Abel, Gregory A.

PURPOSE Representativeness in acute leukemia clinical research is essential for achieving health equity. The National Cancer Institute's mandate for Comprehensive Cancer Centers (CCCs) to define and assume responsibility for cancer control and treatment across a geographic catchment area provides an enforceable mechanism to target and potentially remediate participatory inequities. METHODS We examined enrollee characteristics across 15 Cancer and Leukemia Group B/Alliance cooperative group adult acute leukemia clinical trials (N = 3,734) from 1998 to 2013, including participation in optional companion biobanks. We determined enrollment odds by race-ethnicity for all participants adjusted for national incidence, and for those enrolled at CCCs adjusted for catchment area incidence. We modeled biobank participation by sociodemographics using logistic regression. RESULTS Non-Hispanic (NH)-White patients were more likely to be enrolled than NH-Black, NH-Asian, or Hispanic patients (odds ratio [OR], 0.75, 0.48, and 0.44, respectively; all P < .001), but less likely than NH-Native American patients (OR, 1.91; P < .001), adjusted for national incidence. Enrollment odds were lower for NH-Black, NH-Asian, and Hispanic patients at CCCs adjusted for catchment area incidence (OR, 0.57, 0.26, and 0.32, respectively; P < .001); differences were driven by overenrollment of NH-White patients from outside self-defined catchment areas (18.1% v 12.3%; χ2 P = .01) and by CCCs with less absolute enrollee diversity (rank sum P = .03). Among all enrollees, NH-White race-ethnicity and lower neighborhood deprivation correlated with biobank participation (OR, 1.81 and 1.45, respectively; P = .01 and .03). For CCC enrollees, the correlation of race-ethnicity with biobank participation was attenuated by a measure accounting for their site's degree of enrollment disparity but not neighborhood deprivation. CONCLUSION Acute leukemia clinical research disparities are substantial and driven by structural trial enrollment barriers at CCCs. Real-time CCC access and enrollment monitoring is needed to better align research participation with local populations.

Abstract Introduction Race-ethnic disparities in clinical trial enrollment have the potential to bias findings, limit generalizability, misdirect drug development, and reduce equitable access to novel therapy. The degree to which such disparities exist within acute myeloid leukemia (AML) North American cooperative group trials, biobanks, and correlative studies remain unclear, as are the factors that influence biobank and correlative study participation among trial enrollees. In addition, the National Cancer Institute's (NCI) mandate for Comprehensive Cancer Centers (CCC) to designate catchment areas has not been explored as a mechanism through which AML enrollment disparities can be addressed. Methods We analyzed enrollment data from the 9 Alliance/CALGB AML treatment trials, 2 biobank protocols, and 2 correlative studies active from 1998-2013 and with published results. Trial enrollees could consent to biobank and/or correlative study participation. We compared participation rates of United States (US) enrollees for the mutually exclusive racial-ethnic groups of non-Hispanic (NH)-white, NH-Black, NH-Asian, NH-Native American, and Hispanic using X 2 testing, with NH-white as the comparator and reporting odds ratios (OR) and 95% confidence intervals (CI). Rates were adjusted by national incidence according to the Surveillance, Epidemiology, and End Results program and the US Census. Testing was repeated for the 55% of participants enrolled at 15 NCI CCCs recruiting ≥10 patients, where incidence was adjusted for catchment area size and demographics. Logistic regression models, clustered by trial, were performed to assess the following predictors for biobank and correlative study participation among trial enrollees: race-ethnicity (NH-white vs non-white), site type (CCC status), age (10-year increments), sex, neighborhood urbanity (urban vs rural) and poverty (&lt;20% vs ≥20% below poverty line) by zip code, and distance from site (10-mile increments). Results There were 3041 trial enrollees at US sites; participant characteristics and demographics by race-ethnicity are shown in Table 1. 93.9% of patients participated in a biobanking study and 60.0% in a correlative study. National incidence adjusted enrollment odds by race-ethnicity are shown in the Figure (top); NH-Black, NH-Asian, and Hispanic persons were enrolled at significantly lower rates than NH-whites; NH-Native American enrollment was significantly higher. Enrollment odds were even lower for NH-Black, NH-Asian, and Hispanic enrollees at CCC sites when adjusted by catchment area incidence (Figure; bottom). Among trial enrollees, there were no univariable predictors of biobank participation, however, male sex (OR 1.12; 95% CI 1.01, 1.37; p=0.04) and NH-white race-ethnicity (OR 1.33; 95% CI 1.12,1.57; p&lt;0.001) were associated with correlative study participation. Multivariable models of correlative study participation, with predictors selected based on univariable significance, are shown in Table 2 for all trial enrollees and when restricted to biobank enrollees; in both cases, NH-white race predicted participation. Conclusions Across 15 years of AML cooperative group studies, there were several enrollment disparities by race-ethnicity, which were more pronounced at CCC sites. Over 90% of trial enrollees participated in biobanking, with no race-ethnic differences seen. However, correlative study participation among trial enrollees was higher for NH-whites. Taken together, these data suggest that efforts should focus on increasing trial and correlative study participant diversity-but not biobanking-within NCI-designated CCC catchment areas. Reasonable next steps include identifying key structural, provider, and patient-based barriers to trial and correlative study participation at CCC sites and developing inclusive, multilevel interventions to address them. Figure 1 Figure 1. Disclosures Eisfeld: Karyopharm (spouse): Current Employment. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Stone: AbbVie Inc, Actinium Pharmaceuticals Inc, Aprea Therapeutics, BerGenBio ASA, ElevateBio, Foghorn Therapeutics, GEMoaB, GlaxoSmithKline, Innate Pharma, Syndax Pharmaceuticals Inc, Syros Pharmaceuticals Inc, Takeda Oncology: Other: Advisory Committee; Agios Pharmaceuticals Inc, Novartis;: Research Funding; ACI Clinical, Syntrix Pharmaceuticals, Takeda Oncology: Other: Data Safety & Monitoring. DeAngelo: Abbvie: Research Funding; Blueprint: Research Funding; Takeda: Consultancy; Autolus: Consultancy; Forty-Seven: Consultancy; Incyte: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Servier: Consultancy; Amgen: Consultancy; Agios: Consultancy; Glycomimetrics: Research Funding. Byrd: Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria.

Abstract Background: Financial burden during cancer treatment is associated with compromised patient-reported outcomes (PROs). Being aware of impending costs may help preserve affected PROs during treatment, as patients can adjust their financial expectations. We aimed to determine if the relationship between financial burden and PROs differs among those who were aware versus unaware of transplant-related costs before hematopoietic cell transplantation (HCT) for hematologic malignancy. Methods: In 2015, we administered a mailed survey to adult patients at least 150 days after autologous or allogeneic HCT at three centers: Dana-Farber Cancer Institute, Roswell Park Cancer Institute, and Mayo Clinic Arizona. We assessed pre-treatment awareness of transplant-related costs, decreased household income after HCT, and financial hardship (defined as any one or two of the following: reporting being either unsatisfied with present finances, having difficulty meeting monthly bill payments, or not having enough money at the end of the month; given that experiencing all three would represent extreme hardship likely to impact PROs regardless of awareness, we excluded this group). A seven-point scale was provided for perceptions of overall quality of life (QOL, and patient-reported stress was measured with the Perceived Stress Scale (PSS-4). We fit regression models-stratified by awareness-to assess for the association of income decline and financial hardship with QOL below the median and perceived stress above the median (adjusting for transplant type, sex, age, race, marital status, income, distance to transplant center, and time since diagnosis). Results:In the overall survey cohort (n=325; response rate = 65.1%), 21.6% reported being unaware of HCT-related costs, with no differences due to age, race, income, or education as compared to those who were aware. Patients who reported being aware prior to transplant most often reported being informed of costs by a social worker (40.6%) and least often by a physician (23.4%; sources not mutually exclusive). Among aware patients, income decline after HCT was not associated with QOL below the median (AOR 1.4 [0.8, 2.5]; p=0.24); in contrast, among the unaware, income decline increased the odds of reporting worse QOL (AOR 4.3 [1.1, 16.7]; p=0.04). Among the aware, self-reported financial hardship was associated with worse QOL after HCT (AOR 2.7 [1.5, 4.8]; p=&lt;.001), but the odds were even higher among the unaware (AOR 4.7 [1.2, 19.4]; p=0.03). Similar increases were observed among the unaware for the association of decline in income and financial hardship with increased perceived stress. Conclusions: In this large multi-institutional cohort of patients post-HCT, more than one-fifth reported being unaware of transplant-related costs before the procedure. Moreover, this analysis suggests that pre-treatment awareness of transplant-related costs may ameliorate the impact of post-HCT financial burden on patient-reported outcomes. Figure Figure. Disclosures Khera: Novartis: Consultancy. Zafar: Novartis: Other: Spouse's Employment.

Introduction: Patient-reported outcomes (PROs) such as quality of life (QOL) are variably affected in patients with myelodysplastic syndromes (MDS), but the heterogeneous composition of disease states grouped together as "MDS" increases the difficulty of assessing and understanding these outcomes. Moreover, little is known about the potential relationship between QOL and frailty in this population. Methods: The NHLBI MDS Natural History Study (NCT02775383) is a prospective cohort enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasms (MPNs) in the setting of cytopenias. Untreated participants undergo bone marrow assessment with centralized histopathology review at enrollment for assignment into subcategories for longitudinal follow-up: MDS, MDS/MPN, ICUS, AML (&lt;30% blasts), and "At-Risk" (cases with sub-threshold dysplasia or select karyotypic or genetic mutations). PRO and frailty data are collected at enrollment and every six months thereafter. PRO instruments include MDS-specific (QUALMS) and general (FACT-G, PROMIS Fatigue Short Form 7a, EQ-5D-5L) instruments, and a measure of frailty (VES-13). While no frailty instrument alone has been shown to be a substitute for comprehensive geriatric assessment, VES-13 has been successfully used in cancer-related studies for basic screening, where a score of 3 or more is considered frail (vulnerable). An analysis of variance (ANOVA) was used for the overall comparisons of mean baseline scores between diagnostic categories. Pairwise comparisons of scores between diagnostic categories and vulnerability subgroups were performed via two-sample t-tests. Results : Of 835 participants assessed for eligibility, 369 (44%) were classified as MDS, MDS/MPN, AML, ICUS or At-Risk, and further evaluated. Mean age was 72 years (standard deviation (SD)=10.7) and 68% were male. Mean baseline scores on the PRO measures are compared between diagnostic categories in the Table; scores did not differ significantly across categories. In particular, no significant differences were found between MDS and the other diagnostic categories. ICUS had similar QOL scores to MDS and MDS/MPN (e.g., means (SD) on EQ-5D-5L of 74.1 (17.8) in ICUS and 70.8 (19.4) in MDS, p=0.348) but had significantly higher scores than those for AML on EQ-5D-5L (60.7 (28.4), p=0.031). For the 216 participants with diagnostically-confirmed MDS, QOL impairment was similar to that routinely seen in other cancers; for example, the mean total FACT-G was 81.8 (SD=15.9), similar to localized breast cancer (82.4, SD=16.2), localized colorectal cancer (79.6, SD=16.1), and lung cancer with no current evidence of disease (82.6, SD=15.5; comparison means from Pearlman, Cancer, 2014). For frail/vulnerable participants with MDS or MDS/MPN (N=87), the most common reasons for vulnerability were age ≥75 years (68%), overall rating of health as poor or fair (62%), and difficulty with prolonged physical activity (90%) such as walking a quarter mile (75%) or doing heavy housework (70%). A minority also were vulnerable due to requiring help with instrumental activities of daily living (iADLS) such as shopping (28%) or managing money (16%). Mean QOL scores were compared between vulnerability subgroups (Figure). Vulnerable participants pooled over all diagnostic categories had significantly worse PROs than non-vulnerable participants for all measures (p&lt;0.001). In particular, vulnerable MDS participants scored significantly worse on the QUALMS (mean 64.4, SD=13.4) vs. non-vulnerable MDS participants (mean 72.7, SD=13.3), p&lt;0.001. Conclusions: Participants in our cohort with histologically-confirmed MDS-even low-grade MDS-had similar impairments in PROs as those with other cancers. Among those with histologically-confirmed MDS, vulnerable participants had significantly worse QOL on many measures compared to non-vulnerable participants, suggesting that this domain of function be specifically assessed in clinic. Moreover, while a "gestalt" of frailty may be inferred by observing how patients present and move in the office, these data suggest that other contributing domains, such as difficulty with prolonged physical activity and iADLs, should be evaluated explicitly. Disclosures Foran: H3Biosciences: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Takeda: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Agios: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Actinium: Research Funding; Aprea: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding; Revolution Medicine: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Padron:Incyte: Research Funding; Kura: Research Funding; Novartis: Honoraria; BMS: Research Funding. Sekeres:BMS: 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; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: The NHLBI National MDS Study (NCT02775383) is a prospective cohort study conducted at 92 community hospitals and 29 academic centers. It enrolls patients undergoing work up for suspected MDS to understand the genetic, epigenetic, and biological factors associated with the initiation and progression of the disease. Previously untreated, cytopenic participants undergo both local and centralized pathology review and are assigned a diagnosis, including MDS, MDS/MPN, AML with blasts &lt; 30%, and "Other". Emerging data suggests that Next Generation Sequencing (NGS), along with cytogenetics and clinical variables, may improve MDS diagnostic precision. Given that our study relies on central review (with additional tertiary pathology review used to adjudicate disagreements), we examined whether targeted gene sequencing data could be used to increase the agreement between local and central pathologic diagnosis of MDS vs. Other. Methods: Peripheral blood and bone marrow (BM) biopsy specimens from cytopenic patients, along with clinical history, CBC, and other results including karyotyping, FISH and pathology reports from local pathologists were reviewed by central pathologists. The updated 2016 WHO classifications were used to diagnose MDS. Targeted exon sequencing of 96 genes was performed using BM specimens. A subset of 648 individuals that were classified as MDS (n=212) or Other (n=436, including 90 CCUS and 89 individuals with other cancers) by pathology assessments were selected. A mean coverage of 1,317X was achieved and variants had a minimum variant allele frequency (VAF) of 2% (except FLT3). Variants for 596 subjects were manually reviewed to retain likely disease-causing variants to build a binary classifier (MDS vs. Other) using the maximum VAF per gene as input (Figure 1). Subjects diagnosed with MDS or Other by both central and local pathology were used for training, validation, and testing, and were considered "gold standard" (GS) cases (n=546). These subjects were split into 4 random groups with equal proportions of MDS cases. 75% of the GS cases were used to train and validate lasso-regularized logistic regression models using 3-fold cross validation. ROC curve analysis was carried out using the remaining 25% of GS cases (Test Set 1) on the best model to identify an optimal probability cut off point for classifying subjects as MDS. Model performance was then tested on 50 subjects for which the central and local pathology diagnosis disagreed (Test Set 2), as well as on 52 additional subjects irrespective of agreement (Test Set 3). Results : The best performing logistic regression model retained 7 genes as most informative in a discriminating diagnosis of MDS from Other based on their VAFs, in order of impact: TP53, SF3B1, U2AF1, ASXL1, TET2,STAG2, and SRSF2. We used this model to assign probabilities for each of the subjects in Test Set 1 and to estimate the performance using ROC analysis (Figure 1), resulting in a high area under the curve (AUC) of 0.89. We chose a probability cut-off of ≥0.17, being associated with a high percentage of correct classification of MDS with a sensitivity and specificity of 0.90 and 0.81, respectively. Among the cohort of 50 subjects with a discordant local and central pathology diagnosis (Test Set 2), the classifier accurately reassigned 37 subjects (accuracy = 74%) from the local to the central pathology. The blinded tertiary pathology reviewer agreed with central in all Test Set 2 cases. This included 24/34 MDS cases that had been labeled as Other by local pathology (positive predictive value [PPV]=0.89). 3/16 final pathology-classified Other cases were mis-classified as MDS by the local pathologist (negative predictive value [NPV] = 0.57). Next, we assessed the ability of the model to predict MDS vs. Other for 52 additional independent subjects using the third pathologist's diagnosis to break any ties (Test Set 3). The classifier correctly predicted 15/21 MDS cases (PPV=0.83) and misclassified 6/31 Others as MDS (NPV=0.82). The overall accuracy was 83%. Conclusions: We identified that VAFs for 7 genes can correctly re-classify subjects as either MDS or Other in 74% of cases that were misclassified between local and central pathology review. Further assessment on an independent cohort showed an accuracy of 83% of the model. Taken together, these data suggest that complementing pathology reviews with targeted sequencing of 7 genes could improve MDS diagnosis. Disclosures Lindsley: MedImmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy; Takeda Pharmaceuticals: Consultancy. Bejar:Aptose Biosciences: Current Employment; AbbVie/Genentech: Honoraria; Astex/Otsuka: Honoraria; Takeda: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Forty-Seven/Gilead: Honoraria; Genoptix/NeoGenomics: Honoraria. DeZern:MEI: Consultancy; Astex: Research Funding; Abbvie: Consultancy; Celgene: Consultancy, Honoraria. Foran:H3Biosciences: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Revolution Medicine: Consultancy; Xencor: Research Funding; Agios: Honoraria, Research Funding; Aprea: Research Funding; Actinium: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Komrokji:Acceleron: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Geron: Honoraria; Novartis: Honoraria. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Padron:Novartis: Honoraria; BMS: Research Funding; Incyte: Research Funding; Kura: Research Funding. Starczynowski:Captor Therapeutics: Consultancy; Tolero Therapeutics: Research Funding; Kurome Therapeutics: Consultancy, Current equity holder in private company, Research Funding. Sekeres:BMS: Consultancy; Takeda/Millenium: Consultancy; Pfizer: Consultancy.

Abstract Background: Older adults with acute myeloid leukemia (AML) represent a vulnerable population in whom disease-based and clinical risk factors, patient goals, prognosis, and practitioner- and patient-perceived treatment risks and benefits influence treatment recommendations. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about management of AML in older adults. Methods: ASH formed a multidisciplinary guideline panel that included specialists in myeloid leukemia, geriatric oncology, patient-reported outcomes and decision-making, frailty, epidemiology, and methodology, as well as patients. The McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline-development process, including performing systematic evidence reviews (up to 24 May 2019). The panel prioritized clinical questions and outcomes according to their importance to patients, as judged by the panel. The panel used the GRADE approach, including GRADE’s Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 6 critical questions in managing older adults with AML, mirroring real-time practitioner-patient conversations: the decision to pursue antileukemic treatment vs best supportive management, the intensity of therapy, the role and duration of postremission therapy, combination vs monotherapy for induction and beyond, duration of less-intensive therapy, and the role of transfusion support for patients no longer receiving antileukemic therapy. Conclusions: Treatment is recommended over best supportive management. More-intensive therapy is recommended over less-intensive therapy when deemed tolerable. However, these recommendations are guided by the principle that throughout a patient’s disease course, optimal care involves ongoing discussions between clinicians and patients, continuously addressing goals of care and the relative risk-benefit balance of treatment.

Abstract BACKGROUND: Previous work has demonstrated that smokers have higher white blood cell counts than nonsmokers, but the effect of biochemically-confirmed smoking cessation on peripheral leukocyte counts has not been demonstrated in a large prospective study. METHODS: Subjects were healthy smokers enrolled in a trial of sustained-release bupropion for relapse prevention after smoking cessation. White blood cell (WBC) counts and absolute neutrophil counts (ANC) were measured at baseline, week 7 and week 52. Smoking status was assessed at weeks 7 and 52 by self-report and biochemically confirmed with expired air carbon monoxide levels. Multivariate analyses compared changes in WBC count and ANC between smokers who did and did not stop smoking, adjusting for treatment group, age, sex, and body mass index. RESULTS: Of 784 smokers enrolled, 461 had biochemically-confirmed tobacco abstinence after 7 weeks of bupropion; 429 were randomly assigned to receive continued bupropion or placebo until week 52. At baseline, the mean WBC count was 8.4 x 109/L (SD ±2.3) and the mean ANC was 5.3 x 109/L (SD ±1.9). The baseline WBC count and ANC were higher in smokers with greater tobacco exposure, measured by daily cigarette consumption and serum cotinine level. Between baseline and week 7, there was a significantly larger decrease in WBC count in continuously abstinent subjects compared with continuing smokers (adjusted p =.031). At 52 weeks, biochemically-confirmed continuously abstinent subjects, as compared with continuing smokers, had a greater decline from baseline in WBC count (1.2 x 109/L versus 0.1 x 109/L, p&lt;0.001) and ANC (0.1 x 109/L versus 0.2 x 109/L, p&lt;0.001). CONCLUSION: The WBC count and ANC of healthy smokers increase with increasing tobacco exposure. Biochemically-confirmed tobacco abstinence leads to a rapid and sustained decrease in WBC count and ANC, possibly reflecting a decrease in an underlying state of tobacco-induced inflammation.

Introduction: Myelodysplastic syndromes (MDS) are a heterogenous group of blood disorders defined by peripheral cytopenia(s), bone marrow failure, morphological dysplasia, and risk of progression. To understand the genetic, epigenetic and biological factors associated with the initiation and progression of MDS, NHLBI created the National MDS Study (NCT02775383). This is a prospective cohort study conducted at 92 community hospitals and 29 academic centers enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasm (MPN) overlap syndrome. Eligible patients have yet to receive any therapy directed at their cytopenias. Previously untreated cytopenic participants underwent centralized histopathology and data review at the time of enrollment for assignment into distinct subcategories: MDS, MDS/MPN overlap, AML, and Other. Targeted exon sequencing of 96 genes was performed using marrow specimens from the first 300 consecutive individuals in the study. Here we report the genetic mutations for this cohort. Methods: NovaSeq 6000 was used for deep sequencing at a mean coverage of 1,286X and mean breadth (bases covered at ≥100X) of 99.8%. Reads were aligned against build GRCh38 using BWA-MEM, and VarScan2 was used to detect SNVs and INDELS. Variants were filtered for those with an allele base quality of >25 in combination with rule-based and manual review criteria. Subjects in the Other category without an identified malignancy were considered clonal cytopenias of undetermined significance (CCUS) when a mutation or a clonal cytogenetic change was present. Fisher's exact and Wilcoxon rank sum tests in combination with Bonferroni correction were applied to compare groups. Results : A total of 350 putative nonsynonymous pathogenic variants in 36 genes with an allele frequency of >.05 were identified across 150 patients (50%). At least one variant was noted in the following proportion of individuals: 61/72 (85%) with MDS, 13/13 (100%) with MDS/MPN, 15/17 (88%) with AML, and 61/198 (31%) in the Other category, of which 48 were CCUS and 13 were other cancers. Two CCUS patients only had a cytogenetic abnormality. Table 1 shows the distribution of variants in each subcategory of patients for the most commonly mutated genes in our cohort of 300 subjects. Mutations in these genes were enriched in specific groups: SF3B1, STAG2,TP53, and ASXL1 in MDS; TET2 in MDS/MPN; and IDH2 and TP53 in AML (one-sided p<0.0012). None were enriched in the Other group. Within the CCUS subset, 21 genes were mutated, with 37 of 50 (74%) patients having a mutation in TET2, ASXL1, SRSF2, SF3B1, or DNMT3A. The heatmap presented in Figure 1 summarizes variants by subject and allele frequency. Pair-wise comparisons of baseline characteristics of subjects between MDS, MDS/MPN, AML, or CCUS groups revealed no significant differences for age or sex. The CCUS group had significantly higher hemoglobins than the MDS group with median hemoglobin levels of 11.35 and 9.40 g/dL, respectively (p<0.0084). AML had significantly lower platelets compared to all other groups (median of 53 vs. > 110x109/L , respectively, p<0.0084). All groups significantly differed in their median ANC with AML having the lowest (0.8x109/L), followed by MDS (1.5x109/L), CCUS (2.45x109/L), and MDS/MPN overlap (5.95x109/L) (p<0.0084). There was no difference in the median number of variants per patient between groups or correlation with age (rs=0.11, p=0.18). The maximum variant allele frequency (maxVAF) per patient was highest in the MDS/MPN group (median = 0.42, range = 0.38-0.91) and lowest in the CCUS group (median = 0.37, range =0.06-0.98) with the MDS/MPN group having a significantly higher maxVAF compared to the MDS and the CCUS groups (p<0.0084). The proportions of subjects with mutations was similar for those who had abnormal (92% [34/37]) and normal (91% [80/88]) cytogenetics. Conclusions: Incorporation of gene-panel sequencing in the comprehensive evaluation of 300 adult cytopenic patients identified half of the cohort with potentially pathogenic variants. Ultimately, a diagnosis of CCUS was possible in 48 of 183 subjects (26%) not diagnosed with MDS, MDS/MPN overlap syndrome, AML, other cancers or clonal cytogenetics. This study continues to serially bank samples from patients with CCUS, in addition to MDS, MDS/MPN, and ICUS, with the goal to better understand the natural history of these diseases and their progression. Disclosures Lindsley: Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding. Bejar:Celgene: Consultancy; Takeda Pharmaceuticals: Research Funding; AbbVie/Genentech: Consultancy, Honoraria; Astex/Otsuka: Consultancy; Modus Outcomes: Consultancy; Daiichi-Sankyo: Consultancy. Al Baghdadi:Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Tracon: Equity Ownership; Epizyme: Equity Ownership; Bristol Myer Squibb: Consultancy, Honoraria; Sunesis: Equity Ownership; Portola: Equity Ownership; Heron therapeutics: Equity Ownership; Cardinal health: Consultancy, Honoraria; Bristol Myer Squibb: Equity Ownership; Celgene: Equity Ownership; Spectrum pharmaceutical: Equity Ownership; Astrazeneca: Equity Ownership; Seattle genetics: Equity Ownership; Roche: Consultancy, Honoraria. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Foran:Agios: Honoraria, Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Komrokji:DSI: Consultancy; Agios: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; pfizer: Consultancy; celgene: Consultancy; Incyte: Consultancy; JAZZ: Consultancy. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Starczynowski:Kurome Therapeutics: Consultancy. 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.