Citations

128 Background: Treatment for neoplastic fevers and sweating (NFS) is usually accomplished successfully with non-steroidal drugs (NSAIDs) such as naproxen, but such therapies may be contraindicated in some patients due to drug interactions, bleeding diathesis, renal disease, or cirrhosis. Options for treating NFS in such patients are limited. Methods: We report the first use of oxybutynin (OxyB), commonly used for hyperhidrosis and increasingly used for hormonally mediated hot flashes (Smith TJ, NEJM 2018; Leon-Ferre R, SABCS 2018, under review in JNCI Cancer Spectrum, for NFS in NSAID-ineligible or refractory patients. Results: Two patients with NFS were treated. The first was a 70 year old (yo) woman with cholangiocarcinoma with 3 months of NFS for whom naproxen was ineffective and who was starting chemotherapy. Within 2 hours after 2.5 mg OxyB q12h her sweating was gone, and her fever, which had been up to 100.4F, never resumed. The second was a 52 yo male with cirrhosis and hepatocellular carcinoma who was prescribed 2.5 mg q12h OxyB with lysis of his fever within hours and cessation of his sweating. To date, over one month has passed with no reduction in efficacy. Conclusions: OxyB may be a successful treatment modality for patients with NFS who cannot be treated with or are refractory to NSAIDs. Further research is warranted to ensure stability of results over time and to monitor for side effects.

Abstract Background Recent genome wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified several associations at both HLA and non-HLA loci. However, much of HL heritability remains unexplained. Methods To identify novel risk loci, we performed a meta-analysis of 3 HL GWAS including a total of 1,810 cases and 7,879 controls. Results were replicated in an independent set of 1,163 cases and 2,580 controls, for a total of 3,097 and 11,097 cases and controls combined, respectively. participants in discovery and replication stages were of European descent. quality control and imputation we conducted a meta-analysis addressing 1,004,829 variants (λ= 1.10, λ1000= 1.03). Associations between SNP genotypes and HL risk were evaluated under a log-additive model of inheritance adjusting for sex, study center and significant principal components to control for population stratification. We performed an analysis with all HL cases and then conducted stratified analyses by histological subtype (classical, nodular sclerosis and mixed cellularity), age at diagnosis (nodular sclerosis among those diagnosed at 15- 35 years in all studies, and those diagnosed at 35 and older years in the European Study only) and EBV tumor status (negative and positive). We then used a bioinformatic approach (FunciSNP) to identify potential functional variants associated with HD risk correlated with risk loci of interest. We extracted publically available ENCODE data on biofeatures to identify potential functional motifs associated with the index SNP or correlated SNPs. Finally, we measured expression levels of the two alternative mRNA transcripts in lymphoblastoid cell lines (LCLs) from 49 post-therapy HL patients and 25 unaffected controls. RT-PCR was carried out in triplicate. Relative expression levels were calculated relative to TBP as housekeeping gene. Linear models were used to assess correlation between genotype and TCF3expression levels. Results The meta-analysis identified a novel susceptibility variant at chromosome 19p13.3 (rs1860661) associated with HL risk (Odds Ratio [OR]= 0.78, P=2.0*10-8, I2=0%). variant is located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment. was also significantly associated with HL (OR= 0.85, P=0.002) in the replication series of 1,281 cases and 3,218 controls. the combined analysis consisting of the discovery and replication sets, rs1860661was strongly associated with HL (OR=0.81,=3.5*10-10), with no evidence of heterogeneity between contributing studies (Phom=0.41, I2=0%). The number of G alleles defined by rs1860661 was significantly associated with a reduced risk of each HL subtype except EBV positive HL. rs1860661 and two correlated SNPs, rs10413888 (r2=0.90) and rs8103453 (r2=0.89) identified by FunciSNP analysis map in or near marks of open chromatin and in DNAse hypersensitivity sites in TCF3 in CD20+ B cell lines., the protective minor alleles of these SNPs as defined by the G-G-G haplotype map to the binding sites for ZBTB7a (rs10413888 and rs1860661) and (rs8103453) transcription factors, likely improving the binding efficiency to the sites which may result in increased transcription rates of TCF3. TCF3 is encoded by two alternative transcripts (E12 and E47). Higher expression levels of TCF3-E47, whose transcription start site is located close to rs1860661, was associated with the rs1860661-G allele in controls (P=0.02), but not in HL patients (P=0.22). Conclusion/Discussion TCF3 is essential for the commitment of lymphoid progenitors to both B-cell and T-cell lineage development. A molecular and phenotypic hallmark of classical HL is the loss of the B-cell phenotype in HRS cells, including lack of demonstrable B-cell receptor and most B-cell specific markers such as CD19 or CD20. HRS cells have a low level of TCF3, particularly homodimers of the isoform E47, due to expression of the ABF-1 and ID2 inhibitors that bind to TCF3. Thus, higher TCF3 levels in HRS precursor cells may lead to enhanced retention of the B cell phenotype, thereby conferring a protective effect. These data suggest a link between the 19p13.3 locus including TCF3 and HL risk, indicating that TCF3 could be relevant to HL etiology and pathogenesis. Disclosures: Link: Genentech: Consultancy; Millenium: Consultancy; Pharmacyclics: Consultancy; Spectrum: Consultancy.

Multiple myeloma (MM) is a neoplasm thought to arise from a damaged germinal center B-cell that progresses to a plasma cell clone arising in bone marrow. MM comprises 20% of all hematologic cancer deaths. Persons of African ancestry (AA) have a 1.5 to 2-fold higher risk compared to individuals of European ancestry (EA). Genetically driven differences in hematopoiesis may lead to variation in the levels white blood cell (WBC) subsets which could, in turn, be associated with MM etiology. There are differences in genetic determinants of WBC traits between EA and AA populations, with possible implications for the racial disparity in risk. We tested the above hypothesis using Mendelian randomization (MR), an approach that leverages genetic determinants of specific traits (i.e. WBC counts) to estimate their effects on the risk of an outcome; and a transcriptome-wide association study (TWAS), which utilizes genetic predictors of gene expression to identify susceptibility genes. These analytic approaches were applied to data from the African American Multiple Myeloma Study (AAMMS) consisting of 1813 cases and 8871 AA cancer-free controls to examine how differences in heritable WBC gene expression profiles influence MM risk. Genetic determinants of variation in WBC subsets in AA were obtained from the literature and supplemented with new genome-wide association findings in AA subjects from the UK Biobank cohort (n=6108). Odds ratios (OR) for MM per 1 standard deviation (SD) increase in each WBC phenotype were estimated using independent (linkage disequilibrium (LD) r2<0.10) variants with P<10-6 as genetic instruments. Analyses based on variants associated with WBC traits in AA populations did not identify any statistically-significant associations between MM risk and WBC overall (p=0.81, using 15 SNPs) or subsets (lymphocytes, monocytes, eosinophils, neutrophils and basophils, p>0.05 for each). However, when we applied genetic determinants of WBC identified in 330,000 cancer-free EA UK Biobank participants (P<10-8, replication P<0.05, LD r2<0.05), a statistically significant inverse relationship emerged between increasing lymphocyte counts and MM risk (OR=0.80, 95% CI: 0.66-0.97, p=0.02, using 385 SNPs), as well as increasing basophil counts (OR=0.63, 95% CI: 0.41-0.96, p=0.03, using 140 SNPs). Next, we examined the association between WBC gene expression profiles and MM risk in AAMMS data. We applied published and validated ancestry-specific models developed using the PrediXcan approach, which leverage germline genetic and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (MESA) (Mogil et al. PMID: 30096133). The primary TWAS used gene expression models trained in AA subjects (n=233), with sensitivity analyses using models developed in AA and Hispanic subjects (n=585). The TWAS significance threshold was based on the number of genes with significant germline prediction models (p<0.05 and R2 ≥0.05) in AA, corresponding to P < 0.05/2700 = 1.85×10-5. The expression of two genes was significantly associated with MM risk: KANK1at 9p24.3 (P = 1.01×10-5) and DNAJC27at 2p23.3 (P = 1.56×10-5). KANK1is a candidate tumor suppressor gene for renal cell carcinoma and has recently been associated with MM risk in AA [Du, Blood 2017 130:3058]. Here we provide additional evidence for its role in MM etiology via gene expression-mediated mechanisms. DNAJC27 (previously known as RBJ) is a novel MM risk gene linked to constitutive activation of ERK in solid tumors. We also identified two suggestively associated genes: PRR14 (P = 1.34×10-4; combined AA-Hispanic sample: P = 1.56×10-6), which has been linked to MM risk in EA populations, and PARP16 (P = 9.46×10-5). To our knowledge this is the first study to comprehensively examine variation in WBC traits and gene expression profiles with respect to MM risk in AA. Our TWAS analysis leveraged data from the largest collection of genetic and gene expression data in AA, enabling ancestry-matched inference and identification of two novel risk genes. Although the limited availability of genetic instruments for WBC limited the power of MR analysis, findings using variants identified in European populations may offer some insight into trans-ethnic etiologic pathways and contribute to risk stratification strategies using genetic and blood cell count biomarkers. Future studies, particularly with MGUS-free controls, are needed to validate these results. Disclosures Song: Millennium Pharmaceuticals Inc: Employment. Rand:Ancestry.com: Employment. Ailawadhi:Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy. Nooka:Takeda: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation. Singhal:Bureau of Millennium/Takeda, Celgene, Janssen, Celgene, Bristol-Myers Squibb and Bluebird: Speakers Bureau. van Rhee:Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy; Adicet Bio: Consultancy; Kite Pharma: Consultancy; Karyopharm Therapeutics: Consultancy. Mehta:Millennium/Takeda, Celgene; stock in Celgene, Bristol-Myers Squibb and Bluebird: Speakers Bureau. Wolf:Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Fiala:Incyte: Research Funding. Terebelo:Jannsen: Speakers Bureau; Celgene: Honoraria; Newland Medical Asociates: Employment. Anderson:Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi-Aventis: Other: Advisory Board. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding. Bernal-Mizrachi:TAKEDA: Research Funding; Kodikas Therapeutic Solutions, Inc: Equity Ownership; Winship Cancer Institute: Employment, Patents & Royalties. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Zonder:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Huff:Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Karyopharm, Sanofi, MiDiagnostics: Consultancy. Lonial:Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Celgene Corporation: Consultancy, Research Funding; Genentech: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding.

Background Genome-wide association studies (GWAS) conducted in populations of European ancestry (EA) have identified and confirmed 23 germline susceptibility loci for multiple myeloma (MM). The effect sizes of single nucleotide polymorphisms (SNPs) at these loci are small, therefore combining them into a single summary measure, known as a polygenic risk score (PRS), may provide a more meaningful risk factor. We have previously shown a PRS comprised of the 23 SNPs for MM contributes to increased risk of MM, with a 2.7-fold increase for highest vs. lowest PRS quintiles. Whether the MM-PRS is also associated with overall survival (OS) in MM cases has not been evaluated. We examined the association between MM-PRS and OS in two EA studies. Methods The first study consisted of 2,179 EA MM cases from ten studies included in the Multiple Myeloma Working Group within the International Lymphoma Consortium (InterLymph). Cases were diagnosed between 1970 and 2015 and genotyped using multiple platforms (Oncoarray, Affymetrix, Human660W-quad Beadchip, and Illumina arrays); 885 cases also had stage [based on International Staging System (ISS)] available. Each of the GWAS was subjected to rigorous standard quality control independently (prior to imputation via the Michigan imputation server based on the Haplotype Reference Consortium (HRC). The second study consisted of 515 newly diagnosed EA MM cases from CoMMpass (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile), diagnosed from 2011-2013, who had whole genome sequencing (WGS) performed on germline DNA. The WGS data was used to call common germline genetic variants through the Mayo Clinic bioinformatics pipeline. Briefly, genetic variants were detected with GenomeGPS, aligned to the hg19 reference genome, called using the GATK (V3.6) Haplotype Caller, and merged for multiple-sample joint calling. To reduce the false positive variants, variant quality score recalibration (VQSR) was applied for both SNPs and INDELs. After quality control, 458 EA samples remained. Follow-up was available for both studies and consisted of time from MM diagnosis date until death or date of last known follow-up. The PRS was constructed from the 23 MM SNPs using the published per allele odds ratio associated with MM risk. The published log odds ratios for each SNP were multiplied by the number of risk alleles (0, 1, 2) for the corresponding SNP, and summed, resulting in a unique score per person. Kaplan-Meier curves and Cox proportional hazard models were used to assess the association between PRS with MM OS considering two models: 1) adjusted for age, sex, study and 2) additional adjustment by stage (ISS). Hazard ratios (OR) and 95% confidence intervals (CI) were estimated. The PRS was evaluated both as a continuous variable, per standard deviation (SD), and as a categorical variable (quintiles). Results MM cases (N=2,179) in the InterLymph study were 59% male and 41% female and the median age was 61.0 years (26-90 years). Median follow-up time was 57.2 months (1.0-509.0 months) with 868 reported deaths. MM cases with stage information available consisted of 20% stage I (n=178), 53% stage II (n=466), and 27% stage III (n=241). No association was observed between PRS and OS in MM patients regardless of adjustment for stage (continuous PRS (HR: 1.03, 95% CI: 0.83-1.28, P=0.80) or by quintile PRS (p>0.05)) (Table). The CoMMpass EA MM cases (n=458) had similar distributions for sex (61% male and 39% females) but were slightly older 65 years (27-93 years) and had shorter follow-up time (median=39.75 months (0.13-77.2)) with 117 deaths. Stage was available for 96% of CoMMpass cases including 36% stage I (n=159), 33% stage II (n=146), and 31% stage III (n=134). We also observed no association of PRS and OS in the CoMMpass study (HR=1.02, 95% CI: 0.72 -1.46, P= 0.89), adjusted for age, sex, and stage (Table). Discussion A PRS score for MM risk is not associated with OS for MM cases in two EA populations. Given that prior studies have shown association of genetic variation with MM survival, efforts to identify additional loci associated with OS or MM specific survival are warranted. Future studies should also consider germline variants impact on molecular subtypes, specific therapies, and outcomes. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Introduction Long-term hematopoietic stem cell transplant (HCT) survivors are burdened by a high prevalence and early onset of chronic diseases. Healthy dietary patterns have been associated with lower risks of chronic health conditions in the general population, yet no study to date has comprehensively documented the adherence of HCT survivors to the Dietary Guidelines for Americans (DGA), specifically designed to provide guidance for making healthy food choices. The aims of this study were to evaluate the extent to which HCT survivors adhere to the DGA and to determine nutrient intake adequacy. A secondary aim was to assess their willingness to take part in a future nutritional program or dietary intervention. Methods The study population included adults (≥18 y), who had undergone autologous or allogeneic HCT for a hematologic disease and were at least 1-year post-transplantation. Dietary intake was assessed using the Block 2014 food frequency questionnaire and diet quality (adherence to the DGA) was estimated using the Healthy Eating Index-2015 (HEI-2015). A HEI score of ≤50 indicates "poor diet quality", 51-80 suggests a "diet that needs improvement", and >81 indicates "good diet quality" out of maximum of 100. HEI-2015 scores by patient and transplant characteristics were analyzed by ANCOVA. Nutrient intake adequacies of the group were estimated by determining the percentage of the group falling below the Estimated Average Requirement (EAR) of the Dietary Reference Intakes. Receptivity to participate in a dietary intervention to stay healthy was measured by the question, "How willing would you be to take part in a healthy nutrition program or diet intervention?" Response categories included, "not at all," "somewhat," and "definitely". Results Between December 2017 and September 2018, 124 survivors were invited to participate, of whom 90 (51 autologous and 39 allogeneic HCT survivors) completed the dietary intake assessment and were included in the analysis. Majority were male (56%), White (72%), married (81%) and completed some college education (57%). Most participants were overweight (34%) or obese (37%). The median time from the HCT was 5.2 years. Mean ±SE HEI-2015 scores were 61.6 ± 1.3 and 60.7 ± 2.2 for the 18-64 y and ≥65 y age groups, respectively, slightly higher than the US general population. Adherence to a good quality diet was reported by only 10% of survivors. The majority of the survivors reported a diet in need of improvement (82%) or a poor-quality diet (8%). Intakes of vitamin A (720 ± 447 mcg/d), vitamin C (82 ± 73 mg/d), vitamin D (4.4 ± 3.4 mcg/d), magnesium (253 ± 133 mg/d), and calcium (781 ± 430 mg/d) suggested inadequacy, as more than 50% of the group fell below the specific EARs. Sodium intake at 2834 ± 1345 mg/d exceeded the DGA recommendation of 2300 mg/d. Fiber intake at 8.9 g per 1000 kcal/d was significantly below the Adequate Intake of 14 g per 1000 kcal/d. "Change in taste" was the only variable associated with lower quality of diet (p=0.02). Interestingly, 29% of HCT survivors reported persistent altered taste sensation. No significant relationships were seen for participant's demographics and diet quality which may be due to a sample population skewed toward older, causations and socioeconomically advantaged individuals. More than two thirds of participants (73%) indicated an interest in participating in dietary intervention. HCT survivors within 2 years of transplant were more likely to be receptive to participation in a diet intervention study compared to survivors beyond 2 years (52% vs 28%, p=0.0013). Conclusion Adult HCT survivors report poor adherence to the 2015 Dietary Guidelines for Americans and have numerous short-fall nutrient intakes. However, the willingness to participate in a nutritional program or dietary intervention in this survivorship population was relatively high. These findings reinforce the need to incorporate nutrition into HCT survivor care. Disclosures Wingard: Celgene: Consultancy; Merck: Consultancy; Shire: Consultancy; Ansun: Consultancy; Pluristem: Consultancy.

Background : CD47 is a transmembrane protein ubiquitously expressed in human cells. CD47 is overexpressed in various malignancies and is correlated with negative prognosis in AML and MDS (Chao et al. Curr Opin Immunol.2012; Majeti et al. Cell.2009). Interaction of CD47 with signal-regulatory protein alpha (SIRPα) expressed on macrophages inhibits phagocytosis (Kim et al. Leukemia.2012). CC-90002, a humanized anti-CD47 monoclonal antibody, blocks CD47/SIRPα interactions, thereby enabling macrophage-mediated killing of tumor cells. In preclinical studies, CC-90002 demonstrated antibody-mediated phagocytosis of several hematologic cancer cell lines, including AML cells. CC-90002 also demonstrated a rapid and substantial reduction in tumor burden in AML xenograft models. Herein, we report results from CC-90002-AML-001 evaluating CC-90002 in patients (pts) with R/R AML and high-risk MDS. Methods : In this phase I multicenter study (NCT02641002), CC-90002 was administered intravenously once/week for 4 weeks of each 42-day cycle during cycles 1−4 then once every 4 weeks during a maintenance phase of 28-day cycles. Pts were enrolled in cohorts of escalating dose levels using a modified 3+3 design. The primary objectives were to determine preliminary safety and tolerability, non-tolerated dose (NTD), maximum tolerated dose (MTD), and/or recommended phase 2 dose. Secondary objectives were to measure preliminary efficacy, pharmacokinetics, and the presence and frequency of anti-drug antibodies (ADAs). Results: As of July 18, 2018, 24 pts with R/R AML and 4 pts with high-risk R/R MDS were enrolled. Pts received CC-90002 at 0.1 mg/kg (n=6), 0.3 mg/kg (n=6), 1 mg/kg (n=6), 2 mg/kg (n=4), and 4 mg/kg (n=6). Median age was 70 years (range, 28-85) and 16 (57%) were male. The most common AML subtypes were AML with myelodysplasia-related changes (n=9) and AML not otherwise specified (n=9). All 4 pts with MDS were classified as having refractory anemia with excess blasts-2 and high- or very high-risk disease per the Revised International Prognostic Index Scoring System. The median number of prior systemic anticancer regimens was 3 (range, 1-10), and 29% of pts had prior stem cell transplants. The median treatment duration was 6.9 weeks (range, 2-44). Four pts experienced a dose-limiting toxicity, consisting of grade 4 disseminated intravascular coagulation and grade 4 cerebral hemorrhage in 1 pt (0.1 mg/kg), grade 3 purpura in 1 pt (0.3 mg/kg), grade 4 congestive cardiac failure and grade 4 acute respiratory failure in 1 pt (1 mg/kg), and grade 4 sepsis in 1 pt (4 mg/kg). The most common (≥30%) any-grade treatment-emergent adverse events (TEAEs) were diarrhea (46%); thrombocytopenia (39%); febrile neutropenia and aspartate aminotransferase increased (36% each); and anemia, alanine aminotransferase increased, and cough (32% each). A total of 23 pts (82%) had serious TEAEs with febrile neutropenia (n=10), bacteremia (n=4), pneumonia (n=4), and general physical health deterioration (n=3) occurring in&gt;2 pts. No TEAEs led to dose reductions; however, 7 pts (25%) discontinued due to TEAEs. Overall, 82% of pts were dependent on red blood cell (RBC) transfusions and CC-90002 treatment did not interfere with continued RBC transfusion in pts on study. No pts experienced hemolysis, tumor lysis syndrome, or macrophage activation/cytokine release syndrome. Sixteen pts died during the study. The best overall response observed was stable disease in 2 pts with MDS. CC-90002 serum exposures appeared to increase with doses above 0.3−4.0 mg/kg and the terminal half-life ranged from 4.6−17.0 hours. Development of ADAs targeting CC-90002 occurred at all dose levels tested and the proportion of pts testing positive for ADAs in cycle 1 increased over time (4/27 pts at day 8, 6/25 pts at day 15, and 8/22 pts at day 22). ADAs continued to be present across different doses with increases in median serum ADA titers after cycle 1. No apparent dose-ADA relationship was observed. Conclusion: CC-90002 showed a lack of objective responses in pts with R/R AML and high-risk MDS. The MTD and NTD were not established. The CC-90002-AML-001 study was discontinued in dose escalation for lack of preliminary monotherapy activity and evidence of ADAs in most pts. CC-90002 in combination with rituximab is being explored in CD20+ NHL to enhance efficacy of CD47 blockade while reducing ADAs (CC-90002-ST-001; NCT02367196). Disclosures Zeidan: BeyondSpring: Honoraria; Seattle Genetics: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; 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. DeAngelo:Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals Inc: Consultancy; Shire: Consultancy; Incyte: Consultancy; Blueprint: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Consultancy; GlycoMimetics: Research Funding; Celgene: Consultancy; Abbvie: Research Funding; Takeda Pharmaceuticals: Consultancy. Seet:University of California, Los Angeles: Employment. Tallman:Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Cellerant: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Biosight: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; UpToDate: Patents & Royalties; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding. Wei:Celgene Corp.: Employment, Equity Ownership. Li:Celgene Corp.: Employment, Equity Ownership. Hock:Celgene Corp.: Employment, Equity Ownership. Burgess:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof; University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees. Stock:Agios: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; UpToDate: Honoraria; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Background: Lymphoma patients exposed to chest RT during adolescence/young adulthood are at increased risk for BC; the cumulative incidence exceeds 20% by age 45 and the BC risk is comparable to that in women with BRCA1 mutations. These findings present an urgent yet unmet need to reduce the risk of BC in RT-exposed lymphoma survivors. The risk of BC is 50% lower in chest RT-exposed survivors who also receive ovarian radiation, suggesting a critical role of endogenous estrogens in RT-related breast carcinogenesis, making tamoxifen (a selective estrogen receptor modulator) an attractive risk-reducing option. Tamoxifen administered at 20 mg/d is effective in BC prevention in other high risk populations, but severe adverse events (SAE: venous thromboembolism, endometrial cancer) have limited its broad use. Previous biomarker trials in the general population have shown that LDTam (5mg/d) is not inferior to tamoxifen at 20 mg/d in reducing BC risk, and is associated with a safer AE profile. Mammographic breast density (MBD) is an established biomarker of BC risk; high MBD is associated with a 4-fold higher risk of BC. We hypothesized that LDTam would be effective in reducing BC risk (using MBD as a primary endpoint) in chest RT-exposed lymphoma survivors. We used an investigator-initiated, multi-institutional, randomized phase IIb, double blind, placebo controlled trial (FDA IND 107367) to test this hypothesis. Methods: Female patients from 13 sites were ≥25y at enrollment, with a history of exposure to chest RT at ≥12 Gy by age 40 for their primary cancer, and were off therapy for ≥6 mo. Subjects with a prior history of BC/DCIS, B/L mastectomy, or baseline MBD <25% in both breasts were excluded. Tamoxifen 5mg or identical placebo tablets were provided by Sharp Clinical Services (Allentown, PA) under good manufacturing practice. Subjects were randomized 1:1 in a double-blinded fashion by a Web-based system to receive LDTam or placebo daily for 2y. MBD (in both breasts) was measured centrally on digital scans independently by 3 radiologists at baseline, 1y and 2y. Using an intention-to-treat analysis, the efficacy of LDTam in reducing MBD was compared between the LDTam and placebo arms by applying a linear mixed effects model for bivariate normally distributed data with random intercept and time*treatment arm effects. Correlations between the left and right breasts and within radiologists were accounted for in the model. Treating clinicians and all research staff were blinded to the treatment arm. Results: A total of 72 patients (LDTam: n=34; placebo: n=38) participated in the trial; primary diagnosis: Hodgkin lymphoma (86%); non-Hodgkin lymphoma (10%); other (3%); median age at diagnosis of primary cancer: 21.5y (IQR, 16-28), and at trial enrollment: 43.8y (35-49); median time from diagnosis of primary cancer to study: 17.0y (12-26). Median chest RT dose: 30.3 Gy (21-37.3); 11% had received pelvic radiation; 39% were post-menopausal at study. Participant characteristics were comparable between the two treatment arms, as was the mean baseline MBD (LDTam: 52.6% vs. placebo: 50.4%, p=0.6). The time*treatment arm effect was statistically significant (LDTam vs. placebo: estimate = -1.7, SE = 0.5, p = 0.001), indicating a significantly lower mean fitted MBD for LDTam (43.9%) vs. placebo (47.3%) at 2y (Figure). This represented a 16.5% relative reduction in MBD on the LDTam arm, corresponding to an estimated 33% lower risk of BC (assuming that reductions in MBD have the same benefit in lymphoma survivors as they do in the general population). There were no grade 3 or 4 AEs related to LDTam. Grade 2 AEs did not differ between treatment arms (LDTam: 44.1% vs. placebo: 36.8%, p=0.6). There was no difference in the prevalence of moderate-to-severe patient-reported outcomes between the treatment arms (Table). Conclusion: Low-dose tamoxifen was associated with a significantly steeper decline in MBD in chest RT-exposed lymphoma survivors, when compared with placebo, and was safe and well-tolerated. This is the first trial demonstrating efficacy of a pharmacologic intervention in reducing a biomarker strongly associated with breast cancer risk in lymphoma survivors with a past history of chest radiation. Disclosures Palomares: Covance: Other: Medical monitoring. Henderson:Seattle Genetics: Research Funding. OffLabel Disclosure: The drug is a low-dose tamoxifen, a selective estrogen receptor modulator. Tamoxifen in standard doses is used to reduce the risk of breast cancer in high risk populations. Tamoxifen in standard or low doses have not been tested before for chest-irradiated cancer survivors to reduce the risk of radiation-related breast cancer.

Background: NGS of myeloid mutations is an integral part of AML clinical decision-making. There is currently no information regarding concordance between NGS panels in AML using samples from the same patient across various platforms in different diagnostic laboratories. To study this important question, we analyzed NGS of myeloid mutations in diagnostic samples from The Beat AML Master Trial (BAMT) for newly diagnosed older AML patients, and compared variant calls made between institutional laboratories enrolling the study subject with those made by Foundation Medicine (FM), the central laboratory used for treatment assignment in this precision medicine trial. Methods: We identified newly diagnosed AML patient samples (peripheral blood (PB) and/or bone marrow (BM)) from 2 lead institutions in the BAMT(Ohio State, OSU and Oregon Health and Sciences University, OHSU) that were analyzed by both the institutional and by FM from Nov 15, 2016 to Apr 15, 2019. Samples sent to both laboratories >3 days apart were excluded. Samples were analyzed at the institutional laboratories using their respective NGS mutational panels and by FM using the FoundationOne®Heme(FMH) NGS panel which utilizes capture based sequencing. The OSU NGS assay utilizes sequencing on Illumina MiSeq. The OHSU NGS assay employs semiconductor-based sequencing (Ion Torrent PGM platform). The variant allele frequency (VAF) sensitivity for detection for all 3 laboratories range from 1-2%. We evaluated the ability to identify mutations in 8 genes : FLT3, IDH1/ 2, NPM1, TET2, DNMT3A, WT1 and TP53 used in treatment assignment in theBAMT. A detection cutoff of 2% was used to define the presence or absence of a mutation. Overall, agreement was defined as the number of times the local and central laboratories made the same call divided by the total number of patients. Sensitivity was defined as the number of present calls made locally divided by the number of present calls made centrally, and specificity as the number of absent calls made locally divided by the number of absent calls made centrally. The overall kappa statistic, controlling for institution, provided another measure of agreement between local and central calls, where a value of 1 indicates perfect agreement. Results: 194 patient samples were identified using methods above and analyzed locally at the screening institution (125 at OSU, 69 at OHSU) and centrally at FM. Type of tissue analyzed for variants between local site and FM were 59 PB, 129 BM, and 6 with BM/PB mismatch. Overall agreement in presence/absence calls between local and central results for each of the 8 genes was over 95% (Table 1). There was perfect agreement for NPM1. The sensitivity was above 94% for all genes except TP53 (88.6%) and WT1 (63.6%). Failure to detect a mutation locally was primarily due to reporting of all TP53 variants, including variants of unknown significance (VUS) (5) by FM as agreed upon in the study protocol, detection at low levels below local site sensitivity cutoff (1), detection of variants in a portion of gene not covered at the local site(1)and possible artifact (1). For the WT1 gene, discordance in 5 samples included VUS (3) reported by FM ,a variant detected in a portion of the gene not covered at the local site(1).and difference in leukemic tissue analyzed with mutation not detected by the central laboratory on a PB sample, and present at the institutional lab on a BM sample; affecting the overall agreement and specificity but not sensitivity. Specificity was at least 98% for each of the 8 genes. Finally, most discrepancies in reported mutations in FLT3 (n=2), IDH1 (n=1), IDH2 (n=2), DNMT3A (n=4) and TET2 (n=5) were due to reporting of VUS in one laboratory and not by another. Conclusion: Detection of pathogenic myeloid mutations using orthogonal assays showed a high degree of concordance for genes used in therapeutic assignment on the BAMT.The small number of discordant results, in TP53 and WT1, were attributed to the reporting of VUS. This study illustrates the importance of quality control and standardization as NGS continues to be widely utilized in AML for clinical decision making, with a variety of platforms across multiple laboratories. Our next steps involve evaluating the differences in VAFs reported between local and central laboratories when a given mutation is identified, as well as the potential reasons for observed differences and clinical implications of known pathogenic mutations vs putative VUS. Disclosures Borate: Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy. Vergilio:Foundation Medicine: Employment; Roche Holding AG: Equity Ownership. Stein:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baer:Astellas: Research Funding; Abbvie: Research Funding; AI Therapeutics: Research Funding; Forma: Research Funding; Incyte: Research Funding; Kite: Research Funding; Takeda: Research Funding. Stock:Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Schiller:Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Agios: Research Funding, Speakers Bureau. Blum:AmerisourceBergen: Consultancy; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Astellas,: Research Funding; Xencor: Research Funding; Forma: Research Funding. Kovacsovics:Pfizer: Research Funding; Jazz: Consultancy; Novartis: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding. Foran:Agios: Honoraria, Research Funding. Druker:Pfizer: Research Funding; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Cepheid: Consultancy, Honoraria; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; ALLCRON: Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; Patient True Talk: Consultancy; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Beat AML LLC: Other: Service on joint steering committee; CureOne: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Gilead Sciences: Other: former member of Scientific Advisory Board; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Monojul: Other: former consultant; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding. Byrd:Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S. Levine:C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Prelude Therapeutics: Research Funding; Novartis: Consultancy; Gilead: Consultancy; Lilly: Honoraria; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees. Mims:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 102 Myelodysplastic Syndromes (MDS), and Chronic Myelomonocytic leukemia (CMML) patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not. M ethods: Landmark response based on 2006 IWG criteria, and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Objective response (OR) was defined as patients who had Complete Response (CR), Partial Response (PR), marrow (m)CR, or Hematological Improvement (HI). Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only. Results: The study completed enrolment with 102 patients: 53 patients after HMA failure (relapsed/refractory or r/r), and 49 HMA-naive patients (Treatment Naïve or TN) with a median follow up for the entire study of 3.2 years (IQR 2.9-3.5 years). Median age was 71 and 72 years for TN MDS/CMML and r/r MDS/CMML patients respectively. Median OS was 23.4 months (m) for TN MDS/CMML patients and 11.7 m for r/r MDS/CMML patients. Of the 102 patients treated, 37 patients (36.3%) and 58 (56.9%) received less than 4 and 6 cycles respectively. The landmark analysis population was 91 patients for the 4-cycle analysis and 87 patients for the 6-cycle analysis. In those patients, the primary reasons for treatment discontinuation before cycle 4 or 6 respectively were patient decision (9.8% and 11.8%), and investigator decision (5.9% and 9.8%) while early progression accounted for 3.9% and 10.8% of those patients. There were no major baseline characteristics difference between patients who received at least 4 and 6 cycles and those who did not in the patients included in the landmark analyses. In the landmark analysis, patients who received at least 4 cycles (65 patients) had an OR rate of 68% compared to 15% in 26 patients who received <4 cycles (p <0.0001) and median OS of 20.4 m compared to 15.2 m respectively (HR 0.78, 95% CI 0.45-1.3, p 0.36). Those who received at least 6 cycles (44 patients) had an OR rate of 82% compared to 26% in 43 patients who received < 6 cycles (p<0.0001), and median OS of 23.8 m vs 13.6 m respectively (HR 0.51, 95% CI 0.3-0.85, p 0.009). Results were consistent when r/r MDS/CMML and HMA-naïve MDS/CMML were analyzed separately. Landmark OS analysis also favored those who received guadecitabine for at least 4 or 6 cycles compared to those who received <4 and < 6 cycles even in the absence of objective response (OS HR of 0.82 and 0.42 respectively) but the sample size was small to show statistical significance (p 0.58 and 0.10 respectively) Summary/Conclusions: In a prospective phase 2 study of 102 MDS/CMML patients treated with the HMA guadecitabine, patients who were alive at the planned start of cycle 4 and cycle 6 did not continue treatment primarily because of patient or investigator decision in addition to early progression. Those who were alive and continued treatment for at least 4 or 6 cycles achieved highly significant objective response benefit compared to those who did not. Survival benefit was highly significant for those who received at least 6 cycles and was not restricted to patients who had an objective response. It is important to weigh reasons for treatment discontinuation carefully before discontinuing guadecitabine HMA treatment in MDS/CMML patients before 6 cycles to maximize response and survival benefit. Disclosures Savona: Selvita: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Takeda: Honoraria; Astex: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: 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; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Connell:Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Yee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Research to Practice: Honoraria; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Griffiths:Appelis Pharmaceuticals: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; Boston Scientific: Consultancy; Persimmune: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Podoltsev:Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Research Funding; Astellas Pharma: Research Funding; Samus Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Celgene: Other: Grant funding, Research Funding; Arog Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AI Therapeutics: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding. Su:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Garcia-Manero:AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; Amphivena: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.