Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3840-3840

Abstract: Human hematopoietic system produces various types of differentiated and short-lived cells with specialized functions, which require continuous replenishment through the function of hematopoietic stem cells (HSC). HSC failure is a common distal endpoint of various pathogenic mechanisms in almost all bone marrow failure (BMF) syndromes and associated diseases. Hematopoietic growth factor cocktails (HGF) used in expanding bone marrow cells e.g., to increase cellularity of the HSC grafts, lead to differentiation and decreased HSC count. Theoretically, when used in vivo, they may act on progenitors rather than HSC and lead to stimulation of clonal outgrowth. Our current ability to stimulate HSC self-renewal to provide reconstitution of long-term hematopoiesis is limited. Nicotinamide adenine dinucleotide (NAD+) serves as an essential cofactor and substrate for a number of critical cellular processes. NAD+ depletion may occur in response to DNA damage due to free radical/ionizing radiation attack, resulting in significant activation of NAD+ consuming PARPs. Because of their long lifespan, maintenance of the genomic integrity of HSCs by efficient and accurate DNA repair to reduce the risk of BMF and cellular transformation is essential. NAD+ is also required for the maintenance of sirtuins activity, important class III HDAC essential for the prevention of senescence. Aging or chronic immune activation and inflammatory cytokine production result in upmodulation of NAD+ degrading enzyme CD38 that rapidly depletes cellular and extracellular levels of NAD+. Various lines of evidence suggest that regulation of CD38 NADase activity is essential for maintenance of physiologic NAD+ levels. Enhancing NAD+ level can profoundly reduce oxidative cell damage in catabolic tissue, including blood. Consequently, promotion of intracellular NAD+ by preventing NAD+ catabolism represents a promising therapeutic strategy for degenerative diseases in general, and BMF and associated diseases in particular. Therefore; CD38, a major NAD+ degrading enzyme, can be an excellent therapeutic target to increase the cellular levels of NAD+ and consequently improve the function of HSC. Here we report the development of inhibitors of CD38 NADase activity that extends the self-renewal and proliferative life span of HSC. We used structure-guided virtual screening followed by docking simulation to develop CD38 inhibitors. The compounds were synthesized using rational chemical synthesis and characterized by high-resolution mass spectroscopy and C13 & H1NMR. HPLC based assays were performed to assess the ability of compounds to inhibit NAD+ degradation by recombinant CD38. Using an iterative approach of synthesis characterization and activity, we selected the most potent compound, designated as ccf1172, for further studies. Docking simulations, surface plasmon resonance, and HPLC based assays demonstrate that ccf1172 binds (KD=12 nM) and inhibits CD38 (IC50=10 nM) (Fig.1B, C & D). To further characterize the ability of ccf1172, colony forming assays (CFU-A) and long-term culture-initiating cell assays (LTCIC-A) were performed with cord blood, human and murine bone marrows. No GF-like activity was observed, but in combination with GF mix ccf1172 increased the number of erythroid and myeloid colonies (n=9) in dose-dependent manner with a maximal effect seen at 100 nM in a serial replating assay. Significant extension of proliferative life span of hematopoietic progenitors (n=5) were observed (Fig 1E). When we studied the ability of CD38 inhibitor to expand LTCICs in stromal cultures (n=3) as best in vitro surrogates of HSC, ccf1172 increased LTCIC numbers 2.6-fold at 10 nM. The effect did not require the presence of accessory cells as ccf1172 treatment resulted in ~2-fold increase in CD34+Lin-/CD45+ cells in stem cell culture media supplemented with growth factors over a period of 25 days (Fig 1F). The CD38 inhibitor demonstrated cytotoxic effects on nine different leukemic cell lines with IC 50 ranging from 1 to 5 µM while no effect was observed on normal bone marrow. Here, we demonstrate that CD38 inhibition may be a potential therapeutic principle for ex vivo and in vivo expansion of HSC. Decreasing levels of NAD+ have been linked to aging and stem cell dysfunction, as a key aspect of various BMF syndromes. The strategy of CD38 inhibition to preserve NAD+ is innovative and relevant therapeutic strategy. Disclosures Saunthararajah: Novo Nordisk, A/S: Patents & Royalties; EpiDestiny, LLC: Patents & Royalties. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-119300

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2472-2472

Abstract: Hematopoietic stem cells (HSCs) are responsible for the adaptation capacity in times of need but are also subjected to disease processes, natural or iatrogenic damage, and age-related attrition. The latter can lead to deficient production, decreased compensatory capacity and degenerative diseases such as MDS. In childhood, hereditary BMF predominates but increasingly with age, acquired idiopathic AA is a leading cause of HSC failure. Throughout life iatrogenic cases and cumulative exposures to environmental toxicities may lead to failure of the HSC compartment. Pharmacologic HSC boosters capable of expanding HSCs would have a wide range of clinical applications in acquired and inherited BMF states, including reconstitution of exhausted hematopoiesis after chemotherapy, aging, or HSC grafting. Currently, hematopoietic growth factors (HGF) are used but lead to progenitor rather than HSC expansion despite their success in clinical application. Depletion of TET2 in murine models leads to impairment of cellular differentiation and increases the proportion of HSCs and progenitors suggesting that TET2 is a key regulator of hematopoietic homeostasis and HSC self-renewal. Alterations of TET2 via somatic mutations and/ or deletion are frequent in MDS whereby HSC and progenitor expansion may be a key component of neoplastic evolution. We hypothesized that chemical agents reversibly inhibiting TET2 activity might phenocopy HSC expansion due to mutations and be applied as HSC boosters. Using structure guided approaches, we designed, synthesized and subsequently optimized bioavailable TET inhibitors (TETi). Among them, the one of the most effective TETi, named TETi76, showed dose-dependent inhibitory activity against TET dioxygenases in in vitro cell-free and cell culture systems with 5hmC production as a read out. We developed esterified forms of TETi76 and used in our cellular experimental models. Esterified TETi is bioavailable and non-toxic to normal bone marrow (BM) cells in therapeutically effective doses. Treatment of TETi76 resulted in a 44+15% and 42+17% increase in the clonogenic potential of human and murine BM cells consistent with the proliferative advantage gained by loss of TET activity in HSCs. We then performed serial replating experiments to determine the effect of TET inhibition on immature hematopoietic progenitor cells. Over 3 consecutive passages, TETi76 treatment prolonged the durability and capacity of human HSCs to maintain colony-forming cells (155+24 vs.107+14 colonies per 1x105 P1 cells). As long-term culture initiating cells (LTC-IC) are the best in vitro surrogates of HSCs, we also investigated the effect of TETi76 in LTC-IC cultures (n=3). The weekly addition of 1μM-TETi76 resulted in nearly 2-fold increase in LTC-IC numbers at the end of the culture (116±27 vs. 64 ±26 colonies per 2x106 P1 cells, p=.011). Expansion of grafts e.g., in the setting of umbilical cord HSC transplant (UCHSC) could be an important medical area of application of TETi76. We performed suspension cultures (n=3) with an optimal cocktail of hematopoietic growth factors (HGF) in the presence or absence of TETi76 (1μM). In control cultures, total cellular output peaked on day 14, but in the presence of TETi, growth continued beyond day 28. Cumulatively, total cellular output per 106 input was 27+2.61 x106cells/mL in control cultures and 32+0.642 x106 cells/mL in TETi treated cultures on day 28. CD34+ cell output was significantly higher in cultures treated with TETi vs. vehicle (2.5x105vs. 0.9X106)CD34+ cells per 1x104 CD34+ cell input). Similar effects were observed in murine BM suspension cultures. BM cells from C57BL/6 mice (n=3) were supplemented with HGF± TETi76 (1μM). TETi treatment led to a 5-fold HSC expansion compared to vehicle treated cells at 20 days of culture. The effect of TETi76 was reversed by treatment with ascorbic acid (50 μM), a known TET activator. Cumulatively our in vitro results suggest that the presence of TETi prevents exhaustion of immature cells, observed with growth factor driven expansion. In summary, our study indicates that novel agents modulating TET activity prevent exhaustion of HSC and may help expand the HSC in vitro. In vivo experiments examining the effects of TETi on hematopoietic recovery following radiation-induced aplasia, and competitive transplant experiments of grafts exposed in vivo and in vitro to TETi are underway. Disclosures 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. Maciejewski:Novartis: Consultancy; Alexion: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129056

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. 112, No. 11 ( 2008-11-16), p. 638-638

Abstract: Genetic predisposition to MDS and AML is likely polygenic and may involve several low penetrance alleles which in concert with exogenous factors result in highly variable presentation, not easily amenable to genetic studies. With the advent of whole genome scanning (WGS) technologies utilizing various SNP array (SNP-A) platforms, large scale investigations in various disorders have been conducted. In hematological malignancies to date no systematic disease-association studies using SNP-A have been reported, likely due to lower prevalence of these conditions and a highly variable phenotype. We have applied SNP-A to conduct the first GWS in MDS and MDS-derived AML with the goal to identify possible low prevalence genetic variants that contribute to the pathogenesis of these conditions and explain individual disease risk. We have studied 189 patients with MDS and secondary AML as well 119 internal controls using SNP-A. Affymetrix GeneChip 6.0 (924644 SNP probes covering most of the known LD blocks) is designed to capture 67%-89% of SNP variation among Caucasians. Following exclusion of SNP’s with a call rate of & lt;95%, and those with serious violation of Hardy Weinberg equilibrium, single allele X2 statistics for all autosomal markers was performed. For the purpose of this study, SNP’s with minor allele frequency (MAF) & lt;10% and p & lt;0.001 after false discovery rate correction, were selected. Top 11 polymorphisms were chosen pointing directly to 4 genes or indirectly to informative loci through LD, informative genes include e.g., LAMC2, SGCE, FRAP1 and PTPRT. Remarkably, several informative LD blocks were also identified represented by multiple markers pointing to the presence of an informative polymorphisms in the corresponding regions. For example, 5/30 markers (all p & lt;8×10−4) including, rs2477436, rs503243, rs3768593, rs4651151 and rs549191 are part of an LD block spanning NMAT2 and LAMC2 loci. The corresponding minor variant frequencies were 6.6% and 37.6% in homozygous and heterozygous constellation, respectively (controls: 0% and 21.6%). Second potential locus identified in our study consisted of 4 markers, all of them located on SGCE gene (rs1357318, rs2037496, rs4330611, rs13225971; p & lt;1.9×10−4) with frequencies of homozygous variant in patients at 0.8% and 28.9% with heterozygous variant (controls 0% and 15.2%), respectively. FRAP1 (MTOR) gene was represented by singular rs3730380 marker (p=2.7×10−6), occurring at the heterozygous frequency of 17.8% vs. allelic frequency of 0% in controls. FRAP1 is a critical downstream effector of Akt involved in cell cycle regulation and angiogenesis being central regulator in PI3K/Akt/mTOR pathway. Genetic alterations of the pathway are frequent events in preneoplastic lesions and advanced cancers. Similarly, increased frequency of minor alleles of rs6030469 in PTPRT locus was found in homozygous and heterozygous constellation at 1.4% vs. 0% and 27.3% vs. 8.5% (p=4.80 × 10-5) in patients and controls, respectively. PTPRT gene was also found to be frequently mutated in cancer and is involved in growth regulation. For example, overexpression of PTPRT may lead to reduced expression of STAT3 target genes. In sum, our study constituting the first systematic approach of WGS to identify genetic risk factors in AMS and AML, suggests that several informative loci can be selected for delineation of the causative polymorphisms.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.638.638

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 734-734

Abstract: Abstract 734 Genetic predisposition to MDS and AML is likely polygenic and may involve several low penetrance alleles which in concert with exogenous factors result in highly variable phenotype and late presentation, not easily amenable to genetic studies. With the advent of whole genome scanning (WGS) technologies utilizing various SNP array (SNP-A) platforms, large scale investigations in various disorders have been conducted. A systems level understanding of particular disease allows for identification of candidate genetic variants as prognostic or diagnostic markers. We have applied 6.0 SNP-A containing 924.644 SNP probes to conduct a comprehensive genome-wide association study (GWAS) in MDS including sAML with the aim of identifying low prevalence genetic variants that contribute to individual disease risk. We have studied 189 patients with MDS and sAML and a cohort of 2230 controls. After exclusion of SNP's with call rate of 〈 95% and those with violation of Hardy Weinberg equilibrium (p 〈 .01), 809.802 SNPs (87.5% of initial set) were passed for further investigation. Single allele χ2 for all autosomal markers was performed. A set of 3600 SNP's pointing towards genes with minor allele frequency (MAF) 〈 10% and p 〈 .001 after Bonferroni correction (more conservative multiple hypothesis correction than False Discovery Rate) were selected. Out of 38 significant non-synonymous SNPs 3 were selected, while 3/64 exonic non synonymous SNPs were prioritized for final investigation. These included rs805267, rs2499953 and rs2681417 pointing towards LY6G5B with (OR 4.9), MMP26 (OR 4.7) and CD86 (OR2.9), respectively. LY6G5B gene was represented by marker rs4656334 (p 〈 1×10–12) occurring at the heterozygous frequency of 16.3% vs. 5.4% in controls, and in homozygous frequency of 4.1% vs. 0.04% in controls resulting in MAF of 12.2% vs. 2.7% in controls (p 〈 1×10-12). Rs2499953 and rs2499956 pointed towards MMP26 and was found in the heterozygous variant in 17.0% vs. 3.7% in controls. CD86 gene was represented by singular rs2681417 marker (p 〈 1×10–7) occurring at the heterozygous frequency of 29.0% vs. 13.6% frequency in controls, and in homozygous frequency of 4.0% vs. 0.4% in controls. The 3/3536 strongest intronic SNPs included rs4656334, rs4647493 and rs700060 and directed via LD to informative genes ATF6 with odds 3.15, FANCC (OR 135.3) and RABGAP1 (OR 37.1) respectively. Of interest is that ATF6/αaRheb-mTOR signalling promotes survival of dormant tumour cells in vivo. ATF6 gene was represented by marker rs4656334 (p 〈 1×10–7) and occurred at a heterozygous frequency of 7% vs. 8.3% in controls, while the homozygous constellation was 7 × higher in patients (14.6% vs. 2.4% in controls) with the corresponding MAF of 18.0 vs. 6.5%. Another 2 SNPs within this locus were highly significant (rs16860777, p 〈 1×10–6; and rs12401299, p 〈 1×10–6). Second potential locus identified in our study (FANCC gene) was represented by singular rs4647493 marker (p 〈 1×10–20) occurring at the heterozygous frequency of 16.9% vs. 0.05% in controls. RABGAP1 gene was represented by singular rs700060 marker (p 〈 1×10–17) occurring at the heterozygous frequency of 13.9% vs. allelic frequency of 0.3% in controls. While these results of analysis targeting individual SNP provide intriguing research avenues, such an approach offers only limited understanding of the complex genetic traits as not an individual SNP, but rather a joint action of several SNPs results in particular outcomes. Consequently, in study of MDS, we applied the network gene association analysis as a new paradigm incorporating both “operator OR” and “operator AND” thereby allowing for dependence and independence testing and possibly, to identification of meaningful pathways. We performed a simulation study, where genotypes were drawn including homozygous reference, heterozygous and homozygous variant for each SNP Si = 1,… 64 where the MAF of SNP is chosen uniformly at random. We have identified rs236113 and rs2499953 (MCM8 and MMP26), both in homozygous variant with occurrence of 19% in patients and 1.8% in controls at a specificity score 98.2% and p 〈 1×10–32. Accordingly the presence of both SNP's increases relative risk given the specificity when both SNPs are present. In sum, our study constituted the first network analyses of predisposing factors taken in consideration as groups and identified informative loci that can lead to delineation of causative genetic profiles. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.734.734

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2630-2630

Abstract: Abstract 2630 Poster Board II-606 Single nucleotide polymorphism array (SNP-A) karyotyping improves detection of chromosomal defects in myeloid malignancies, including acquired somatic uniparental disomy (AS-UPD). AS-UPD comprises ∼30–35% of new lesions in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). To date, impact of AS-UPD on treatment responses and clinical outcomes has not been established. We hypothesized that AS-UPD is a clinically and prognostically important chromosomal lesion in MDS and associated myeloid neoplasms. To that end, we studied bone marrow (BM) from 403 patients using Affymetrix 250K and 6.0 SNP-A: 235 MDS, 80 MDS/ myeloproliferative neoplasms (MPN), 8 idiopathic myelofibrosis (IMF), and 80 AML that evolved from MDS (sAML). Median follow up was 23 months. All gains and deletions with 〉 50% overlap with copy number variants (CNVs) in our internal control (N=1003) and publicly-available databases were excluded. We also excluded germ line, non-clonal regions of homozygosity (ROH) defined by criteria established through analysis of our control cohort. ROH were present in 12% of controls. Based on 95th percentile for interstitial and telomeric locations, ROH 〈 24Mb and 〈 7.4Mb, respectively, were excluded. Clinical parameters measured included survival outcomes (overall [OS], event free [EFS] , and progression free [PFS] survival) analyzed using the Kaplan-Meier method. The two sided Fischer's-exact test were used for categorical comparisons. The Cox-proportional hazards model was used to assess univariate and multivariate analyses for OS, PFS, and EFS; factors assessed included age (≥60 vs. 〈 60 years), BM blasts (≥5 vs. 〈 5 %), number of cytopenias (≥2 vs. 〈 1), metaphase cytogenetics (MC) risk groups using International Prognostic Scoring System (IPSS) criteria (good, intermediate, poor) and AS-UPD (with lesions vs. no lesions). Each variable was retained in the multivariate model regardless of its statistical significance or lack thereof. Only variables with p 〈 .05 in multivariate analysis were considered significant. AS-UPD accounts for 30%, 32%, 31% of lesions in MDS, MDS/MPN and sAML, respectively. Sole AS-UPD was seen at 〉 5% for chromosomes 1, 4, 6, 7, 9, 11, 17, 21, while 2 and ≥3 lesions occurred at 8.1% and 12.1%. Regardless of prior MC and type of myeloid neoplasm, patients with AS-UPD had worse OS [11 vs. 24 mo, p=.0004], PFS [15 vs. 33 mo, p=.0004] , and EFS [13 vs. 21 mo, p=.003] compared to those with no AS-UPD. Patients with normal MC and AS-UPD had inferior survival outcomes (OS [13 vs. 45 mo, p=.002] , EFS [13 vs. 28 mo; p=.004, PFS [14 vs. not reached {NR}; p=.01], as did those with AS-UPD and non-informative MC (OS [7 vs. 17 mo, p=.01] , EFS [5 vs. 17 mo, p=.002], PFS [4 vs. 40 mo, p= 〈 .0001]. When patients were stratified according to disease types, patients with AS-UPD had a worse OS [17 vs. 46 months; p=.02] in MDS; OS [3 vs. 5 mo, p=.01], PFS [3 vs. 7 mo, p=.0002] , and EFS [3 vs. 6 mo, p=.03] in sAML. When patients were grouped according to WHO classification, the presence of AS-UPD conferred worse outcomes in low risk (OS [35 vs. 81 mo, p=0.05] ) and high risk patients (OS [5 vs. 9 mo, p=.006], PFS [4 vs. 11 mo, p=.002] , and EFS [4 vs. 8 mo, p=.004]). When individual AS-UPD lesions were analyzed, the worst OS was seen in patients with AS-UPD involving chromosomes 5(3 mo), 7(3 mo),13 (2 mo), 14 (3 mo), 16 (4 mo), 17 (3 mo) , 21(5 mo), and 22 (3 mo). AS-UPD also influences responses and outcomes related to treatment types. Overall response (CR + PR + HI) rates were worse in patients with AS-UPD (26% vs.42%, p=.003). Patients with AS-UPD treated with low intensity chemotherapy (LIC [lenalidomide, 5-azacitidine, decitabine, arsenic, thalidomide] ) [6 vs. 16 mo, p=0.01] and allogeneic BM transplantation/intensive chemotherapy [6 vs. 14 mo, p=.09] have worse OS compared to those with no AS-UPD. In multivariate analyses, presence of AS-UPD (OS [HR=1.66, p=.01]; EFS [HR=1.5, p=.04] ), BM blasts ≥5% (OS [HR=2.24, p= 〈 .0001]; EFS [HR=2.04, p=.0001] ), and poor risk cytogenetics by MC (OS [HR=1.57, p=.0002]; EFS [1.58, 〈 .0001]) were poor predictors of both OS and EFS in MDS, MDS/MPN and sAML while age ≥60 remain a poor predictor of OS (HR=1.52, p=.01). In conclusion, AS-UPD is a chromosomal defect commonly seen in patients with MDS, MDS/MPN and sAML. The presence of AS-UPD influences treatment responses and outcomes to LIC and BMT/IC. More importantly, AS-UPD is an independent predictor of OS and EFS in myeloid malignancies. Disclosures: Advani: Cephalon: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.2630.2630

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3481-3481

Abstract: Abstract 3481 A significant proportion of patients with idiopathic AA respond to immunosuppressive therapy (IST), suggestive an ex juvantibus autoimmune pathogenesis. Refractory cases may be due to either insufficient intensity of IST or exhaustion of stem cell reserves. Similarly, there may be a non-immunological component of the disease that cannot be distinguished clinically to date. Multiple trials of various ISTs often delay potentially curative therapy with bone marrow transplantation (BMT); hence, identification of this subtype is of great importance. Immune-mediated AA may have measurable immunogenetic determinants, such as HLA genes, that modify susceptibility to, character of, or intensity of autoimmune reactions. We hypothesize that genetic polymorphisms may exist in immune cytokines, cytokine receptors, and immune regulatory genes that may be markers of immune-mediated disease. We applied a custom cancer chip (Illumina) containing 211,155 probes for mostly non-synonymous single-nucleotide polymorphisms (SNPs) to perform focused bioanalysis on 32 immunogenetic polymorphisms. Our cohort included 152 patients; AA (N=91), AA/PNH (N=38), and PNH (N=23). Results were compared to internal control and previously published results with comparable populations. Median age was 45 years (5–80 years); 92% (N=109) had normal cytogenetics; 67% (N=96) had IST with an overall response rate (ORR) of 65%; 11% (N=17) underwent hematopoietic stem cell transplant; 43% (N=49/114) were positive for HLA DR15. The following genotypes had higher incidence in our AA cohort vs. controls: IL1A C(1202)T (rs1800794) CC 60% vs. 35% (p= 〈 .001), IL4 –33 T 〉 C (rs2070874) CC 68% vs. 29% (p= 〈 .001), IL4 –590 C 〉 T (rs2243250) CC 95% vs. 74% (p= 〈 .001), IL2 T-330-G (rs2069762) TT 47% vs. 37% (p=.04), IL6 NT565A 〉 G (rs1800797) AA 17% vs. 8% (p=.006), IL10 –1082G 〉 A (rs1800896) AA 39% vs. 20% (p= 〈 .001), TNF -308 G 〉 A (rs1800629) GG 95% vs. 71% (p= 〈 .001) and IL10 –592 A 〉 C (rs1800872) AA 16% vs. 6% (p=.005). Among AA subtypes, we compared the frequency of each genotype: IL10 –592 A 〉 C (rs1800872) was more frequent in AA vs. PNH (p=.003); both homozygous genotypes, CC and TT of TGF b1 codon 10 +869 C/T (rs1800470) were increased in AA vs. AA/PNH (p=.007). Frequency of CC genotype of CR2 C 〉 T (rs2802221) was increased in AA vs. PNH (p=.003). Differences were also present in CR2 (S663P exon 11, rs4308977) and CR2 (rs6667140) in AA vs. AA/PNH (p=.001), AA vs. PNH (p=.031), and in AA vs. AA/PNH (p=.002). Next, we identified prognostic factors for response via univariate analysis which showed a trend towards higher ORR in AA/PNH vs. AA (88% vs. 59%, p=.06), as previously described. However, neither karyotype nor presence of HLA DR15 affected ORR. Interestingly, there was a trend towards higher ORR in patients with the following genotypes: IL4 –33 T 〉 C CC vs. CT vs. TT (80% vs. 53% vs. 50%, respectively), p=.08; IL4 –590 C 〉 T CC vs. CT vs. TT (69% vs. 33.3% vs. 0, respectively), p=.06. We analyzed (logistic regression) 3 variables (presence of PNH, IL4 –33 T 〉 C SNP, and IL4 –590 C 〉 T SNP) identified in univariate analysis (p 〈 .15) and found that polymorphism in IL4 –33 T 〉 C particularly the CC genotype is prognostic for response (p=.038) while IL4 –590 C 〉 T polymorphism showed a trend towards significance (p=.09). We also employed unbiased screening of non-synonymous SNPs in 116 cases and confirmed in an additional 120. 3 SNPs were outstanding based on differential frequency between patients and controls. There was a difference between dominant/minor (C/T) alleles rs13050238 (CRYZL1) between patients and controls [213/9 (95%, dominant allele) vs. 3747/25 (99%), p 〈 1×108] suggesting carriers of at least one copy of the T allele (CT/TT) are at higher risk of developing AA. Similarly, the minor allele G (A/G) in rs6451268 (RANBP3L) has protective potential [194/30 (87%) vs. 3721/207 (95%), p 〈 1×107]. Minor allele T (C/T) in rs911178 (ZKSCAN3) may also be a protective allele [193/33 (85.53%) vs. 3641/287 (92.69%), p= 〈 1×105]. This gene may regulate expression of genes favoring tumor progression in colorectal cancer. In summary, the T allele of IL1A 1202, IL4 –33, IL4–590; G allele of IL2 –330, IL6 NT565, IL10 –1082; A allele of TNF -308 and C allele of IL10 –592 may be protective against development of AA. SNPs in IL4 –33 T 〉 C and IL4 –590 C 〉 T may be predictive of response to IST and may be considered along with the presence of PNH as favorable prognostic factor. Disclosures: Maciejewski: NIH: Research Funding; Aplastic Anemia & MDS International Foundation: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.3481.3481

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

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. 3096-3096

Abstract: Background: For some rare cancers, better outcomes have been reported for patient (pts) treated at high volume or specialty centers compared to pts who did not receive such care. Greater availability of interventional clinical trials may be one of the drivers of better outcomes in specialty centers. However, not all pts referred to specialty centers are eligible or willing to participate in trials, and it is not known how outcomes compare for pts treated at specialty centers on clinical trials versus standard of care. In this study, we compared the outcomes of higher-risk MDS pts treated in and out of clinical trials at MDS specialty centers. Methods: Pts treated at MDS Clinical Research Consortium institutions (Moffitt Cancer Center, Cleveland Clinic, MD Anderson Cancer Center, Cornell University, Dana-Farber Cancer Institute, and Johns Hopkins) from 2006-2016 were included. Pts were diagnosed with MDS according to 2008 WHO criteria and identified as having "higher-risk" disease based on the revised IPSS (IPSS-R) criteria that included Intermediate, High and Very high risk categories. All pts treated outside clinical trials received hypomethylating agents (HMAs), either azacitidine (AZA) or decitabine (DAC). Trial and non-trial pts were matched 1:1 based on age, sex, number of treatment regimens prior to HMA (for non-trial pts) or experimental regimen (for trial pts) and IPSS-R categories. All non-trial pts included in the analysis received at least 4 cycles of AZA or DAC at the same institution. Transplant rates and overall survival (OS) were evaluated for association with trial participation. OS was estimated by the Kaplan-Meier method and compared using Cox proportional hazard regression with two-sided Wald test with adjustment for matching variables. The relative odds of transplant following initial treatment were estimated using logistic regression and compared with two-sided Wald test. Results: Of 774 pts in the MDS CRC database for whom complete data were available, 323 were treated in clinical trials and 451 were treated with AZA or DAC. The trial and non-trial MDS cohorts were well matched with regards to median age (68.5 vs 68.2 yrs; P=0.65), females (28.4% vs 29.9%, P=0.75), numbers of regimens (3 vs 3, P=0.77) and IPSS-R risk categories (P=0.86). Estimated median OS of pts treated in and out of clinical trials was 44.5 and 50.6 months (P=0.67), respectively. Compared to standard of care, trial participation was not associated with any survival advantage [Hazard ratio (HR), 95% CI, 0.94 (0.72-1.24), P=0.67] (Figure 1). Clinical trial participation did not significantly increase the odds of proceeding to transplant [Odds Ratio (OR) (95% CI), 1.5 (0.68, 1.61), P = 0.83)] . As shown in Table 1, in multivariate analyses, among all factors, increasing number of regimens received was significantly associated with better survival, possibly reflecting a bias towards healthier pts who survived longer to receive multiple regimens. Conclusions: In a matched-pair analysis, we found comparable survival outcomes between trial and non-trial higher-risk MDS pts treated at specialty centers. Our matched analysis failed to identify any statistical evidence to suggest that an average patient benefited from trial participation within the MDS CRC sites. Additional research is necessary to interrogate these comparisons for specific patient subpopulations by genetic alterations, co-morbidities and regimen sequence, for which trial participation may have been beneficial. Based on the population-average findings, however, we expect any improvement in survival to be modest. Disclosures Komrokji: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Roboz:Orsenix: Consultancy; Celltrion: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Eisai: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Celgene Corporation: Consultancy; Orsenix: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Argenx: Consultancy; Otsuka: Consultancy; Aphivena Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Cellectis: Research Funding. Nazha:MEI: Consultancy. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-117174

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1093-1093

Abstract: Abstract 1093 Poster Board I-115 While immune mechanisms are involved in the pathogenesis of idiopathic aplastic anemia (AA), due to the impact of exogenous factors and the low prevalence of AA, this disease is not easily amenable to genetic studies. With the advent of whole genome scanning (WGS) technologies such as single nucleotide polymorphism arrays (SNP-A), large scale investigations in various disorders have been conducted. A systems level understanding of particular disease can allows for identification of candidate genetic variants as prognostic and diagnostic markers. We have applied 6.0 SNP-A containing 924644 SNP probes to conduct a comprehensive GWAS in AA with the aim of identifying low prevalence genetic variants that contribute to the pathogenesis of this condition and contribute to individual disease risk. We studied 124 AA patients and significant cohort of 2230 controls that increase detection power using SNP-A. After exclusion of SNP's with call rate of 〈 95% and those with violation of Hardy Weinberg equilibrium (p 〈 .01), 809.802 SNPs (87.5% of initial set) were passed for further investigation. Single allele χ2 statistics for all autosomal markers were performed. 1935 SNP's pointing towards genes with minor allele frequency (MAF) 〈 10% and p 〈 .001 after Bonferroni correction (more stringent than False Discovery Rate) were selected. Of great interest was the top scoring non synonymous SNP (1/38) rs1028180 located in BLZF1 (OR 6.62) involved in cell proliferation and growth. It was represented by singular marker (p 〈 1×10–4) occurring at a heterozygous frequency of 15% vs. 3.5% in controls, and a homozygous frequency of 3.7% vs. 0% in controls. A total of 1 non-synonymous and 3 strongest intronic SNPs were prioritized for final investigation. These included rs9566991, rs1773557 and rs1495963 and directed to informative genes TNFSF11 (OR 6.24), CD247 (OR 3.52) and IL12RB2 (OR 7.04), respectively. Remarkably, several informative LD blocks were identified represented by multiple markers pointing to the presence of informative polymorphisms in the corresponding regions. TNFSF1 gene was represented by marker rs9566991 (p 〈 1×10–3) occurring at the heterozygous frequency of 15.4% vs. 2.7% in controls. The corresponding MAF was 7.6% vs. 1.3%. A second potential locus identified in our study (CD247) was represented by rs1773557 marker (p 〈 1×10–20) occurring at a heterozygous frequency of 19.6% vs. 5.9% in controls, and in homozygous frequency of 0% vs. 0% in controls. Other SNPs including rs1737501, rs1737502 pointed to the same locus. IL12RB2 was represented by a singular marker rs1495963 (p 〈 1×10–6) occurring at the heterozygous frequency of 24% vs. allelic frequency of 3.2% in controls. MAF were 12% versus 1.9%. Another potential loci marked by rs17131583 was TGFBR3. Analysis targeting individual SNP has been the primary focus of GWAS but such an approach offers only limited understanding of the complex diseases as not an individual SNP, and rather a joint action of several SNPs results in particular outcomes. Consequently, in study of AA, we applied the network gene association analysis as a new paradigm incorporating both “operator OR” and “operator AND” thereby allowing for dependence and independence testing. Consequently, the proposed paradigm may lead to identification of meaningful pathways. We performed a simulation study, where genotypes were randomly drawn including homozygous reference, heterozygous and homozygous variant for each SNP Si = 1, 50 where the MAF of SNP is chosen uniformly at random. Of great interest was a pair consisting of rs1737501 CD247 and rs1495963 IL12RB2 both in heterozygous variant, involving operator AND at p 〈 1×10–23. It was reported with occurrence of 12.2% in patients and 0.005% in controls giving a specificity score of 99.995%. In addition to the described pair, SNP in strong LD within CD247 (rs1737502) was scored again together with rs1495963. Functionally, both genes are involved in regulation response. Another pair rs16908086 and rs1773557 that pointed together to CD247 and MRVI2 created a pair with occurrence 21% versus and 3% in controls. In sum, our study constituted the first network analyses of predisposing factors and complex genetic traits enriched in informative loci in immunoregulatory genes. Rare polymorphic variants of these genes may constitute risk factors for development of AA. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.1093.1093

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 2646-2646

Abstract: Dysfunction of the DNA repair machinery may be one of the potential mechanisms leading to DNA damage and subsequent evolution of chromosomal abnormalities in MDS. However, the complexity of the possible mechanisms that could result in increased propensity to chromosomal breaks constitutes one of the obstacles in the rational targeting of deficient repair pathways for future investigations. Our study involved 37 patients with MDS (19 RA/RARS, 16 RAEB/AML, 2 CMML) and 10 controls. As expression arrays constitute a suitable hypothesis-forming tool, we have applied a specialized expression array to interrogate the most important DNA repair mechanisms in highly purified CD34+ progenitor cells from controls (N=10) and MDS patients (N=12). Based on the expression cut off value of ( 〉 1.5 x background) we detected 22/113 genes present on the array in all samples tested. 16/22 DNA repair genes were concordantly upregulated ( 〉 2 fold above the control values established in pooled control reference). As a defective base pair excision repair (BER) pathway could play a role in the generation of chromosomal breaks, we focused our investigation on enzymes involved in this pathway. Expression array analysis showed that the MPG gene was significantly overexpressed, and we have validated this finding using TaqMan PCR in original samples and additional cohort of patients; 21/37 cases showed significantly elevated MPG transcripts. Overexpression of MPG may be in response to increased alkylation of DNA or may serve as a marker of CpG island methylation. While the latter alternative has been the subject of intense study, increased level of MPG is consistent with the presence of chemically modified bases incorporated into DNA during a toxic insult. Polymerase b (POLB) is a downstream enzyme in BER pathway, and its upregulation could indicate increased activity of this repair mechanism. Consequently, to test the integrity of the BER pathway, we set out to determine POLB expression levels by TaqMan PCR; two distinct subsets of patients ( 〉 2 and ≤ 2 fold of the expression in controls) were identified (5/21 and 16/21). While 4/5 vs. 7/16 patients had chromosomal abnormalities in high vs. low POLB group respectively, these patient groups were otherwise clinically indistinguishable. Hence, we devised our next set of experiments that would discern the differences between these patients at a molecular level. Increased POLB would be consistent with the adequate BER activity. Here, we chose to further investigate the consequences of POLB upregulation in order to distinguish whether BER function results in appropriate DNA repair (upregulation of POLB and MPG) or whether it constitutes response to the deficiency of the AP endonuclease (upregulation of MPG and normal or downregulation of POLB) located immediately downstream of MPG. The content of apurinic sites per genome constitutes a suitable parameter to distinguish the aforementioned possibilities. An apurinic site-specific genomic ELISA assay clearly identified patients (6/19) in whom low POLB expression coincided with an elevated number of apurinic sites ( 〉 0.50 apurinic sites per 1x105bp). We conclude that such a constellation is reflective of altered function of AP endonuclease or inadequate expression of MPG that could predispose to single and double-stranded breaks, and consequently lead to evolution of abnormal clone.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.2646.2646

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

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. 1801-1801

Abstract: Introduction Myeloid leukemia are heterogeneous groups of diseases composed of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms (MPN) and others. While these leukemias have distinct pathological and clinical manifestations, MDS, CMML, and MPN commonly share the risk of AML transformation. Clinical similarity and difference among the myeloid leukemia might be the reflection of underlying homogeneous and heterogeneous genetic basis of the diseases. We analyzed mutation data on a large cohort of pan-myeloid leukemia cases and tested whether mutation data can predict the clinical phenotype and the outcomes using machine-learning (ML) algorithms. Methods Bone marrow samples from 868 patients (pts) with myeloid leukemias (AML: N = 505, MDS/CMML: N = 255, and MPN: N = 108) were analyzed by the targeted capture sequencing of 295 cancer genes (N = 638, median 561x) or whole exome sequencing (N = 230, median 200x). The cohort was divided in the ratio of 4:1 to create a training set and validation set. Using a training set, we generated a ML-based model that predicts clinical phenotype based on the somatic mutation data. Performance of the model was assessed in the validation set based on the parameters including accuracy, precision, recall and area under receiver operating characteristic curve. In addition to the internal validation, we tested our ML-based model in 279 MDS/CMML pts data from the Cleveland Clinic (Makishima et al. Nature Genetics 2017). Results DNA sequencing detected 2,311 high-confidence somatic mutations (1,372 SNVs and 939 indels) in 87 genes in 769 (89%) pts (median 3 [IQR 2-4] mutations/pt in AML, 2 [IQR 1-4] in MDS/CMML, and 2 [IQR 1-3] in MPN). Most commonly shared mutations across all myeloid leukemias were ASXL1 (frequency in AML/MDS CMML/MPN: 16%/30%/24%), TET2 (17%/26%/16%), SRSF2 (14%/21%/7%), DNMT3A (26%/8%/6%), and RUNX1 (14%/15%/5%), which is consistent with the often preleukemic nature of these mutations. Mutations in NPM1, FLT3, KIT, and MYC were almost exclusively detected in AML, whereas mutations in CALR and MPL were specific to MPN. Accuracy of phenotype prediction by ML algorithm relying solely on mutation data was 88% in AML, 63% in MDS/CMML and 85% in MPN. Mutations in FLT3 (co-efficient: 2.2289), NPM1 (1.58176), IDH2 (1.43436), GATA2 (1.38649), IDH1 (1.34405), CEBPA (1.2631), WT1 (1.2577), DNMT3A (1.1073), and KIT (1.07877) had the strong power in predicting AML, whereas mutations in SF3B1 (1.32368) and CUX1 (1.00176) had the strong power in predicting MDS/CMML. JAK2 (3.42899), CALR (2.6211) and MPL (2.17668) mutations had the strong power in predicting MPN. MDS/CMML or MPN cases that were misclassified (predicted) as AML (pAML) by the ML algorithm likely had a genetic similarity with AML, which might predict their risk to AML transformation. Indeed, in the internal validation set, MDS/CMML pts who were predicted as AML (MDS/CMML-pAML) by the ML algorithm had significantly worse transformation free survival (TFS) and cumulative incidence of transformation (CIT) compared to MDS/CMML pts who were predicted as MDS/CMML (MDS/CMML-pMDS/CMML) (2-year TFS: 63% [95% CI: 48-74] in MDS/CMML-pAML vs. 79% [95% CI: 69-86] in MDS/CMML-pMDS/CMML, p = 0.01, 2-year CIT: 30% [95% CI: 20-41] in MDS/CMML-pAML vs. 18% [95% CI: 12-26] in MDS/CMML-pMDS/CMML, p = 0.02), Figure 1 a-b). The similar association was also seen in MPN where MPN pts who were predicted as AML by the ML algorithm (MPN-pAML) had significantly worse TFS and CIT compared to MPN pts who were predicted as MPN (MPN-pMPN) (2-year TFS: 67% [95% CI: 27-88] in MPN-pAML vs. 96% [95% CI: 86-99] in MPN-pMPN, p 〈 0.01, 2-year CIT: 27% [95% CI: 6-55] in MPN-pAML vs. 4% [95% CI: 1-11] in MPN-pMPN, p 〈 0.01, Figure 1 c-d). We further validated our ML-based algorithm in the external cohort of 279 MDS/CMML pts from the Cleveland Clinic. (2-year TFS: 60% [95% CI: 50-69] in MDS/CMML-pAML vs. 76% [95% CI: 65-84] in MDS/CMML-pMDS/CMML, p 〈 0.01, 2-year CIT: 34% [95% CI: 26-42] in MDS/CMML-pAML vs. 18% [95% CI: 11-26] in MDS/CMML-pMDS/CMML, p 〈 0.01, Figure 2 a-b). Conclusion Morphology agnostic, mutation based classification of myeloid leukemia identified MDS/CMML and MPN cases that have high risk of AML transformation. These data support the idea to supplement the conventional morphological and clinical classification by the molecular alterations. Disclosures Kadia: Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; BMS: Research Funding. Daver:Incyte: Consultancy; Incyte: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy; Otsuka: Consultancy; BMS: Research Funding; Alexion: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; ImmunoGen: Consultancy; Sunesis: Consultancy; Pfizer: Research Funding; Sunesis: Research Funding; Karyopharm: Research Funding; ARIAD: Research Funding. Pemmaraju:SagerStrong Foundation: Research Funding; Affymetrix: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. DiNardo:Abbvie: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Agios: Consultancy; Karyopharm: Honoraria; Medimmune: Honoraria. Ravandi:Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding. Verstovsek:Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; Arog: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-116685

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7