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Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) that is resistant to chimeric antigen receptor T-cell (CAR-T) therapy have poor outcomes (Chow VA, et al. Am J Hematol. 2019;94:E209-E13). The majority of patients with DLBCL who relapse after CAR-T therapy do so with disease that continues to express CD19 surface antigen (Shah NN, Fry TJ. Nat Rev Clin Oncol. 2019;16:372-85); however, it is unknown whether treatment with CD19-targeted agents is an effective strategy for patients with prior failure of anti-CD19 CAR-T therapy. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA-approved CD19-directed antibody-drug conjugate (ADC) which had encouraging phase 1 antitumor activity and acceptable safety in non-Hodgkin lymphoma (Hamadani M, et al. Blood. 2021;137:2634-2645). In the Phase 2 LOTIS-2 trial (NCT03589469) the efficacy and safety of Lonca was evaluated in patients with relapsed or refractory (R/R) DLBCL after ≥2 lines of systemic treatments (Caimi PF, et al. Lancet Oncol. 2021;22:790-800). The overall response rate (ORR) was 48.3%. The aim of this post-hoc analysis of the LOTIS-2 trial was to investigate the antitumor activity of Lonca in patients with DLBCL relapsed or refractory after CAR-T therapy. Methods: The methodology of the LOTIS-2 trial has been published. Briefly, patients were treated with Lonca (0.15 mg/kg for the first 2 cycles then 0.075 mg/kg for subsequent cycles) administered as a single 30-minute infusion, once every 3 weeks for up to 1 year, or until progressive disease or unacceptable toxicity. Patients with previous anti-CD19 CAR-T therapy were required to have persistent CD19 expression, evaluated by local review of immunohistochemistry of a post-CAR-T biopsy. The primary endpoint was ORR, defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), determined by independent review. Secondary endpoints included overall survival (OS), progression free survival (PFS), and duration of response (DOR). PET/CT imaging was performed 6 and 12 weeks after the first Lonca dose and every 9 weeks thereafter. Response was assessed using the Lugano 2014 criteria. Kaplan Meier survival analysis was performed from initiation of Lonca treatment. Results: The characteristics of 13 patients with DLBCL with disease relapse or progression after anti-CD19 CAR-T therapy are shown in table 1. The median time interval between CAR-T infusion and Lonca treatment was 7 months (range, 45-400 days). Ten (77%) patients received Lonca as the first therapy after CAR-T failure, 3 patients received other treatments prior to Lonca (chemoimmunotherapy [R-GemOx], n = 1; allogenic stem cell transplant, n = 1; chemoimmunotherapy [R-GemOx] followed by venetoclax + bromodomain inhibitor, n =1). The ORR to Lonca was 46.2% (n=6; CR, 15.4% [n = 2]; PR, 30.8% [n = 4]) after a median of 2 cycles (range, 1-9). Of the 6 patients who achieved a response to Lonca, 5 had a previous response to CAR-T and 1 had prolonged, stable disease for >1 year after CAR-T. With a median follow-up of 8 months, the median OS and PFS were 8.2 and 1.4 months, respectively (Figure 1); the 1-year OS estimate was 33.3%. The median DOR to Lonca was 8 months. Conclusions: Lonca achieved a response in 6 out of 13 patients who had failed prior CAR-T therapy. Five out of 6 responding patients had previously presented at least a partial response after CAR-T therapy. These data suggest that in patients without CD19 antigen loss, repeat therapy with another agent targeting this antigen can result in disease control. Prior response to anti-CD19 therapy may be associated with subsequent response to a second anti-CD19 treatment. Further studies are needed to confirm the feasibility and value of repeated anti-CD19 treatments in patients with B-cell non-Hodgkin lymphoma. Funding: This study was funded by ADC Therapeutics; medical writing support was provided by CiTRUS Health Group. Figure 1 Figure 1. Disclosures Caimi: Amgen Therapeutics.: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy; Verastem: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Honoraria. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding; Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees. Reid: Aptose Biosciences: Other: Serves as Principle Investigator, Research Funding; ADC Therapeutics: Other: Serves as Principle Investigator, Research Funding; Millennium Pharmaceuticals: Other: Serves as Principle Investigator, Research Funding; Xencor: Other: Serves as Principle Investigator, Research Funding. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Lunning: Myeloid Therapeutics: Consultancy; Spectrum: Consultancy; Daiichi-Sankyo: Consultancy; Verastem: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Beigene: Consultancy; Legend: Consultancy; ADC Therapeutics: Consultancy; Acrotech: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; Kite, a Gilead Company: Consultancy; TG Therapeutics: Consultancy; Novartis: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy. Zain: Secura Bio, DaichiSankyo, Abbvie: Research Funding; Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria; Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy. Solh: ADCT Therapeutics: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; Partner Therapeutics: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Hamadani: Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau.

Introduction: There is increased risk of congestive heart failure (CHF) following anthracycline-based chemotherapy in patients with Diffuse Large B-cell lymphoma (DLBCL). Other than increased cumulative anthracycline dose, little is known about risk factors for developing CHF and other cardiovascular events (CVE). Methods: We conducted a retrospective analysis of 539 DLBCL patients diagnosed at University Hospitals Seidman Cancer Center between 2002 - 2016. Baseline patient and disease characteristics, patterns of treatment and outcomes after therapy, including response, survival, relapse, CVE, and causes of death were collected. Time-to-CVE was measured from the date of DLBCL diagnosis to the date of CVE diagnosis and censored at the date of last follow-up for those without CVE, considering death as competing risk. The cumulative incidence of CVE was estimated taking death as competing risk into account. Univariate and multivariable analysis on time-to-CVE was done using Gray's method. Multicollinearity was tested and some of the highly correlated covariables were excluded in the final analysis. CVE risk scores were computed for each patient as a linear combination of the factors included in the multivariable model and their respective coefficients. The optimal cutoff point was identified by searching the spectrum of the risk scores to have the best discrimination of time-to-CVE among patients at low/high risks. All tests were two-sided and p-value ≤ 0.05 were considered statistically significant. Results: We identified 463 patients who received anthracycline to be included in the statistical analysis. Baseline clinical and disease characteristics including comorbidities, clinical risk factors are outlined in Table 1. After a median follow up of 71.1 (range: 0.3 - 216.1) months, 5-year PFS was 59% with median PFS of 82.7 (95% Cl: 71.1 - 115.7) months and 5-year OS was 71% with median OS of 152.6 (95% CI: 127.5 - 162) months. CVE were identified in 92 patients (19.9%), with 128 events identified. The most common CVE was new onset of CHF in 10.4% of patients, followed by atrial fibrillation (4.9%) and asymptomatic heart failure ( 3%) (Table 2). The 3, 6 and 9-year cumulative incidence of CVE for early stage was 13.1%, 15.2% and 18.5%, respectively and 22.2%, 31.4% and 36.5% for advanced stage, respectively (p-value = 0.026). Similarly, the cumulative incidence of CVE was increased in patients with diabetes, with a 3-year cumulative incidence of CVE of 9.4% vs. 17.5% in patients with and without diabetes, respectively. Proportional hazards regression for time-to-CVE identified age >65 years, CD10 expression by IHC, diabetes, and hypertension as significant predictors of time-to-CVE on univariate analysis. On multivariable regression analysis with advanced age at diagnosis, stage, baseline lymphocyte count, and diabetes; stage was still significant in predicting time-to- CVE controlling the effects of advanced age and diabetes, which were also marginally significant. A predictive formula was created to help identify patients at highest risk for cumulative incidence of CVE. Using advanced age (over 65 years of age), baseline lymphocyte count above 800/µL, advanced stage at diagnosis and history of diabetes patients could be stratified into groups with low, intermediate and high risk for CVE (Table 4 and Figure 1). Risk score = Age >65 (3 points) + Lymphocyte count > 800/µL (-1 point) + Stage III/IV(8 points) + Diabetes (3 points) (Table 3) One-year cumulative incidence of CVE was 5.3% for low-risk patients, 7.9% for intermediate risk patients and 13.4% for high risk patients (Figure 1). Conclusions: Our analysis indicates a high risk of CVE in anthracycline treated DLBCL patients, with 19.9% of patients having a CVE in our cohort. The proposed CVE predictive score uses clinical and laboratory parameters routinely collected on all new DLBCL patients and can be easily assessed in the clinical setting. Patients in the high-risk group have a cumulative incidence of CVE of 13.4% at 1 year and would likely benefit from surveillance and interventions. Use of a clinical risk score can aid in the identification of patients at highest CVE risk to conduct studies of surveillance and prevention of this common complication. Figure 1 Figure 1. Disclosures Boughan: Beigene: Speakers Bureau. Caimi: Seattle Genetics: Consultancy; Verastem: Consultancy; Amgen Therapeutics.: Consultancy; Kite Pharmaceuticals: Consultancy; TG Therapeutics: Honoraria; ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; XaTek: Patents & Royalties: Royalties from patents (wife).

Introduction: Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA-approved CD19-directed antibody-drug conjugate (ADC) indicated for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after ≥2 lines of systemic therapy, including patients with high-grade B-cell lymphoma. In the Phase 2 LOTIS-2 trial (NCT03589469), Lonca was evaluated as a single agent in patients with R/R diffuse large B-cell lymphoma (DLBCL) and the overall response rate (ORR) was 48.3% (Caimi PF, et al. Lancet Oncol. 2021; 22:790-800). In an analysis of the 11 patients from the LOTIS-2 clinical trial with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL; data cutoff: April 6, 2020), 45.5% (n=5) achieved an overall response. In this patient subgroup, the median duration of response was 13.37 months, and the median progression-free survival was 9.13 months. The aim of this analysis (data cut off: March 1, 2021) was to further characterize the clinical characteristics and efficacy of Lonca in patients with HGBCL enrolled in the LOTIS-2 clinical trial. Methods: The methodology for the LOTIS-2 trial has been published. Briefly, Lonca (0.15 mg/kg for the first 2 cycles followed by 0.075 mg/kg for subsequent cycles) was administered as a single 30-minute infusion, once every 3 weeks for up to 1 year, until progressive disease or unacceptable toxicity. The primary outcome was ORR defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), assessed by independent review. Investigator assessment of histopathology according to the 2016 WHO classification was used to define HGBCL. Results: The demographics and disease characteristics of the 11 patients with HGBCL are shown in Table 1. The median age was 74 years; 5 patients (45.5%) were age ≥75 years. The majority of patients received ≥3 prior lines of therapy (n = 8; 72.7%). One patient had a prior stem cell transplant (autologous; 9.1%). Of the 11 patients with HGBCL, the overall response rate was 45.5%, with all 5 patients achieving CR. The median (min, max) time to first CR or PR response was 43.0 (38, 148) days and the median time to first CR response was 79.0 (38, 148) days. All five responding patients (45.5%) had a duration of response ≥1 year; median duration of response has not been reached at the time of data cutoff. Conclusions: Efficacy data from this small subgroup of patients with HGBCL enrolled in the LOTIS-2 clinical trial are consistent with the overall trial population. These results suggest that Lonca is active in the treatment of this high-risk lymphoma subgroup, achieving comparable response rates with other risk groups and with long-term disease control in responding patients. Funding: This study was funded by ADC Therapeutics; medical writing support was provided by CiTRUS Health Group. Figure 1 Figure 1. Disclosures Alderuccio: Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Puma Biotechnology: Other: Family member; ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Forma Therapeutics: Other: Family member. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Radford: ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company. Solh: Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; Partner Therapeutics: Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding; Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees. Lunning: AbbVie: Consultancy; Novartis: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Spectrum: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Verastem: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Kite, a Gilead Company: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Legend: Consultancy. Hess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy. Zinzani: EUSAPHARMA: Consultancy, Other, Speakers Bureau; SANDOZ: Other: Advisory board; ROCHE: Other, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; Incyte: Other, Speakers Bureau; ADC Therap.: Other; SERVIER: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Stathis: Abbvie and PharmaMar: Other: travel grant; Pfizer, ADC Therapeutics, Bayer, Roche, Merck, Novartis, MEI Therapeutics and Abbvie: Research Funding; Bayer / Eli Lilly: Consultancy. Carlo-Stella: Sanofi: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hamadani: Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Ungar: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kilavuz: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Yu: ADC Therapeutics: Current Employment. Qin: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Caimi: TG Therapeutics: Honoraria; Amgen Therapeutics.: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); ADC Theraputics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Verastem: Consultancy; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy.

Background: AntiCD19 CAR-T cells are effective against chemorefractory B cell lymphoma. Patients (pts) with rapidly progressive disease and urgent need for therapy have very poor prognosis and may not be able to receive CAR-T cells in time. Decreasing the apheresis to infusion time can make CAR-T cells rapidly available. We conducted a dual-center phase I trial using on-site manufacture of CAR-T cells for treatment of relapsed and refractory (r/r) B cell lymphoma. Methods: Adult pts with r/r CD19+ B cell lymphomas who failed ≥ 2 lines of therapy were enrolled. Autologous T cells were transduced with a lentiviral vector (Lentigen Technology, Inc, LTG1563) encoding an antiCD19 binding motif, CD8 linker, TNFRS19 transmembrane region, and 4-lBB/CD3z intracellular signaling domains. GMP-compliant manufacture was done using CliniMACS Prodigy in a 12-day culture, subsequently shortened to 8 days. Dose escalation was done using 3+3 design. Lymphodepletion included cyclophosphamide (60mg/kg x 1) and fludarabine (25mg/m2/d x 3). Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were graded using the Lee and CARTOX criteria, respectively. CAR-T persistence was measured with qPCR and flow cytometry. Plasma cytokine concentrations were measured using electrochemiluminescence (MesoScale Diagnostics, Inc). Results: Thirty-one pts were enrolled and treated. Baseline patient and disease characteristics are listed in table 1. Twenty-nine (94%) pts were refractory to the prior line of therapy and 21 (68%) had symptomatic disease at the time of lymphocyte collection. CAR-T cell product manufacture was successful in all pts. Median transduction rate was 45% [range 15-66], median culture expansion was 36-fold [range 3-79]. CAR-T cell doses were 0.5 x 10 6/kg (n = 4), 1 x 10 6/kg (n = 16), and 2 x 10 6/kg (n = 11). Median time from apheresis to lymphodepletion was 7 days (range 2 - 15) and median time from apheresis to CAR-T cell infusion time was 13 days (range 9 - 20). Twenty-eight pts were infused fresh product. Seventeen pts (55%) experienced CRS. Grade 1-2 CRS was observed in 15 pts (48%), grade ≥ 3 was observed in 3 pts (10%). One patient had grade 4 CRS that was later complicated by hemophagocytic syndrome and died on day 21; a second patient had grade 5 CRS in the context of bulky disease and died on day 8. Ten pts (32%) had ICANS and 4 pts had grade 3-4 ICANS. Treatment for CRS / ICANS included tocilizumab (n = 12), siltuximab (n = 4), anakinra (n = 3) and corticosteroids (n = 10). The most common all grade non - hematologic toxicity was fatigue, observed in 19 pts, all grade 1. Hematologic toxicity was common, with grade ≥ 3 neutropenia observed in all subjects. Twenty-five (81%) presented disease response and twenty-two pts (71%) achieved complete response (CR). There were no statistically significant differences in the overall and complete response rates between dose levels. After a median follow up of 18 months (range 1 - 32), 5 pts relapsed, and 7 pts have died. Causes of death include progressive disease (n=5), CRS (n=1) and CRS/HLH (n=1). Two-year estimates of PFS and OS for the whole cohort were 67% (95%CI 52-88%) and 75% (95%CI 60-93%)(fig1), respectively. Two-year estimates for patients achieving disease response (CR or PR) were 82% (95%CI 67-99%) and 90% (95%CI 78-100%), respectively. The median duration of response has not been reached (95% CI 74-100). Among pts achieving CR, 94% (95% CI 61-100%) had sustained remission at 12 months. Median time to peak CAR-T expansion, measured by PCR, was 14 days (IQR 14-19), without differences between dose levels, culture duration or fresh vs. cryopreserved infusion. All evaluable subjects had persistent CAR-Ts on PCR measurements done on days 30, 60 and 90. CAR-T cell dose did not have an impact in the time to peak in vivo CAR-T cell expansion or in the rate of CAR-T cell persistence (fig 2). Cytokine measurements have been conducted in 19 pts, with area under the curve (AUC) analyses showing pts with CRS had higher plasma concentrations of multiple cytokines (fig 3). Patients achieving CR had higher plasma concentrations of MIP3B. Conclusions: Second generation antiCD19 CAR-T cells with TNFRS19 transmembrane domain have potent clinical activity. On-site manufacture was successful in all pts. This strategy, in combination with fresh product infusion, can make CAR-T cell therapy rapidly available for pts with high-risk r/r B cell lymphoma. Figure 1 Figure 1. Disclosures Caimi: Amgen Therapeutics.: Consultancy; TG Therapeutics: Honoraria; XaTek: Patents & Royalties: Royalties from patents (wife); Kite Pharmaceuticals: Consultancy; Genentech: Research Funding; ADC Theraputics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Verastem: Consultancy. Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Schneider: Lentigen Technology: Current Employment. Boughan: Beigene: Speakers Bureau. Metheny: Incyte: Speakers Bureau; Pharmacosmos: Honoraria. Krueger: Lentigen: Current Employment. Kadan: Lentigen: Current Employment. Orentas: Lentigen: Patents & Royalties. Dropulic: Lentigen: Ended employment in the past 24 months, Patents & Royalties. de Lima: Miltenyi Biotec: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: AntiCD19 CAR-T cells with TNFRSF19 transmembrane domain for treatment of relapsed and refractory B cell lymphomas.

Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Advanced age is an important adverse feature in prognostic models, and nearly one third of cases occur in patients older than 75 years. There is no clear accepted standard of care for older patients with DLBCL due to under-representation of this group in randomized clinical trials. R-miniCHOP, a dose attenuated version of standard R-CHOP, is often chosen based on a prospective, single-arm phase II trial which showed a 2-year progression-free survival (PFS) of 47% (Peyrade, 2011), far lower than observed outcomes in patients younger than 80 yrs (Coiffier, 2002). Precise identification of older DLBCL patients who should be considered for curative versus palliative chemoimmunotherapy is difficult at an individual level; the challenge is to avoid both overtreatment with excessive toxicity and undertreatment with inferior outcomes. The FIL (Fondazione Italiana Linfomi; Italian Lymphoma Foundation) has developed an assessment tool accounting for age, comorbidities, and ability to perform activities of daily living (ADLs) and instrumental activities of living (IADLs). The FIL Tool classifies patients as "fit," "unfit," or "frail." When the FIL tool was prospectively applied to 1163 patients, 55% were fit, 28% were unfit, and 18% were frail. Three-year OS for the whole cohort was 65% and was strongly driven by fitness: 3-year OS was 75% for fit patients, 58% for unfit, and 43% for frail; similar outcomes were seen in a validation cohort (Merli F, 2021). However, treatment was not uniformly directed and was up to the treating physician. Epigenetic deregulation is a feature of DLBCL in older patients, and provides a rationale for targeting methylation. Pre-clinical models show that pre-treatment with hypomethylating agents improves the anti-tumor effect of R-CHOP (Clozel T, 2013). This work has led to early clinical studies of the hypomethylating agent azacitidine with R-CHOP in newly diagnosed DLBCL, with promising early efficacy and acceptable toxicity. The availability of oral azacitidine is an appealing additive approach and is agnostic to cell-of-origin. Based upon the need for improved outcomes in older patients and the promise of azacitidine in this setting, the National Clinical Trials Network (NCTN), led by SWOG, developed S1918, a randomized trial comparing R-miniCHOP to R-miniCHOP + oral azacitidine for older patients (> age 75) with newly diagnosed aggressive B-cell non-Hodgkin lymphomas. This study incorporates the FIL Tool for baseline frailty assessment and a serial comprehensive geriatric assessment (CGA) to evaluate effects of therapy on quality of life and functional status. This is the first randomized study in this population conducted in North America by the NCTN and will enroll a total of 384 eligible patients after a safety run-in phase. All patients will receive pre-phase therapy with vincristine 1mg x 1 and prednisone 60mg/m2 x 7 days (capped at 100mg/day); pre-phase therapy has been shown to improve performance status and decrease early treatment-related mortality (Owens CN, 2015). The primary objective of the phase II component is to determine if oral azacitidine + R-miniCHOP regimen should be tested further (Phase III) against R-miniCHOP alone based on estimates of 1-year progression-free survival (PFS). The primary objective of the phase III component is to compare the OS at 2 years between oral azacitidine + R-miniCHOP and R-miniCHOP alone. Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma in a number of ways given its randomized design, incorporation of geriatric assessments, and utilization of ctDNA correlatives. The prospective assessment of frailty, serial comprehensive geriatric assessments, and introduction of epigenetic modulation will hopefully improve outcomes for this population with significant need. Trial registration: ClinicalTrial.gov Identifier NCT04799275 Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820, and U10CA180821 Figure 1 Figure 1. Disclosures Brem: Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Consultancy; SeaGen: Speakers Bureau; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees. Caimi: Seattle Genetics: Consultancy; Verastem: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); Amgen Therapeutics.: Consultancy; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy; ADC Theraputics: Consultancy, Research Funding; TG Therapeutics: Honoraria. Cerchietti: Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Alizadeh: Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Roche: Consultancy, Honoraria; Janssen Oncology: Honoraria; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Bristol Myers Squibb: Research Funding. Olin: Amgen: Honoraria; Cellectis: Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Abbvie: Honoraria; Actinium: Honoraria; Astellas: Honoraria, Research Funding. Friedberg: Novartis: Other: DSMC ; Bayer: Other: DSMC ; Acerta: Other: DSMC . Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator.

Background: Chimeric antigen receptor T cell (CAR-T) therapy is known to produce durable remissions in the treatment of CD19 + relapsed/refractory B cell malignancies. Nonetheless, many patients receiving CAR-T cells will fail to respond for unknown reasons. Here, we employed single cell RNA sequencing and protein surface marker profiling of serial CAR-T cell samples from patients with non-Hodgkin's lymphoma (NHL) to reveal CAR-T cell evolution, identify biomarkers of response, and test for evidence of exhaustion in CAR-T cells of poor responders. Methods: To describe the evolution of CAR-T cells after infusion into NHL patients and to identify mechanisms and biomarkers of response, our study examined manufactured CAR-T cell products and FACS isolated CAR-T cells from post-infusion blood samples from patients treated for CD19 + relapsed/refractory NHL. Utilizing scRNA sequencing and flow cytometry, we investigated time points after infusion that are known from previous studies to be associated with peak expansion (day 14) and contraction (day 30) and represent key changes in CAR-T cell activity. Altogether, our datasets include 14 manufactured CAR-T cell products, 13 samples from day 14, and 12 samples from day 30. This sampling represents 10 patients with favorable response (complete or partial remission (CR; PR)) and 4 patients with poor response (stable or progressive disease (SD; PD)). To isolate CAR-T cells for scRNA sequencing, viable CD3 +CAR + cells were sorted from cryopreserved CAR-T cell products or PBMCs. Next, libraries were generated with the 10x Genomics Chromium single cell 3' platform with feature barcoding technology to allow simultaneous and paired quantification of transcriptional and cell surface protein expression in individual CAR-T cells. The libraries were sequenced and the data stringently filtered. Batch effect removal was applied to remove differences due to sample preparation or sequencing. Results: Post-filtering, our dataset contained 94,000 cells with an average of 3,917 cells per sample, 8,518 reads per cell, and 2263 unique detectable genes per cell. After dimension reduction and clustering, eleven high-frequency clusters were identified with cluster patterns corresponding with time point, cell cycle phase, cell type, or patient (Figure 1). At the transcriptional level, post-infusion CD8 CAR-T cells displayed significant upregulation of transcription factors (PRDM1, EOMES) and cytotoxic effector molecules (GZMB, PRF1, GZMK, CCL5) associated with differentiation into cytotoxic effector cells as well as transcription factors associated with exhaustion (TOX, TOX2, NR4A2, NR4A3) (p.adj < 0.05) (Figure 2). These data were corroborated by enrichment of effector and exhaustion gene set signatures after infusion as well as global increases in the protein expression of activation and exhaustion markers CD45RO, CD69, CD57, PD1 (CD279), and TIGIT. Contrasts of CAR-T cells between response groups displayed enrichment of an exhaustion profile in CD8 CAR-T cells of poor responders characterized by significant upregulation of the transcription factors FOS, JUNB, JUND, FOSB, JUN, NR4A2, NFKBIA, and PRDM1 and other markers of exhaustion at the RNA level (p.adj < 0.0001). At the protein level, the frequency of TIGIT expression was 20% greater on average in the CD8 CAR-T cells of poor responders compared to favorable responders (Figure 3). CD8 CAR-T cells expressing TIGIT compared to TIGIT negative CD8 CAR-T cells were enriched in an exhaustion transcriptional profile by gene set enrichment analysis and expressed consistently higher levels of exhaustion markers (PD1, CTLA4, LAG3, TIM3) by flow cytometry, regardless of response group or time point (Figure 4). Conclusions: At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a non-proliferative, highly-differentiated, and exhausted state that is enriched in CAR-T cells of patients with poor response. Furthermore, we identified the checkpoint receptor TIGIT as a novel prognostic biomarker and potential driver of CAR-T cell exhaustion. Figure 1 Figure 1. Disclosures Dropulic: Lentigen: Ended employment in the past 24 months, Patents & Royalties. Caimi: Kite Pharmaceuticals: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); Seattle Genetics: Consultancy; Genentech: Research Funding; ADC Theraputics: Consultancy, Research Funding; Verastem: Consultancy; Amgen Therapeutics.: Consultancy; TG Therapeutics: Honoraria. de Lima: Miltenyi Biotec: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

Introduction: Approximately one-third of patients (pts.) with diffuse large B-cell lymphoma (DLBCL) develop relapsed or refractory (R/R) disease after frontline rituximab-(R) based chemo immunotherapy. Variability in expression of the B-cell surface antigen CD20, and possibly CD19, is thought to be an important mechanism of treatment failure, but there is vast heterogeneity in the reported incidence, with most reports utilizing Immunohistochemical (IHC) staining which is non-quantitative in nature. New therapeutics including CAR T-cells, antibodies (Ab) (tafasitimab) and Ab-drug conjugates (loncastuximab teserine) target CD19, while several bispecific engager Abs. in development target CD20. Understanding the evolution of target antigen expression in R/R DLBCL can provide information regarding selection and sequencing of therapies. We sought to quantitate the change in surface expression of CD19 and CD20 in R/R DLBCL after R-based chemo immunotherapy relative to pretreatment levels, to provide insight into the relative stability of these targets. Methods: Pts. diagnosed with DLBCL after January 2014, who were R/R to frontline R-based chemo immunotherapy (R-CHOP or R-EPOCH) were retrospectively identified. Pt. and disease related clinical variables at diagnosis (Dx) and first R/R were recorded. Data from IHC were obtained, as were archival flow cytometry assays performed on tumor biopsies at Dx and in the R/R setting. Using FCS Express® software, neoplastic cells were gated, and fluorescence intensity (FI) of CD19 and CD20 expression were reported (using fluorochromes APC-A for CD19 and PECy7 for CD20, respectively). Multivariate linear mixed model was used to compare median and geometric mean FI of CD19 and CD20 between Dx and R/R, while adjusting for other clinical variables. Results: A total of 51 flow cytometry assays (26 Dx and 25 R/R) were analyzed for 33 pts. Median age at Dx was 64 (range, 41-76) yrs., 24 pts. (73%) were male and 29 (88%) had IPI ≥ 2. 11 (33%) pts. had a prior indolent lymphoma. Cell of origin at Dx was GCB in 16 (49%) and non-GCB in 12 (36%) pts., while two had a double-hit rearrangement at diagnosis. Treatment was R-CHOP in 27 cases (82%) and R-EPOCH in 6 (18%). Median time to R/R was 10.4 months. There was a significant reduction in median FI of CD20 from Dx [median: 40,610 (range: 167 - 259,962)] to R/R [median: 11,596 (range: 63 - 79,592)], representing a mean reduction of 63% at R/R relative to Dx (P= 0.01; 95% CI: 20-73%). Similar change was observed in geometric mean FI of CD20, which was reduced 65% at R/R relative to Dx (P< 0.01; 95%CI: 31-82%). In comparison, on IHC, CD20 was reported to be negative at R/R relative to Dx in only one of 16 pts. for whom IHC results were available. Median and geometric mean FI of CD19 at R/R were 38% and 20% lower compared to Dx, respectively, but these differences were not statistically significant (P= 0.08 and 0.39, respectively) (Table). When examining the relative change in FI at R/R in individual cases, compared to the mean FI of all Dx cases, we observed that 21 out 25 R/R cases (84%) had reduction of CD20 whereas only 14/25 (56%) had reduction of CD19. Interestingly, 7/25 (28%) R/R cases had an increase in CD19 expression by >80% (Figure).When adjusting for clinical variables such as age, sex, presence of B symptoms, bone marrow (BM) involvement, PS and prior indolent lymphoma, the change in CD20 median FI from Dx to R/R maintained statistical significance (p=0.01). Reduction in CD20 geometric mean FI from Dx to R/R was significantly associated with age >60 years (p=0.04), BM involvement (p 1 site of extra nodal involvement (p= 0.03) at Dx. Conclusions: Quantitative assessment by flow cytometry revealed a significant decline in expression of CD20 at R/R compared to Dx in the majority of patients with DLBCL treated with R-based chemo immunotherapy. CD19 expression was unchanged in most R/R cases but was found to be dramatically upregulated in a subset of R/R cases. Given the role of CD19 mediated pathways in B-cell NHL and its association with PI3K pro-survival signaling, these data merit further exploration as a potential mechanism of treatment resistance. These findings also highlight the importance for repeat tissue biopsy at the time of suspected R/R DLBCL, with focus on therapeutic target expression, as it may influence treatment decisions or enrollment in clinical trials exploring efficacy of newer agents. Figure 1 Figure 1. Disclosures Caimi: TG Therapeutics: Honoraria; Seattle Genetics: Consultancy; Amgen Therapeutics.: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); Verastem: Consultancy; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy; ADC Theraputics: Consultancy, Research Funding. Hill: Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding.

Venous thromboembolic events (VTE) are common after the diagnosis of lymphoma. Although various risk factors have been associated with VTE in cancer patients, there is no specific VTE risk prediction score for diffuse large B cell lymphoma (DLBCL) patients. The Khorana score is a prediction-model of VTE in cancer patients receiving chemotherapy that incorporates clinical and laboratory parameters. We evaluated the risk factors for VTE, the effect of VTE on the outcomes of DLBCL patients and the utility of the Khorana score in DLBCL patients. Methods: We searched the Hematologic Malignancies Database of University Hospitals Seidman Cancer Center for newly diagnosed DLBCL patients between 2002 and 2014. Data on patient characteristics including risk factors, disease characteristics, treatment, outcomes and VTE was collected. The Khorana score was calculated using clinical (disease type, body mass index) and laboratory (hemoglobin level, platelet and leukocyte count) parameters. Risk factors identified as having statistical significance on univariate Cox proportional hazards analysis (p Results: Four hundred DLBCL patients were included for analysis. Median age at diagnosis was 63 with 235 patients above the age of 60. Two hundred and thirty seven patients (59.3 %) had advanced stage at diagnosis and 14 patients (3.5%) had a prior history of VTE. Baseline characteristics are listed in Table 1. Sixty percent of patients had a Khorana score of 1 with no risk factors in addition to the diagnosis of lymphoma. At median follow up of 33 months, 70 patients (18%) presented a VTE, with 1-year and 3-year cumulative incidence of 10.1% (95% CI 7.1-13.6) and 14% (95 % CI 10.8-18), respectively. Fifty-seven VTE (81% of all VTEs) were diagnosed in patients with active disease (at diagnosis, relapse or during active therapy). The Khorana score separated DLBCL patients in three VTE risk groups: intermediate (1 point), high (2 points) and very high (3 or more points) with 1 year cumulative incidence of VTE of 6.4%, 11.6% and 22.2%, respectively (p = 0.009) (Figure 1). On univariate analysis, bone involvement by lymphoma, elevated corrected calcium (>12g/dL), increased white cell count (>11,000/mcl), hemoglobin (800/mcl) and chromosomal translocations involving MYC presented statistically significant increases in hazard of VTE (Table 2). On multivariate analysis only bone involvement (p=0.017) and anemia (p=0.035) retained statistical significance as risk factors for VTE. Three-year OS for patients presenting with VTE within 1 year of DLBCL diagnosis was 46.7 % (95% CI 30-63.3) vs. 72.3% (95% CI 67.4-77.3) in subjects without early VTE (p=0.05) (Figure 2). Presence of VTE at any time after DLBCL diagnosis was also associated with worse OS rates, with estimated 3-year OS of 52.2 % (95 % CI 39.8-64.7) for subjects experiencing VTE and 74 % (95 % CI 69-79) for those without VTE after DLBCL diagnosis (p Conclusion: Venous thromboembolic events are common after diagnosis of DLBCL and are associated with worsened outcomes. The Khorana score is capable of identifying patient subgroups with increased risk of VTE. Additional parameters associated with aggressive disease and advanced stages could further help in VTE risk stratification for selection of patients who may benefit from antithrombotic prophylaxis. Prospective validation of VTE risk assessments and clinical trials of VTE prevention are needed in this high=risk population. Disclosures Caimi: Gilead: Consultancy; Novartis: Consultancy; Genentech: Speakers Bureau; Roche: Research Funding.

Introduction Umbilical cord blood transplantation (UCBT) is often complicated by delayed engraftment and higher rates of engraftment failure. We sought to investigate the outcomes of patients undergoing UCBT2 after engraftment failure compared to those who had autologous hematopoietic recovery and did not receive UCBT2. Methods We reviewed the medical records of 186 patients who received UCBT between 2001 and 2011 at the Case Comprehensive Cancer Center [Seidman Cancer Center, University Hospitals Case Medical Center and Taussig Cancer Institute, Cleveland Clinic]. Standard definitions of engraftment were used. Patients who died or had progressive disease before day 30 were excluded (n=9), as they were considered inevaluable for engraftment. Results Twenty-seven patients (15%) had primary engraftment failure; twelve had autologous hematopoietic recovery and 15 presented no recovery (Table). The median total nucleated cell dose for the first UCBT was 2.56x107 cells/kg (range 1.23 x107 - 5.69x107), not statistically different from patients achieving engraftment (p = 0.29). The cause of engraftment failure could not be identified in 22 patients. Among patients with engraftment failure without autologous recovery, 2 patients did not receive further salvage and died at 40 and 48 days after first UCBT; 2 others received backup autologous hematopoietic cell infusions and 11 received UCBT2. In patients with autologous hematopoietic recovery, 8 did not receive a UCBT2 because disease remission had been attained (n=4), active infection (n=1), relapsed disease beyond 40 days after UCBT (n=1) or absence of compatible donor (n=1). Fifteen patients (engraftment failure [n=11]); autologous recovery, [n=4]) underwent UCBT2, at a median of 43 days (range 33-244) from first to second UCBT. All patients received non–myeloablative second conditioning regimens. Four patients received one UCB unit and 11 received two units. Neutrophil engraftment after UCBT2 was observed in 10 of 15 patients at a median of 30 days (range, 13-35). The median survival for the entire cohort was 272 days (range 40–2130); one year overall survival was 36%. Engraftment and overall survival were not statistically different between those receiving 1 or 2 UCB units for UCBT2. Overall survival was not statistically different between patients who underwent UCBT2 and those who had autologous recovery or backup autologous infusions without further salvage. The proportion of patients in remission was similar in the 2 subgroups (UCBT2, 53%; autologous recovery, 50%). Relapse occurred in 2/15 patients who underwent UCBT2 and 8/10 patients who had autologous recovery or backup infusions. Forty months after transplantation, the cumulative incidence of relapse was 92% after autologous recovery vs. 50% after UCBT2 (Figure). Non–relapse mortality after UCBT2 was 73%. Conclusion Engraftment failure after UCBT frequently has no identifiable cause, and is associated with high morbidity and mortality. UCBT2 is feasible and can result in engraftment in the majority of patients, but is limited by patient condition after transplant as well as the availability of compatible grafts. UCBT2 is associated with significantly better disease control than continued autologous hematopoiesis, but additional efforts are necessary to reduce the high risk of non-relapse mortality in this group of patients. Disclosures: Hill: Celgene: Honoraria, Research Funding.

Abstract 3006FN2 Transplant related mortality (TRM), drug toxicities, life-threatening infections, poor quality of life, and graft versus host disease (GVHD) are significant risks of hematopoietic cell transplantation (HCT). In addition, pre-transplant comorbidities can have significant impact on the transplant outcomes of elderly patients (pts). Two comorbidity measurement tools, the CCI and the HCT-CI have been inconsistent in predicting TRM and overall survival (OS) after conventional HCT. The HCT-CI and CCI scores have correlated less well with TRM and OS in UCB transplantation. These results may have been limited by the heterogeneity of the UCB transplantation study population in age, disease, disease-risk, comorbidities, and conditioning regimens used. This study was performed to explore the accuracy of the HCT-CI and CCI in predicting post-transplant outcomes in elderly pts with high risk hematologic malignancies undergoing uniform RIC UCB transplantation. A retrospective chart review was performed on 35 consecutive elderly (age ≥ 55 years (yrs)) UCB transplant recipients receiving the RIC regimen fludarabine, cyclophosphamide, ATG, and 200 cGy TBI. All pts received cyclosporine and mycophenolate mofetil for GVHD prophylaxis. Information on pre-transplant comorbidities was obtained from each pt's CIBMTR pre-TED form and retrospective chart reviews. Demographic information, ECOG performance status (PS), identification of comorbidities, and post-transplant outcomes were obtained. HCT-CI and CCI scores were distributed in the following comorbidity risk groups 0, 1, > 1. Between 2002 and 2011, 35 pts underwent UCB transplantation with the above regimen. Median age was 65 yrs (range 55–71), 21 were male (60%) and 14 female (40%). Most pts had advanced stage or high risk hematologic malignancies; 28 had MDS/AML (80%) and 7 had other hematologic malignancies. All pts had a PS ≤ 2. Twenty-seven pts were in CR ≤ 2, with 31 pts having received ≤ 2 prior therapies. Eight pts had received prior transplants, including 2 pts with prior UCB transplantations and 6 pts with prior autografts. UCB cell dose was calculated on actual body weight (median 84 kg, range 56.1–135.1 kg). A total of 66 UCB grafts matched at a minimum 3/6 (3/6 = 4, 4/6 = 34, 5/6 = 22, 6/6 = 6) were infused. Pts received a range of 1 to 5 UCB units (1 unit = 12 pts, 2 units = 19 pts, 3 units = 2 pts, 5 units = 2 pts). VNTR/FISH analyses confirmed engraftment with median time of 21 days (d) (95% CI: 14–40 d) to achieve > 60% chimerism. Nine pts failed to achieve chimerism > 60%, and 3 had secondary engraftment failure. Median time to ANC > 500/μL for 3 consecutive values was 27 d (95% CI: 21–32 d) and median time to platelets > 20, 000/μL on the first day of 7 consecutive days without a platelet infusion was 40 d (95% CI: 35–71 d). No patient developed grade 4 acute GVHD. Grade 3 acute GVHD was seen in 3/35 pts (9%) and chronic GVHD was seen in 6/27 pts (22%). To date 31% (n = 11) of pts have relapsed. Pre-transplant cardiac comorbidities, A-fib/flutter and coronary artery disease, were the most common. Six pts had prior solid tumor malignancies, not active at the time of HCT, including breast (n=2), prostate (n=2), bladder (n=1), and kidney (n=1). After a median follow up of 13 months (range 1–70), 1 yr OS and progression free survival (PFS) were 61% and 55%, respectively. Median PFS and OS were both 16 months (mos) (PFS 95% CI: 8–70 mos, OS 95% CI: 9–70 mos). CCI but not PS or HCT-CI was a significant predictor of OS and PFS (Table and Figure).OS (%)PFS (%)FactorN1 yr2 yr4 yrp-value1 yr2 yr4 yrp-valuePS 0175750330.885252350.81 1-218654534584538CCI 016805822675932 14100500.04100500.04 >115333333333333HCT-CI 012544314564415 1108069690.296969690.25 >113533535453636 TRM occurred in 8 pts (23%). CCI was associated with TRM (p=0.05): pts with CCI ≥ 2 had a 40% (6/15) TRM vs 10% (2/20) with CCI 0–1. PS (p=0.69) and HCT-CI (p=0.47) did not correlate to TRM. In conclusion, elderly pts undergoing RIC UCB transplantation for high risk hematologic malignancies, the CCI was a statistically significant predictor of TRM, PFS, and OS. This index and not HCT-CI or PS identified elderly pts undergoing RIC UCB transplantation at higher risk of TRM and poor post-transplant outcomes. Larger validation studies of the predictive capacity of these comorbidity indexes need to be performed in the multi-institutional setting. Disclosures: Cooke: Amgen:.