entity's Board of Directors or advisory committees; IPSEN: Other: travel grant. Scheid: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goethert: Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support; Incyte: Consultancy, Honoraria, Other: Travel support; zr pharma & : Honoraria; BMS: Consultancy, Honoraria, Other: Travel support; AOP Orphan Pharmaceuticals: Honoraria, Other: travel support; Proteros Biostructures: Consultancy. Schafhausen: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum AB: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees. Radsak: Otsuka: Consultancy, Honoraria; Abbvie: Other: e.g. travel support; Astellas: Other: e.g. travel support; TEVA: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: e.g. travel support; Daiichi Sankyo: Consultancy, Honoraria, Other: e.g. travel support; Celgene/BMS: Consultancy, Honoraria, Other: e.g. travel support; Amgen: Other: e.g. travel support; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Corat: Consultancy, Honoraria; Cogent Biosciences: Consultancy, Honoraria; JAZZ: Other: e.g. travel support. Gattermann: Takeda: Research Funding; Novartis: Honoraria; Celgene: Honoraria. von Bubnoff: Novartis: Honoraria; Takeda: Honoraria. Brümmendorf: Bristol Myers: Research Funding; Janssen: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Repeat Diagnostics: Research Funding; Takepart Media: Honoraria. Döhner: Celgene: Honoraria, Research Funding; Agios: Honoraria, Research Funding; GEMoaB: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Janssen: Honoraria; Helsinn: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Berlin-Chemie: Honoraria; Roche: Honoraria; Pfizer: Research Funding. Griesshammer: Amgen: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Stegelmann: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: Abbvie: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Jazz Roche: Consultancy, Honoraria; Daiichi Sankyo: Honoraria, Other: Advisory Board; Astellas: Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Agios and Astex: Research Funding. OffLabel Disclosure: Pomalidomide was shown to be active in patients with myelofibrosis in particular in the treatment of anemia (Tefferi et al 2009, Begna et al 2011, Mesa et al 2010)

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-150361

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

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detail.hit.zdb_id: 80069-7