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In: The Lancet, Elsevier BV, Vol. 395, No. 10227 ( 2020-03), p. 878-887

Type of Medium: Online Resource

ISSN: 0140-6736

URL: Article

DOI: 10.1016/S0140-6736(20)30258-0

Language: English

Publisher: Elsevier BV

Publication Date: 2020

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detail.hit.zdb_id: 3306-6

detail.hit.zdb_id: 1476593-7

SSG: 5,21

In: Annals of Oncology, Elsevier BV, Vol. 29, No. 3 ( 2018-03), p. 544-562

Type of Medium: Online Resource

ISSN: 0923-7534

URL: Article

DOI: 10.1093/annonc/mdx413

Language: English

Publisher: Elsevier BV

Publication Date: 2018

detail.hit.zdb_id: 2003498-2

In: The Journal of Thoracic and Cardiovascular Surgery, Elsevier BV, Vol. 129, No. 3 ( 2005-03), p. 607-614

Type of Medium: Online Resource

ISSN: 0022-5223

URL: Article

DOI: 10.1016/j.jtcvs.2004.07.064

Language: English

Publisher: Elsevier BV

Publication Date: 2005

detail.hit.zdb_id: 2007600-9

In: JAMA Network Open, American Medical Association (AMA), Vol. 4, No. 11 ( 2021-11-05), p. e2132376-

Type of Medium: Online Resource

ISSN: 2574-3805

URL: Article

DOI: 10.1001/jamanetworkopen.2021.32376

Language: English

Publisher: American Medical Association (AMA)

Publication Date: 2021

detail.hit.zdb_id: 2931249-8

In: The Lancet Oncology, Elsevier BV, Vol. 19, No. 11 ( 2018-11), p. 1530-1542

Type of Medium: Online Resource

ISSN: 1470-2045

URL: Article

DOI: 10.1016/S1470-2045(18)30618-1

Language: English

Publisher: Elsevier BV

Publication Date: 2018

detail.hit.zdb_id: 2049730-1

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3821-3821

Abstract: Background In myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML), achievement of morphologic complete response (CR) is a prerequisite for potential cure. In AML, CR is deemed the major outcome associated with improved overall survival (OS); patients (pts) without CR are considered non-responders, and hematologic improvement (HI) without bone marrow blast (BMB) clearance is considered treatment (trt) failure (Cheson 2003). Evidence suggests that these definitions may not be applicable to older pts treated with hypomethylating agents (HMA), and that achievement of CR may not be necessary for prolonged OS (Pleyer 2013, 2014, 2015; Schuh 2015; Bloomfield 2018). IWG response criteria for HI do not differentiate between pts who qualify for response (QFR) vs those that do not. Pts with 'normal' blood counts at trt start are per definition HI non-responders. This may obscure potential survival benefits of responding pts. Aims 1) Assess the impact of HI irrespective of BMB clearance and excluding immortal time bias via landmark analyses. 2) Differentiate between pts who QFR, and those with 'normal' baseline values (not-QFR) defined according to IWG prerequisites for CR. 3) Introduce 3 new categories of HI: peripheral blood blasts (PBB), elevated white blood cells (WBC), and PB-CR (defined as Hb ≥11 g/dl, ANC ≥1.0 G/l, WBC 〈 15 G/l, PB blasts: 0%) in analogy to the concept of complete hematologic response in chronic myelogenous leukemia. Methods 1301 consecutive pts with azacitidine (AZA) trt were analyzed (NCT01595295). Data cut-off 26.07.19. HI was assessed according to IWG criteria (Cheson 2006) and the definitions specified in 3) above. More recent proposals of revision for low-risk MDS pts included in trials (Platzbecker 2018) remain largely idem. Human errors in HI assessment for each AZA cycle and lineage were excluded by automated computational calculation from electronic case report form (eCRF) data. Landmark analyses were performed at 3 months (mo) (HI requires ≥8 weeks response duration) and 6 mo (91, 92 and 88% of MDS, CMML and AML pts respond by cycle 6 [Silverman 2011; Pleyer 2013, 2014]). Statistics were performed by Unidata Geodesign GmbH using DeployR Open 8.0.0. Results In total, 462, 113, and 720 pts had MDS, CMML and AML (n=6 unknown). At AZA start, median age was 73 (range 23-93) years. One, 2 or 3 cytopenias were present in 25, 41 and 29% of pts and 46% were transfusion dependent. 55% received AZA 1st line (26% of whom received prior growth factors or iron chelators). Median AZA dose was 889 mg/cycle and 73 mg/m2/day. Median time to 1st response was 3.0 mo and 95% of pts responded by cycle 6. During AZA trt 1091 BM evaluations (BME) were performed in 599 (46%) pts. At the 3 (6) mo landmark, 44% (47%) of pts with BME achieved CR or CR with incomplete blood count recovery (CRi). Early mortality was 5.6 and 10.3% at 30 and 60 days. Of 932 (598) pts that met the 3 (6) mo landmark, a total of 39% (25%) had no BME. The impact of HI on OS became smaller the later the landmark (Tables 1 and 2). The impact of response on OS was 0.4-4.4 mo longer and significance at the 6 mo landmark was retained using IWG criteria with (Table 1) vs without (Table 2) differentiating between pts who did or did not QFR. Pts who did not QFR had similar or better OS compared with responders. At the 3 mo landmark, proposed additional response parameters HI-PBB, HI-elevated WBC and PB-CR were assoc. with a survival benefit of +7.4, +5.0 and +12.9 mo (Table 1, Fig 1A-C). Conclusions 1) The impact of HI on OS is overestimated without landmark analyses. Median time to 1st response was 3.0 mo and ≥8 weeks response duration required. We therefore suggest using a 3 mo landmark when assessing HI. 2) Using IWG criteria for HI assessment underestimates the impact of response, as non-responders are diluted by pts who do not QFR. Distinguishing QFR/not-QFR seems necessary. 3) Proposed additional HI categories (HI-PBB, HI-elevated WBC, PB-CR) add value to current response criteria. It is often the case that BME are not performed in elderly pts in real-world settings (Dinmohamed 2015; current study). Achievement of HI in any lineage and especially PB-CR might be used as a surrogate for response in pts unable or unwilling to undergo BME for response assessment. This large and growing database is suitable to allow future validation of potential novel response criteria. Disclosures Pleyer: Celgene: Other: Advisory board; Novartis: Other: Advisory board; Inflection Point Biomedical Advisors: Other: Advisory board; Agios: Other: Advisory board; Abbvie: Other: Advisory board. Pfeilstocker:Novartis: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Celgene: Consultancy, Honoraria. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva (Ratiopharm): Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding. Heibl:Daiichi Sankyo: Honoraria; Pfizer: Honoraria; Mundipharma: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sill:Astex: Other: Advisory board; Novartis: Other: Advisory board; AbbVie: Other: Advisory board; Astellas: Other: Advisory board. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria. Petzer:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Personal fees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vallet:MSD: Honoraria; Pfizer: Honoraria; Roche Pharmaceuticals: Consultancy. Geissler:Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; AOP: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Roche: Honoraria; Ratiopharm: Honoraria. Sperr:Novartis: Honoraria; Celgene: Consultancy, Honoraria. Leisch:Novartis: Honoraria, Other: Travel support; Celgene: Other: Travel support; Bristol-Myers-Squibb: Honoraria. Egle:Celgene: Honoraria, Other: Advisory board and Travel support. Melchardt:MSD: Honoraria; Merck: Honoraria, Research Funding; Takeda: Honoraria; Janssen-Cilag: Honoraria; Roche: Honoraria; Novartis: Honoraria; Cephalon: Research Funding. Piringer:Amgen: Research Funding; Roche: Other: Travel support; Merck: Other: Travel support; Bayer: Research Funding. Zebisch:Roche: Honoraria; Novartis: Honoraria, Other: Advisory board; Celgene: Honoraria; AbbVie: Other: Advisory board. Machherndl-Spandl:Celgene: Other: Advisory board. Wolf:Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Keil:Bionorica: Honoraria, Research Funding; Roche: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Novartis: Honoraria; Merck: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Greil:Ratiopharm: Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Sandoz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria. OffLabel Disclosure: Azacitidine is not approved for the treatment of MP-CMML, CMML with 〈 10% BM blasts and IPSS low-risk MDS in the EU

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-128153

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Der Nervenarzt, Springer Science and Business Media LLC

Abstract: Magnetic resonance imaging (MRI) is of exceptional importance in the diagnostics and monitoring of multiple sclerosis (MS); however, a close interdisciplinary cooperation between neurologists in private practice, (neuro)radiological practices, hospitals or specialized MS centers is only rarely established. In particular, there is a lack of standardized MRI protocols for image acquisition as well as established quality parameters, which guarantee the comparability of MRI records; however, this is a fundamental prerequisite for an effective application of MRI in the treatment of MS patients, e.g., for making the diagnosis or treatment monitoring. To address these challenges a group of neurologists and (neuro)radiologists developed a consensus proposal for standardization of image acquisition, interpretation and transmission of results and for improvement in interdisciplinary cooperation. This pilot project in the metropolitan area of Essen used a modified Delphi process and was based on the most up to date scientific knowledge. The recommendation takes the medical, economic, temporal and practical aspects of MRI in MS into consideration. The model of interdisciplinary cooperation between radiologists and neurologists with the aim of a regional standardization of MRI could serve as an example for other regions of Germany in order to optimize MRI for MS.

Type of Medium: Online Resource

ISSN: 0028-2804 , 1433-0407

URL: Article

DOI: 10.1007/s00115-023-01531-2

Language: German

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

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detail.hit.zdb_id: 123291-5

SSG: 2,1

In: Cancers, MDPI AG, Vol. 14, No. 10 ( 2022-05-17), p. 2459-

Abstract: Background: Azacitidine is the treatment backbone for patients with acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia who are considered unfit for intensive chemotherapy. Detailed reports on adverse events in a real-world setting are lacking. Aims: To analyze the frequency of adverse events in the Austrian Registry of Hypomethylating agents. To compare real-world data with that of published randomized clinical trials. Results: A total of 1406 patients uniformly treated with a total of 13,780 cycles of azacitidine were analyzed. Hematologic adverse events were the most common adverse events (grade 3–4 anemia 43.4%, grade 3–4 thrombopenia 36.8%, grade 3–4 neutropenia 36.1%). Grade 3–4 anemia was significantly more common in the Registry compared to published trials. Febrile neutropenia occurred in 33.4% of patients and was also more common in the Registry than in published reports. Other commonly reported adverse events included fatigue (33.4%), pain (29.2%), pyrexia (23.5%), and injection site reactions (23.2%). Treatment termination due to an adverse event was rare (5.1%). Conclusion: The safety profile of azacitidine in clinical trials is reproducible in a real-world setting. With the use of prophylactic and concomitant medications, adverse events can be mitigated and azacitidine can be safely administered to almost all patients with few treatment discontinuations.

Type of Medium: Online Resource

ISSN: 2072-6694

URL: Article

DOI: 10.3390/cancers14102459

Language: English

Publisher: MDPI AG

Publication Date: 2022

detail.hit.zdb_id: 2527080-1

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4266-4266

Abstract: Abstract 4266 Twelve participating centers in Austria included 257 unselected, consecutive patients with MDS, CMML or AML, who received azacitidine (AZA) between 02/2007 and 07/2011, in the nationwide Austrian Azacitidine Registry (AAR) of the AGMT-study group. This registry was approved by the national Ethics Committee and includes 128 patients with AML of all FAB-subtypes, as well as de novo AML (39%), t-AML, MDS-AML and post-CMPD-AML. This registry comprises a large number of patients with 〉 30% bone marrow blasts (83/128) (currently off-label indication for AZA), as well as myeloproliferative AML (35/128), as defined by presence of 〉 10.000 WBC/μ l at diagnosis. The AAR includes a high proportion of very old AML patients (median age 73a, 20% 75–79a, 24% 〉 80a). Although the PS was generally low (22% ECOG-0, 47% ECOG-1), AML patients suffered from coronary artery disease (n=29), renal insufficiency (n=26), diabetes mellitus (n=21), a prior/concomitant solid tumor (n=17), COPD (n=14) and/or mild liver disease (n=13), respectively. Only 40% of all AML-patients included were treatment-naïve, whereas the rest was pretreated with G-CSF (12%), ESA (9%), ICT (3%) revlimid or thalidomide (6%), other agents (11%) and/or intensive chemotherapy (47%), respectively. Thus, this registry more accurately reflects a real-life treatment scenario, than most clinical trials that have strict inclusion/exclusion criteria. In the 93 patients in whom pre-AZA cytogenetics were performed, 56.9%, 25.8% and 17.2% could be grouped into IPSS good, intermediate and poor risk categories, respectively. Of these, 43 patients had MDS-specific cytogenetic aberrations (5q-, +8, -7, -7q, -Y and -20q). Most AZA-cycles were applied s.c. (89%), whereas 11% were applied i.v. Median and mean number of AZA-cycles was 4.0 and 5.6 (range 1–24), respectively. 60% of patients predominantly received the FDA-approved d1-7 schedule, whereas the non-approved alternative schedules 5-2-2, d1-5 and ‘others’ were most often given in 17%, 16% and 7% of patients, respectively. The FDA-approved target dose (75mg/m2 over 7 days) was achieved in 58% of all cycles and in 61% of patients, respectively. Longitudinal repetitive analysis of serum GOT, GPT, bilirubin and creatinine over up to 24 cycles shows no relevant variation or worsening tendency of these parameters during treatment with AZA, including patients with reduced baseline renal and/or hepatic function. Reasons for termination of treatment were death for any reason (26%), disease progression or relapse (27%), no response (6%), toxicity (7%), recurrent infectious complications (2%) and other reasons (23%). Adverse events will be presented in detail (number, grade, duration, hospitalization rate, effects on AZA (dose reductions/treatment pause/termination)). Any kind of hematologic improvement (HI) was noted in 38% of patients. When looking at each lineage separately, 21/128 had HI-ery, 23/128 HI-PLT and 24/128 HI-neutrophils. 35/85 patients who were RBC-TD and 19/55 patients who were PLT-TD prior to AZA-treatment achieved transfusion independence (TI). In patients, in whom (repetitive) bone marrow analyses were performed for response evaluation (n= 56), the following best marrow responses were observed: CR (19.6%), marrow CR (7.1%), PR (33.9%), SD (30.4%) and primary PD (8.9%). At the time of writing, 35 patients had received ≤2 cycles. This number largely accounts for the patients in whom no bone marrow response evaluation was performed. The OR rate observed prior to 07/2011 was 38% (CR + marrow CR + PR + HI). When limiting response analysis to patients who received ≥2 AZA cycles, which is required for achievement of hematologic response by the IWG-criteria, ORR was 57%. The median OS was 9.5mo (95%CI 8.15–10.9). In univariate analyses, ECOG 〉 =2 (p=.0026), circulating blasts (9.3 vs. 24.8mo; p=.0014), IPSS poor risk cytogenetics (p=.0037) and failure to achieve any HI (8.6 vs. 22.4mo; p=.0001), significantly negatively impacted OS. Prior treatment with G-CSF and/or ESA, age 〉 80a, WBC 〉 10G/l, BM blasts 〉 30%, LDH 〉 225U/l, number of cytopenic lineages as well as RBC-TD and/or PLT-TD at baseline, did not significantly impact OS (p 〉 0.05) (detailed statistics will be presented). In conclusion, in this population of partly heavily pretreated very old patients with AML, AZA was well tolerated and yielded substantial clinical and hematological benefit, irrelevant of baseline BM blast or PB WBC count. Disclosures: Pleyer: Celgene: Research Funding. Off Label Use: Azacitidine for treatment of AML including patients with 〉 30% bone marrow blasts. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Fridrik:Cephalon: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.4266.4266

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 945-945

Abstract: Abstract 945 In 2001, the WHO defined the category MDS with del(5q) due to unique cytogenetic, morphologic, hematologic, clinical, prognostic and therapeutic features. The survival of these patients, as well as patients with refractory cytopenia with unilineage dysplasia (RCUD) and refractory anemia with ring sideroblasts is favorable in comparison to other MDS types. Data on disease progression to a more advanced MDS category or to acute leukemia (AML) are sparse and have not been examined in detail. In order to address this issue we collated data of all patients with MDS and del(5q) characterized by low or intermediate-1 IPSS risk score that had been included into various collaborating MDS registries. Patients were followed from diagnosis and data on cell counts, transfusion dependency, and MDS progression were documented. No patients received treatment other than best supportive care. The status of 62 patients was censored at the time of the initiation of Lenalidomide therapy. AML progression was defined as 〉 20% marrow blasts. Estimates of survival probability were calculated with the Kaplan-Meier method. The cumulative incidence of progression to AML was calculated both with the Kaplan-Meier method and with the competing risk method where “death without progression to AML” is considered as competing event, not as censoring. For both events the cumulative incidences are estimated simultaneously. This method has the advantage that it takes into account that there is a difference between end of follow-up and death. Depending on the number of competing events, the curves are lower than those calculated with the Kaplan-Meier estimator. We identified 303 patients, median age at diagnosis 65 years (28-91), 71% were females. Median follow up time was 3 years. Median survival was 71.5 months. Patients with del(5q) as a sole chromosomal aberration had a median survival of 73 months as compared to 19.3 months in patients with more than 1 additional aberrations. Patients who had red cell transfusion need at diagnosis had a median survival of 39 months vs. 97 months in transfusion independent patients (p=0.00005). Transfusion need at diagnosis was the most important parameter for survival. Patients in the WPSS very low risk group had a median survival of 107 months, as compared to 73 and 56 months in the low and intermediate risk group and 37 months in the high risk group. 44 of the 303 patients (15%) progressed to AML ( 〉 20% marrow blasts). The cumulative AML progression rate calculated with the Kaplan-Meier method was 7% at 2 years and 18.2% at 5 years. The cumulative risk of AML progression calculated with the competing risk method was 6.6% at 2 years and 15.1% at 5 years. Factors associated with the risk of AML transformation were intermediate-I IPSS risk and high risk WPSS score, marrow blast count 〉 5%, and red-cell transfusion need at diagnosis. Survival and progression rates did not differ among the participating centers. In conclusion, survival of patients with MDS and del(5q) is high and is comparable to patients with RCUD and RARS, but is associated with a risk of AML-transformation similar to RCMD without del(5q). Further cytogenetic and molecular studies are warranted in order to identify patients at greater risk of progression. Disclosures: Germing: Novartis, Celgene: Honoraria, Research Funding. Lauseker:Celgene: Research Funding. Hildebrandt:Celgene: Research Funding. Symeonidis:Celgene: Research Funding. Cermak:Celgene: Research Funding. Pfeilstöcker:Celgene: Research Funding. Nösslinger:Celgene: Research Funding. Sekeres:Celgene: Research Funding. Maciejewski:Celgene: Research Funding. Haase:Celgene: Research Funding. Schanz:Celgene: Research Funding. Seymour:Celgene: Research Funding. Weide:Celgene: Research Funding. Lübbert:Celgene: Research Funding. Platzbecker:Celgene: Research Funding. Valent:Celgene: Research Funding. Götze:Celgene: Research Funding. Stauder:Celgene: Research Funding. Blum:Celgene: Research Funding. Kreuzer:Celgene: Research Funding. Schlenk:Celgene: Research Funding. Aul:Celgene: Research Funding. Kündgen:Celgene: Research Funding. Hasford:Celgene: Research Funding. Giagounidis:Celgene: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.945.945

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

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