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In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3434-3434

Abstract: Abstract 3434 Introduction: Several clinical trials established treatment with horse ATG (hATG) and cyclosporine A (CsA) as standard treatment of AA in patients (pts) who are not candidates for stem cell transplantation (SCT). In 2007 the hATG brand Lymphoglobulin® was withdrawn from the market. As the hATG brand ATGAM®, is not approved in Europe, hATG was replaced by rabbit ATG (rATG). Recently a large prospective randomized one-center study from NIH, USA comparing hATG ATGAM®/CsA and rATG Thymoglobulin®/CsA in untreated AA showed significantly lower response rates and survival with rATG. To obtain further information on rATG treatment in an unselected AA population, especially with a higher median of age and use of different rATG dosages we performed a retrospective data collection of first line rATG therapy on several centers. This shall reflect outcome after rATG in a real-world situation. Methods: Retrospective data collection and analysis of first line rATG treatment of AA after approval by Ethical Committee. Results: Up to now retrospective data of 64 pts from 18 centres in Germany were analysed. Characteristics of the pts: 30 male, 34 female; median age at time of therapy 54 years (6–80 years); 87.5% of pts had idiopathic AA. 51.6% of pts had severe AA, 32.8% very severe AA and 15.6% non-severe AA. Median granulocyte count was 0.3 G/l. 86% of the pts required red blood cell and 92% platelet transfusions. 56 of the evaluable pts received Thymoglobulin® and 5 pts Fresenius ATG S®. 52 of the 56 Thymoglobulin®-treated pts got this therapy in the years 2007–2011, i.e. not as deliberate primary choice of rATG but because hATG was no longer available. Median daily dose of Thymoglobulin® was 3.5 mg/kg (range from 2.5 – 3.75 mg/kg) for 5 days. 62 of 64 pts received additional immunosuppressive therapy with CsA and 19 of 64 pts received G-CSF. The median follow-up for surviving pts was 558.5 days (range, 78–3800 days). Response rates at time of best response of pts were CR in 10/58 pts (17%), PR in 18/58 pts (31%) and NR in 30/58 pts (52%) (only surviving patients with a minimum follow-up of 120 days were analyzed). Median interval to best response was 217 days. Response rate (PR+CR) was 16/33 (48.5%) in pts who received a Thymoglobulin® dose of 〉 3.5 –3.75 mg/kg/day versus only 4/14 (28.6%) group of 14 pts with a dose of 〉 2.5 to 〈 3.5 mg/kg/day (p=0.17; Fisher`s exact test). Relapses occurred in 3/28 responders and clonal evolution was observed in 3 pts (2 PNH, 1 MDS). Eighteen of 63 evaluable pts received allogenic SCT after ATG-therapy and were censored at the date of SCT. 23% of 44 pts without SCT died. In 6 of these 10 pts death was caused by infections. Other causes of death were bleeding, cardiac event, acute respiratory distress syndrome, adynamia. Overall probability of survival at 3 years was 75.8% (95% confidence interval (CI): 61.8 – 89.9%) and survival censored for SCT was 79.9% (CI: 66.0–92.8%). Survival was significantly better in responders (PR and CR) (94.1% at 3 years; CI: 82.9–100%) than in non-responders (58.0% at 3 years; CI 34.0 – 81.3%) (p=0.04; log-rank test). Adverse events were reported in 79.4% of 63 evaluable pts consisting of anaphylaxis/allergy in 27.3%, serum sickness in 12.7%, fever/chills in 34.5%, and bacterial/viral/fungal infections in 54.5% of pts. Conclusion: Response rate and survival after rATG+CsA in this retrospective analysis is lower than in historical controls (e.g. hATG+CsA treatment in previous controlled studies of the German AA Study Group and the EBMT AA Working Party; Frickhofen et al., Blood 2003; Tichelli et al., Blood 2011) and rate of (early) infections seem to be high. Our results are in accordance with recent reports from other groups. Additionally the results of this retrospective data analysis suggest a benefit for the patient group treated with a Thymoglobulin® dosage of 〉 3.5 –3.75 mg/kg/day compared to lower doses ( 〈 3.5 mg/kg/day). There is growing evidence that best results in terms of response and survival are obtained by hATG-based immunosuppression. hATG can not be replaced by rATG without negative impact on patient outcome. There is need for action to achieve availability of hATG worldwide. If hATG is not available, treatment with rATG should be considered instead of no treatment or treatment with CsA alone since still about half of the patients respond to rATG. Disclosures: Höchsmann: Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: The use of the horse ATG ATGAM in Aplastic Anemia is off-label in Europe. At the moment no horse ATG with approval is available in Europe. Schrezenmeier:Genzyme: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.3434.3434

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. 130, No. Suppl_1 ( 2017-12-07), p. 897-897

Abstract: Background Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400mg/day (n=400) could be optimized by doubling the dose (n=420), adding IFN (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). Methods From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. The impact of patients' and disease factors on survival was prospectively analyzed. At the time of evaluation, at least 62% of patients still received imatinib, 26.2% were switched to 2nd generation tyrosine kinase inhibitors. Results After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival 80% and 10-year relative survival 92%. In spite of a faster response with IM800mg, the survival difference between IM400mg and IM800mg was only 3% at 5 years. In a multivariate analysis, the influence on survival of risk-group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs. other) was significant in contrast to any form of initial treatment optimization. Patients that reached the response milestones 3, 6 and 12 months, had a significant survival advantage of about 6% after 10 years regardless of therapy. The progression probability to blast crisis was 5.8%. Blast crisis was proceeded by high-risk additional chromosomal aberrations. Conclusions For responders, monotherapy with IM400mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease and blast crisis, more life-time can currently be gained by carefully addressing non-CML determinants of survival. Disclosures Hehlmann: Novartis: Research Funding; BMS: Consultancy. Saussele: Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Pfirrmann: BMS: Honoraria; Novartis: Honoraria. Krause: Novartis: Honoraria. Baerlocher: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Bruemmendorf: Novartis: Research Funding. Müller: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Jeromin: MLL Munich Leukemia Laboratory: Employment. Hänel: Roche: Honoraria; Novartis: Honoraria. Burchert: BMS: Honoraria. Waller: Mylan: Consultancy, Honoraria. Mayer: Eisai: Research Funding; Novartis: Research Funding. Link: Novartis: Honoraria. Scheid: Novartis: Honoraria. Schafhausen: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Hochhaus: Incyte: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V130.Suppl_1.897.897

Language: English

Publisher: American Society of Hematology

Publication Date: 2017

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 2010-2013

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-166084

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. 23 ( 2015-12-03), p. 1581-1581

Abstract: During the course of chronic myeloid leukemia (CML) progression to blast crisis (BC) is thought to be caused by genetic instability such as cytogenetic aberrations in addition to the translocation t(9;22)(q34;q11). We have shown previously that major route ACA indicate an unfavorable outcome (Fabarius et al., Blood 2011). We now investigate whether there is a correlation in time between appearance of major route ACA and increase in blast count. Methods: Cytogenetic data and blast count in the peripheral blood were available from 1,290 CML patients recruited to the German CML-studies III (621 patients) and IIIa (669 patients) from January 1995 to January 2004. Treatments were interferon-alpha-based or related allogeneic stem cell transplantation (HSCT). Presence of ACA and major route ACA was considered as a time-dependent covariate. Multivariate proportional hazards models were estimated taking Euro CML score, study III vs. IIIa and stem cell transplantability into account. Cumulative incidences of blast increases were calculated starting at the date of the first ACA or major route ACA, respectively, regarding death as a competing risk. Patients were censored at the date of HSCT with an unrelated donor. Results: 1,287 patients were evaluable with median observation times of 13 and 12 years and a 10-year survival of 48% and 61% in CML studies III and IIIa, respectively. 258 patients progressed to BC with a cumulative 10-year incidence of 20%. 195 patients displayed ACA during the course of disease. 45 patients (15.7%) showed ACA already at diagnosis. 44 patients showed unbalanced minor route, 29 balanced minor route aberrations, 23 -Y. 109 patients showed major route aberrations including 10 with other prior ACA. In a multivariate analysis on 1,257 patients, patients with ACA had a hazard ratio (HR) for a blast increase of between 2.0-2.2 (p 〈 0.001) for blast increases to ≥1%, ≥5%, ≥10%, ≥15%, ≥ 20% and ≥30% compared with patients without ACA (Table). When the same model was performed for major route ACA only at any time during disease, HRs of 2.2-2.7 (p 〈 0.001) were found. For ACA without major route ACA HRs were 1.6-2.1 (p 〈 0.001). In the multivariate analyses of major route ACA vs. no major route ACA a blast increase of 1-5% after diagnosis of major route ACA seems already indicative of progression. 5 years after the diagnosis of any ACA the cumulative incidence for a blast increase was 30% (95%- confidence interval (CI): 23-38%), of a major route ACA 40% (95%- CI: 28-49%). The 6-year probability of death without blast increase was 10%. 14 additional patients received an unrelated transplant of which 6 died. We conclude that ACA, particularly major route ACA, precede an increase of blasts. Major route ACA have to be considered as a prognostic indicator for disease progression at any time. Table 1. Blast increase to HR (univariate): ACA vs. no ACA HR(multivariate)*: ACA vs. no ACA HR (univariate): major route ACA vs. no major route ACA HR (multivariate)*: major route ACA vs. no major route ACA ≥30% 2.409 2.139 2.646 2.203 ≥20% 2.413 2.144 2.656 2.211 ≥15% 2.415 2.161 2.868 2.426 ≥10% 2.416 2.160 2.799 2.357 ≥5% 2.286 2.047 2.719 2.278 ≥1% 2.209 1.999 3.171 2.684 *adjusted to Euro-Score, study (III vs. IIIa) and transplantability Disclosures Saussele: ARIAD: Honoraria; BMS: Honoraria, Other: Travel grant, Research Funding; Pfizer: Honoraria, Other: Travel grant; Novartis Pharma: Honoraria, Other: Travel grant, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Scheid:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Baerlocher:Geron Corporation: Research Funding; Novartis: Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Müller:BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Pfirrmann:BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Baccarani:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1581.1581

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 6, No. 18 ( 2022-09-27), p. 5345-5355

Abstract: We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR] , 0.55; P & lt; .001); both in younger (HR, 0.59; P & lt; .001) and older patients (HR, 0.42; P & lt; .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P & lt; .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2022007223

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 2876449-3

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 81-81

Abstract: Background: Mutations of the NPM1 gene are one of the most frequent genetic aberrations in adult AML. AML with mutated NPM1 is categorized as a disease entity according the WHO-2016 classification and clinically associated with female sex, high white blood cells at diagnosis, normal karyotype and high CD33 antigen expression. We recently showed that patients with NPM1-mutated AML benefit from all-trans retinoic acid (ATRA) as adjunct to intensive induction therapy (Ann Hematol. 2016; 95:1931-1942; Haematologica. 2009;94:54-60). Based on the regular high CD33 expression in AML with mutated NPM1 we hypothesized that gemtuzumab ozogamicin (GO) added to intensive therapy with ATRA may further improve clinical outcome in AML with mutated NPM1. Aim: To evaluate GO in combination with intensive induction and consolidation therapy and ATRA in NPM1 mutated AML within the randomized AMLSG 09-09 trial (NCT00893399) Methods: Between May 2010 and September 2017, patients ≥18 years of age and considered eligible for intensive therapy were randomized up-front for open-label treatment with GO. Induction therapy consisted of two cycles of A-ICE (idarubicin 12mg/m² iv, day 1,3,5 [in induction II and for patients 〉 60 years reduced to d 1, 3]; cytarabine 100mg/m² continuous iv, day 1 to 7; etoposide 100mg/m² iv, day 1-3 [in induction II and for patients 〉 60 years reduced to d 1, 3]; ATRA 45 mg/m²/day po on days 6-8 and 15mg/m² days 9-21, +/- GO 3mg/m² iv day 1). Consolidation therapy consisted of 3 cycles of high-dose cytarabine (HiDAC; 3g/m² [reduced to 1g/m² in patients 〉 60 years] bid, days 1-3; Pegfilgrastim 6mg sc, day 10; ATRA 15 mg/m²/day po, days 4-21; +/- GO 3mg/m² on day 1 [first consolidation only] ). The primary endpoints of the study were event-free survival (EFS) as early endpoint tested 6 months and overall survival (OS) tested 4 years after study completion with sequential testing according the fallback procedure described by Wiens (Statistics 2003;2:211-215). This report focusses on the early EFS endpoint. Further secondary endpoints were response to induction therapy, cumulative incidence of relapse (CIR) and cumulative incidence of death (CID). Results: In total 588 patients were evaluable for analysis (n=296, standard-arm; n=292 GO-arm). Median age was 58.7 years (range, 18.4-82.3 years), ECOG performance status was 0 in 34.1% and 1 in 55.1%, and FLT3-ITD was present in 16.8% of the patients, with baseline characteristics well balanced between the two arms. After first induction therapy death rates were significantly higher in the GO-arm (7.5%) (p=0.02) compared to the standard-arm (3.4%); in both study-arms causes of death were mainly infections. Following induction therapy complete remission (CR) and CR with incomplete count recovery (CRi) were 88.5% and 85.3% (p=0.28), refractory disease (RD) 6.1% and 5.1% (p=0.72), death 5.4% and 9.6% (p=0.06) in the standard- and GO-arm, respectively. Due to prolonged thrombocytopenia after second induction therapy in the GO-arm, the protocol was amended in that GO was omitted in second induction and first consolidation cycles, if prolonged cytopenias were observed during first induction therapy. The study treatment was completed in 197 and 171 patients (p=0.11), allogeneic hematopoietic cell transplantation in first CR was performed in 18 and 21 patients (p=0.51) in the standard- and GO-arm, respectively. Median follow-up was 2.6 years (95%-CI, 2.4-3.1 years). Two- and 4-year EFS were 53% (95%-CI, 48-60%) and 58% (95%-CI, 52%-64%), and 44% (95%-CI, 38-52%) and 52% (95%-CI, 46%-59%) in the standard- and GO-arm, respectively. According to the pre-specified significance level of 0.025, EFS in the GO-arm was not different to that in the standard-arm (p=0.21). In patients achieving CR/CRi after induction therapy, CIR was significantly reduced in the GO-arm compared to the standard-arm (p=0.018), whereas no difference in CID was noted between both arms (p=0.89). Conclusion: The addition of GO to intensive induction therapy with ICE plus ATRA was associated with a higher death rate. In patients achieving a CR/CRi after induction therapy significantly less relapses occurred in the GO- compared to the standard-arm. Disclosures Schlenk: Pfizer: Research Funding, Speakers Bureau. Paschka:Astex: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Otsuka: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Jazz: Speakers Bureau; Amgen: Other: Travel support; Janssen: Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel support. Fiedler:Amgen: Other: support for meetíng attendance; Gilead: Other: support for meeting attendance; Pfizer: Research Funding; Amgen: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSO: Other: support for meeting attendance; Teva: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; Daiichi Sankyo: Other: support for meeting attendance. Lübbert:Cheplapharm: Other: Study drug; Celgene: Other: Travel Support; Janssen: Honoraria, Research Funding; TEVA: Other: Study drug. Götze:Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; JAZZ Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding. Schleicher:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Eissai: Other: Investigator; Astra Zeneca: Other: Investigator; Pfizer: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau. Greil:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heuser:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; BergenBio: Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Research Funding; Sunesis: Research Funding; Tetralogic: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; StemLine Therapeutics: Consultancy; Janssen: Consultancy. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Agios: Consultancy, Honoraria; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Jazz: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-113442

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 692-692

Abstract: BACKGROUND: Midostaurin is a first-generation, type I multi-targeted kinase inhibitor with inhibitory activity against FLT3-ITD and -TKD mutations. Midostaurin is approved by FDA and EMA in combination with intensive induction and consolidation chemotherapy for adult patients with AML exhibiting an activating FLT3 mutation; the EMA label also includes single-agent maintenance therapy following consolidation chemotherapy. We conducted a phase-II trial (AMLSG 16-10) to evaluate midostaurin with induction chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a one-year midostaurin maintenance therapy in younger and older patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (ITD). METHODS: Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free (EFS) and overall survival (OS); results were compared to those of a historical control cohort of 415 patients with FLT3-ITD AML. Statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Major differences in trial design compared to the pivotal CALGB 10603/RATIFY trial were: i) only AML with FLT3-ITD were eligible; ii) AML with FLT3 tyrosine kinase domain mutations (only) and core-binding factor AML were not eligible; iii) older patients 60-70 years of age were eligible; iv) all patients were assigned to allogeneic HCT; v) a one-year maintenance treatment with midostaurin was included also after allogeneic HCT; vi) a continuous dosing schedule of midostaurin was applied with the aim to achieve a better target inhibition. Results: The trial accrued 440 patients, including 312 younger (18-60 yrs) and 128 older (61-70 yrs) patients. Complete remission (CR)/CR with incomplete hematologic recovery rate, median EFS and OS of the 440 patients were 74.9%, 13.6 and 36.2 months, respectively. Multivariate analysis of EFS showed a highly significant hazard reduction for an event for patients treated within AMLSG 16-10 trial compared to the historical controls (HR 0.55; 95%-confidence interval [CI], 0.47, 0.65; P & lt;0.001); this effect was significant in the younger (HR 0.59; 95%-CI, 0.49, 0.71; P & lt;0.001) and the older patient cohort (HR 0.42; 95%-CI, 0.30, 0.60; P & lt;0.001). Multivariate analysis also showed a highly significant beneficial effect on OS (HR 0.57; 95%-CI, 0.47, 0.68; P & lt;0.001), again for both age subgroups. Allogeneic HCT in first CR/CRi was performed according to protocol in 199 of 440 (45%) patients (48% and 38% in younger and older patients, respectively), and an additional 60 patients received allogeneic HCT in firstline therapy (n=33 pts. in CR/CRi after salvage therapy and 27 pts. with active disease); the treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT (n=259) as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. Conclusions: In comparison to a historical control cohort, the addition of midostaurin to intensive therapy led to a significant improvement in EFS and OS in both younger and older adult patients with AML and FLT3-ITD. Figure: Survival distribution for the primary endpoint event-free survival (EFS) and key secondary endpoint overall survival (OS) according to study population and age group. A EFS by cohort and age group (≤60 versus & gt;60 years) B OS by cohort and age group (≤60 versus & gt;60 years) Figure 1 Figure 1. Disclosures Döhner: Astellas: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Pfizer: Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Ulm University Hospital: Current Employment. Fiedler: Servier: Consultancy, Other: Meeting attendance, Preparation of information material; Stemline: Consultancy; Daiichi Sanyko: Consultancy, Other: Meeting attendance, Preparation of information material; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; MorphoSys: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material; Celgene: Consultancy, Honoraria; Ariad/Incyte: Honoraria; Amgen: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material, Patents & Royalties, Research Funding; Abbvie: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material. Wulf: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Salih: BMS: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Synimmune GmbH: Honoraria; Novartis: Honoraria. Lübbert: Imago BioSciences: Honoraria; Janssen: Honoraria, Research Funding; Pfizer: Honoraria; Syros: Honoraria; Aristopharm: Research Funding; Cheplapharm: Research Funding; Janssen: Research Funding; Teva: Research Funding; Hexal: Honoraria; Astex: Honoraria; Abbvie: Honoraria. Kühn: Abbvie: Honoraria; Kura Oncology: Honoraria, Research Funding; Pfizer: Honoraria. Schroeder: Abbvie: Honoraria; Astellas: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Pfizer: Honoraria. Salwender: Oncopeptides: Honoraria; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Chugai: Honoraria; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pfizer: Honoraria. Götze: Abbvie: Honoraria; Celgene/BMS: Honoraria, Research Funding. Westermann: Amgen: Consultancy, Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Stem Cell Line: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Astellas: Honoraria. Fransecky: Abbvie: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Medac: Honoraria. Mayer: Novartis: Other: Travel support; Celgene: Other: Travel support; Roche: Other: Travel support; Amgen: Other: Travel support; BMS: Other: Travel support; Pfizer: Other: Travel support; Jazz: Other: Travel support; Astellas: Other: Travel support. Hertenstein: Sanofi: Honoraria; Novartis: Honoraria; Celgene: Honoraria; BMS: Honoraria. Tischler: AstraZeneca: Other: Travel support; Novartis: Other: Travel support; Janssen: Honoraria; GSK: Other: Travel support; Sanofi-Aventis: Other: Travel support; Abbvie: Other: Travel support. Paschka: Abbvie: Honoraria, Other: Travel support; Agios: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Astex: Honoraria; Celgene: Honoraria, Other: Travel support; Jazz: Honoraria; Novartis: Honoraria, Other: Travel support; Otsuka: Honoraria; Pfizer: Honoraria; Sunesis: Honoraria; BMS: Other, Speakers Bureau; Celgene: Honoraria; Janssen: Other; Takeda: Other. Gaidzik: Janssen: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Thol: Abbvie: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Heuser: Tolremo: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; BMS/Celgene: 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, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; BergenBio: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schlenk: Astellas: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Hexal: Honoraria; Neovio Biotech: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Honoraria; Agios: Honoraria. Bullinger: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Astellas: Honoraria; Bristol-Myers Squibb / Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini: 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: Amgen: Honoraria; BMS/Celgene: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria, Research Funding; Roche: Honoraria; Daiichi Sankyo: Honoraria; Agios: Research Funding; Astex: Research Funding; Astellas: Research Funding. Ganser: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Midostaurin as single-agent maintenance therapy following allogeneic hematopoietic cell transplantation

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-147256

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 762-762

Abstract: The selective tyrosine kinase inhibitor imatinib eradicates bcr-abl+ cells in chronic myeloid leukemia patients (pts). Although a previous clinical trial showed superiority of an imatinib therapy over an interferon-α containing regimen, a significant number of pts eventually relapse with leukemia because of either point mutations within the imatinib-binding site, amplification of the Philadelphia chromosome or other mechanisms, e.g. clonal evolution. AMN107 (Novartis Pharma AG) is a new anilino-pyrimidine derivative (MW: 529.5) structurally related to imatinib. AMN107 was tested in three human bcr-abl positive lines (K562, KCL-22, Lama-84) and in primary cells derived from two bcr-abl + CML pts who were resistant to imatinib, as well as in one newly diagnosed chronic phase patient. In all pts sequencing of the bcr-abl kinase domain excluded any point mutations, but cytogenetic analysis of the bone marrow revealed clonal evolution in the resistant pts including t(1;5) and t(3;21) translocations, trisomy of chromosome 8 and monosomy of chromosome 7. Determination of the proliferative activity by XTT-assay in cell lines demonstrated a decrease of the IC50 in imatinib versus AMN107 treated samples from 0.08μM to 0.0075μM in Lama 84, from 0.25μM to 0.08μM in K562 and from 0.45μM to 0.03 in KCL-22 cells. No activity of either compound was observed in the bcr-abl negative HL-60 and KG-1 cells. In primary cells from imatinib-resistant pts, a decrease of the IC50 in imatinib versus AMN107 treated peripheral blood cells from 0.75μM to 0.1μM and from 4 to 0.4μM was detected. In addition, in primary cells from one newly diagnozed CML patient the IC50 of AMN107 (2.5μM) was reduced when compared to imatinib (5μM). Immunoblotting showed that in LAMA84 cells a concentration of 0.01μM AMN107 completely inhibited the tyrosine kinase activity as detected by use of an anti-phosphotyrosine antibody in contrast to almost 5μM in imatinib treated samples. Further, induction of apoptosis was detected using annexin V and propidium iodide by double fluorescence. After 48 hours of incubation with either 0.25 μM imatinib or 0.005 μM AMN107 induction of early apoptosis was detected in 8.8% of imatinib treated and 26% of AMN107 treated cells. Finally, HPLC analysis in HL-60 cells showed increased uptake by 1,5 fold for AMN107 when compared to imatinib. In addition, in MDR1 over-expressing CCRF cells co-culture with either AMN107 or imatinib revealed elevated AMN107 levels (3.7 fold) indicating that this substance is less susceptible to MDR1 driven resistance than imatinib. Conclusions: 1. AMN107 showed elevated activity when compared to imatinib in bcr-abl + cell lines and primary cells derived from imatinib resistant leukemic pts. 2. Complete inhibition of the bcr-abl tyrosine kinase activity and induction of apoptosis was achieved at lower concentrations in AMN107 treated samples when compared to imatinib. 3. Preliminary data indicate favourable cellular uptake of AMN107 when compared to imatinib. 4. AMN107 may be useful in the treatment of bcr-abl + leukemic pts.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V104.11.762.762

Language: English

Publisher: American Society of Hematology

Publication Date: 2004

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2675-2675

Abstract: Abstract 2675 Background: Resminostat is an oral pan-histone deacetylase (HDAC) inhibitor that has shown anti-tumor activity in a broad panel of preclinical models and revealed a favorable safety and efficacy profile in a first-in-man phase I study in patients (pts) with various solid tumor types. Resminostat is currently in phase II clinical development in pts with hepatocellular carcinoma (HCC), colorectal carcinoma (CRC) and Hodgkin Lymphoma (HL). Methods: The SAPHIRE trial involved HL pts who relapsed or progressed after prior therapy including high-dose chemotherapy and autologous stem cell transplantation (ASCT) or were refractory to treatment. The study was designed as an open-label, single-arm, international trial consisting of two recruitment stages according to the Simon Minimax design. Resminostat was administered orally at a once daily dose of 600 mg during the 1st recruitment stage and at a higher daily dose of 800 mg in the 2nd stage. Patients were treated in cycles of five consecutive days followed by a nine-day treatment-free period (5+9 schedule), constituting one 14 day cycle. Patients underwent assessment of their disease status by computed tomography in combination with positron emission tomography (PET/CT) after Cycle 3 and Cycle 6 and thereafter every fourth cycle during an optional extension phase of the study in which pts continued on treatment until disease progression. The primary endpoint of the study was defined as the overall objective response rate (ORR) based on the best response during treatment. Response was defined as complete response (CR) or partial response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007) or as partial metabolic response (PMR) according to EORTC criteria (Young 1999). Secondary endpoints include time to response (TTR), duration of response (DOR), progression free survival (PFS), overall survival (OS), safety and tolerability and the evaluation of drug regulated biomarkers including the CC thymus and activation related chemokine TARC. Results: The enrolment was complete in June 2011 with 37 pts at 5 study sites available for safety evaluation. Median age of the safety population was 34 years (range 19–64 years). 21 pts (57%) had ASCT and 14 pts (67% of all ASCT pts) relapsed within one year after ASCT. 26 patients (70%) had ≥ 5 prior lines of therapy; median number of prior regimens was 6 (range 1–12). Stage of disease according to Ann Arbor classification at baseline was: 6 pts with stage 2, 4 pts with stage 3 and 27 pts with stage 4. 17 pts had B-symptoms at baseline (46%). Dosing with 600 mg or 800 mg resminostat was well tolerated with common treatment-related grade 2–3 AEs being anemia and thrombocytopenia that were well manageable by dose modification. Assessment of PK parameters confirmed the favorable profile of the oral administration route and dose dependent resminostat plasma concentrations. As of August 2011 out of 37 pts 35 pts had ≥ 1 post-baseline PET/CT tumor assessments and 2 pts discontinued early due to AE. Two out of 35 pts are still on study therapy in the optional extension phase after Cycle 6. Up to now 33 pts were evaluated centrally for tumor response. Of those, 11 pts qualified as responders (ORR=33%). Responders included 1 complete response (CR), 3 partial responses (PR) and 7 partial metabolic responses (PMR). Median time to response was 3 cycles. Additional 7 patients achieved stabilization of the disease. Thus, in total 18 pts (55%) obtained a clinical benefit from resminostat monotherapy. Conclusion: Results of the SAPHIRE study demonstrated substantial anti-tumor activity of the HDAC inhibitor resminostat in heavily pre-treated HL patients. Resminostat can be safely administered as oral monotherapy up to 800 mg once daily in a 5+9 day treatment schedule. Disclosures: Walewski: 4SC AG: Consultancy. Hauns:4SC AG: Employment. Mais:4SC: Employment. Henning:4SC AG: Employment. Hentsch:4SC AG: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.2675.2675

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7