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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. 136, No. Supplement 1 ( 2020-11-5), p. 1-2

Abstract: Introduction: Anemia is the predominant cytopenia observed in patients with myelodysplastic syndromes (MDS), with many patients requiring regular red blood cell (RBC) transfusions. Erythropoiesis-stimulating agents (ESAs) remain a standard of care among patients with lower-risk MDS (LR-MDS), defined by International Prognostic Scoring System-Revised (IPSS-R) as Very Low-, Low-, or Intermediate-risk MDS, and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L. Recent studies of epoetin alfa and darbepoetin alfa have demonstrated efficacy among patients with LR-MDS, but the patient population in whom a clinically significant effect is seen may be limited (Fenaux P, et al. Leukemia 2018;32:2648-2658; Platzbecker U, et al. Leukemia 2017;31:1944-1950). A novel therapeutic option that increases the frequency of response and the duration of RBC transfusion independence (TI) in patients with LR-MDS would provide an important clinical benefit in this patient population. Luspatercept is a first-in-class erythroid maturation agent with a mechanism of action distinct from ESAs (Suragani RNVS, et al. Nat Med 2014;20:408-414). It is now approved in both the US and EU for patients with LR-MDS with ring sideroblasts (RS) who require RBC transfusions and are refractory, intolerant, or ineligible to receive ESAs on the basis of results from a phase 3 study (Fenaux P, Platzbecker U, et al. N Engl J Med 2020;382:140-151). Luspatercept may also be beneficial in treating anemia in patients with ESA-naive, LR-MDS who require RBC transfusions. In a phase 2 study in anemic patients with LR-MDS, 63% of patients receiving luspatercept (0.75-1.75 mg/kg) achieved a modified hematologic improvement - erythroid (mHI-E) response (Platzbecker U, et al. Lancet Oncol 2017;18:1338-1347); when analyzed by RS status, 69% of patients with ≥ 15% RS and 43% of patients with & lt; 15% RS achieved mHI-E response. Study Design and Methods: The COMMANDS trial is a phase 3, open-label randomized study to compare the efficacy and safety of luspatercept versus epoetin alfa in anemic patients with IPSS-R defined LR-MDS, either with or without ≥ 15% RS, who are ESA naive, and who require regular RBC transfusions. Eligible patients must be aged ≥ 18 years at time of consent, have a documented diagnosis of IPSS-R defined LR-MDS with & lt; 5% blasts in the bone marrow, have sEPO levels & lt; 500 U/L, and require RBC transfusions (defined as an average transfusion requirement of 2-6 RBC units/8 weeks for ≥ 8 weeks immediately prior to randomization). Exclusion criteria include prior use of ESAs (≤ 2 doses of prior epoetin alfa permitted if ≥ 8 weeks from randomization date and sEPO confirmed as ≤ 500 U/L), granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for the treatment of febrile neutropenia; disease-modifying agents (e.g. lenalidomide), or hypomethylating agents; and presence of del(5q) cytogenetic abnormality. A total of approximately 350 eligible patients will be randomized in a 1:1 ratio to receive either luspatercept (starting dose 1.0 mg/kg with titration up to 1.75 mg/kg) subcutaneously (SC) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg with titration up to 1,050 IU/kg) SC once every week, for a minimum of 24 weeks (Figure). Best supportive care, including RBC transfusions, may be used in combination with study treatment in both arms. Randomization will be stratified by baseline RBC transfusion burden ( & lt; 4 vs ≥ 4 RBC units per 8 weeks), RS status (with RS+ defined as RS ≥ 15%, or ≥ 5% [but & lt; 15%] if SF3B1 mutation is present), and baseline sEPO level (≤ 200 U/L versus & gt; 200 U/L). In addition, ≥ 40% and ≤ 60% of randomized patients will be RS+, and ≥ 25% will have sEPO & gt; 200 U/L. The primary endpoint is the proportion of patients who achieve RBC-TI for 12 weeks within the first 24 weeks on study, with a concurrent mean hemoglobin (Hb) increase of ≥ 1.5 g/dL compared with baseline. Key secondary endpoints include duration of RBC-TI, change in Hb levels, achievement of HI-E response per International Working Group (IWG) 2006 criteria, and safety. The COMMANDS trial is registered at ClinicalTrials.gov (NCT03682536) and EudraCT (number 2017-003190-34). Disclosures Platzbecker: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria. Santini:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Merck: Research Funding. Komrokji:Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-140284

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 907-907

Abstract: Background Somatic mutations identified in patients with myelodysplastic syndromes (MDS) are associated with disease features and carry prognostic information independent of the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R). Risk models that include mutation information have been proposed, but not widely adopted. In practice, there is no consensus on how to best combine clinical information with tumor sequencing data to predict prognosis. To accomplish this, we must define the relevant genes to consider and accurately measure their prognostic impact. Here we examine the relationship between mutations in MDS-associated genes and clinically relevant measures, including overall survival, in a large, multi-center analysis of MDS patient cohorts collected around the globe. Methods Data on 3392 MDS patients gathered by members of the International Working Group for Prognosis in MDS-Molecular Committee were combined under the aegis of the MDS Foundation. Patients gave informed consent for collection of their data and tumor samples at their respective institutions in accordance with the Declaration of Helsinki. Samples were examined for somatic mutations primarily by next generation sequencing. Categorical variables were compared using a chi-squared test, while continuous variables were compared using a Wilcoxon rank-sum test. Overall survival (OS) was calculated from the date of the sequenced sample to the date of death and was censored at transplant or the last known follow-up time. P-values are two-sided and considered significant at the 〈 0.001 level to adjust for multiple comparisons. Results Survival data were available for 3200 patients with a median follow up of 3.7 years and included 1671 deaths. Median survival of the cohort was 2.88 years. The 27 genes sequenced in at least half of the cohort and mutated in 〉 1.5% of samples were included for analysis (Figure 1). Mutations in 12 genes were strongly associated with shorter OS in univariate analyses (p 〈 0.001 for each gene): ASXL1, CBL, EZH2, IDH2, NF1, NRAS, PTPN11, RUNX1, SRSF2, STAG2, TP53, and U2AF1. Only mutations of SF3B1 were associated with a longer OS at this significance threshold. The large size of the cohort allowed for more precise estimates of survival in less frequently mutated genes. For example, mutations of IDH2 (present in 3.4% of cases, n=103) were associated with shorter OS (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.26-2.05; p=0.0001) whereas IDH1 mutations (present in 2.4% of cases, n=77) were only marginal (HR 1.29, CI: 0.97-1.72; p=0.082), demonstrating the distinct impact of mutations in these highly related genes. IPSS-R risk groups could be determined for 2173 patients and were strongly associated with OS. Adjusting the hazard ratio of death for IPSS-R risk groups identified several mutated genes with independent prognostic significance: TP53 (HR 2.37, CI 1.94-2.90), CBL (HR 1.57, CI 1.22-2.03), EZH2 (HR 1.55, CI 1.22-2.03), and RUNX1 (HR 1.50, CI 1.24-1.83). Mutations of U2AF1 (HR 1.29, CI 1.06-1.58) and ASXL1 (HR 1.21, CI 1.04-1.41) retained a more modest association with shorter OS. Adjustment for IPSS-R risk groups also moderated the favorable risk associated with mutations of SF3B1 (HR 0.83, CI 0.70-0.99). Patients without mutations in any of the 6 adverse genes above represented 58% of the fully sequenced cohort and had a longer median survival than patients with adverse mutations (4.8 years vs. 1.6 years respectively, p 〈 0.0001; Figure 2) even after correction for IPSS-R risk groups (adjusted HR 0.59, CI 0.51-0.67). Multivariable analysis of this dataset will examine the combined contribution of mutated genes to prognosis. A mutation score based on survival risk will be proposed and internally validated. The impact of somatic mutation in patients traditionally considered lower risk will be explored. Conclusions This large study definitively validates the prognostic value of mutations in several MDS-associated genes while clarifying the significance of other, less frequently mutated ones. Mutations in several genes retain their prognostic significance after adjustment for IPSS-R risk groups, indicating that these select abnormalities could refine the prediction of prognosis when incorporated into a clinical scoring system such as the IPSS-RM. The results of this analysis will serve as the template with which to build an integrated molecular risk model for MDS. Disclosures Bejar: Alexion: Other: ad hoc advisory board; Celgene: Consultancy, Honoraria; Genoptix Medical Laboratory: Consultancy, Honoraria, Patents & Royalties: MDS prognostic gene signature. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Fenaux:Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Shih:Novartis: Research Funding. Komrokji:Celgene: Consultancy, Research Funding; Incyte: Consultancy; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau. List:Celgene Corporation: Honoraria, Research Funding. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Campbell:14M genomics: Other: Co-founder and consultant. Ebert:Celgene: Consultancy; Genoptix: Consultancy, Patents & Royalties; H3 Biomedicine: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.907.907

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1063-1063

Abstract: Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients treated with HMAs for RR-AML. Responses were defined by International Working Group criteria. Kaplan-Meier methods estimated overall survival (OS) from initiation of HMAs to death or end of follow-up. Multivariable logistic regression models estimated odds for response, and multivariable Cox Proportional Hazard (CPH) models estimated hazards ratios (HR) for OS. Covariates considered included HMA received, age at diagnosis (in years), AML classification at diagnosis (AML with myelodysplasia-related changes [AML-MRC], therapy-related [t] -AML), disease status (relapsed vs. refractory), number of therapy lines prior to HMA (1 vs. 2 vs. 〉 =3), duration of first complete remission (CR1), white blood cell count, peripheral blood blast percentage, bone marrow (BM) cellularity ( 〈 =20% vs. 〉 20%), BM blast percentage ( 〈 =20% vs. 〉 20%), cytogenetic risk group, and the presence of complex or chromosome 7 abnormalities. Results: Of 514 patients, 217 patients (42.2%) had refractory and 297 (58%) had relapsed AML. By end of study, 415 patients (88.5%) had died. Median follow-up for living patients was 11.6 months.Median age at diagnosis was 64 years (range [R], 16-92). AML-MRC was diagnosed in 29.0% while 8.2% had t-AML. Median number of prior therapies was 2 (R, 1-7), with 48.3% receiving 1 prior line, 30.2% receiving 2 prior lines, and 21.5% receiving 〉 =3 prior lines. Prior alloSCT was performed in 21.2%. Only 1.9% had good risk (core binding factor) karyotype, while 56.2% had intermediate risk karyotype, and 41.9% had poor risk karyotype. Azacitidine was used in 45.8% and decitabine in 54.2%; median number of azacitidine cycles was 4 (Interquartile range [IQR], 2-6) compared to 2 for decitabine (IQR, 1-4, p 〈 0.001). Best response to HMAs was CR in 11.7% (95%CI, 9%-14%), CRi in 6.4% (95%CI, 4.3%-8.8%), hematologic improvement (HI) in 8% (95%CI, 5.7%-10.5%), stable disease (SD) in 9.8% (95%CI, 7.2%-12.5%), while 64.1% (95%CI, 57.7%-66.2%) had progressive disease (PD). Median OS from HMA initiation for all patients was 6.9 months (IQR, 3.0-13.3). There was a significant difference in OS based on best response achieved [Figure 1]. Unadjusted OS showed an insignificant trend for worsening with increasing number of prior lines of therapy [Figure 2A] . In unadjusted analyses, there was no difference in OS based on HMA received in all patients [Figure 2B] or the subset who received only 1 prior line of therapy (median OS: Azacitidine vs. decitabine 8.4 vs 7.3 months, p=0.88). Following HMA therapy, the median number of subsequent therapies was 0 (R, 0-6), and only 12.8% underwent alloSCT. In multivariate CPH models, HMA used was not significantly associated with OS (HR=0.80, 95%CI, 0.42-1.51, p=0.49), while increasing age, and presence of complex cytogenetics and chromosome 7 abnormalities were significantly associated with risk of death [Table 1] . In multivariable logistic regression models, HMA used was not associated with achieving CR+CRi (Odds ratio=0.56, p=0.32). Conclusions: In this largest reported cohort of patients with RR-AML treated with HMAs, we found that HMAs are often used as alast line of therapy, with a minority of patients receiving subsequent treatment. Nonetheless, the minority of patients who achieve CR (11.7%) with HMA therapy had a median OS of 25.6 months. Therefore, use of HMAs for management of RR-AML is a reasonable intervention in the absence of clinical trial options. There appears to be no difference in OS or probability of achieving CR+CRi based on HMA used. Ongoing analyses in this dataset include further evaluations of predictors, including genetic mutations, and the development of prediction tools for clinical outcomes with HMA therapy. Figure 1. Figure 1. Disclosures Podoltsev: Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Arian: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gore:celgene: Consultancy, Honoraria. Zeidan:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1063.1063

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: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1669-1669

Abstract: Introduction: Myelodysplastic syndromes (MDS) are characterized by bone marrow dysplasia and ineffective hematopoiesis. Zhou et al. showed that transforming growth factor-beta (TGF-β) signaling was constitutively activated in MDS CD34+ cells and that this over-activation and subsequent myelosuppression was based on reduced expression of SMAD7, the natural inhibitor of TGF-β, in MDS CD34+ cells (Zhou L et al. Cancer Res 2011;71:955-963). Galunisertib specifically inhibited the kinase activity of the TGF-β receptor type I (TGF-βRI) also known as ALK5 and its downstream signaling pathway theoretically replaced the SMAD7 function. Galunisertib reversed hematopoietic suppression in human MDS bone marrow assays, and in a murine model of TGF-β derived bone marrow failure. Based on these preclinical studies that demonstrate hematological improvement (HI) in MDS models following galunisertib treatment, a single-arm phase 2 part of a phase 2/3 proof-of-concept study in very low-, low-, and intermediate-risk patients with MDS was conducted. Methods: The primary objective of this study was to estimate the HI rate based on International Working Group (IWG) 2006 criteria in patients with very low-, low-, and intermediate-risk MDS by Revised International Prognostic Scoring System (IPSS-R), treated with galunisertib. Eligible patients were treated with galunisertib 300 mg/day (150 mg BID) orally for 14 days, followed by 14 days off, constituting a cycle of 28 days. Eligibility criteria permitted any prior therapy, all of which were required to be discontinued at least 28 days prior to initiation of galunisertib. Supportive therapies including ongoing transfusions were allowed. Eligibility criteria included confirmed diagnosis of MDS, anemia with hemoglobin ≤10.0 g/dL, and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Safety was assessed and summarized using the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Descriptive statistics were used to report baseline characteristics and response rates. Results: In this phase 2 study, 41 patients received galunisertib orally (N=39, 150 mg BID and N=2, 80 mg BID for PK comparison). Patients were 62% males. The median age was 71 years (range: 52-84), the majority of patients were classified as refractory cytopenia with multilineage dysplasia (66.7%) or refractory anemia with ringed sideroblasts (20.5%) based on WHO MDS classification. ECOG PS was 0/1 in 53.8%/46.2% of patients. Sixty-two percent of the patients received ≥6 cycles of treatment. Among the 39 patients receiving 150 mg BID, a total of 15 (38%) patients discontinued from the study within 6 cycles; one due to AE and 9 due to patient/physician decision. The most common possibly related any grade treatment-emergent adverse events (TEAEs) included fatigue (20.5%), diarrhea (15.4%), pyrexia (10.3%), vomiting (10.3%), anemia (7.7%), nausea (7.7%), urinary tract infection (7.7%), neutrophil count decreased (5.1%), and platelet count decreased (5.1%); 12 (30.8%) patients had grade 3/4 TEAEs, 4 (10.3%) were drug-related. One of the 39 patients was protocol ineligible and was removed from the efficacy analysis. Among the 38 evaluable patients in the ITT population, 14 of whom required fewer than 4 units of transfusion per 8 weeks, 10/38 (26%) patients achieved HI, defined as at least a continuous 8-week response with at least a 4-unit reduction in transfusion requirement from baseline or hemoglobin increase by at least 1.5 g/dL per 8-week period. Of these 10 patients, 4 became transfusion-independent, and 5 had transfusion reduction. In a subgroup of 24/38 patients who had a transfusion requirement of at least 4 units every 8 weeks at baseline, 9 (38%) of these patients achieved a transfusion reduction of at least 4 units. No apparent correlation between cytogenetics or MDS subtype including ringed sideroblasts and response was identified; however, only 14 patients had abnormal cytogenetics. No platelet or neutrophil responses were observed. Conclusion: Galunisertib is well tolerated in this MDS population where this ALK5 inhibitor was investigated for the first time. Patients most commonly discontinued from study treatment due to patient/physician decision and not for toxicity. The clinical endpoint of HI was observed in 26% of the ITT population, and no specific response sub-group was identified. Disclosures Valcarcel: GSK: 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; AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Boehringer: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Díez-Campelo:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Janssen: Research Funding. Schlenk:Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Gaidano:MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards; Celgene: Research Funding. Perez de Oteyza:Eli Lilly and Company: Research Funding. Cleverly:Eli Lilly and Company: Employment, Equity Ownership. Chiang:Eli Lilly and Copany: Employment. Lahn:Eli Lilly and Company: Other: Former employee. Desiaih:Eli Lilly and Company: Employment. Guba:Eli Lilly and Company: Employment, Equity Ownership. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Pharmacylics: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Incyte: Consultancy; Celgene: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1669.1669

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 10-12

Abstract: Introduction: Patients with myelodysplastic syndromes (MDS) experience severe anemia, which is commonly managed with frequent red blood cell transfusions (RBCT) in patients refractory to erythropoiesis-stimulating agents. At diagnosis, 85% of patients have anemia and 30-50% depend on RBCT. The administration of RBCT itself provides transient relief in anemia-related symptoms. Per protocol, MEDALIST investigators were advised to transfuse for symptoms related to anemia at the investigators' discretion. Hence, cessation or reduction of RBCT may increase anemia-related symptoms and negatively impact health-related quality of life (HRQoL). Luspatercept is a first-in-class erythroid maturation agent providing clinically meaningful reduction in transfusion burden in patients with transfusion-dependent anemia due to Revised International Prognostic Scoring System (IPSS-R)-defined Very low-, Low-, or Intermediate-risk MDS with ring sideroblasts in the phase 3 MEDALIST trial (NCT02631070). However, the impact of luspatercept on patients' HRQoL has not been evaluated. This analysis aimed to evaluate the effect of luspatercept versus placebo on HRQoL of patients treated for MDS from baseline through Week 25 of the MEDALIST study. Methods: Patients received luspatercept or placebo every 3 weeks for 24 weeks, plus best supportive care (BSC), including tailored amounts of RBCT. Effects of luspatercept versus placebo on HRQoL were evaluated as secondary and exploratory endpoints in the MEDALIST study. In the primary analysis, mean change from baseline to Week 25 (clinical assessment visit) in the European Organisation for Research and Treatment of Cancer's core quality of life questionnaire, version 3.0 (EORTC QLQ-C30) and in the QoL assessment in MDS questionnaire (QOL-E) was determined using mixed-effects repeated measures analysis. Clinically meaningful change within each treatment arm was defined as a ≥ 10-point change in patient-reported outcome (PRO) score from baseline for all EORTC QLQ-C30 domains, and ≥ 0.5 standard deviation of the baseline domain score for all QOL-E domains. Differences between luspatercept and placebo were considered clinically meaningful if the change from baseline between treatment arms exceeded the threshold for a clinically meaningful difference. In an exploratory analysis, patient-reported impact of transfusion dependence and overall side effects on their daily life was estimated using the QOL-E instrument. Results: A total of 229 patients were randomized; 153 patients to luspatercept and 76 to placebo. The HRQoL-evaluable population, consisting of patients with ≥ 1 post-baseline HRQoL score, was 149 patients in the luspatercept arm and 76 patients in the placebo arm. Questionnaire compliance rates among patients remaining on treatment were similar between luspatercept and placebo treatment groups at Week 25 (EORTC QLQ-C30, 88.2% vs 79.4% and QOL-E, 72.5% vs 69.7%). At baseline, MEDALIST patients had a clinically meaningfully worse HRQoL compared with the general population in 5 of 15 EORTC QLQ-C30 domains: physical functioning, role functioning, social functioning, fatigue, and dyspnea. Through Week 25, there was no clinically meaningful difference in change from baseline between and within the luspatercept and placebo arms across all EORTC QLQ-C30 (Global health status shown in Figure A) and QOL-E domains. A greater proportion of patients in the luspatercept arm relative to placebo reported improvements in daily life from the impact of transfusion burden (Figure B). Relative to baseline, the proportion of patients reporting a lower impact of transfusion dependence on their daily life was 39% versus 22% in luspatercept versus placebo at Week 25; in contrast, the proportion of patients reporting a higher impact of transfusion dependence on their daily life was 12% versus 22% in luspatercept versus placebo. Impact of treatment side effects on patients was comparable between luspatercept and placebo. Conclusions: Luspatercept with BSC reduced RBCT burden and patient-reported transfusion impact on their daily life, while maintaining other aspects of HRQoL from baseline through Week 25 in the MEDALIST study. Disclosures Oliva: Alexion: Consultancy; BMS: Consultancy, Honoraria, Patents & Royalties, Speakers Bureau; Novartis: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Apellis: Consultancy. Platzbecker:Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Novartis: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding. Mufti:BMS, Novartis: Research Funding; Abbvie, Novartis: Consultancy. Santini:Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Acceleron, BMS, Menarini, Novartis: Consultancy; BMS, J & J, Novartis: Honoraria. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Komrokji:BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Novartis: Honoraria. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Guo:BMS: Consultancy. Zhang:BMS: Current Employment. Ha:Bristol Myers Squibb: Current Employment. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Lord-Bessen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Backstrom:BMS: Current equity holder in publicly-traded company; Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Fenaux:Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-136276

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

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

Abstract: Introduction: MDS is associated with an erythroid maturation defect, characterized by ineffective erythropoiesis leading to anemia and RBC transfusion dependence. Treatment of anemia in lower-risk MDS remains an unmet medical need. Luspatercept is a first-in-class erythroid maturation agent which binds to select TGFβ superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis (Suragani RN, et al. Nat Med. 2014;20:408-14). Preliminary clinical studies have shown promising activity in MDS (Platzbecker U, et al. Lancet Oncol. 2017;10:1338-47). We report the results of a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of luspatercept in patients with anemia due to Revised International Prognostic Scoring System (IPSS-R)-defined Very low-, Low-, or Intermediate-risk MDS with RS who require RBC transfusions. ClinicalTrials.gov identifier: NCT02631070. Methods: Eligible patients were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS according to the WHO 2016 criteria; were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents (ESAs); and required RBC transfusions. Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.75 mg/kg, if needed, or placebo, subcutaneously every 3 weeks for ≥ 24 weeks. The primary endpoint was RBC transfusion independence (RBC-TI) for ≥ 8 weeks between week 1 and week 24. A key secondary endpoint was RBC-TI for ≥ 12 weeks between week 1 and 24. Achievement of modified hematologic improvement-erythroid (mHI-E) response using IWG 2006 criteria was also assessed. Results: † A total of 229 patients were randomized and treated. Median age was 71 years (range 26-95), median time from diagnosis was 41.8 months (range 3-421), and 62.9% were male. Overall, patient baseline characteristics were balanced between the treatment groups. Patients received a median of 5 RBC units (range 1-20) transfused over 8 weeks during the 16 weeks prior to treatment (43.2% of patients had ≥ 6 RBC units/8 weeks, 27.9% had ≥ 4 to & lt; 6 RBC units/8 weeks, and 28.8% had & lt; 4 RBC units/8 weeks). At baseline, 138 (60.3%), 58 (25.3%), and 32 (14.0%) patients had serum erythropoietin levels & lt; 200 IU/L, 200-500 IU/L, and & gt; 500 IU/L, respectively. A total of 218 (95.2%) patients had previously received ESAs. Overall, 206 (90.0%) patients had an SF3B1 mutation. Of 153 patients receiving luspatercept, 58 (37.9%) achieved the primary endpoint of RBC-TI for ≥ 8 weeks compared with 10 of 76 patients (13.2%) receiving placebo (odds ratio [OR] 5.1, P & lt; 0.0001). Of those receiving luspatercept, 43 of 153 (28.1%) achieved the key secondary endpoint of RBC-TI for ≥ 12 weeks (weeks 1-24) compared with 6 of 76 (7.9%) receiving placebo (OR 5.1, P = 0.0002). Patients receiving luspatercept were more likely to achieve an mHI-E response, defined as a reduction in transfusion of ≥ 4 RBC units/8 weeks or a mean hemoglobin increase of ≥ 1.5 g/dL/8 weeks in the absence of transfusions, compared with patients receiving placebo (52.9% vs 11.8% during weeks 1-24; P & lt; 0.0001). The safety profile of luspatercept was consistent with that reported in the phase 2 PACE-MDS study (Platzbecker U, et al. Lancet Oncol. 2017;10:1338-47). Conclusions: Treatment with luspatercept resulted in a significantly reduced transfusion burden compared with placebo in patients with anemia due to IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS, who require RBC transfusions, and was generally well tolerated. P.F. and U.P. contributed equally to this abstract as lead co-authors. R.S.K. and A.F.L. contributed equally to this abstract as senior co-authors. † As of May 8, 2018, cutoff date. Disclosures Fenaux: Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Platzbecker:Celgene: Research Funding. Mufti:Celgene: Research Funding. Buckstein:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Santini:Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Finelli:Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Ilhan:Alexion: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Celgene: Speakers Bureau. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Falantes:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Giai:Novartis: Consultancy; Pfizer: Consultancy. Selleslag:Kiadis Pharma: Other: Financial support for study-related issues. Jurcic:Actinium Pharmaceuticals, Inc: Research Funding; Daiichi-Sankyo: Research Funding; Astellas: Research Funding; Incyte: Consultancy; AbbVie: Consultancy, Research Funding; Kura Oncology: Research Funding; Genetech: Research Funding; Celgene: Research Funding; Forma Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Research Funding. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Götze:Takeda: Honoraria, Other: Travel aid ASH 2017; Celgene: Honoraria, Research Funding; Novartis: Honoraria; JAZZ Pharmaceuticals: Honoraria. Quesnel:Celyad: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Sunesis: Honoraria. Beyne-Rauzy:Novartis: Research Funding. Cluzeau:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Consultancy; Pfizer: Speakers Bureau. Voso:Celgene: Research Funding, Speakers Bureau. Zeidan:Otsuka: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria. Laadem:Celgene: Employment, Equity Ownership. Benzohra:Celgene: Employment, Equity Ownership. Zhang:Celgene: Employment, Equity Ownership. Rampersad:Celgene: Employment, Equity Ownership. Linde:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership; Fibrogen: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Komrokji:Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding. List:Celgene: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-110805

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7