Kooperativer Bibliotheksverbund

In: Journal of Biological Chemistry, Elsevier BV, Vol. 286, No. 52 ( 2011-12), p. 44716-44725

Type of Medium: Online Resource

ISSN: 0021-9258

URL: Article

DOI: 10.1074/jbc.M111.289033

Language: English

Publisher: Elsevier BV

Publication Date: 2011

detail.hit.zdb_id: 2141744-1

detail.hit.zdb_id: 1474604-9

SSG: 12

In: British Journal of Haematology, Wiley, Vol. 201, No. 6 ( 2023-06), p. 1129-1143

Abstract: Oral azacitidine (Oral‐AZA) maintenance therapy improved relapse‐free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML‐001 study. Immune profiling was performed on the bone marrow (BM) at remission and on‐treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on‐treatment immune effects by Oral‐AZA with clinical outcomes. Post‐IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T‐cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD‐L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD‐L2+. High co‐expression of T‐cell exhaustion markers PD‐1 and TIM‐3 was associated with inferior outcomes. Oral‐AZA augmented T‐cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T‐cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T‐cell content and expression of T‐cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral‐AZA modulates T‐cell activity in the maintenance setting of AML, and these immune‐mediated responses are associated with clinical outcomes.

Type of Medium: Online Resource

ISSN: 0007-1048 , 1365-2141

URL: Issue

URL: Article

DOI: 10.1111/bjh.v201.6

DOI: 10.1111/bjh.18783

Language: English

Publisher: Wiley

Publication Date: 2023

detail.hit.zdb_id: 1475751-5

In: Annals of Surgery, Ovid Technologies (Wolters Kluwer Health)

Abstract: This study compared outcomes in patients with solid tumor treated for pericardial effusion with surgical drainage vs. interventional radiology (IR) percutaneous drainage and compared incidence of paradoxical hemodynamic instability (PHI) between cohorts. Summary Background Data: Patients with advanced-stage solid malignancies may develop large pericardial effusions requiring intervention. PHI is a fatal and underreported complication that occurs following pericardial effusion drainage. Methods: Clinical characteristics and outcomes were compared between patients with solid tumors who underwent s urgical drainage or IR percutaneous drainage for pericardial effusion from 2010 to 2020. Results: Among 447 patients, 243 were treated with surgical drainage, of which 27 (11%) developed PHI, compared with 7 of 204 patients (3%) who were treated with IR percutaneous drainage ( P =0.002); overall incidence of PHI decreased during the study period. Rates of reintervention (30-day: 1% vs. 4%; 90-day: 4% vs. 6%, P =0.7) and mortality (30-day: 21% vs. 17%, P =0.3; 90-day: 39% vs. 37%, P =0.7) were not different between patients treated with surgical drainage and IR percutaneous drainage. For both interventions, OS was shorter among patients with PHI than among patients without PHI (surgical drainage, median [95% confidence interval] OS, 0.89 mo [0.33–2.1] vs. 6.5 mo [5.0–8.9], P 〈 0.001; IR percutaneous drainage, 3.7 mo [0.23–6.8] vs. 5.0 mo [4.0–8.1] , P =0.044). Conclusions: With a coordinated multidisciplinary approach focusing on prompt clinical and echocardiographic evaluation, triage with bias toward IR percutaneous drainage than surgical drainage and post-intervention intensive care resulted in lower incidence of PHI and improved outcomes.

Type of Medium: Online Resource

ISSN: 0003-4932

URL: Article

DOI: 10.1097/SLA.0000000000006114

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2023

detail.hit.zdb_id: 2002200-1

In: American Journal of Hematology, Wiley, Vol. 98, No. 4 ( 2023-04)

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v98.4

DOI: 10.1002/ajh.26847

Language: English

Publisher: Wiley

Publication Date: 2023

detail.hit.zdb_id: 1492749-4

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 505-505

Abstract: BACKGROUND The immunologic effects of maintenance therapy in patients (pts) with AML in remission are not well-characterized but of high clinical interest, as rapid recovery of bone marrow (BM) after intensive chemotherapy (IC) may help delay relapse. Post IC, immunological interactions in the BM microenvironment present several immunosuppressive mechanisms. PD-L1 is commonly overexpressed on AML blasts, which is associated with worse prognosis. Oral azacitidine (Oral-AZA [CC-486]) is a hypomethylating agent recently approved in the US for pts with AML in complete remission (CR) or CR with incomplete hematologic recovery (CRi). To better understand the effects of Oral-AZA on immune cells, checkpoint expression of PD-L1/2 on AML blasts and normal myeloid progenitors (MPs), and the kinetics of T cell recovery and activation/exhaustion (eg, PD1, TIM3) were assessed. METHODS Biomarker-evaluable pts aged ≥ 55 years with AML were randomized 1:1 to Oral-AZA 300 mg (n=56) or placebo (PBO, n=52) post IC within 4 months of achieving CR. Flow cytometry evaluations of BM aspirates were performed at screening (ie, baseline [BL]), every 3 cycles until cycle 24 and every 6 cycles thereafter to cycle 36, or as clinically indicated. Correlative analyses of baseline immune parameters with median (med) relapse-free survival (RFS) were computed using Kaplan-Meier methods. RESULTS In the biomarker-evaluable pts, PD-L1 and PD-L2 expression at BL were higher on AML blasts (med intensity 7.1 and 2.9) than normal MPs (0.7 and 1.6). Most AML blasts were PD-L2+ (79%), whereas only 1.9% were PD-L1+. When stratified by the med, higher BL CD3 T cell numbers (as a % of total BM ) were associated with favorable RFS in both Tx arms (Oral-AZA: ≥ med, 562 days[d] and & lt; med, 235d [P = .0308]; PBO: ≥ med, 325d and & lt; med, 155d [P = .0391]). At cycle 3, pts in the Oral-AZA arm had a 1.7-fold increase in CD3 T cells from BL (PBO, 1.1; P = .0450), suggesting Oral-AZA can promote immunologic recovery during early Tx cycles. There was an inverse correlation between T cell exhaustion marker phenotypes (PD1/TIM3+) with CD4 (r = -.5967; P & lt; .0001) and CD8 (r = -.2484; P = .0095) T cell numbers. An increase in RFS was seen in the PBO arm with lower PD1/TIM3+ CD4 numbers ( & lt; med, 429d; ≥ med, 155d; P = .0037), with a nominal increase observed in the Oral-AZA arm ( & lt; med, 428d; ≥ med, 303d; P = .6764). In a subset of pts, Oral-AZA appeared to suppress CD4 T cell exhaustion (PD1/TIM3+) compared with PBO. CONCLUSIONS Pts in CR/CRi post-IC have a unique immune profile defined by high expression of PD-L1 on a subset of blasts and a high % of PD-L2+ blasts. A higher BL CD3 T cell count after IC in BM was prognostic. Additionally, Oral-AZA appears to contribute to an increase in T cells while also suppressing exhaustion, potentially promoting T cell signaling that could activate functional immune-mediated responses against residual leukemic cells. Citation Format: Daniel L. Menezes, Wendy L. See, Alberto Risueno, Jianglin Ma, Ignazia La Torre, Barry Skikne, CL Beach, Keshava Kumar, Anjan Thakurta. Oral azacitidine modulates the immune microenvironment in acute myeloid leukemia (AML) patients in remission: A subanalysis from the QUAZAR AML-001 Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 505.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2021-505

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2021

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: The Lancet Haematology, Elsevier BV, Vol. 7, No. 4 ( 2020-04), p. e309-e319

Type of Medium: Online Resource

ISSN: 2352-3026

URL: Article

DOI: 10.1016/S2352-3026(19)30284-4

Language: English

Publisher: Elsevier BV

Publication Date: 2020

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 804-804

Abstract: BACKGROUND: Current guidelines for AML ascribe disease-risk partly based on NPM1 and FLT3 mutational status. NPM1 mutations (mut) occur in 25%-30% of patients (pts) with AML and are associated with favorable prognosis in the absence of co-occurring FLT3-ITD. FLT3-ITD alterations are observed in ~15-30% of AML pts and confer poor prognosis, whereas the prognostic implication of FLT3-TKD point mutations (~7% of pts) is less clear. Post-IC, absence of MRD is associated with favorable relapse-free and overall survival (RFS/OS). In the randomized, phase 3 QUAZAR AML-001 trial, Oral-AZA (CC-486) significantly prolonged OS and RFS vs placebo (PBO) in older pts with AML in first remission after IC (Wei, NEJM 2020). It is of high interest to understand the effects of Oral-AZA in pts with NPM1 and/or FLT3 mutations, and whether their outcomes are influenced by post-IC MRD status. OBJECTIVE: Evaluate survival outcomes with Oral-AZA vs PBO in pts with NPM1mut ± FLT3mut at AML diagnosis (Dx), and OS by baseline (BL) MRD status (+/-) in pts with NPM1/FLT3 mutations. METHODS: In QUAZAR AML-001, pts aged ≥55 years with AML and NCCN intermediate or poor-risk cytogenetics at Dx were randomized 1:1 to receive Oral-AZA 300 mg or PBO QD within 4 mo after attaining first CR/CRi with IC (induction ± consolidation). NPM1 and FLT3 statuses (mut or wild-type [wt]) at AML Dx (before IC) were collected from pt diagnostic case report forms. MRD analyses were conducted by MFC (≥0.1% MRD+ cutoff) in bone marrow aspirate samples collected at screening (post-IC; ie, BL). OS and RFS were estimated from the time of randomization using Kaplan-Meier methods. Multivariate (MV) Cox regression analyses of the prognostic effects on OS/RFS were performed, with NPM1 and FLT3 mutational status and cytogenetic risk at Dx; post-IC MRD status (+/-) at BL, and randomized Tx (Oral AZA vs PBO) as variables. RESULTS: Of 472 pts enrolled , 469 (99.4%) had mutational data available at Dx, and the MRD-evaluable cohort comprised 463 pts (98.1%). In all, 137 pts (29%; Oral-AZA n = 66, PBO n = 71) had NPM1mut at AML Dx, and NPM1mut was significantly correlated with MRD- status at BL (post-IC)(P = 0.0178). Among pts with NPM1mut, OS was significantly improved in pts receiving Oral-AZA vs PBO, whether pts were MRD- (median 48.6 vs 26.2 mo, respectively) or MRD+ (median 39.4 vs 10.3 mo) at BL (both P & lt; 0.0001) (Figure). While median OS for NPM1mut pts in the Oral-AZA arm was nominally improved for MRD- pts vs. those MRD+ (48.6 vs. 39.4 mo, respectively), median OS for NPM1mut pts in the PBO arm was substantially influenced by post-IC MRD status (26.2 vs 10.3 mo for MRD- and MRD+ pts, respectively) (Figure). Similarly, median RFS for pts with NPM1mut/MRD- in the Oral-AZA and PBO arms was 24.9 vs 9.9 mo, respectively, and for pts with NPM1mut/MRD+ was 19.4 vs 4.6 mo. In all, 66 pts (14.1%) had FLT3-ITD (n = 46) and/or FLT3-TKD mut (n = 24) at AML Dx; NPM1 and FLT3-ITD status was NPM1mut + FLT3-ITD - in 107 pts, NPM1mut + FLT3-ITD + in 30 pts, and NPM1wt + FLT3-ITD + in 16 pts. In the Oral-AZA arm, median OS in pts with FLT3mut was not meaningfully different from that in pts with FLT3wt (28.2 and 24.7 mo, respectively), but FLT3mut conferred a negative prognosis in the PBO arm (median OS 9.7 mo, vs 15.2 mo for FLT3wt pts). Risk of death was reduced 46% with Oral-AZA vs PBO in pts with FLT3mut (HR 0.54 [95%CI 0.25, 1.14]). When considering MRD status, median OS in FLT3mut/MRD- pts was 28.2 vs. 15.9 mo in the Oral-AZA (n = 14) and PBO (n = 17) arms, respectively, and was 24.0 vs 8.0 mo in FLT3mut/MRD+ pts (Oral-AZA, n = 16; PBO, n = 18). In MV analyses, Oral-AZA significantly improved OS vs PBO when adjusted for other variables (P = 0.035); NPM1 status (P = 0.001), FLT3status (P = 0.035), and cytogenetic risk at Dx (P & lt; 0.001) were each also significantly predictive of OS, as was post-IC MRD status (P & lt; 0.001). All except FLT3 status (P = 0.737) were significantly predictive of RFS. CONCLUSIONS: Oral-AZA prolonged OS and RFS vs PBO in pts with NPM1mut, with improvements beyond the prognostic benefit conferred by MRD-, suggesting that pts with NPM1mut and MRD- can attain substantial OS benefit with Oral-AZA maintenance. An OS benefit was also observed with Oral-AZA vs PBO in pts in FLT3mut at Dx, but outcomes may be confounded by co-occurring NPM1mut, so further investigation is needed. MV analyses confirmed the independent prognostic influence of Oral-AZA, NPM1 and FLT3 mutations at Dx, cytogenetic risk at Dx, and post-IC MRD status on OS. Figure 1 Figure 1. Disclosures Döhner: Janssen: Honoraria; Helsinn: Honoraria; Gilead: Honoraria; GEMoaB: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Berlin-Chemie: Honoraria; AstraZeneca: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Pfizer: Research Funding; Roche: Honoraria. Wei: Astellas: Honoraria; Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees. Roboz: Glaxo SmithKline: Consultancy; Helsinn: Consultancy; AbbVie: Consultancy; Jasper Therapeutics: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Actinium: Consultancy; Agios: Consultancy; Blueprint Medicines: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Jazz: Consultancy; Daiichi Sankyo: Consultancy; Astex: Consultancy; Mesoblast: Consultancy; Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Bristol Myers Squibb: Consultancy; Janssen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy. Montesinos: Agios: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy. Thol: Abbvie: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Ravandi: AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Astex: Honoraria, Research Funding; Prelude: Research Funding; Taiho: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Sandhu: Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Bioverativ: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Gilead: Consultancy. Skikne: Bristol Myers Squibb: Current Employment. See: Bristol Myers Squibb: Current Employment. Ugidos: Bristol Myers Squibb: Current Employment. Risueño: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Chan: Bristol Myers Squibb: Current Employment. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-147465

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. 134, No. Supplement_1 ( 2019-11-13), p. 2999-2999

Abstract: Background: Luspatercept is a first-in-class erythroid maturation agent that binds TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. The phase 3 MEDALIST trial evaluated luspatercept in pts with RBC transfusion-dependent, IPSS-R-defined very low-, low-, and intermediate-risk MDS with ring sideroblasts (RS+) who were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents. This study explored associations of gene mutations, as analyzed by next-generation sequencing (NGS), with response to luspatercept, as well as dynamics of gene mutations on therapy in MEDALIST pts. Methods: DNA was isolated from bone marrow (BM) mononuclear cells from 222 of 229 pts enrolled in the study (148 luspatercept, 74 placebo) at screening and, when available, following treatment. NGS of 23 MDS-relevant genes was performed at screening and every 24 weeks; mean coverage was 1,000-fold and the variant allele frequency (VAF) cutoff was ≥ 1%. BM cell populations were analyzed by cytomorphology. Response criterion of RBC transfusion independence (RBC-TI) of ≥ 8 weeks within the first 24 weeks of treatment was used for correlative analyses. Results: Mutations in SF3B1 were found in 91.0% of pts analyzed at screening (median VAF 42%, range 6-71%), consistent with the study population being RS+. Overall, a median of 2 (range 0-5) of the 23 MDS-relevant genes analyzed were mutated per pt. In addition to SF3B1, the most frequently mutated genes were TET2 (41.9%), DNMT3A (18.9%), ASXL1 (13.1%), and SRSF2 (8.1%). Mutation profiles were similar to those found in previous studies of refractory anemia with RS (RARS; Malcovati L, et al. Blood. 2015;126:233-41) and balanced between luspatercept and placebo arms. Numbers of mutated genes at baseline were distributed similarly in luspatercept responders (R) and non-responders (NR) (Figure A), and comparable response rates were achieved irrespective of number of mutations, with response rates of 36.4%, 34.9%, 42.4%, and 33.3% for pts with 1 mutation, 2 mutations, 3 mutations, and 4 or 5 mutations in the 23 MDS-relevant genes analyzed, respectively. Response to luspatercept was independent of the presence of mutations in any of the genes analyzed individually (Figure B) or when grouped by functional categories (e.g. spliceosome, epigenetic regulation, transcription factor, etc.) (Figure C). Circos plots of co-occurring mutations showed similar mutation profiles in R and NR (Figure D). Response rates were also similar regardless of baseline SF3B1 allelic burden (R: 43%, NR: 42%; P = 0.11). At baseline, BM erythroid precursors were higher in R (R: 32.8%, NR: 26%; P = 0.008; while R and NR had similar levels of RS+ cells [R: 80%, NR: 84%; P = 0.25], Figure E), consistent with the postulated activity of luspatercept on the erythroid lineage. When comparing the frequency of mutation changes in luspatercept- vs placebo-treated pts at week 24 of the study, no statistically significant differences were observed in the frequency of newly acquired mutations (13/126 [10.3%] pts in luspatercept vs 8/64 [12.5%] pts in placebo, P = 0.63) or mutation losses (4/126 [3.2%] in luspatercept vs 5/64 [7.8%] in placebo, P = 0.17). Evaluation of changes in allele burden (median VAF at week 24 vs baseline) for mutations in genes associated with adverse prognosis (ASXL1, SRSF2, U2AF1, NRAS, IDH2, GATA2, TP53, RUNX1, and EZH2; Bejar R. Curr Opin Hematol. 2017;24:73-8) showed no change between luspatercept- or placebo-treated pts (1.01-fold, n = 58 and 0.95-fold, n = 19, respectively, P = 0.69). Conclusions: Pts enrolled in the MEDALIST study had mutations consistent with RS+, lower-risk MDS with a preponderance of SF3B1 mutations; genes associated with poor prognosis (and other genes) were balanced between study arms. RBC-TI responses with luspatercept were achieved regardless of SF3B1 allelic burden, number of baseline mutations, and presence of individual mutations, including adverse mutations, or co-mutations. Disclosures Platzbecker: Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dunshee:Celgene Corporation: Employment, Equity Ownership. Komrokji:DSI: Consultancy; pfizer: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau. Mufti:Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Garcia-Manero:Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding. Buckstein:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Santini:Celgene Corporation: 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; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. See:Celgene Corporation: Other: Contractor. Tsai:Celgene Corporation: Employment. Risueño:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Named in Celgene patent filings related to predictive patient response biomarkers in hematological malignancies. Ma:Celgene Corporation: Employment, Equity Ownership. Schwickart:Celgene Corporation: Employment, Equity Ownership. Rampersad:Celgene Corp: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Laadem:Celgene Corporation: Employment, Equity Ownership. Menezes:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Linde:Acceleron Pharma: Employment, Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership; Fibrogen, Inc.: Equity Ownership. Reynolds:Acceleron Pharma: Employment, Equity Ownership. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123655

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Haematology, Scientific Archives LLC, Vol. 4, No. 1 ( 2023-8-28), p. 20-35

Abstract: IDH2 gene mutations, typically at residues R140 and R172, occur in 8–19% of patients with acute myeloid leukemia (AML). These mutations induce production of 2-hydroxyglutarate (2-HG), an oncometabolite that causes DNA and histone hypermethylation, and subsequent blockade of hematopoietic cell differentiation. In a phase 1b/2 trial (NCT02677922), combination therapy with azacitidine + enasidenib significantly improved overall response rate compared with azacitidine only therapy (74% vs 36%; P 〈 0.001) in patients with newly diagnosed IDH2-mutated AML not eligible for intensive chemotherapy. We investigated the association between molecular features and clinical outcomes from that trial. In all, 101 patients were randomized to enasidenib + azacitidine (n=68) or azacitidine only (n=33); 74% of patients had IDH2-R140. Baseline 2-HG levels and IDH2 variant allele frequency (VAF) were similar between treatment arms and IDH2 variants and were not significantly different between clinical response categories. Significant 2-HG and IDH2 VAF reductions from baseline were observed with combination therapy compared with azacitidine only. Molecular profiling revealed SRSF2 preferentially co-mutated with IDH2-R140, and DNMT3A co-mutated with IDH2-R172. IDH2 VAF was reduced to 〈 1% in 50% of patients who achieved CR with combination therapy (18/36) and azacitidine only (2/4). VAFs of genes in the DNA methylation, receptor-tyrosine-kinase, and RAS canonical pathways were reduced in patients achieving CR. Of note, combination therapy improved event-free survival in patients with RAS-pathway mutations, which have been associated with resistance to enasidenib monotherapy.

Type of Medium: Online Resource

ISSN: 2766-4686

URL: Issue

URL: Journal

URL: Article

DOI: 10.33696/haematology.4.1

DOI: 10.33696/haematology

DOI: 10.33696/haematology.4.054

Language: English

Publisher: Scientific Archives LLC

Publication Date: 2023

In: Cell Cycle, Informa UK Limited, Vol. 9, No. 8 ( 2010-04-15), p. 1562-1567

Type of Medium: Online Resource

ISSN: 1538-4101 , 1551-4005

URL: Article

DOI: 10.4161/cc.9.8.11259

Language: English

Publisher: Informa UK Limited

Publication Date: 2010

detail.hit.zdb_id: 2102687-7