ALBERT

Description: Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukaemia (CMML) are haematological disorders that develop in haematopoietic stem or progenitor cells (HSPCs) and are characterised by ineffective haematopoiesis. 5'-Azacitidine (AZA) is a DNA demethylating agent that is effective in treating MDS and CMML. However, response rates are less than 50% and the basis for poor response is currently unknown. A patient's potential to respond cannot be currently determined until after multiple cycles of AZA treatment and alternative treatment options for poor responders are limited. To address these fundamental questions, we enrolled patients on a compassionate access program prior to the listing of AZA on the pharmaceuticals benefit scheme in Australia. We have collected bone marrow from 18 patients (10 MDS, 8 CMML) at seven different stages of treatment, starting from before treatment until after six cycles of AZA treatment, and isolated high-purity CD34+ HSPCs at each stage. 10 of these patients (5 MDS and 5 CMML) responded completely to AZA while 8 did not achieve complete response. We performed next-generation sequencing (RNA-seq) of these HSPCs to identify the basis of poor response to AZA therapy. Analysis of the RNA-seq data from pre-treatment HSPCs has revealed a striking differential expression of 1148 genes between patients who were subsequently complete (CR) or non-complete responders (non-CR) to AZA therapy (Figure 1A). Using a Fluidigm nanofluidic system, we have validated the differential expression of a subset of these genes between CR and non-CR patients in two independent cohorts, totalling 67 patients, from the U.K. and Sweden. We have additionally confirmed that our gene signature does not simply segregate patients based on disease severity or poor overall survival, but rather uniquely prognosticates best AZA response. Pathway analyses of the differentially expressed genes indicates that the HSPCs of non-CR patients have decreased cell cycle progression and DNA damage pathways, while concomitantly possessing increased signalling through integrin and mTOR/AKT pathways. Using computational methods, we have determined that the expression of 15 genes (within the 1148 gene set) is sufficient to separate CRs from non-CRs across independent cohorts (Figure 1B). We have also developed a predictive AZA response algorithm that utilises the expression of these genes to identify potential complete and non-complete responders to AZA with high specificity and sensitivity (Figure 1C). Furthermore, we have identified statistically significant correlations between recurrent DNA mutations in MDS and our prognostic gene signature (SF3B1 & TET2 with CR, STAG2 and NUP98 with non-CR, p

Description: Introduction Heterozygous RTEL1 mutations have recently been described in familial pulmonary fibrosis (PF) but are not known to be associated with cytopenias or bone marrow failure (BMF), in contrast to heterozygous mutations in other telomere maintenance genes TERT, TERC and TINF2. Constitutional BMF syndromes typically present with less severe pancytopenia and it is often unclear if they have hypocellular MDS (hypoMDS) or non-severe AA (NSAA) morphologically. Methods We screened 284 patients with idiopathic AA or uncharacterised BMF and 172 patients with MDS or acute myeloid leukemia (AML) for TL and RTEL1 variants, and for the other currently known telomere gene complex (TGC) mutations, after excluding patients with Fanconi anemia, DBA or other known inherited BMF syndrome. TL was measured using a monochrome multiplex quantitative PCR method on peripheral blood mononuclear cells. Illumina Nextera-amplicon sequencing was used to screen exons of the DC genes (DKC1, TERC, TERT, RTEL1, CTC1, NHP10, NOP2, USB1, WRAP53, TINF2, PARN and ACD) by MiSeq platform. Constitutional DNA was also analysed in 10 patients (skin 9, buccal swab 1) with RTEL1 variants. A targeted gene panel of 24 genes of an Illumina Tru-Seq Custom Amplicon workflow and platform was used to identify genes frequently mutated in MDS/AML. Impact of mutations was predicted based on 3D structure information from comparative modelling for the helicase domain, comprising the HD1 and HD2 subdomains, a Fe-S cluster and an ARCH domain, and for two harmonin-like (HML) domains and a RING finger domain, located in the C-terminal regulatory region of RTEL1. Results Heterozygous RTEL1 variants were identified in 20 (4.4%) patients. RTEL1 variant allele frequency (VAF) was 45-70% consistent with heterozygous inheritance in all cases. TL was short in 18 (90%) patients, being 〈 1st centile in 15 and

Description: Introduction The majority of patients with Essential Thrombocythaemia (ET) have mutations in JAK2, MPL, and CALR, causing activation of the JAK/STAT pathway; but 10-15% of ET patients lack detectable mutations in these genes, so-called 'Triple Negative' (TN). We applied a systematic approach to investigate mutational status and epigenetic signatures in a cohort of TN ET patients. Methods and Results We investigated 46 patients (72% female), median age at diagnosis 35 years (range 8-77 years) including a father and son. All patients were TNusing standard diagnostic assays. We applied deep, error corrected, next generationsequencing (NGS) of 24 genes using the HaloPlexHS platform to peripheral blood samples. Whole exome sequencing was also performed in 23 patients using skin as constitutional control. Overall we identified somatic mutations in 10/46 patients including MPL(3 patients, W515R, W515G, W515S, R537W, VAF 0.02-0.1) JAK2V617F (4 patients, VAF 0.02-0.08); and germline MPLmutations in a further 3 patients (P453R, S505N); including the father and son pair. We selected patients lacking somatic or germline mutations ("true TN") to analyse gene expression using RNA-seq and DNA methlyation status using 850K Epic Arrays. Patients with JAK2V617Fand CALRmutations and healthy donors (HC) were included as controls. Concerning RNA-seq data, we performed multiple differential analysis of HC vs TN, CALRand JAK2V671F; as well as HC vs all ET samples (adjusted for subtype). Each HC comparison highlighted clear differences between gene expression profiles of HC and disease (Figure 1A). The differentially expressed genes (DEGs) in each comparison overlapped significantly, suggesting that all ET samples have consistent gene expression differences to HC samples regardless of their driver mutation status. In total 1444 differentially expressed genes (ET vs HC) were highlighted (figure 1B). Functional analysis identified significant enrichment for genes involved in the MAPK pathway. Addtionally, we noted upregulation of GATA1,ITGA2B and GP6 genes, not previously reported to be dysregulated in ET. Correlation of gene expression data with DNA methylation status identified a consistent signature of 306 hypomethylated genes, showing significant enrichment for genes involved in transcriptional misregulation and upregulation of inflammatory regulators such as TNF and NFκB signaling pathways. Next, we identified which transcription factor motifs preferentially bind within these methylation blocks. The blocks showed an enrichment for 6 key transcriptional regulators: ATF3, ATF4, CEBPA, CEBPB, MAX, and RARA. All 6 were significantly upregulated in all ET samples. To validate the motifs, we processed ChIP-seq data from the K562 cell line and identified a significant proportion of the hypo methylated regions are bound by these, transcription factors: 374/410 (91%) regions; 43/410 (10%) are bound by all 6 transcription factors. Conclusions A significant proportion (22%) of patients assigned as 'TN' ET via traditional diagnostic techniques in fact harbor known driver mutations at a low allele frequency, suggesting that error corrected NGS approaches may be diagnostically useful in this setting. Additionally, for a group of "true" TN ET patients we demonstrate that patterns of gene expression and DNA methylation are more similar to patients with ET with known driver mutations than healthy controls. Among the upregulated genes are key platelet regulatory genes: GP6, GP1BB, ACTN1and ITGA2B. Furthermore, we identify consistently hypomethylated genes with increased expression across all molecular subtypes of ET which are highly enriched for genes involved in proinflammatory pathways and show that binding of 6 key transcription factorsmay underlie these changes regardless of driver mutation status. Our observations suggest that the ET disease phenotype may, at least in part, be driven by transcriptional misregulation and may be propagated downstream via the MAPK, TNF and NFKappa pathways in addition to activation of JAK/STAT pathways. These findings identify novel mechanisms of disease initiation which require further evaluation. Disclosures Dillon: Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TEVA: Consultancy, Honoraria. 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. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Harrison:Shire: Speakers Bureau; CTI: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; AOP: Honoraria; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; Promedior: Honoraria; Gilead: Speakers Bureau; Sierra Oncology: Honoraria; Incyte: Speakers Bureau.

Description: 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 〉 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 〈 4 U RBCs (30.1% and 26.3% of pts receiving luspatercept and placebo, respectively), 64 received ≥ 4 to 〈 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 〉 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), respectively. Of the 97 luspatercept-treated pts evaluable for clinical benefit, median duration of clinical benefit in pts with baseline transfusion burden of 4 to 〈 6 U/8 wks was 87.9 (range 13-125) wks, of 〈 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.

Description: Abstract 2801 Background: Recommendations for use of erythropoiesis-stimulating agents (ESAs) in anemic patients with MDS are based on baseline endogenous erythropoietin levels and red blood cell transfusion requirements, factors which predict the likelihood of a response to ESA treatment. These recommendations for ESA use have been incorporated into quality-of-care treatment guidelines for MDS. We examined whether baseline endogenous thrombopoietin (TPO) levels and platelet transfusion requirements likewise predict response of thrombocytopenic MDS patients to treatment with romiplostim, a TPO receptor agonist. Patients and Methods: In a placebo(PBO)-controlled trial of romiplostim (randomized 2:1) in 250 thrombocytopenic [median (Q1, Q3) baseline platelet count 19.3 (12.5, 30.3) × 109/L] IPSS low/int-1 MDS patients, study drug was discontinued early due to data monitoring committee concerns that the potential small benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML and that the transient increases in blast cell counts may put patients at risk for diagnosis of and treatment for AML. Hematologic improvement of platelets (HI-P, per IWG 2006) is defined as 8 consecutive weeks of an absolute platelet increase of 30×109/L (for patients with baseline platelet counts 〉20×109/L) or an increase from 20×109/L and by at least 100% (for patients with baseline platelet counts

Description: The majority of patients with adult acute myeloid leukaemia (AML) that present with an apparently normal karyotype (NK-AML) are grouped together in the “intermediate” risk category and constitute 40-45% of all adult AML patients. Mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor whether it is internal tandem duplication (ITD) of its juxtamembrane domain or point mutations in its kinase domain are one of the most common mutations in NK-AML. The presence of FLT3-ITD mutation in NK-AML results in a more aggressive disease, resistance to therapy and poor survival. Acquired copy neutral loss of heterozygosity (CN-LOH) also referred to as uniparental disomy (UPD) is a common phenomenon of myeloid malignancies where an oncogenic allele is duplicated on the other chromosome. The use of single nucleotide phenotype analysis (SNP-A) karyotyping detects CN-LOH in 20% and 40% of newly diagnosed and relapsed AML respectively. CN-LOH at 6p or at the FLT3 locus 13q associated with a FLT3-ITD mutation in NK-AML results in an even more aggressive disease compared to NK-AML + FLT3-ITD without CN-LOH. It has been proposed that CN-LOH is the result of a homologous recombination (HR) DNA repair event. However, the underlying mechanisms that confer CN-LOH have yet to be determined. To elucidate the mechanisms that produce CN-LOH in NK-AML we determined whether oncogenes such as FLT3-ITD have the propensity to generate CN-LOH through up-regulation of inter chromosomal (between maternal and paternal chromosomes) HR DNA repair. We have showed previously that constitutional FLT3-ITD kinase activity increased reactive oxygen species resulting in elevated double strand breaks. Moreover, FLT3-ITD mutation increases homologous recombination activity through transcriptional augmentation of HR factor, RAD51 expression. Firstly, to evaluate FLT3-ITD induced genomic instability we measured sister chromatid exchanges (SCE) that result from HR mediated chromosome cross-over. It has been shown previously in the pre-leukaemic chromosomal instability disorder, Blooms syndrome is characterised by increased SCE and an increased propensity for CN-LOH. FLT3/ITD primary AML (n=17), MOLM-13 and FLT3-ITD transfected U937 cells show a significant increase in SCE compared to WT FLT3 primary AML cells, U937 cells transfected with empty vector, (10 vs. 6 SCE per metaphase, p

Description: 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.

Description: Key Points There is 100% concordance in the cytogenetic and mutation profile between PB and BM in myelodysplastic syndrome.

Description: Abstract 1704 Background: Lenalidomide (LEN) is approved in the US for the treatment of RBC transfusion-dependent patients with IPSS Low- or Int-1-risk myelodysplastic syndromes (MDS) with del(5q), with or without other cytogenetic abnormalities. In a phase 3 trial, treatment with LEN 5 mg and 10 mg resulted in RBC transfusion independence (TI) for ≥ 26 weeks in 43% and 56% of such patients, cytogenetic response in 25% and 50%, and a significant improvement of health-related quality of life (p

Description: Abstract 4551 The diagnosis of intrapulmonary nodules in patients with haematological malignancies is problematic as such lesions are often small and impalpable and “non-targeted” surgical biopsy is difficult. The aim was to evaluate the utility of image-guided “targeting” of small pulmonary nodules with methylene-blue before video-assisted thoracoscopic (VATS) biopsy. Eleven patients (8M:3F) with median (range) age of 48 (27-62) years with haematological malignancies (lymphoma, n=6, AML/MDS, n=3, ALL, n=1,Castleman's disease, n=1) were referred for VATS biopsy. Equal volume of iodinated contrast) was injected in the vicinity of the target lesion and along a track (including the pleural surface and the overlying chest wall), using a 20G needle. The platelet count, diameter of targeted nodules, “perpendicular” distance from the pleural surface and complications were recorded. Patients were transferred to surgery from the CT suite. The median (range) platelet count was 256×109/L (54-453). The mean (range) diameter of targeted nodules was 12.5(5-22) mm and these were at a mean distance of 14.3±8.3mm from the pleural surface. Complications included small pneumothoracis in 4/11 (36%) patients and pain in 1/11 (9%). A definitive histopathological/microbiological diagnosis was achieved in 10/11 (91%) patients and included: organising pneumonia (n=4), respiratory bronchiolitis (n=2), Kaposi's sarcoma (n=1), mycobacterium fortuitum infection (n=1) and chronic GVHD (n=1). There were no cases of angioinvasive aspergillosis. This preliminary data suggest that pre-biopsy methylene-blue targeting of intrapulmonary lesions is a safe and promising technique for the diagnosis of indeterminate lung nodules in patients with haematological malignancy. Disclosures: Mufti: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.