Kooperativer Bibliotheksverbund

In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 106, No. 12 ( 2021-05-27), p. 3100-3106

Abstract: The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide and all-trans retinoic acid. All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. The acute promyelocytic leukemia was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) of the patients were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after starting therapy. With a median follow-up of 1.99 years (95% confidence interval: 1.61-2.30 years) 1-year and 2-year overall survival rates were 97% (95% confidence interval: 94-100%) and 95% (95% confidence interval: 91-99%), respectively. Age above 70 years was associated with a significantly shorter overall survival (P 〈 0.001) compared to that of younger patients. So far no relapses have been observed. Six patients (4%) died in complete remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of arsenic trioxide and all-trans retinoic acid therapy in the primary management of adults with low-/intermediate-risk acute promyelocytic leukemia in the real-life setting, irrespective of age.

Type of Medium: Online Resource

ISSN: 1592-8721 , 0390-6078

URL: Article

DOI: 10.3324/haematol.2021.278722

Language: Unknown

Publisher: Ferrata Storti Foundation (Haematologica)

Publication Date: 2021

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detail.hit.zdb_id: 2030158-3

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In: Leukemia, Springer Science and Business Media LLC, Vol. 35, No. 3 ( 2021-03), p. 701-711

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0892-z

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 3338-3340

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-166748

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 3 ( 2015-07-16), p. 291-299

Abstract: Azacitidine increased median overall survival by 3.8 months vs current commonly used AML treatments (10.4 vs 6.5 months; P = .1009). Azacitidine safety in patients age ≥65 years with AML ( 〉 30% blasts) was consistent with its known safety profile in other trials.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2015-01-621664

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Leukemia & Lymphoma, Informa UK Limited, Vol. 47, No. 9 ( 2006-01), p. 1872-1880

Type of Medium: Online Resource

ISSN: 1042-8194 , 1029-2403

URL: Article

DOI: 10.1080/10428190600685467

Language: English

Publisher: Informa UK Limited

Publication Date: 2006

detail.hit.zdb_id: 2030637-4

In: The Journal of Neuroscience, Society for Neuroscience, Vol. 30, No. 37 ( 2010-09-15), p. 12329-12339

Abstract: Audiovisual synchrony enables integration of dynamic visual and auditory signals into a more robust and reliable multisensory percept. In this fMRI study, we investigated the neural mechanisms by which audiovisual synchrony facilitates shape and motion discrimination under degraded visual conditions. Subjects were presented with visual patterns that were rotated by discrete increments at irregular and unpredictable intervals while partially obscured by a dynamic noise mask. On synchronous trials, each rotation coincided with an auditory click. On asynchronous trials, clicks were noncoincident with the rotational movements (but with identical temporal statistics). Subjects discriminated shape or rotational motion profile of the partially hidden visual stimuli. Regardless of task context, synchronous signals increased activations bilaterally in (1) calcarine sulcus (CaS) extending into ventral occipitotemporal cortex and (2) Heschl's gyrus extending into planum temporale (HG/PT) compared with asynchronous signals. Adjacent to these automatic synchrony effects, synchrony-induced activations in lateral occipital (LO) regions were amplified bilaterally during shape discrimination and in the right posterior superior temporal sulcus (pSTS) during motion discrimination. Subjects' synchrony-induced benefits in motion discrimination significantly predicted blood oxygenation level-dependent synchrony effects in V5/hMT+. According to dynamic causal modeling, audiovisual synchrony increased connectivity between CaS and HG/PT bidirectionally, whereas shape and motion tasks increased forwards connectivity from CaS to LO or to pSTS, respectively. To increase the salience of partially obscured moving objects, audiovisual synchrony may amplify visual activations by increasing the connectivity between low level visual and auditory areas. These automatic synchrony-induced response amplifications may then be gated to higher order areas according to behavioral relevance and task context.

Type of Medium: Online Resource

ISSN: 0270-6474 , 1529-2401

URL: Article

DOI: 10.1523/JNEUROSCI.5745-09.2010

Language: English

Publisher: Society for Neuroscience

Publication Date: 2010

detail.hit.zdb_id: 1475274-8

SSG: 12

In: Blood, American Society of Hematology, Vol. 139, No. 1 ( 2022-01-06), p. 87-103

Abstract: Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP] ). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P & lt; .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P & lt; .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P & lt; .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2020009680

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 1-3

Abstract: Background Double induction using two subsequent 7+3 regimens of cytarabine plus anthracycline is commonly performed in AML patients with an adequate performance status in order to maximize dose intensity upfront. However, for patients with a good early response at day 15 of first induction, there is no prospective randomized evidence on the necessity or value of a second induction cycle. Aims In order to answer the question if good responders of the first 7+3 induction could be spared a second induction cycle, we set up randomized-controlled SAL DaunoDouble trial. The study prospectively assesses the outcome of patients with a good early response with respect to the number of induction cycles (single versus double). We assumed non-inferiority of single induction in terms of complete remission (CR/CRi) rate, based on a margin of 7.5%. Here, we present the results of the planned interim analysis. Methods Patients (pts) 18-65 years with newly diagnosed AML, normal cardiac and organ function received a first induction cycle with seven days of cytarabine plus three days of daunorubicin ("7+3"). Response assessment in bone marrow was done on day 15 after the initiation of chemotherapy and confirmed by central review. A blast count & lt;5% was defined as good response. Pts with good response were randomized to receive a second induction cycle (arm D) or no second induction cycle (arm S). Primary endpoint was CR/CRi after completion of induction, secondary endpoints were RFS, and OS. Results Between 2014 and 2020, 624 evaluable pts were enrolled and received the first induction cycle with 7+3. A marrow blast clearance below 5% on day 15 was achieved in 298 pts (48%), providing eligibility for randomization. Of these patients, 150 were randomized into arm S and 148 into arm D, respectively. Median age was 52 years, 92% had de novo AML, NPM1 mutation was present in 53%, FLT3-ITD in 25% of pts. Favorable, intermediate and adverse risk (ELN 2017) were present in 56%, 34% and 10% of pts, respectively. CR/CRi rates at the end of induction were 86% after single induction and 85% after double induction. The CR/CRi rates in 224 pre-defined per-protocol pts were 88% versus 91%, resulting in a CR difference of 3% (95%-CI -0.047-0.111; p for non-inferiority test 0.145). After a median follow-up time of 24 months, RFS was slightly but not significantly lower after single induction with a 3-year RFS of 53% versus 64% (HR 1.4, p=0.125), whereas no differences were seen in 3-year OS, with a of rate of 74% versus 75% (HR 1.1, p=0.645) after single versus double induction. Conclusion The interim analysis results show that in good responders, the difference between CR rates after single versus double induction was even smaller than the predefined 7.5% margin, suggesting a trend for non-inferiority of single induction, although statistical significance was not reached. The trial continued recruitment. These findings suggest that in good responders, it may be safe to omit a second induction cycle if a second cycle poses a high risk. Figure. CR + CRi, RFS and OS after randomization to single versus double induction. Disclosures Alakel: Pfizer: Consultancy. Jost:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; JAZZ: Other: travel support; Celgene: Other: travel support. Novak:Roche: Consultancy; Janssen: Other: Travel expenses; Takeda: Consultancy; Amgen: Consultancy, Other: Travel expenses; Pfizer: Consultancy; Novartis: Consultancy. Krause:Takeda: Honoraria; Celgene: Other: Travel Support; MSD: Honoraria; Pfizer: Honoraria; Siemens: Research Funding; Gilead: Other: Travel Support. Held:Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy; Acrotech: Research Funding; Spectrum: Research Funding; Amgen: Research Funding. Platzbecker:AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Müller-Tidow:Daiichi Sankyo: Research Funding; Pfizer: Research Funding, Speakers Bureau; BiolineRx: Research Funding; Janssen-Cilag GmbH: Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-140246

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 644-644

Abstract: Background: Measurable residual disease (MRD) can identify patients (pts) with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in complete hematological remission (CR) at high risk of relapse even after allogeneic hematopoietic stem cell transplantation (HSCT). We have recently shown in 53 pts treated within the first cohort of the RELAZA2 trial that pre-emptive therapy with azacitidine (AZA) at the time of MRD-positivity (MRDpos) can successfully prevent imminent hematological relapse (Platzbecker et al. Lancet Oncol. 2018). We now report on the results of the second cohort of 41 pts undergoing MRD-guided treatment in the RELAZA2 trial (ClinicalTrials.gov NCT01462578) by the Study Alliance Leukemia (SAL). Methods: Between 2015 and 2018, 166 MDS/AML pts were screened and centrally monitored for MRD in bone marrow or peripheral blood at monthly intervals for a period of 2 years prospectively in 9 centers in Germany. Of these 166, 41 pts with either advanced MDS (n=6) or AML (n=35) in CR after either conventional chemotherapy only (n=13) or consecutive allogeneic HSCT (n=28) developed MRD above a threshold defining imminent hematological relapse. Still being in morphological CR, these pts pre-emptively received 6 cycles of AZA (75mg/m2, s.c. days 1-7), which was followed by a risk-adapted AZA-maintenance therapy based on MRD-response for up to 18 additional months. Pts developing a hematological relapse went off study. MRD was detected by either the quantification of NPM1 mutation level (n=19), leukemia-specific fusion genes DEK-NUP214 (n=1) or RUNX1/RUNX1T1 (n=2) or a sensitive donor chimerism analysis of sorted CD34(+)/CD117(+) peripheral blood cells (n=28) in pts undergoing allogeneic HSCT. Here, we report the analysis of the primary endpoint of the 41 pts in the second cohort as well as the data for the entire 94 pts who entered the treatment phase of the RELAZA-2 study. Results: At a median of 110 days (range 28-476) after start of screening, 41 (25%) out of 166 prospectively screened pts became MRDpos as defined by either a decrease of CD34(+)/CD117(+) donor chimerism to & lt;80% (n=23) or a detectable mutation level & gt;1% (NPM1 n=18) while being still in hematological CR. All of these MRDpos pts started AZA-based pre-emptive treatment to prevent imminent hematological relapse. Six months after start of MRD-guided therapy, 25 out of 41 pts were still in CR (61%, 95%-CI 45-76%, p & lt;0.001, one-sided binomial test for H0: pexp≤0.3) while a total of 15 pts (37%) developed hematologic relapse after median of 3 AZA cycles. In fact, 19 pts (46%) responded with either a decline of MRD below a predefined threshold (increasing CD34(+) donor chimerism to ≥80% or mutation level & lt;1%), while a stabilization in the absence of relapse was achieved in 6 pts (15%). Overall response rate was not statistically different between pts with (57%) or without (69%) antecedent allogeneic HSCT (p=0.5). After 6 months of initiation of MRD-guided treatment, 21 pts (51%) continued to receive a median of 6 (range 1-15) subsequent AZA cycles. Eventually, hematologic relapse occurred in 6 of those pts (29%), but was delayed until a median of 320 days (range 219-375 days) after initial MRD detection. With a median follow-up of 9 months after start of MRD-guided pre-emptive treatment the 12-months overall and progression free survival rate is 94% and 44%, respectively. When combining results for the primary endpoint with the first cohort, the 6 months relapse free survival for all 94 pts was 60% (56/94 pts.; 49-70%; p & lt;.001 one-sided binomial test for H0: pexp≤0.3; Fig. 1). Conclusion: These multicenter prospective data provide further strong evidence that continuous MRD monitoring is feasible and can identify MDS/AML pts at high risk of hematological relapse. Pre-emptive MRD-guided therapy with AZA is an effective treatment to prevent or at least substantially delay hematologic relapse in these pts. Disclosures Platzbecker: Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Wolf:Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Krämer:Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding. Bug:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Hexal: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Other: travel grants; Celgene Neovii: Other: travel grant. Götze:AbbVie: Membership on an entity's Board of Directors or advisory committees. Stelljes:Novartis: Honoraria; Amgen: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; MDS: Consultancy. Subklewe:AMGEN: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Miltenyi: Research Funding; Oxford Biotherapeutics: Research Funding; Janssen: Consultancy; Roche: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Morphosys: Research Funding. Hänel:Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Amgen: Honoraria; Roche: Honoraria. Dührsen:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Alexion: Honoraria; Takeda: Consultancy, Honoraria; Teva: Honoraria; Celgene: Research Funding; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; CPT: Consultancy, Honoraria. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Thiede:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AgenDix GmbH: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129926

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 333-333

Abstract: Abstract 333 Background: Standard chemotherapy for elderly AML patients results in a median overall survival of only about one year. Case reports and early phase I/II data have shown that the kinase inhibitor Sorafenib might show clinical benefit for Flt3-ITD-positive AML patients (Metzelder S Blood 2009; 113:6567) and that its addition to standard chemotherapy is feasible (Ravandi F JCO 2010; 28:1856). Sorafenib is a potent Raf, c-Kit and FLT3 inhibitor that may also affect AML blasts and bone marrow (BM) stroma cells via VEGFR and PDGFR-β inhibition. Therefore, we performed a multicenter, randomized, placebo-controlled, double-blind phase II trial in elderly ( & gt;60 y) AML patients analyzing the effect of Sorafenib in addition to standard chemotherapy and as a maintenance therapy for up to one year. Methods: 197 AML patients in 16 centers received up to two cycles of standard 7+3 induction chemotherapy plus two cycles of consolidation therapy with intermediate dose (6 × 1g/sqm) AraC. Before start of treatment, they were randomly assigned to receive either placebo or Sorafenib (400 mg bid between the cycles and after chemotherapy for up to one year after start of induction). The primary aim was to compare the event-free survival (EFS) of the two treatment groups. Secondary end points were to compare EFS and overall survival (OS) of predefined subgroups according to NPM and FLT3 mutation status and toxicity of treatment. Results: Among the 197 evaluable patients, 102 pts received Sorafenib and 95 pts placebo. EFS and OS were not significantly different between the two treatment groups (placebo vs. Sorafenib: EFS: Median: 7 vs. 5 months, hazard Ratio (HR): 1.261(p=0.13); OS: Median: 15 vs. 13 months, HR 1.025 (p=0.89)). CR or blast clearance without complete blood count recovery was observed in 49 (48%) and 9 (8.8%) Sorafenib patients and 57 (60%) and 4 (4.2%) placebo pts, respectively. Exploratory subgroup analyses did not reveal any significant difference between the treatment groups but showed a tendency towards decreased EFS in the Sorafenib arm for NPM1-wild type AML cases. Flt3-ITD mutations were found in 28 out of 197 patients (14.2%), in line with the reported incidence in the target population. No differences in EFS or OS were to be noted in this small patient population. Also, CR rate was not improved by the study drug in this subgroup of patients. Sorafenib was relatively well tolerated. The most frequent adverse events (AE) ≥grade 3 were febrile neutropenia, pneumonia in neutropenia, sepsis, diarrhea, skin rash, mucositis, hypertension (77 vs 74, 54 vs 35, 15 vs 15, 17 vs 6, 14 vs 7, 9 vs 6, 8 vs 5 events in the Sorafenib vs the placebo group). A hand-foot-skin reaction (≥grade 3) was noted in 5 vs 0 events in Sorafenib vs control pts. There was a trend of slower regeneration of leukocytes and thrombocytes within the Sorafenib arm compared to the control arm after the first and second induction course but not after consolidation cycles. Conclusion: Although the combination regimen appeared to be feasible and tolerable in elderly AML pts, Sorafenib treatment did not improve EFS or OS in this unselected elderly AML patient population. Further studies should focus on selected AML target populations for Sorafenib, especially FLT3-ITD+ AML patients. Disclosures: Off Label Use: Sorafenib (multikinase inhibitor) is given in combination with standard chemotherapy in elderly AML patients. (See title of the abstract!).

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.333.333

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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