Kooperativer Bibliotheksverbund

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 13 ( 2021-05-01), p. 1426-1436

Abstract: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion–dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 10 9 /L, and absolute neutrophil count was 1.3 × 10 9 /L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 10 9 /L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.20.02619

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2021

detail.hit.zdb_id: 2005181-5

In: Leukemia, Springer Science and Business Media LLC, Vol. 36, No. 12 ( 2022-12), p. 2939-2946

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-022-01724-9

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6971-6973

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157487

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. 140, No. Supplement 1 ( 2022-11-15), p. 4079-4081

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157489

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. 134, No. Supplement_1 ( 2019-11-13), p. 841-841

Abstract: Introduction: Few treatment options are available to RBC transfusion-dependent pts with lower-risk MDS (LR-MDS) who are refractory/ineligible for erythropoiesis-stimulating agents (ESAs). Luspatercept is a first-in-class erythroid maturation agent that binds select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. In the phase 3, randomized, double-blind, placebo-controlled MEDALIST study (NCT02631070), luspatercept significantly reduced transfusion burden vs placebo. Longer-term efficacy analyses of the MEDALIST study (data cutoff Jan 7, 2019), including multiple responses, and safety are presented here. Methods: Eligible pts were ≥ 18 years of age with IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS (World Health Organization 2016 criteria); were refractory, intolerant, or unlikely to respond to ESAs (serum erythropoietin & gt; 200 U/L); and required regular RBC transfusions. Pts were randomized 2:1 to luspatercept (1.0 mg/kg titrated up to 1.75 mg/kg, if needed) or placebo, subcutaneously every 3 weeks (wks). This analysis assessed the achievement and number of individual response periods of RBC transfusion independence (RBC-TI) ≥ 8 wks. Clinical benefit, defined as achieving RBC-TI ≥ 8 wks and/or modified hematologic improvement-erythroid (HI-E) response per International Working Group 2006 criteria, was also assessed, along with total duration of clinical benefit (time from achieving clinical benefit to discontinuation due to loss of benefit, adverse events [AEs], or other reasons). Longer-term efficacy and safety were also evaluated. Results: Pts were assessed for RBC transfusion burden/8 wks in the 16 wks before randomization: 66 pts received 2 to & lt; 4 U RBCs (30.1% and 26.3% of pts receiving luspatercept and placebo, respectively), 64 received ≥ 4 to & lt; 6 U (26.8% and 30.2%, respectively), and 99 received ≥ 6 U (43.1% and 43.4%, respectively); both arms had a median baseline burden of 5 RBC U/8 wks. Compared with our previous analysis and earlier data cutoff of May 8, 2018 (Fenaux P, et al. Blood. 2018;132:1), we now report that as of Jan 7, 2019, 72 (47.1%) pts treated with luspatercept and 12 (15.8%) treated with placebo achieved RBC-TI ≥ 8 wks. Analysis of multiple response periods of RBC-TI ≥ 8 wks in the luspatercept responders (i.e. initial RBC-TI ≥ 8 wks, followed by transfusion, followed by another period of RBC-TI ≥ 8 wks) demonstrated that 48 (66.7%) pts had ≥ 2 separate response periods, 22 (30.6%) had ≥ 3, 12 (16.7%) had ≥ 4 , and 7 (9.7%) had ≥ 5. Of the 12 pts achieving RBC-TI ≥ 8 wks with placebo, 4 (33.3%) had ≥ 2 responses; none had & gt; 3. Overall, 48 (31.4%) pts receiving luspatercept and none receiving placebo remained on treatment as of the Jan 7, 2019 data cutoff. Median treatment duration was 50.9 (range 5.9-147.0) wks in pts receiving luspatercept vs 24.0 (range 7.4-103.0) wks in pts receiving placebo. Median duration of the longest period of RBC-TI ≥ 8 wks during Wks 1-48 was 30.6 (95% confidence interval [CI] 20.6-50.9) wks with luspatercept and 18.6 (95% CI 10.9-not evaluable) wks with placebo. Median total duration of clinical benefit was 83.6 and 26.8 wks for pts responding to luspatercept (n = 97) and placebo (n = 20), respective ly. Of the 97 luspatercept-treated pts evaluable for clinical benefit, median duration of clinical benefit in pts with baseline transfusion burden of 4 to & lt; 6 U/8 wks was 87.9 (range 13-125) wks, of & lt; 4 U/8 wks was 84.7 (range 21-147) wks, and of ≥ 6 U/8 wks was 64.9 (range 8-122) wks. Twelve luspatercept-treated pts did not require a transfusion after the first dose of luspatercept up to Wk 48 or until time of analysis; as of Jan 7, 2019 data cutoff, 3 (25%) of those pts maintained response. AEs occurring more frequently with luspatercept vs placebo (fatigue, diarrhea, asthenia, dizziness) occurred early (Cycles 1-4), were mainly grade 1 or 2, decreased over time, and were not associated with a higher dose level. Progression to acute myeloid leukemia was similar in pts receiving luspatercept (n = 3 [2.0%]) and those receiving placebo (n = 1 [1.3%] ). Conclusions: Most LR-MDS pts achieving RBC-TI and/or HI-E with luspatercept in the MEDALIST study had multiple responses with durable clinical benefit superior to that of pts receiving placebo, including those with a high baseline transfusion burden. AEs were mainly grade 1 or 2, decreased over time, and were not correlated with a higher dose level. Disclosures Fenaux: Aprea: Research Funding; Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. 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. 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. Finelli:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Ilhan:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: 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, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Komrokji:DSI: Consultancy; JAZZ: Consultancy; celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; Incyte: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan:Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Verma:Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding; Janssen: Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Ito:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Rampersad:Celgene Corp: Employment, Equity Ownership. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Linde:Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Platzbecker:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. 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-2019-123064

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 382, No. 2 ( 2020-01-09), p. 140-151

Type of Medium: Online Resource

ISSN: 0028-4793 , 1533-4406

URL: Article

DOI: 10.1056/NEJMoa1908892

Language: English

Publisher: Massachusetts Medical Society

Publication Date: 2020

detail.hit.zdb_id: 1468837-2

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2818-2818

Abstract: Background: Patients (pts) aged 〉 65 years (yrs) with AML have a median overall survival (OS) of ~3 months (mos), with worsening OS as age increases: median OS for pts ages 66-75 yrs is ~6 mos, but is only ~2.5 mos for pts ages 76-89 yrs (Walter, Leukemia, 2015). Treatment (Tx) options are limited for these pts, who often have disease features associated with Tx resistance, such as prior hematologic disorders, and a greater risk of Tx-related mortality. With current Tx options, in this setting many physicians or pts do not pursue active AML Tx. The phase 3, randomized AZA-AML-001 study compared AZA and CCR in older pts with AML (Dombret, Blood, 2015). Aims: Assess outcomes with AZA vs CCR in elderly pts (age ≥75 yrs) with AML in the AZA-AML-001 study overall and in the subset of pts with myelodysplasia-related changes (AML-MRC), and descriptively compare them with outcomes for pts aged 65-74 yrs. Methods: Pts aged ≥65 yrs with newly diagnosed AML ( 〉 30% bone marrow blasts), ECOG performance status ≤2, intermediate- or poor-risk cytogenetics, and WBC counts ≤15x109/L were eligible. Pts were randomized to receive AZA (75 mg/m2/day [d] x7d/28d) or CCR: low-dose ara-C (20mg SC BID x10d/28d), intensive chemotherapy (7+3), or best supportive care only. These analyses evaluated outcomes in pts aged 65-74 yrs (" 〈 75 yrs") and pts aged ≥75 yrs. WHO-defined AML-MRC was centrally confirmed. OS was estimated using Kaplan-Meier (KM) methods, with hazard ratios (HR) and 95% confidence intervals (95%CI) from an unstratified Cox proportional hazards model and P values from log-rank test. Survival at 3, 6, 9, and 12 mos was estimated using KM methods. Overall response rate (ORR) included complete remission (CR) and CR with incomplete hematologic recovery (CRi). Incidence rates (IRs; ie, rate normalized for Tx exposure) of grade 3-4 Tx-emergent adverse events (TEAEs) and infections leading to death per 100 pt-years of Tx exposure are reported for safety-evaluable pts (those who received ≥1 dose of study drug [at randomization for BSC only] and had ≥1 safety assessment post-dose). Results: In all, 223 pts were aged 〈 75 yrs (AZA n=103; CCR n=120) and 265 were aged ≥75 yrs (AZA n=138; CCR n=127), including 27 pts aged 〉 85 yrs (AZA n=14; CCR n=13). Median age in the 〈 75 yrs cohort was 71 yrs, and in the ≥75 yrs cohort was 78 and 79 yrs for the AZA and CCR groups, respectively (Table 1). Median OS was meaningfully prolonged with AZA vs CCR in pts aged 〈 75 yrs (14.2 vs 9.6 mos; HR 0.73, 95%CI 0.54, 0.99; P=0.0420). OS was also prolonged with AZA in pts aged ≥75 yrs vs CCR, but was not statistically different (median 7.0 vs 4.9 mos; HR 0.91, 95%CI 0.69, 1.2; P=0.46). Higher proportions of AZA-treated pts were alive at each 3-mo landmark in both age cohorts (Table 2). ORR was similar with AZA and CCR in pts ages 〈 75 yrs (32% and 30% respectively) and ≥75 yrs (25% and 21%), with a trend for a higher rate of CRi in AZA-treated pts aged ≥75 yrs (8% vs 2%; P=0.054). In the AML-MRC subgroup (n=262), median OS in pts aged 〈 75 yrs was meaningfully prolonged with AZA (n=52) vs CCR (n=64) (14.2 vs 7.3 mos, respectively; HR 0.64, 95%CI 0.42, 0.97) and nominally so with AZA (n=77) vs CCR (n=69) in pts ≥75 yrs (5.9 vs 3.8 mos; HR 0.77, 95%CI 0.54, 1.09). IRs of the most frequent grade 3-4 hematological TEAEs were lower with AZA vs CCR in the both age cohorts (Table 3), except the IR for grade 3-4 pneumonia in pts aged ≥75 yrs was higher with AZA. IRs of infections leading to death in the AZA and CCR groups were 14.9 and 38.2 per 100 pt-yrs, respectively, for pts aged 〈 75 yrs, and 33.3 and 28.0 per 100 pt-yrs in pts aged ≥75 yrs. Conclusions: As expected, OS and response rates were lower in elderly pts in both Tx arms than in younger pts. Median OS was meaningfully prolonged with AZA (+4.6 mos) vs CCR in pts aged 65-74 yrs. Higher proportions of AZA-treated pts remained alive at each 3-month landmark than CCR-treated pts, mainly in the younger age group, although 1-year survival was also higher in pts aged ≥75 yrs. Given the higher IR of infections, prophylactic use of antimicrobials or growth factors might be considered for elderly pts treated with AZA. Pts with AML-MRC retained the relative OS benefits of AZA vs CCR. While OS for AML-MRC pts aged ≥75 yrs was longer with AZA (+2.1 mos) vs CCR, pts with AML-MRC aged ≥75 yrs in both treatment groups had decreased OS compared with the median OS for all pts aged ≥75 yrs, consistent with reports that AML-MRC is more difficult to treat than AML not otherwise specified (Weinberg, Blood, 2009). Disclosures Seymour: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Buckstein:Celgene: Honoraria, Research Funding; Novartis: Honoraria. Santini:Astex: Consultancy; Onconova: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Stone:Seattle Genetics: Consultancy; Jansen: Consultancy; Amgen: Consultancy; Novartis: Consultancy; ONO: Consultancy; Agios: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Pfizer: Consultancy; Juno Therapeutics: Consultancy; Xenetic Biosciences: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Roche: Consultancy; Sunesis Pharmaceuticals: Consultancy; Celator: Consultancy. Songer:Celgene: Employment, Equity Ownership. Weaver:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Dombret:Agios: Honoraria; Sunesis: Honoraria; Ambit (Daiichi Sankyo): Honoraria; Karyopharm: Honoraria; Kite Pharma.: Honoraria, Research Funding; Menarini: Honoraria; Menarini: Honoraria; Astellas: Honoraria; Janssen: Honoraria; Servier: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.2818.2818

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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 Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 7056-7056

Abstract: 7056 Background: Luspatercept was previously shown to improve anemia in the phase 3 MEDALIST trial of pts with LR-MDS ineligible, intolerant, or refractory to erythropoiesis-stimulating agents (ESAs). Here, we report the long-term clinical value of luspatercept treatment (Tx) in pts from the MEDALIST study including dosing and rates of progression to acute myeloid leukemia (AML) and high-risk MDS (HR-MDS). Methods: Eligible pts were ≥ 18 y of age, had LR-MDS requiring regular red blood cell (RBC) transfusions, and were ineligible/intolerant or refractory to ESAs. Pts were randomized 2:1 to subcutaneous luspatercept or placebo every 3 wk for 24 wk. The primary endpoint was RBC transfusion independence (RBC-TI) ≥ 8 wk during wk 1–24. MEDALIST pts were eligible for enrollment into the long-term follow-up study. Median duration of Tx and cumulative duration of response were determined by Kaplan–Meier (KM) analysis. Total person-years for pts at risk of HR-MDS/AML progression was calculated from LR-MDS diagnosis to HR-MDS/AML diagnosis, or to last HR-MDS/AML follow-up date for pts who did not progress. Results: As of January 15, 2021, the median duration of Tx was 11.70 (95% CI, 8.97–16.33) mo for luspatercept pts and 5.52 (95% CI, 5.52–5.59) mo for placebo pts. Of those enrolled in MEDALIST, 106/153 (69.3%) pts receiving luspatercept and 64/76 (84.2%) receiving placebo escalated to the maximum dose of 1.75 mg/kg. During the entire Tx phase, RBC-TI ≥ 8 wk was observed in 74/153 (48.4%) and 12/76 (15.8%) pts in the luspatercept and placebo arms, respectively, with a median cumulative duration of response of 80.7 (95% CI, 53.71–154.14) wk and 21.0 (95% CI, 10.86–NE) wk, respectively. During the entire Tx period, RBC-TI ≥ 16 wk was observed in 48/153 (31.4%) and 6/76 (7.9%) pts in the luspatercept and placebo arms, respectively (Table). Among pts randomized to luspatercept, 13/153 (8.5%) progressed to HR-MDS/AML during the entire Tx period, compared with 5/76 (6.6%) for placebo. The total person-years for pts randomized to luspatercept at risk of progressing to HR-MDS/AML was 401.7 y vs 190.9 y for placebo. Conclusions: Pts receiving luspatercept had an extended period of clinical benefit and 〉 50% of pts continued to receive luspatercept for 〉 1 y, the majority of whom underwent dose escalations to achieve an optimal response. Pts experienced durable responses with luspatercept, with a median cumulative duration of RBC-TI response of approximately 20 mo. Pts receiving luspatercept also appeared to have a longer time to HR-MDS/AML progression than those receiving placebo.[Table: see text]

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2022.40.16_suppl.7056

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2022

detail.hit.zdb_id: 2005181-5

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 20 ( 2020-09), p. S318-S319

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/S2152-2650(20)30973-3

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3