Saber, Wael

Abstract Introduction: It has been shown that racial/ethnic minorities have worse survival after matched unrelated donor allogeneic hematopoietic cell transplantation(allo-HCT) compared to Whites. Whether the racial disparity in allo-HCT outcomes persists in long-term survivors, and possibly may even be exacerbated in this population that frequently transitions back from the transplant center to their local healthcare providers, is unknown. In the current study we sought to compare long-term outcomes among one-year survivors, by race/ethnicity and socioeconomic status (SES), after allo-HCT reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods: The CIBMTR database was used to identify 5,473 patients with Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myeloid Leukemia (CML), or Myelodysplastic Syndrome (MDS) who received HCT between 2007-2017, who were alive and in remission for at least 1 year after allo-HCT. Study was restricted to patients transplanted in the United States. Cox regression model was used to determine association of ethnicity/race and SES with overall survival (OS), relapse, and treatment related mortality (TRM). Standardized mortality ratio (SMR) was calculated to compare mortality rates of the study patients to their general population peers matched on race/ethnicity, age and sex. Results: Patients were reported to be Non-Hispanic White (W) (n=4385), Non-Hispanic Black (B) (n=338), Hispanic (H) (n=516), and Asian (A) (n=234). Median follow up after 1 year allo-HCT (months): 69 W, 50 B, 59 H and 57 A (Table 1). Patient neighborhood poverty level was estimated from residential ZIP code at the time of allo-HCT. A ZIP code with ≥20% of persons below the federal poverty level was considered high poverty area. In multivariable analysis, we observed no significant differences in OS, relapse or TRM based on race or poverty level when adjusted for patient-, disease- and transplant-related covariates (Table 2). Conclusions: Our study highlights that among those who survived at least 1-year in remission after allo-HCT, previously reported disparities in post HCT outcomes based on racial/ethnic factors, are not evident in contemporary practice. This might suggest that previously recognized disparity in outcomes could be due to factors that mostly affect patients in their first year post HCT. Future studies are needed to identify these early adverse factors and implement strategies to mitigate them. Figure 1 Figure 1. Disclosures Blue: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; WebMD: Consultancy. Wood: Pfizer: Research Funding; Teladoc: Consultancy; Koneksa Health: Consultancy, Current equity holder in publicly-traded company. Majhail: Incyte Corporation: Consultancy; Anthem, Inc: Consultancy. Saber: Govt. COI: Other.

Abstract Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

Abstract The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.

Abstract There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined. METHODS We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration. RESULTS The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm ( P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined. CONCLUSION We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS.

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 (<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<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<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 T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive malignancy with limited treatment options, frequent relapse, and poor long-term survival. Allogeneic hematopoietic cell transplantation (allo-HCT) is reported to be effective in T-PLL yielding durable remissions and improved survival. Rates of survival and non-relapse mortality vary; data is scant and limited to small retrospective series. Whether regimen intensity - a modifiable factor- is associated with outcomes is unknown. Here, we report an analysis of patients with T-PLL undergoing allo-HCT in 87 centers using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods A retrospective multicenter study was conducted utilizing the CIBMTR dataset, which captures all consecutive patients transplanted in participating centers. The study population included patients aged 18 or older with T-PLL who underwent allo-HCT between 2008 and 2018. All donor types, graft sources, and conditioning intensities are summarized (Table 1). Cox regression analysis was used to assess overall mortality, treatment-related mortality (TRM), relapse or progression, disease-free survival (DFS) and acute and chronic graft-versus-host disease (GVHD). Due to the strong correlation between regimen intensity and patients' age, a combined variable was constructed, and in all models, interactions between age/regimen and significant covariates were examined. Results A total of 266 pts were identified and included in this analysis (Table 1). Median follow up of survivors was 49 months (range 3-117); the completeness of survival data out to four years was 95%. In univariate analysis, the 4-year overall survival (OS) rate was 30% (95% confidence interval [CI]: 23.8-36.5%). The 4-year DFS, relapse, TRM rates were 25.72% (95%CI: 20-32%), 41.9% (95%CI: 35.5-48.4%), and 32.4% (95%CI: 26.4-38.6%), respectively. Cumulative incidences of grade 2-4 acute GVHD at day +180 and chronic GVHD at 1-year were 22.5%% (95%CI: 16.8- 28.9%) and 38.3% (95%CI: 32.9-44.9%), respectively. Multivariate analyses was performed using age (Age >60 vs Age ≤60) and conditioning intensity (myeloablative [MAC] vs. reduced intensity/non-myeloablative [RIC/NMA]) as main effect (Table 2). Poor performance status was associated with inferior TRM, DFS and OS. Compared to MAC/Age ≤ 60, RIC/NMA/Age≤ 60 correlated significantly with less TRM (hazard ratio [HR] 0.28, 95% CI 0.14-0.55, p= 0.0022, superior DFS [HR 0.53, 95% CI 0.35-0.81, p= 0.0029; (Figure 3) and OS HR 0.49, 95% CI 0.32-0.75, p= 0.0009; (Figure 2). Similar trend was observed for RIC/NMA/ Age> 60 for all 3 outcomes but did not reach statistical significance. Remission status at time of allo-HCT (stable disease or progression vs. complete remission) correlated with relapse (hazard ratio [HR] of relapse=2.13, 95%CI 1.23-3.71, p=0.0072), however degree of response (partial response vs. complete remission did not significantly correlate with relapse (HR of relapse=1.41, 95%CI 0.91-2.17, p=0.1257). In vivo T cell depletion with ATG (N=47) or alemtuzumab (N=2) was associated with worse TRM [HR 1.82, 95% CI 1.08-3.08, p= 0.0255] and inferior DFS [HR of death or progression=HR 1.50, 95% CI 1.05-2.15, p= 0.0276]. The most common cause of death was disease relapse (52%) followed by infection (15%) and GVHD (13%). Conclusion This CIBMTR study, with the largest cohort of allo-HCT in T-PLL to date, demonstrates allo-HCT is effective in providing durable remissions. MAC and poor performance status were predictive of inferior TRM and OS. Disease relapse was most common cause of death, and pre-allo-HCT remission inversely correlated with relapse rate. The data suggest that reduced intensity conditioning and avoidance of post-transplant ATG/alemtuzumab may be beneficial. Novel strategies are needed both pre and post-allo-HCT to further improve outcomes. Disclosures Dholaria: J&J: Research Funding; bms: Research Funding; Takeda: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding. Jagadeesh:Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Regeneron: Research Funding. Oran:Celgene: Consultancy; ASTEX: Research Funding; Arog Pharmaceuticals: Research Funding. Nakamura:Viracor: Consultancy; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; NapaJen Pharma: Consultancy; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Kadmon Corporation: Other: Advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation. Sauter:Spectrum Pharamaceuticals: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Gamida Cell: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Celgene: Consultancy, Research Funding; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Consultancy, Research Funding. kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

Background: Recent advances in the treatment of myelodysplastic syndrome (MDS) have improved patient survival and quality of life (QOL), while reducing transfusion burden. However, allogeneic hematopoietic cell transplantation (HCT), widely used in younger MDS patients, remains the only curative therapy for MDS. While transplantation outcomes among selected older patients with MDS are similar to younger patients with MDS, early transplantation for older patients is infrequently offered since the relative benefits of HCT over non-HCT therapy in have not been well defined in this patient group. We conducted a multi-center, biologic assignment trial in older individuals with high risk MDS to define the benefit of HCT over non-HCT therapy. Methods: The study was a multicenter, biologic assignment trial in subjects aged 50-75 with higher risk de novo MDS (IPSS Intermediate-2 (Int-2) or High) who were candidates for reduced-intensity conditioning (RIC) allogeneic HCT, comparing outcomes of those with a suitable 8/8 HLA-matched donor to those without a donor. The trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1102, NCT02016781). Eligible subjects were enrolled prior to a formal donor search, and before or after MDS treatment was initiated. Biological assignment to the Donor or No Donor arm was based on high-resolution HLA typing of eligible family members and a search of the unrelated donor registries. Subjects were initially assigned to the No Donor arm and re-assigned to the Donor arm when a suitable donor was identified. Subjects who died or whose 90-day donor search ended without identifying a suitable donor remained in the No Donor arm. Subjects in the Donor arm were expected to undergo RIC HCT within 6 months of enrollment. Subjects underwent RIC HCT or non-HCT therapy according to institutional standards. The primary analysis compared three-year overall survival (OS) between arms using adjusted survival estimates to account for the potential bias resulting from biological assignment. The sample size was selected to provide at least 80% power to detect a difference of 15% in 3-year OS. Between January 2014 and November 2018, 384 subjects (Donor n=260, No Donor n=124) were enrolled at 34 centers. The study arms were well balanced for age, gender, KPS, IPSS risk, MDS disease duration and responsiveness to hypomethylating therapy (Table). The median follow-up time for surviving patients was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No Donor arm. Results: In an intent-to-treat analysis, adjusted OS at 3 years from study enrollment in the Donor arm was 47.9% (95% CI: 41.3%-54.1%) compared with 26.6% (95% CI: 18.4%-35.6%) in the No Donor arm (p=0.0001, absolute difference 21.3%, 95% CI: 10.2%-31.8%)(Figure). A sensitivity analysis excluding subjects assigned to the No Donor arm who died or withdrew prior to the end of the 90-day search window showed no effect on outcome (Adjusted OS: 48.0% vs. 28.1%, p=0.0004). Leukemia-free survival (LFS) at 3 years was greater in the Donor arm (35.8%, 95% CI: 29.8%-41.8%) compared with the No Donor arm (20.6%, 95% CI: 13.3%-29.1%, p=0.003), with no changes in the sensitivity analysis. An OS and LFS benefit was seen across all subgroups tested (Figure). There were no clinically significant differences in QOL between Donor and No Donor arms as measured by the FACT-G, the MOS-SF36 Physical and Mental Component Scores and the EQ-5D utility score at all time points. The overall non-compliance rate for the trial was 26.3%. Reasons for non-compliance included the use of myeloablative conditioning or failure to proceed to RIC transplant in the Donor arm, and the use of alternative donors in the No Donor arm. In an as-treated analysis, comparison of the HCT and No HCT arms demonstrated a significant advantage in 3-year OS (47.4% vs. 16.0%, p<0.0001) and LFS (39.3% vs. 10.9%, p<0.0001) for subjects who underwent HCT. Conclusions: We observed a significant OS advantage in older patients with Int-2 and High IPSS risk de novo MDS who are RIC HCT candidates and have an HLA-matched donor, when compared with those without a donor. The benefit of having a matched donor was seen across subgroups, including those who were of Medicare age (>65) and below. HCT should be offered to all individuals between the ages of 50-75 with Int-2 and High IPSS risk MDS in whom a suitable donor can be identified. Table Disclosures Nakamura: Magenta Therapeutics: Other: Advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; NapaJen Pharma: Consultancy; Kadmon Corporation: Other: Advisory board meeting; Celgene: Other: Support on seminar; Viracor: Consultancy. Scott:Alexion, Incyte, Novartis, Regeneron: Consultancy; Agios, BMS: Honoraria; BMS, Novartis: Research Funding. Oran:ASTEX: Research Funding; Celgene: Consultancy; Arog Pharmaceuticals: Research Funding. Maziarz:Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Novartis and Athersys: Other: DSMB participant; Athersys: Patents & Royalties; Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Novartis and Juno: Research Funding. McGuirk:Allo Vir: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Bellicum Pharmaceutical: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, 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. Cutler:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: 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; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background Acute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The only curative therapy remains an allogeneic hematopoietic stem cell transplant (HCT), yet it is complicated by non-relapse mortality (NRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in a large cohort of patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1). Methods HCT recipients 60 years or older with AML in CR1 reported to the CIBMTR were included. Cox models were used to compare rates of overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), relapse, acute GHVD, chronic GVHD in 3 separate age groups: 60-64 years vs. 65-70 years vs. 70+ years (Figure 1A). Results 1,327 patients undergoing HCT from 2007-2017 were included. The three age cohorts (60-64; 65-69; 70+) were comparable in demographic and disease characteristics, except the older cohort had more males, more de novo AML, and a higher incidence of measurable residual disease (MRD) pre-HCT. Fewer had sibling donors and more were performed in recent years. With median follow-up of nearly 3 years, patients aged 60-64 had significantly better OS, DFS and lower NRM than those aged 65-69 and 70+. Those aged 65-69 and 70+ had similar outcomes (Figure 1). Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p=0.026). NRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥ 3. Conditioning intensity was not a significant predictor of outcomes with HR for OS for 60-69 cohort of 0.46 for RIC and 0.49 for MAC (p=0.38). There was no difference in the relapse rate, incidence of G3/4 acute GVHD, or incidence of moderate-severe chronic GVHD across the age cohorts. Poor risk cytogenetics, presence of MRD prior to HCT, cord blood as graft source, and transplant prior to 2016 were significant predictors of poor OS. Discussion In this large retrospective series of HCT for AML in CR1, age had a small effect OS and NRM after accounting for other predictors. High-risk features such as poor cytogenetics and presence of MRD prior to HCT were significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection. Table Disclosures Kebriaei: Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Jazz: Consultancy; Amgen: Other: Research Support; Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board. Weisdorf:FATE Therapeutics: Consultancy; Incyte: Research Funding.

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 < 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.