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Introduction: Therapy and immune mediated processes are associated with clonal evolution in multiple myeloma (MM). In this study, we performed whole-exome sequencing (WES) and single cell RNA sequencing (scRNA-seq) on plasma cells (PC) from bone marrow aspirates of the iliac crest (BM) and corresponding osteolytic lesions (OL) to investigate spatial heterogeneity in patients with newly diagnosed (NDMM) and relapsed/refractory MM (RRMM). Next generation flow (NGF) and T-cell receptor sequencing (TCRseq) were performed to investigate the immunogenomic landscape surrounding malignant PC. Methods: In a prospective trial, 18 patients (NDMM: n=10; RRMM: n=8) consented to an imaging-guided biopsy of an OL in addition to the regular BM sampling. At inclusion, 37 different locations were biopsied. Follow-up samples were obtained from 5 patients in remission after therapy. After CD138+ selection, PC were subjected to WES and scRNA-seq (Chromium, 10x genomics). TCRseq was performed using multiplex PCR (ImmunoSEQ, Adaptive biotechnologies) on the CD138- fraction. For scRNA-seq data analyses, Cell Ranger (v3.1.0) and the Seurat R toolkit (v3.1) were used. TCRseq data were analyzed with immunoSEQ ANALYZER (v3.0) and the immunarch R toolkit (v0.6.6.). NGF was performed to study subsets of T-, B-, NK- and dendritic cells (DC). Results: Median PC infiltration was higher in OL compared to random BM (50.0% vs 12.5%, p=0.041). WES revealed more mutations in RRMM compared to NDMM (median; range: 189;120-523 vs 71;23-136, p Conclusion: We report the first prospective clinical trial to investigate spatiotemporal immunogenomic heterogeneity in multiple myeloma as assessed by WES and scRNA-seq of PC and NGF and TCRseq of the non-PC compartment. We demonstrate spatial evolution and reduced TCR diversity especially in patients with RRMM and/or EMD. ScRNA-seq adds another layer of complexity compared to WES and helps identifying how PC create an immune suppressive BM niche. Disclosures Merz: Amgen, BMS, Celgene, Takeda: Honoraria. Block:GlaxoSmithKline LLC: Current Employment. McCarthy:Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Genentech: Consultancy, Honoraria. Hillengass:Adaptive, Amgen, BMS, Celgene, GSK, Janssen, Oncotracker, Takeda: Honoraria.

Osteolytic lesions (OL) characterize symptomatic multiple myeloma. The mechanisms of how malignant plasma cells (PC) cause OL in one region while others show no signs of bone destruction despite subtotal infiltration remain unknown. We report on a single-cell RNA sequencing (scRNA-seq) study of PC obtained prospectively from random bone marrow aspirates (BM) and paired imaging-guided biopsies of OL. We analyze 148,630 PC from 24 different locations in 10 patients and observe vast inter- and intra-patient heterogeneity based on scRNA-seq analyses. Beyond the limited evidence for spatial heterogeneity from whole-exome sequencing, we find an additional layer of complexity by integrated analysis of anchored scRNA-seq datasets from the BM and OL. PC from OL are characterized by differentially expressed genes compared to PC from BM, including upregulation of genes associated with myeloma bone disease like DKK1, HGF and TIMP-1 as well as recurrent downregulation of JUN/FOS, DUSP1 and HBB. Assessment of PC from longitudinally collected samples reveals transcriptional changes after induction therapy. Our study contributes to the understanding of destructive myeloma bone disease.

Clonal hematopoiesis (CH) is a risk factor for the development of therapy-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML). Adoption of targeted-immunotherapeutics since 2011, may alter the risk of CH progression to tMDS/AML. To study this, we evaluated risk of tMDS and tAML in 667 588 ≥ 1-year survivors of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma and multiple-myeloma (MM) diagnosed during: 2000–2005, 2006–2010 and 2011–2016. The risk of tMDS increased significantly after NSCLC across all time periods (Ptrend = 0.002) while tAML risk decreased from 2006–2010 to 2011–2016, coinciding with increasing use of non-chemotherapeutic agents. tAML risk after RCC decreased (Ptrend = 0.007) whereas tMDS risk did not significantly change over time. After melanoma, tMDS and tAML risks were similar to the general population. tMDS and tAML risk after MM increased from the first to second time-period, however, only risk of tMDS decreased during last period. We report diverging trends in the risk of tAML and tMDS after adoption of modern cancer therapies for specific cancers. It is imperative to further explore impact of contemporary treatment strategies on clonal evolution. Modern treatments via their discrete mechanism of actions on pre-existing CH may alter the risk of subsequent tMDS and tAML.

Adult hematopoietic stem cell transplantation (HSCT) recipients are at a high risk of adverse outcomes after COVID-19. Although children have had better outcomes after COVID-19 compared to adults, data on risk factors and outcomes of COVID-19 among pediatric HSCT recipients are lacking. We describe outcomes of HSCT recipients who were ≤21 years of age at COVID-19 diagnosis and were reported to the Center for International Blood and Marrow Transplant Research between March 27, 2020, and May 7, 2021. The primary outcome was overall survival after COVID-19 diagnosis. We determined risk factors of COVID-19 as a secondary outcome in a subset of allogeneic HSCT recipients. A total of 167 pediatric HSCT recipients (135 allogeneic; 32 autologous HSCT recipients) were included. Median time from HSCT to COVID-19 was 15 months (interquartile range [IQR] 7-45) for allogeneic HSCT recipients and 16 months (IQR 6-59) for autologous HSCT recipients. Median follow-up from COVID-19 diagnosis was 53 days (range 1-270) and 37 days (1-179) for allogeneic and autologous HSCT recipients, respectively. Although COVID-19 was mild in 87% (n=146/167), 10% (n=16/167) of patients required supplemental oxygen or mechanical ventilation. The 45-day overall survival was 95% (95% confidence interval [CI], 90-99) and 90% (74-99) for allogeneic and autologous HSCT recipients, respectively. Cox regression analysis showed that patients with a hematopoietic cell transplant comorbidity index (HCT-CI) score of 1-2 were more likely to be diagnosed with COVID-19 (hazard ratio 1.95; 95% CI, 1.03-3.69, P=.042) compared to those with an HCT-CI of 0. Pediatric and early adolescent and young adult HSCT recipients with pre-HSCT comorbidities were more likely to be diagnosed with COVID-19. Overall mortality, albeit higher than the reported general population estimates, was lower when compared with previously published data focusing on adult HSCT recipients.

Objectives To report the epidemiology, treatments, and outcomes of adult patients admitted to the ICU after cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Design Retrospective cohort study SETTING:: Nine centers across the U.S. part of the chimeric antigen receptor-ICU initiative. Patients Adult patients treated with chimeric antigen receptor T-cell therapy who required ICU admission between November 2017 and May 2019. Interventions Demographics, toxicities, specific interventions, and outcomes were collected. Results One-hundred five patients treated with axicabtagene ciloleucel required ICU admission for cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome during the study period. At the time of ICU admission, the majority of patients had grade 3-4 toxicities (66.7%); 15.2% had grade 3-4 cytokine release syndrome and 64% grade 3-4 immune effector cell-associated neurotoxicity syndrome. During ICU stay, cytokine release syndrome was observed in 77.1% patients and immune effector cell-associated neurotoxicity syndrome in 84.8% of patients; 61.9% patients experienced both toxicities. Seventy-nine percent of patients developed greater than or equal to grade 3 toxicities during ICU stay, however, need for vasopressors (18.1%), mechanical ventilation (10.5%), and dialysis (2.9%) was uncommon. Immune Effector Cell-Associated Encephalopathy score less than 3 (69.7%), seizures (20.2%), status epilepticus (5.7%), motor deficits (12.4%), and cerebral edema (7.9%) were more prevalent. ICU mortality was 8.6%, with only three deaths related to cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Median overall survival time was 10.4 months (95% CI, 6.64-not available mo). Toxicity grade or organ support had no impact on overall survival; higher cumulative corticosteroid doses were associated to decreased overall and progression-free survival. Conclusions This is the first study to describe a multicenter cohort of patients requiring ICU admission with cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy. Despite severe toxicities, organ support and in-hospital mortality were low in this patient population.

Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence, and survival after haploidentical donor transplantation with posttransplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1 mismatching with HLA-DQB1 matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-nonpermissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1, and -DPB1 predicted disease-free survival, as did patient and donor cytomegalovirus serostatus, patient age, and comorbidity index. A web-based tool was developed to facilitate selection of the best haploidentical-related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.

A consensus grading schema for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) resulting from chimeric antigen receptor (CAR) T cell therapy was published in 2019. Although this consensus grading schema has been imperative in identifying and monitoring CRS and ICANS in our CAR T cell population, we observed patients exhibiting subtle neurotoxicity symptoms prior to a decrease in their immune effector cell (ICE) score, which is one component of ICANS. Because we treat grade 1 ICANS at our institution, identification of early neurotoxicity symptoms is important. Additionally, we found changes in personality, occupational confusion, or inability to answer dichotomous questions were early signs of neurotoxicity. Therefore, we developed a 3-step command tool to supplement the ICE evaluation. We present 2 examples of patients who exhibited early neurotoxicity symptoms and led us to develop this tool and 1 in whom it was effective. We propose that CAR T cell patients are consistently followed by a clinical care provider who is familiar with the patient to recognize early changes in personality, behavior, and cognition. Additionally, we propose that the multistep command tool be used in conjunction with the ICE score to detect early symptoms of ICANS. Early intervention has the potential to prevent irreversible neurotoxicity.

Purpose A task force of experts from 11 United States (US) centers, sought to describe practices for managing chimeric antigen receptor (CAR) T-cell toxicity in the intensive care unit (ICU). Materials and methods Between June–July 2019, a survey was electronically distributed to 11 centers. The survey addressed: CAR products, toxicities, targeted treatments, management practices and interventions in the ICU. Results Most centers (82%) had experience with commercial and non-FDA approved CAR products. Criteria for ICU admission varied between centers for patients with Cytokine Release Syndrome (CRS) but were similar for Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Practices for vasopressor support, neurotoxicity and electroencephalogram monitoring, use of prophylactic anti-epileptic drugs and tocilizumab were comparable. In contrast, fluid resuscitation, respiratory support, methods of surveillance and management of cerebral edema, use of corticosteroid and other anti-cytokine therapies varied between centers. Conclusions This survey identified areas of investigation that could improve outcomes in CAR T-cell recipients such as fluid and vasopressor selection in CRS, management of respiratory failure, and less common complications such as hemophagocytic lymphohistiocytosis, infections and stroke. The variability in specific treatments for CAR T-cell toxicities, needs to be considered when designing future outcome studies of critically ill CAR T-cell patients.

Key Points CIBMTR prognostic score predicts PFS and OS of patients with DLBCL receiving axicabtagene ciloleucel treatment after a prior autoHCT failure.CIBMTR high/very high-risk score marks an adverse risk cohort where novel immunotherapy or relapse prevention approaches are warranted., Visual Abstract, Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic model to CAR-T recipients. A total of 584 patients were included. The 1-year relapse, nonrelapse mortality, overall survival (OS), and progression-free survival for CAR-T treatment after autoHCT failure were 39.5%, 4.8%, 73.4%, and 55.7%, respectively. The corresponding rates in the alloHCT cohort were 26.2%, 20.0%, 65.6%, and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3%, respectively (P = .002). The corresponding rates for low-, intermediate-, and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (P < .001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in a subset of patients with DLBCL relapsing after a prior autoHCT. The simple CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high-risk patients.

Therapy-related Myeloid Neoplasms (tMNs) constitute 10-20% of newly diagnosed myeloid neoplasms and carry poor prognosis. tMNs develop in a small percentage of patients who receive chemoradiotherapy (CRT), thereby suggesting role of additional factors that may facilitate leukemic transformation. Clonal hematopoiesis (CH) represents a precursor state to overt myeloid neoplasm. CH surviving CRT/genotoxic stress may give rise to tMNs. Do factors beyond CRT aid in the clonal evolution and facilitate leukemia development? We hypothesized that CH-associated comorbidities (cardiovascular disease, infections, autoimmunity etc.) may facilitate CH’s evolution to tMN, beyond CRT. A population-based retrospective cohort study was conducted using cancer registries from the Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims database. Descriptive analyses included adults aged 66-84 who were diagnosed with first primary lymphoma (Diffuse Large B-Cell Lymphoma; DLBCL and Follicular Lymphoma; FL) during 2000 to 2014 (followed up through 2015), and survived at least 1 year, as reported to SEER. Chi-square tests were used to examine associations between comorbidity of interest/potential risk factors and tMDS/AML. Factors associated with tMDS/AML were then included in the multivariable logistic regression model with significance set at p Citation Format: Abhay Singh, Megan M. Herr, Theresa E. Hahn, Swapna Thota. Risk factors beyond chemotherapy exposure for therapy-related myelodysplastic syndrome (tMDS) and Acute Myeloid Leukemia (tAML) development in lymphoma survivors: a 15-year SEER-Medicare analysis. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P063.

Primary central nervous system lymphoma (PCNSL) risk is highly increased in immunosuppressed individuals, such as those with human immunodeficiency virus infection and solid organ transplant recipients, but rates are increasing among immunocompetent older adults (age ≥65 years). We utilized data from a large, nationally-representative cohort of older adults in the United States and found that PCNSL is significantly associated with systemic lupus erythematosus, polyarteritis nodusa, autoimmune hepatitis, myasthenia gravis and uveitis. Immunosuppressive drugs given to treat these conditions may increase PCNSL risk, but these associations cannot explain the observed temporal increase in PCNSL rates, given the low prevalence of these conditions.

This is the first longitudinal study of immune profiles and autologous hematopoietic cell transplant (AHCT) survival in B-cell non-Hodgkin lymphoma (B-NHL) patients and the effect of plerixafor mobilization on immune reconstitution in this population. A comprehensive immunophenotyping panel was performed in 104 consecutive adult B-NHL patients (58% diffuse large B cell and 42% mantle cell) who received AHCT (1/2008–11/2014), at a median of 28 days pre-AHCT (N = 104) and Day +100 (N = 83) post-AHCT. Median follow-up post-AHCT was 61 months (range: 8–120 months). Compared to patients mobilized with filgrastim and plerixafor, patients mobilized with filgrastim alone had a higher proportion of CD4+ naive (p = 0.006) and CD8+ central memory T-cells (p = 0.006) pre-AHCT. For patients transplanted in complete remission (CR), a higher proportion of CD8+ effector memory T-cells pre-AHCT was associated with worse progression-free survival (PFS; p

Acute graft versus host disease (aGvHD) remains a major impediment to successful allogeneic hematopoietic cell transplantation (allo-HCT). To solve this problem, a greater knowledge of factors that regulate the differentiation of donor T cells toward cytotoxic cells or Tregs is necessary. We report that the β2-adrenergic receptor (β2-AR) is critical for regulating this differentiation and that its manipulation can control aGvHD without impairing the graft-versus-tumor (GvT) effect. Donor T cell β2-AR expression and signaling is associated with decreased aGvHD when compared with recipients of β2-AR(–/–) donor T cells. We determined that β2-AR activation skewed CD4(+) T cell differentiation in vitro and in vivo toward Tregs rather than the T helper 1 (Th1) phenotype. Treatment of allo-HCT recipients with a selective β2-agonist (bambuterol) ameliorated aGvHD severity. This was associated with increased Tregs, decreased cytotoxic T cells, and increased donor BM–derived myeloid-derived suppressor cells (MDSCs) in allogeneic and humanized xenogeneic aGvHD models. β2-AR signaling resulted in increased Treg generation through glycogen synthase kinase-3 activation. Bambuterol preserved the GvT effect by inducing NKG2D(+) effector cells and central memory T cells. These data reveal how β-AR signaling can be targeted to ameliorate GvHD severity while preserving GvT effect.

Background It is unclear whether the established association between cutaneous melanoma (CM) and lymphoid neoplasms (LNs) differs across LN subtypes. This study quantifies risk for developing CM after specific LNs and, conversely, for developing specific LNs after CM, as well as assessing clinical impact. Methods We identified a cohort of Caucasian adults (age 20-83 years) initially diagnosed with CM or LN, as reported to 17 US population-based cancer registries, 2000-2014. Standardized incidence ratios (SIRs) quantified second cancer risk. We assessed impact of second cancer development on risk of all-cause mortality using Cox regression. Results Among 151 949 one-or-more-year survivors of first primary LN, second primary CM risk was statistically significantly elevated after chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR = 1.96, 95% confidence interval [CI] = 1.74 to 2.21), follicular lymphoma (SIR = 1.32, 95% CI = 1.09 to 1.58), and plasma cell neoplasms (SIR = 1.33, 95% CI = 1.07 to 1.63). Risks for these same subtypes were statistically significantly elevated among 148 336 survivors of first primary CM (SIR = 1.44, 95% CI = 1.25 to 1.66; SIR = 1.47, 95% CI = 1.21 to 1.77; SIR = 1.25, 95% CI = 1.06 to 1.47; respectively). Risk for CM was statistically significantly elevated after diffuse large B-cell lymphoma (SIR = 1.22, 95% CI = 1.02 to 1.45) and Hodgkin lymphoma (SIR = 1.75, 95% CI = 1.33 to 2.26), but the reciprocal relationship was not observed. There were no statistically significant associations between marginal zone lymphoma and CM. Among survivors of most LN subtypes, CM statistically significantly increased risk of death (hazard ratio [HR] range = 1.52, 95% CI = 1.25 to 1.85, to 2.46, 95% CI = 1.45 to 4.16). Among survivors of CM, LN statistically significantly increased risk of death (HR range = 1.75, 95% CI = 1.15 to 2.65, to 6.28, 95% CI = 5.00 to 7.88), with the highest risks observed for the most aggressive LN subtypes. Conclusions Heterogeneous associations between CM and specific LN subtypes provide novel insights into the etiology of these malignancies, with the mutual association between CM and certain LN suggesting shared etiology. Development of second primary CM or LN substantially reduces overall survival.

INTRO: Immune profiles and immune reconstitution are increasingly studied as important contributors to the prognosis and treatment responses of hematologic malignancy patients. Data on epidemiologic factors influencing immune profiles in hematologic malignancy patients are lacking. METHODS: We performed flow cytometric analyses of immune panels including T-cell, B-cell, NK cell and dendritic cell (DC) subsets in 1,025 consecutive adult hematologic malignancy patients (N=873) and controls/donors (N=152) between 2006-2016. Immune panels were analyzed on fresh peripheral blood samples drawn during workup before autologous or allogeneic hematopoietic cell transplant (HCT). Hematologic malignancy diagnoses were AML (N=235), MM (N=228), NHL (N=197), MDS/MPN (N=85), ALL (N=60), HL (N=33) and other leukemias (N=35). Patients were 58% male, median age 58 years (range 18-77), 91% non-Hispanic white (NHW), 6% African-American (AA), 1.3% Hispanic, 1.5% other. The HCT-comorbidity index (HCT-CI) in patients showed: 63% with > 1 co-morbidity; 26% moderate pulmonary, 22% psychologic (requiring therapy/counseling), 16% severe pulmonary, 12% cardiac (CHF/CAD/MI), 11% diabetes requiring insulin, 9% obese (BMI>35mg/kg 2), 9% prior cancer. Controls were related apheresis or marrow donors of allogeneic HCT patients: 51% male, median age 49 years (range 19-73), 92% NHW, 4% AA, 1.3% Hispanic, 2.6% other. HCT-CI scoring of controls: 45% with > 1 comorbidity, 20% obese, 20% psychologic, 10% mild liver disease, 7% diabetes. Due to inter-individual cell count variability, immune cells were normalized as percent gated of lymphocytes except DC populations which were gated on mononuclear cells, both on forward and side scatter. To control for multiple comparisons, Bonferroni corrected statistically significant P was set at RESULTS: In controls, males had a significantly lower proportion of CD3+ cells/µl than females (68% vs 73%, P=0.001), NHW had a higher proportion of CD8+ central memory (CM) cells than other race/ethnicities (4.6 vs 2.7%, P=0.004) with no other significant differences by sex or race, although some of the race groups were low in our cohort. In contrast, among hematologic malignancy patients, males had significantly lower CD4+, CD4+ naïve, CD4+ recent thymic emigrants (RTEs), total T-regulatory cells (Treg), and CD19+ naïve cells but significantly higher CD8+ CM and effector memory (EM) cells than females. In addition, NHW had higher CD8+ CM than AA, Hispanic and Other races. Significant differences by age in patients and controls are shown in the Table. Across all age groups, patients had higher proportions of CD3+ cells, lower proportions of B-cells and no difference in NK or DCs than controls. As controls increased in age, CD4+ total significantly increased, while CD8+total, CD8+naive, T-γδ cells decreased, and myeloid DCs were highest at each end of the age spectrum. As patients increased in age, activated HLA-DR T-cells significantly increased, while T-γδ, CD8+naïve, and RTEs significantly decreased. The CD4:8 ratio increased while the CD4+ and CD8+ naïve:EM ratio decreased with age in both controls and patients, however patients had lower CD4:CD8 and naïve:EM ratios than controls. Immunophenotypes by patient disease are shown in the Figure. In general, patients with lymphoid diseases had lower CD3+CD4+ but higher CD3+CD8+, NK and DCs. In controls/donors, there were no significant differences in immune cell profiles by the presence or absence of comorbidities: obesity, diabetes, psychologic and mild liver disease. In patients, T-γδ were significantly lower in patients with diabetes, with no other significant differences for cardiac, psychologic, prior cancer, obesity or pulmonary co-morbidities. CONCLUSIONS: Additional analyses are ongoing to investigate the influence of prior therapies (chemotherapy, hypomethylating agents, monoclonal antibodies, etc.) and cytogenetic risk groups within each disease (AML, ALL, MDS/MPN, MM, NHL) on immune cell profiles. Studies of immunophenotyping in hematologic malignancies should include adjustment for confounders such as age, sex and race as biologic variables, as well as consideration of the diseases and treatments given. Interestingly, common co-morbidities did not broadly influence immune cell profiles in our cohort of hematologic malignancy patients. Figure 1 Figure 1. Disclosures Chen: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium. Hillengass: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Beijing Medical Award Foundation: Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Beijing Life Oasis Public Service Center: Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees; Curio Science: Speakers Bureau; Adaptive: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Axxess Network: Membership on an entity's Board of Directors or advisory committees. Wang: Genentech: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Griffiths: Takeda Oncology: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Apellis Pharmaceuticals: Research Funding; Abbvie: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Taiho Oncology: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Boston Biomedical: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. McCarthy: Bluebird: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background and Rationale: Axi-cel is a standard-of-care treatment for relapsed or refractory LBCL after 2 or more lines of systemic therapy. Some patients who would have been ineligible for ZUMA-1 criteria due to comorbidities have been treated with axi-cel in the real-world setting. We interrogated a large registry of patients treated with standard-of-care axi-cel for a definitive report on the impact of age or certain comorbidities on safety and efficacy outcomes after axi-cel infusion. Methods: From October 2017 to August 2020, 1500 patients were enrolled in the postapproval safety observational study of axi-cel treated at 79 centers. Patients eligible for the protocol and followed up for at least 6 months with complete data entry by the time of analyses were included. One patient rescinded consent and 1 was deemed ineligible. Patients previously treated with immune effector cell therapy (n=31), with incomplete follow-up reporting (n=92), or alive but last contacted Results A total of 1343 patients were included in the analysis with a median 25.1 months (range, 10.3-42.7 months) for potential follow-up, defined from infusion to data cutoff date, and a median 11.8 months (range, 0.1-38.8 months) for actual follow-up time, defined from infusion to date of death or last contact. Of these, 38% were 65 years or older (median 62 years), 4% had a performance score ≥2, 13% had cardiac comorbidities, 16% had a prior cancer, 9% were obese, 2% had moderate to severe hepatic comorbidities, and 2% had renal comorbidities. Transformed lymphoma, double or triple-hit by fluorescence in situ hybridization, prior autologous transplant and refractory disease were present in 28%, 15%, 27% and 66%, respectively. Bridging therapy was administered in 21% of patients. Overall, ORR was 74%, (CR 56%), and probabilities of DOR, PFS, and OS at 18 months were 61% (95% CI, 57-65%), 42% (95% CI, 39-45%) and 52% (95% CI, 49-55%), respectively. Overall rates of CRS and ICANS were 83% and 55%, respectively. ORR was 78% (CR 62%, median OS 17.5 [95% CI, 16.0-not evaluated (NE)] months) for patients ≥65 years, ORR 57% (CR 29%; median OS 4.3 [95% CI, 2.5-8.3] months) for patients with hepatic dysfunction, ORR 70% (CR 43%; median OS 8.9 [95% CI, 3.8-NE] months) for patients with renal dysfunction; and ORR 47% (CR 20%, median OS 4 [95% CI, 2.6-6.9] months) for patients with Eastern Cooperative Oncology Group (ECOG) 2 or 3. Multivariate analyses indicated that advanced age (≥65 years vs Conclusion: Advanced age (≥65 years) was not associated with worse efficacy outcomes after axi-cel, despite higher rates of CRS and ICANS, which require closer monitoring. Performance status rather than age should be accounted for in patient selection and treatment decisions with axi-cel. Most coexistent organ dysfunctions have no clinically significant impact on axi-cel objective response and safety outcomes. Figure 1 Figure 1. Disclosures Locke: Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Amgen: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Wugen: Consultancy, Other; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cowen: Consultancy; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Legend Biotech: Consultancy, Other; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role. Jacobson: Axis: Speakers Bureau; Nkarta: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau. Ma: Kite, a Gilead Company: Current Employment. Dong: Kite, a Gilead Company: Current Employment. Hu: Kite, a Gilead Company: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Siddiqi: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncternal: Research Funding; Janssen: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Ghobadi: Atara: Consultancy; Wugen: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Miklos: Pharmacyclics: Patents & Royalties; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Legend: Consultancy; Vineti: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Merck: Research Funding; Takeda: Research Funding. Perales: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Nektar Therapeutics: Honoraria, Other; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; NexImmune: Honoraria; Sellas Life Sciences: Honoraria; Cidara: Honoraria; Merck: Honoraria; Omeros: Honoraria; Servier: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Other; Kite/Gilead: Honoraria, Other; Incyte: Honoraria, Other; Medigene: Honoraria; Karyopharm: Honoraria; Equilium: Honoraria. Lunning: Daiichi-Sankyo: Consultancy; TG Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy; ADC Therapeutics: Consultancy; Spectrum: Consultancy; Beigene: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Legend: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; Novartis: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Acrotech: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy. Hill: Gentenech: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: 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; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Celgene (BMS): Consultancy, Honoraria, Research Funding. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Xu: Gilead Sciences: Other: stock or other ownership ; Kite, A Gilead Company: Current Employment. Pasquini: Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding.

Background. DNA methylation is a key epigenetic process involved in development, aging, and cancer. Mutations in DNMT3A and TET2 in the hematopoietic stem cell compartment lead to increased self-renewal. In addition to mutations in ASXL1, collectively, these DTA mutations are recognized as an aging phenomenon, known as the most common Clonal hematopoiesis of Indeterminate Potential (CHIP) mutations and alone are not predictive of increased risk for hematopoietic malignancy. Recently, DNMT3A mutations in donor hematopoietic cells were suggested to be associated with enhanced T-cell activity in allografted patients. Additionally, role of DNMT3A mutations in creating a proinflammatory state in cardiovascular disease setting and associated elevation of T-cell markers in the myocardium have been recently explored (Sano S et al. Circ Res. 2018). Since an inflamed tumor microenvironment is associated with improved immune checkpoint inhibitors (CPI) activity, we sought to determine the impact of CHIP (a proinflammatory state) on response to CPI and CPI's effects on clonal dynamics. Additionally, while classical chemotherapy (CTX) can create selective external pressure providing survival advantage to mutant stem cells, the selective pressure of T-cell activating therapies on hematopoietic stem cells is unclear. Methods. To study the relationship between CHIP and CPI, we used paired peripheral-blood samples taken before and after treatment with CPI therapy in patients (pts) with melanoma (MEL; n= 32) and non-small cell lung cancer (NSCLC; n=109). Serial samples (or post CPI samples) were evaluable in 5 MEL pts and 6 NSCLC pts. Error-corrected sequencing of a targeted panel of genes recurrently mutated in clonal hematopoiesis (CH) was performed on peripheral blood genomic DNA. Statistical comparisons between baseline and serial sample VAFs were performed using two-sided fisher's exact test, with a p < 0.05 considered significant. Results. In both the MEL and NSCLC cohort, baseline samples were collected before extensive therapy exposure. 90% (29/32) of the MEL cohort had no CTX or targeted therapy prior to the baseline sample; 28% (9/32) had prior radiotherapy (RT). 10% (11/109) of the NSCLC cohort samples had prior CTX, but only 2 of these were treated for more than 1 month before sample collection. CH was frequent in these minimally pre-treated patient samples; 28.1% (9/32) and 37.6% (41/109) of the baseline MEL and NSCLC samples, respectively. As expected, DTA mutations were the most common events in these cohorts. Samples with CH were from patients of older age, but had normal hematological parameters with exception of increased RDW (p=0.022). Primary tumor responses in this cohort were defined as durable (receipt of ≥12 CPI cycles) or not durable ( Conclusions. In this small cohort of pts with MEL and NSCLC, the presence of DNMT3A/TET2 CH was associated with longer checkpoint inhibitor exposure and increased allelic frequency over time. These findings need further validation in larger cohorts and delineation of the relationship between DTA mutations such as DNMT3A and enhanced immune activity. Acknowledgement: Data and samples for this study were provided by the Data Bank and BioRepository (DBBR), which is funded by the National Cancer Institute (P30 CA016056) and is a Roswell Park Cancer Institute Cancer Center Support Grant shared resource. Figure 1 Figure 1. Disclosures Griffiths: Taiho Oncology: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Novartis: Honoraria; Boston Biomedical: Consultancy; Astex Pharmaceuticals: Honoraria, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Genentech: Research Funding; Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Hassane: Tempus Labs, Inc: Current Employment. Guzman: SeqRx: Consultancy; BridgeMedicines: Consultancy; Cellectis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Wang: Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Genentech: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

Poor physical functioning is associated with adverse outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Analytic tools to predict mortality in alloHCT recipients include the HCT Comorbidity Index (HCT-CI) based on comorbidities and the Disease Risk Index (DRI) based on disease and disease status. We developed and replicated a risk model for overall survival (OS), early mortality (ie, death from any cause at or before day +100), initial hospital length of stay (LOS), and percentage of inpatient days within the first year post-alloHCT. In this study, we incorporated a physical therapy (PT) assessment with the HCT-CI and DRI to improve outcome predictions. The well-defined and feasible measure of functional status for assessing risk includes (1) the number of sit-to-stands performed in 30 seconds, (2) performance of 25 step-ups on the right/left side with (3) oxygen saturation recovery and (4) heart rate recovery, (5) weight-bearing ability, (6) assistance with ambulation, (7) motor and grip strength, (8) sensory and coordination impairment (eg, self-reported peripheral neuropathy, imbalance), (9) self-reported pain, and (10) limited endurance (ie, inability to complete step-ups and/or sit-to-stands). Our training cohort (TC) included 349 consecutive alloHCT recipients at Roswell Park treated between 2010 and 2016 and a subsequent replication cohort (RC; n = 163) treated between 2016 and 2019. Four of the 10 metrics-self-reported pain, limited endurance, self-reported neuropathy, and10 sit-to-stands in 30 seconds-were identified as significant predictors and were included in the multivariable models with the HCT-CI and DRI to create a new risk index (HCT-PCDRI: HCT-physical, comorbidity, and DRI) for outcomes. Models were tested in the RC. Shorter OS was associated with self-reported pain, limited endurance, higher HCT-CI, and higher DRI. At a median follow-up of 34 months, the 3-year OS based on the HCT-PCDRI was 30% for the very-high-risk group, 54% for the high-risk group, 49% for the intermediate-risk group, and 80% for the low-risk group. The number of patients identified as very high risk increased from 55 using HCT-CI alone to 120 with the new HCT-PCDRI, whereas the number in the low-risk group decreased from 91 to 45. Early mortality and a higher percentage of inpatient days within the first year post-alloHCT (a proxy for poor quality of life and high healthcare utilization) were associated with self-reported pain, higher HCT-CI, and higher DRI. A shorter initial LOS (ie, initial low healthcare utilization) was associated with performance of10 sit-to-stands in 30 seconds, no self-reported neuropathy, and lower HCT-CI. These PT metrics combined with the HCT-CI and DRI created the HCT-PCDRI, which resulted in more patients being categorized accurately as high risk versus low risk. The HCT-PCDRI results were replicated in an independent cohort. Pre-alloHCT PT metrics with self-reported symptoms (pain and neuropathy) were associated with survival post-alloHCT and prolonged hospital LOS. The HCT-PCDRI scoring system for risk stratification of alloHCT recipients more accurately identifies patients at potential risk of poor outcomes. The HCT-PCDRI can be tested in15 minutes to identify patients for intervention before or during treatment to potentially improve outcomes.

Background The standard of care for diffuse large B-cell lymphoma (DLBCL) relapsing after front-line therapy is high-dose chemotherapy and autologous stem cell transplantation (ASCT). Evidence has suggested that early relapses (ie, within 1 year) after this approach portends exceptionally poor outcomes. However, data examining relapses > 1 year after ASCT for patients with refractory or relapsed DLBCL are limited, in particular, in the rituximab era. We sought to examine the effect of early (≤ 1 year) and late (> 1 year) relapse after ASCT in a single-institution cohort of patients with relapsed and refractory DLBCL treated with chemoimmunotherapy. Materials and Methods A retrospective analysis was performed on the data from 85 consecutive patients who had undergone ASCT for biopsy-confirmed relapsed or refractory DLBCL from 2001 to 2010 at the University of Rochester Medical Center. All patients had received rituximab as a part of treatment. Of the 85 patients, 35 developed relapse after ASCT. These 35 patients were divided into 2 groups according to the timing of the relapse (≤ 1 year and > 1 year after ASCT). Results The median follow-up period was 6.4 years. For all patients, the overall survival (OS) from post-ASCT relapse was 5.2 years. For the 27 patients developing relapse at ≤ 1 year after ASCT, the median OS was 0.6 year and progression-free survival was 0.4 year. For the 8 patients developing relapse at > 1 year after ASCT, the median OS was 5.9 years and progression-free survival was 2.9 years. Conclusion Patients with relapsed or refractory DLBCL experiencing relapse > 1 year after ASCT had good outcomes. Despite the relative rarity in incidence, a significant risk of relapse of DLBCL after ASCT remains, suggesting the need for continued monitoring because of the possibility of later progression.

Background. Clonal hematopoiesis (CH) is an aging associated phenomenon with potential to transform to overt myeloid disease at a rate of 1% per year. CH is hypothesized to represent a precursor state for leukemogenesis. CH is detected in 10% of healthy, elderly (>70 years) individuals at variant allele frequencies (VAFs) above 2%, but prevalence is higher in patients (pts) with malignancies (~25%). We recently demonstrated in a large population database study that recent changes in therapy for melanoma and non-small lung cancer (NSCLC) are associated with a decreased incidence of therapy-related myeloid neoplasms (tMNs).1 This trend may reflect declining utilization of chemo-radiotherapies or even regression of CH clones in the context of immune checkpoint inhibitor therapy (ICI). To improve our understanding of the evolving clonal architecture in patients with CH receiving ICI we analyzed blood samples from pts with melanoma and NSCLC at baseline and after exposure to ICIs. We aimed to characterize (i) baseline prevalence of CH in pts with melanoma and NSCLC (ii) alterations in clonal architecture associated with ICI treatment in serial blood samples from these pts. Methods. In this retrospective analysis, stored blood samples from pts with melanoma (N=32) and NSCLC (N= 109) treated with ICIs were analyzed. To detect CH, genomic DNA collected before treatment initiation and serially on ICI were analyzed using a custom panel targeting 93 genes. A 1% VAF cutoff was used to define CH. Relationships among clinical, laboratory and mutational variables were examined using chi-square test, at a significance level of 0.05. Results. We present preliminary results on 25 pts with melanoma (Table 1). Median age was 61 years. 52% (13/25) were men. One/25 pts had previously received chemotherapy and 4/25 had prior radiation therapy exposure. 64% (16/25) had stage IV disease and 36% (9/25) had stage III disease. 20% (5/25) had a history of autoimmune disease. CH was present in 32% of cohort, consistent with prior reports in solid tumor pts. Mutations in DNMT3A (36%) were most common, followed by TET2 (18%). Mutations in PPM1D, ARID1A, SF3B1, LPA and TGFBR2 accounted for 46% of the mutations (Figure 1). The mutational pattern was similar to prior reports in other cancer cohorts. DNMT3A mutations were most common in this cohort, with only one patient harboring a mutation in the R882 AML/MDS hotspot, previously described in CH. Most common mutation type was single nucleotide variants (55%), followed by frameshift (27%), and splice site mutations and truncations. The mean VAF for somatic mutations was 9%, much higher than the usual VAF cutoff for CH. Mutations were more common in smokers (40% vs 26.7%), and in individuals older than 60 years (37.5% vs 22%). Pts with autoimmune disease did not demonstrate CH mutations (0/5), whereas 40% (8/20) of pts without autoimmune diseases harbored mutations, (p=0.08). Conclusions. Our findings demonstrate a high baseline prevalence of putative CH mutations and high mean VAFs in a cohort of melanoma patients, even in the setting of minimal prior chemotherapy and radiation exposure. Despite this high CH prevalence, risk of tMN development after melanoma is declining with the use of newer therapies, suggesting a possible immune clearance or halt in progression of clonal hematopoiesis with newer therapies (ICI). Lack of CH mutations in individuals with autoimmune disease is an interesting finding and warrants further investigation. Ongoing serial sample analysis of the melanoma cohort after exposure to ICI will provide insight into the impact of ICI on the underlying clonal architecture. These findings are also being tested in the NSCLC validation cohort. References Singh A, Mrad C, Faber MG, et al. Evolving risk of therapy-related myelodysplastic syndromes and acute myeloid leukemia (tMDS/AML) following modern cancer therapies. Journal of Clinical Oncology. 2020;38(15_suppl):7516-7516. Acknowledgement: Data and samples for this study were provided by the Data Bank and BioRepository (DBBR), which is funded by the National Cancer Institute (P30 CA016056) and is a Roswell Park Cancer Institute Cancer Center Support Grant shared resource. Disclosures Griffiths: Persimmune: Research Funding; Boston Biomedical: Honoraria; Genentech Inc: Research Funding; Astex Pharmceuticals: Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; AbbVie Inc: Honoraria; Novartis: Honoraria, Research Funding. Guzman:Cellectis: Research Funding; SeqRx: Honoraria. Wang:Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Genentech: Consultancy.

Excess sarcoma risks after childhood cancer are well established, but risks among young adulthood cancer survivors are poorly understood. Using US population-based cancer registry data, we compared bone and soft-tissue sarcoma risk vs the general population among 186 351 individuals who were diagnosed with nonsarcoma first primary malignancies at ages 20–39 years from 1975 to 2014 (follow-up through 2015) and survived at least 1 year. Bone sarcomas were rare (n = 50), but risk was statistically significantly elevated overall (2.9-fold) and greater than fivefold after Hodgkin lymphoma, non-Hodgkin lymphoma, and central nervous system tumors. Soft-tissue sarcomas were more common (n = 284) and risks were statistically significantly elevated approximately twofold overall and after melanoma and carcinomas of the breast, thyroid, and testis, and greater than fourfold after Hodgkin lymphoma and central nervous system tumors. Risks varied markedly by subtype, with the highest risks (greater than fourfold) for osteosarcoma and the soft-tissue subtypes of rhabdomyosarcoma and blood vessel and nerve sheath sarcomas. These data demonstrate elevated risk for sarcoma after a range of young adulthood cancers.

7552 Background: Axi-cel is approved in the US for the treatment of adult patients with relapsed or refractory LBCL after 2 or more lines of systemic therapy. Post-market long term follow up study of commercial Axi-cel recipients using the Center for International Blood and Marrow Transplant Research was recently completed. Methods: From October 2017 to August 2020, 1,500 Axi-cel recipients from 79 centers were enrolled. Of these, 1001 patients with at least 6 months of follow-up were included in this analysis. Outcomes include complete and overall responses rates (CR and ORR), duration of response (DOR), progression-free and overall survival (PFS and OS), cytokine release syndrome (CRS) (Lee D 2014 and American Society for Transplantation and Cellular Therapy [ASTCT]), immune effector cell associated neurotoxicity syndrome (ICANS), hematologic recovery and subsequent neoplasm (SN). Subgroup analysis by sensitivity to therapy, defined as responsive to the last line of therapy prior to Axi-cel. Median follow-up was 12 months (range, 6-28 months). Results: The median age overall was 62 years, 37% were ≥ 65 years, 83% with Eastern Cooperative Oncology Group (ECOG) performance score 0-1, 28% with transformed lymphoma, 14% with high grade lymphoma, 29% with prior autologous transplant, and 66% with chemotherapy-resistant disease prior to Axi-cel. The median time from diagnosis to Axi-cel infusion was 15 months. Best ORR was 70% (CR 53%). Landmark analysis of patients in CR at 6 months post Axi-cel demonstrates a low number of subsequent progression/death events. With respect to outcomes for chemotherapy-sensitive disease versus resistant disease, the ORR, CR, 12-month PFS and OS were 78% vs. 66%, 60% vs. 48%, 55% (95% CI, 48-62%) vs. 40% (95% CI, 37-44%), and 70% (95% CI, 63-76%) vs. 54% (95% CI, 50-58%), respectively. CRS of any grade was reported in 83% of patients. Incidence of Grades ≥ 3 CRS was 10% according to Lee et al 2014, and 13% according to ASTCT Consensus Grading. Median time to any grade CRS was 4 days (range, 1-28 days), and 93% of CRS cases resolved with a median duration of 7 days (range, 1-121 days). ICANS were reported in 576 (57%) patients, grade >3 was 26%. The median time to onset of ICANS was 7 days (range, 1-82 days), and 86% resolved with a median duration of 9 days (range, 1 to 115 days). Twenty-nine patients (2.9%) reported SN: hematologic (N = 17), solid tumors (N = 12). Conclusions: This is the largest report on Axi-cel in the real-world setting and demonstrates consistent efficacy outcomes and further characterizes safety outcomes. Patients in CR at 6 months have sustained disease control with low number of relapse events. Although patients with therapy-sensitive disease experience better outcomes than patients with therapy-resistant, the overall outcomes on both groups of patients are favorable.

Revaccination after autologous hematopoietic cell transplantation (AHCT) is recommended in post-HCT survivorship guidelines to restore humoral immunity. Data on seroconversion after AHCT and vaccination in multiple myeloma (MM) patients are limited. We investigated the feasibility and effectiveness of vaccination post-AHCT and analyzed the restoration of humoral immunity and patient prognosis. Anti-pathogen titers were measured within a median of 2 days before and 96 days after AHCT and following revaccination in 139 MM patients who had a first AHCT from 2013 to 2016. Most (84%) patients received at least one dose of any planned vaccines. High-dose melphalan with AHCT restored measurable immunity in 18% of patients. In an additional >60% of patients, seroconversion occurred after vaccination; however, despite vaccination, 20% of patients remained seronegative for most pathogens. Attainment of MM complete response post-AHCT was associated with higher rates of seroconversion which yielded significantly longer progression-free and overall survival. Our study demonstrates the feasibility of post-AHCT vaccination, supporting measurement of post-vaccination titers to determine which patients should be considered for antimicrobial prophylaxis, as seroconversion does not occur in all patients. Titer seroconversion is a potential indicator of the immunological effects of AHCT, with restoration of humoral immunity demonstrating improved survival.

Selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants, were found to increase central nervous system (CNS) metastasis in mice. Our study investigated in humans whether antidepressants, and specifically SSRIs, increased the relative odds of CNS metastasis. We identified 189 cases of CNS metastasis amongst breast cancer, melanoma, and non-Hodgkin lymphoma subjects who were diagnosed with CNS metastasis or infiltration between January 1, 2005 and September 30, 2013 and 756 controls (patients without CNS metastasis or infiltration). Using logistic regression, we estimated the relative odds of CNS metastasis associated with antidepressant use adjusting for relevant covariates. The prevalence of antidepressants was 28.6 % in cases and 27.5 % in controls, whereas SSRIs were used in 16.9 % of cases and 17.3 % of controls. Among all patients, antidepressants were not associated with CNS metastasis or infiltration. No consistent patterns of association were observed in the analyses of other cancer subsets or exposure measures, with the possible exception of an increased risk of CNS metastasis associated with 'any SSRI use' among breast cancer patients (OR = 1.73, 95 % CI = 0.75, 4.04). We did not observe clear patterns of association, which may be due in part to the small sample size in many of our analyses.

8524 Background: Osteolytic lesions (OL) characterize symptomatic multiple myeloma (MM). It is still unclear why plasma cells (PC) cause OL in certain regions of the body while other areas show no signs of bone destruction despite significant bone marrow infiltration. We conducted the first study of single cell RNA sequencing (scRNA-seq) and whole-exome sequencing (WES) of PC obtained from random bone marrow samples (RS) and paired OL. Methods: As part of a prospective clinical trial, patients consented to an imaging-guided biopsy of new OL identified by PET/CT in addition to the RS from the iliac crest. Both samples were acquired in the same session. On the same day PC were isolated using a CD138 positive selection kit and single cell gene expression libraries were generated for scRNA-seq. Frozen PC were subjected to DNA extraction and WES. Results: We sequenced 93569 purified, viable PC from paired samples from 15 different locations in the first 7 consecutive patients (median PC from location: 7203; range 1121-10279). Quality assessment of scRNA-seq data revealed no differences between PC in OL and RS. Based on scRNA-seq, 9-24 different subpopulations of PC in individual patients were identified. Over 90% of clusters found in the RS were also present in corresponding OL suggesting a common ancestor. This was true for patients with overlapping as well as divergent mutational profiles in RS and OL as shown by WES. In each patient we found PC clusters that were predominantly present in OL. Respective clusters were characterized by expression of Wnt-signaling inhibitors like DKK-1, Frzb and sFRP-2 and other genes linked to MM bone disease (HGF, CXCL-12, CCL3). Lysosome-associated membrane protein-like molecule 5 (LAMP5) and J-chain were overexpressed in OL clusters. Analysis of genes (IKZF1 and IKZF3) associated with response to treatment and outcome revealed vast heterogeneity and differences in risk scores (UAMS70 and IFM15) on a single cell level from different locations in individual patients. Conclusions: Our study provides the first evidence that PC from OL have distinct transcriptomic profiles that link site-specific gene expression to development of bone disease and adverse outcome.

7516 Background: Data describing risks of tMDS/AML after targeted and immunotherapy (IO) agents are lacking. Melanoma (Mel) and renal cell carcinoma (RCC) are considered chemotherapy insensitive and have been treated with IO (interferon and interleukin) since the 1990s. In 2004, use of tyrosine kinase inhibitors (TKIs) began in non-small cell lung cancer (NSCLC) and expanded to RCC in 2005 and Mel trials in 2011. Checkpoint inhibitor (CPI) use began in 2011 for Mel, 2012 for NSCLC in trials and later for RCC. For multiple myeloma (MM), use of lenalidomide has been increasing since 2007. All these modern therapies have well described immunomodulatory functions. Methods: Using 17 population-based SEER cancer registries, we studied 565,149 patients diagnosed from 2000-2015 with Mel, RCC, NSCLC, or MM who survived ≥1 year and assessed risk of tMDS/AML across periods P1 (2000-2005), P2 (2006-2010) and P3 (2011-2015). Censoring occurred at 5 years of follow up to limit bias and assess risk alteration across approval and utilization periods of these modern therapies. Results: tMDS/AML risk was significantly elevated after RCC in P1 [standardized incidence ratio (SIR): 1.61, possibly from chemo exposure that was still prevalent to some extent in P1 period] and a downtrend noted in P2 (SIR: 1.11) and P3 (SIR: 0.60). tMDS/AML risk after Mel showed similar downtrend, not statistically significant. In contrast, risk for tMDS/AML after MM increased across all periods ( SIRs 4.51 > 5.05 > 5.23), and risk after NSCLC increased from P1 to P2 but decreased thereafter, pattern most pronounced in stage I-III NSCLC ( 1.64 > 3.15 > 1.92). Conclusions: Periods when TKI and CPI use became standard in Mel and RCC, we observed a decrease in tMDS/AML risk. Similar decrease in the most recent period for stage I-III NSCLC was observed, possibly due to progression of these earlier staged cancers resulting in receipt of TKIs and CPI for stage IV disease. tMDS/AML risk after MM increased contradicting the decline in risk previously reported in the literature. Discordance may be due to survival bias as MM patients are now living longer (SEER 5-yr survival in ‘00 was 35% and 53% in ‘15) with more time to develop tMDS/AML. Overall, aside from better efficacy and/or tolerability of modern therapies, another observed benefit was lower tMDS/AML risk. This risk was lower than general population in Mel/RCC, suggesting a possible protective effect of these therapies. SIR tables/graphs with updated SEER data (available 04/2020) with follow up through 2018 will be presented.

Background: Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer. Methods: Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0–2 were treated with panitumumab 6 mg kg−1, GEM 1000 mg m−2 (10 mg m−2 min−1) and OX 85 mg m−2 on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival. Results: Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5–24 months) and median overall survival 20.3 months (95% CI 9–25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%. Conclusions: The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.

β2 adrenergic receptor signaling is a key regulator of various immune cells, including T cells; however, its role in T cell function in the context of graft versus host disease (GvHD) is poorly understood. We previously showed that housing mice at thermoneutral temperature (TT; 30°C), which reduces systemic adrenergic stress, increased the incidence and severity of GvHD after allogeneic hematopoietic cell transplant (allo-HCT) compared to mice housed at standard temperature (ST; 22°C) which exerts a mild but chronic adrenergic stress (Leigh et al J Immunol 2015). The increased incidence and severity of GvHD in TT mice can be reversed by the administration of a β2-adrenergic receptor (β2-AR) agonist, suggesting an important role of epinephrine and norepinephrine in allo-HCT outcome (Leigh et al., J. Immunol 2015; Mohammadpour et al J Immunol 2018). We investigated the mechanisms and downstream events of β2-AR signaling in donor T cells after allo-HCT by using β2-AR knockout (β2-AR-/-) mice and commercially available β2-AR agonists. The main goal here was to explore whether signaling through β2-AR in donor T cells could control GvHD incidence and severity without minimizing the graft-versus leukemia (GvL) effect. We utilized both a major MHC-mismatch C57B6 (H-2kb) into BALB/c (H-2kd) model and a MHC-matched, multiple minor histocompatibility antigen (miHA) mismatched B6 (H-2kb) into C3H/SW (H-2kb) model. Recipient BALB/c and C3H/SW WT mice were lethally irradiated with 850 and 1100 cGy respectively and injected by tail vein with T cell depleted bone marrow (TCD-BM) alone (3 ×106) or TCD-BM and splenic T cells derived from allogeneic WT or β2-AR-/- B6 donors (0.7 × 106 T cells in B6 → BALB/c and 1.5 × 106 in B6 → C3H/SW). We found that donor T cells express β2-AR after allo-HCT and that β2-AR expression on WT T cells plays an important role in controlling GvHD, as evidenced by less severe weight loss, and increased survival compared to mice receiving β2-AR-/- donor T cells (Figure 1A). Histopathologic examination showed that β2-AR-/- T cells induced more damage in the small and large intestine. To explore further the mechanism(s) by which β2-AR signaling controls the severity of GvHD, we used NanoString analysis and discovered that β2-AR-/- T cells have the Th1 phenotype with an increase in Tbx21, Ifng, Irf8 and Emoes genes, while WT CD4+ T cells had higher levels of Th2 and Treg associated genes, including Foxp3, Ptgs5, Tgfb2, Il10, Il21 and Il22. We also observed a significant increase in the inflammatory cytokines IFN-γ and IL-17 in β2-AR-/- CD4+ T cells from the spleen and liver on days 7 and 14 after allo-HCT as compared to WT T cells (Figure 1B), while the expression of IL-10 was significantly higher in WT T cells compared to β2-AR-/- T cells (P< 0.01). We next sought to determine whether GvL may be affected by use of long acting β2-AR agonist (Bambuterol) to control GvHD. Bambuterol was administered daily at a dose of 1mg/kg from day 0. We observed that Bambuterol controlled the severity and mortality of GvHD after allo-HCT in both major and minor mismatch mouse models, as evidenced by reduced weight loss and an improved clinical score and survival rate in mice receiving Bambuterol compared to vehicle (P In conclusion, these data reveal how β-AR signaling can influence donor T cell differentiation and function in murine GvHD models without decreasing GvL effect pointing to the feasibility of manipulation of β2-AR signaling to ameliorate clinical GvHD. Disclosures No relevant conflicts of interest to declare.

It has been hypothesized that vitamin D mediates the inverse relationship between sun exposure and non-Hodgkin lymphoma (NHL) risk reported in several recent studies. We evaluated the association of self-reported sun exposure at ages13, 13-21, 22-40, and 41+ years and 19 single nucleotide polymorphisms (SNPs) from 4 candidate genes relevant to vitamin D metabolism (RXR, VDR , CYP24A1, CYP27B1) with NHL risk.This analysis included 1,009 newly diagnosed NHL cases and 1,233 frequency-matched controls from an ongoing clinic-based study. Odds ratios (OR), 95 % confidence intervals (CI), and tests for trend were estimated using unconditional logistic regression.There was a significant decrease in NHL risk with increased sun exposure at ages 13-21 years (OR(≥15 vs. ≤3 h/week) = 0.68; 95 % CI, 0.43-1.08; p(trend) = 0.0025), which attenuated for older ages at exposure. We observed significant main effect associations for 3 SNPs in VDR and 1 SNP in CYP24A1: rs886441 (OR(per-allele) = 0.82; 95 % CI, 0.70-0.96; p = 0.016), rs3819545 (OR(per-allele) = 1.24; 95 % CI, 1.10-1.40; p = 0.00043), and rs2239186 (OR(per-allele) = 1.22; 95 % CI, 1.05-1.41; p = 0.0095) for VDR and rs2762939 (OR(per-allele) = 0.85; 95 % CI, 0.75-0.98; p = 0.023) for CYP24A1. Moreover, the effect of sun exposure at age 13-21 years on overall NHL risk appears to be modified by germline variation in VDR (rs4516035; p(interaction) = 0.0066). Exploratory analysis indicated potential heterogeneity of these associations by NHL subtype.These results suggest that germline genetic variation in VDR, and therefore the vitamin D pathway, may mediate an association between early life sun exposure and NHL risk.

A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3 + 3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and two patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response.

Previous studies have demonstrated elevated risks for tMDS/AML after chemotherapy for non-Hodgkin lymphoma, Hodgkin lymphoma, and plasma cell neoplasms, but current treatment practices have changed considerably. We utilized large-scale, population-based cancer registry data from the United States to quantify for the first time tMDS/AML risks after chemotherapy for lymphoid malignancies in the current treatment era, including analysis for specific non-Hodgkin lymphoma subtypes. In 17 registries, we identified 121,840 adults without HIV infection who survived ≥1 year following a first primary lymphoid malignancy diagnosis during 2000-2013 and were initially treated with chemotherapy. tMDS/AML risk was compared with that expected in the general population using SIRs. tMDS/AML risk was significantly increased 5- to 9-fold after chemotherapy for the most common lymphoid malignancies, including DLBCL, plasma cell neoplasms, follicular lymphoma, Hodgkin lymphoma, and CLL/SLL (Table 1). Approximately 5-fold increased risks were observed after chemotherapy for marginal zone lymphoma, LPL/WM, and other/unspecified lymphomas. In contrast, risks were strikingly elevated (>10-fold) after chemotherapy for precursor leukemia/lymphoma, Burkitt lymphoma/leukemia, peripheral T-cell lymphoma, and mantle cell lymphoma. Only chemotherapy for hairy cell leukemia was not associated with increased tMDS/AML risk (SIR=1.4), albeit based on small numbers. tMDS/AML risks were higher By time since lymphoid neoplasm diagnosisOverall1.0-4.9 years≥5 yearsFirst primary lymphoid malignancyTotal (N)Mean age at diagnosis (y)NSIR(95%CI)NSIR(95%CI)NSIR(95%CI)Hodgkin lymphoma16,74840.3659.0(6.9, 11.4)4310.7(7.8, 14.5)226.8(4.3, 10.3)CLL/SLL8,47864.31129.4(7.7, 11.3)729.2(7.2, 11.6)409.8(7.0, 13.3)DLBCL31,69259.72045.6(4.8, 6.4)1265.6(4.7, 6.7)785.5(4.4, 6.9)Follicular lymphoma15,65659.51457.8(6.6, 9.2)867.9(6.3, 9.8)597.7(5.8, 9.9)Marginal zone lymphoma4,22362.8295.5(3.7, 7.8)195.7(3.4, 8.9)105.1(2.4, 9.4)Plasma cell neoplasms22,75363.21176.1(5.0, 7.3)795.4(4.3, 6.8)388.2(5.8, 11.2)Precursor leukemia/lymphoma3,53042.73237.3(25.5, 52.7)2852.6(35.0, 76.1)412.3(3.3, 31.4)Mantle cell lymphoma3,52163.44010.1(7.3, 13.8)279.9(6.5, 14.4)1310.7(5.7, 18.3)LPL/WM1,95466.0134.3(2.3, 7.3)105.0(2.4, 9.2)32.8(0.6, 8.2)Peripheral T-cell lymphoma3,15655.73012.7(8.6, 18.1)2315.5(9.8, 23.2)78.0(3.2, 16.5)Burkitt lymphoma/leukemia1,18048.41924.3(14.6, 37.9)1328.6(15.2, 48.9)618.3(6.7, 39.8)Hairy cell leukemia1,70554.631.4(0.3, 4.2)~~Other, unspecified7,24462.0535.7(4.3, 7.4)386.6(4.7, 9.1)154.2(2.3, 6.9) Abbreviations: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); confidence interval (CI); diffuse large B-cell lymphoma (DLBCL); lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM); standardized incidence ratio (SIR); Surveillance, Epidemiology, and End Results (SEER); treatment-related myelodysplastic syndrome/acute myeloid leukemia (tMDS/AML). Citation Format: Lindsay M. Morton, Graca M. Dores, Megan M. Herr, Martha S. Linet, Margaret A. Tucker, Rochelle E. Curtis. Risk of tMDS/AML after chemotherapy for first primary lymphoid malignancy, 2000-2013 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-236. doi:10.1158/1538-7445.AM2017-LB-236

Lymphoma cells are subject to higher levels of oxidative stress compared with their normal counterparts and may be vulnerable to manipulations of the cellular redox balance. We therefore designed a phase 2 study of imexon (Amplimexon/NSC-714597), a prooxidant molecule, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Imexon was administered at 1000 mg/m(2) IV daily for 5 days in 21-day cycles. Gene expression analysis performed on pretreatment tumor specimens included 13 transcripts used to generate a redox signature score, previously demonstrated to correlate with lymphoma prognosis. Twenty-two patients were enrolled having follicular (n = 9), diffuse large B-cell (DLBCL) (n = 5), mantle cell (n = 3), transformed follicular (n = 2), small lymphocytic (n = 2), and Burkitt (n = 1) lymphoma. The most common grade 3/4 adverse events were anemia (14%) and neutropenia (9%). The overall response rate was 30%, including responses in follicular lymphoma (4 of 9) and DLBCL (2 of 5). Gene expression analyses revealed CD68 and the redox-related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses. Therefore, pretreatment markers of oxidative stress may identify patients likely to respond to this therapeutic approach. This trial was registered at www.clinicaltrials.gov as #NCT01314014.

Introduction: Infection is a major source of morbidity and mortality in CLL. Improved treatment efficacy and decreased immune toxicity of treatment could have altered the spectrum and consequences of infections in patients with CLL. A better understanding of infections complicating the course of non-selected patients with CLL could be useful in improving medical management. Methods: Demographic and clinical information was retrospectively extracted from medical records for clinic visits between May 1st, 2000 and May 1st, 2016 for all patients enrolled in the Wilmot Cancer Institute (WCI) CLL database. Data collected on incident infections included site, etiology, treatment, and setting of care. Major infections were defined as requiring either an inpatient stay or IV antimicrobial treatment. Minor infections were defined as any infectious episode requiring oral antimicrobials and outpatient treatment. Incidence rate ratios (IRR) were generated using Poisson regression to compare infection rates across treatment categories. Results: Two hundred and seventy-five CLL patients contributed 937.7 person-years (p-yrs) of follow up from their first clinic visit at WCI (median follow up 2.1 yrs). Median age at diagnosis was 61.6 and only 8.2% of patients had advanced stage CLL. Most patients were CD38 negative (64.7%), ZAP70 negative (54.6%), and IGHV mutated (51.2%, n=89) and 75.1% had either 13q14 deletion as the only defect or no abnormality on FISH analysis. Sixty percent of patients needed treatment for progressive CLL; among those treated, 50.9% were ever treated with either a purine analog or alemtuzumab, 30.4% were treated with other chemotherapies, and 18.6% had non-chemotherapy treatment. B-cell receptor inhibitor (BCR) therapy was used in sixty-seven patients (63 ibrutinib, 4 idelalisib) and was the only therapy in 18 of them (BCR only). Thirty percent of patients experienced at least one major infection (incidence rate 20.4 per 100 p-yrs) and 62.9% experienced at least one minor infection (69.3 per 100 p-yrs). The most common sites of major infections were the lower respiratory tract (7.8 per 100 p-yrs), skin (2.6 per 100 p-yrs), and urogenital tract (2.0 per 100 p-yrs). Minor infections most commonly affected the upper respiratory tract (26.8 per 100 p-yrs), skin (11.0 per 100 p-yrs, including shingles: incidence rate of 2.8 per 100 p-yrs), and bronchi (9.3 per 100 p-yrs). Patients treated for CLL had a higher risk of major infections (IRR 4.15, 95%CI 2.53, 6.80) and minor infections (IRR 1.48, 95%CI 1.23, 1.79) compared to those never treated. The age and gender adjusted risk of both major and minor infections were significantly increased by treatment with a purine analog or alemtuzumab (Table 1). The risk of major infection in the BCR only group was significantly higher than treatment-naive patients (IRR 3.31 95%CI 1.13, 9.80) and was 43% lower compared to patients treated with other modalities (IRR 0.57, 95%CI 0.21,1.55). The BCR group had a significantly higher risk of a minor infection compared to untreated patients (IRR 1.86 95% 1.14, 3.04), but had a slightly lower risk compared to those treated with other modalities (IRR 0.93 95%CI 0.57, 1.48). The BCR only group had a longer infection free survival compared to those on BCR inhibitor salvage therapy (Figure 1). An intra-patient comparison of infection risk for patients receiving BCR inhibitor salvage therapy compared to their previous chemoimmunotherapy showed an 33% increase in the risk of a major infection (IRR 1.33 95%CI 0.96, 1.86) and a 185% increased risk of a minor infection (IRR 2.85 95%CI 1.57, 5.18). Conclusion: CLL is complicated by a large number of infections, especially in patients with progressive disease who require treatment. Minor infections contribute to considerable disease burden and can have serious sequelae (e.g. post herpetic neuralgia). Given their decreased immune toxicity profile, BCR inhibitors may decrease the risk of infections; however, this has not yet been confirmed. Our sample of CLL patients treated solely with BCR inhibitors experienced higher rates of infection compared to untreated patients. Additionally, patients treated with BCR inhibitors as salvage therapy still experienced higher rates of infection compared to their time on chemoimmunotherapy. Therefore, patients treated with BCR inhibitors should be carefully monitored for infections that can cause significant morbidity or mortality. Disclosures Barr: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy.

Introduction. Advances in treatment have improved prognosis after diagnosis with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Understanding factors that impact long-term morbidity and mortality of lymphoma survivors is therefore of increasing clinical importance. Elevated risk for developing cutaneous melanoma after lymphoma is well-established, but the potential extension of this association for rarer NHL subtypes and other types of cutaneous malignancies is unknown. Methods. We identified a cohort of 129,850 non-HIV infected adults (age ³20 years) who were initially diagnosed with one of the seven most common types of lymphoma (Table 1) during 2000-2013 and who survived ³1 year, as reported to 17 United States population-based cancer registries from the Surveillance, Epidemiology, and End Results program. Standardized incidence ratios (SIRs) and corresponding 95% confidence intervals (95% CI) quantified risks for second primary melanoma, Merkel cell carcinoma, and sebaceous carcinoma, comparing the observed number of cases to that expected in the general population based on age-, race-, sex- and calendar period-specific incidence rates. Results. Melanoma occurred in 258 survivors of CLL/SLL, nearly two-fold more often than expected in the general population (SIR=1.94, 95% CI=1.71-2.20). Risk also was significantly elevated among survivors of follicular lymphoma (N=108, SIR=1.32, 95% CI=1.08-1.32) and peripheral T-cell lymphoma (N=22, SIR=1.68, 95% CI=1.05-2.54), whereas SIRs were non-significantly greater than unity after other NHL subtypes except marginal zone lymphoma (N=37, SIR=1.06, 95% CI=0.74-1.46). Merkel cell carcinoma and sebaceous carcinomas were much rarer but were associated with substantially higher risks compared with melanoma. Merkel cell carcinoma also occurred most commonly after CLL/SLL (N=20, SIR=3.90, 95%CI=2.38-6.02) with significantly elevated SIRs after follicular lymphoma (N=8, SIR=2.99, 95%CI=1.29-5.89) and mantle cell lymphoma (N=7, SIR=16.04, 95% CI=6.45-33.04). In contrast, the risk patterns differed for sebaceous carcinoma, with elevated risks after CLL/SLL (N=10, SIR=5.04, 95% CI=2.42-9.27), DLBCL (N=7, SIR=5.13, 95% CI=2.06-10.57), marginal zone lymphoma (N=4, SIR=7.67, 95% CI=2.09-19.63), and lymphoplasmacytic lymphoma/Waldenstršm macroglobulinemia (N=3, SIR=14.15, 95% CI=2.92-41.35). Conclusions. Survivors of specific lymphoma subtypes have differential risks of developing a range of subsequent cutaneous malignancies. CLL/SLL is the lymphoma subtype most closely associated with cutaneous malignancy risk, whereas DLBCL survivors only have strongly elevated risk for sebaceous carcinoma. Further studies should investigate potential roles for immune dysfunction, infection, and genetic susceptibility in the etiology of cutaneous malignancies developing after NHL. Survivors and clinicians should consider the importance of regular full skin examinations to maximize opportunities for early detection of cutaneous malignancies to reduce morbidity. Disclosures No relevant conflicts of interest to declare.

Introduction Survivors of non-Hodgkin lymphoma (NHL) have elevated risk for developing new malignancies. Although infections have been associated with the etiology of certain NHL subtypes, understanding of the patterns of potential infection-related new malignancies among NHL survivors is limited. Methods We conducted a registry-based cohort study among non-HIV infected adult (aged ≥20 years) one-year survivors of NHL diagnosed and treated in the modern era (2000-2013). The eligible cohort survived at least one year following diagnosis with one of the four most common NHL subtypes [diffuse large B-cell lymphoma (DLBCL, n=36,869), chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL, n=38,377), follicular lymphoma (FL, n=27,388), and marginal zone lymphoma (MZL, n=12,773)], as reported to 17 Surveillance, Epidemiology, and End Results registries. Standardized incidence ratios (SIRs) and 95% confidence intervals were used to quantify risks of infection-related second cancers, defined according to the International Agency for Research on Cancer to include cancers of the lung, stomach, liver, salivary gland, cervix, and anus. Results Non-small cell lung cancer was the most commonly occurring infection-related second cancer, with consistently elevated 1.2-1.5-fold risk among survivors of all four NHL subtypes. Similarly, risk of salivary gland cancer was elevated but with a greater magnitude of risk, with SIRs ranging from 2.4 among DLBCL survivors to 3.0 after FL. In contrast, stomach cancer risk was only elevated among survivors of DLBCL (SIR=1.5) and MZL (2.8). Stratifying the cohort of NHL survivors by the NHL site revealed the highest stomach cancer SIRs among survivors of gastric DLBCL (2.8) and MZL (6.8). Liver cancer also was only elevated among DLBCL (1.8) and MZL (2.0) survivors. Anal cancer risk was elevated after DLBCL (2.3) and borderline significantly elevated for MZL (2.4) and CLL/SLL survivors (1.7). Risk for cervical cancer was not elevated among survivors of any of the four most common NHL subtypes. Discussion Certain infection-related cancers have elevated risks among all NHL survivors; in contrast, others are only elevated after DLBCL and MZL, which may reflect differences in infectious disease prevalence among primary NHL subtypes. For example, H. pylori and hepatitis C virus have been associated with the development of DLBCL and MZL and are also associated with second liver and stomach cancers, likely due to the increased prevalence of these infections among DLBCL and MZL survivors compared with the general population. In contrast, the persistently elevated risks for non-small cell lung cancer and cancer of the salivary gland among survivors of all four of the most common NHL subtypes warrants further investigation into potential infectious origins or immune dysfunction. Alternatively, the excess risk may be due to surveillance bias, as these patients receive regular CT scans and monitoring after their NHL diagnosis. To contradict this theory, when we investigated second lung and salivary gland cancer risks stratified by latency, we did not find a consistently elevated risk immediately following NHL diagnosis ( Conclusion Survivors of the four most common NHL subtype have elevated risks of certain infection-related cancers. Differential patterns of risk provide clues to second cancer etiology as well as highlighting survivors at higher risk who might benefit the most from more intensive surveillance. Table Table. Disclosures No relevant conflicts of interest to declare.

CNS metastasis is the spread of a primary cancer to the CNS and occurs in up to 25% of cancer patients. Antidepressant therapy, used in 15-30% of cancer patients, affects the blood-brain barrier, potentially making patients more susceptible to CNS metastasis. This hypothesis is supported by an experimental study reporting increased CNS metastasis from breast cancer in mice receiving fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRIs). However, no human studies have looked at this association. We conducted a case-control study to examine whether antidepressants, and specifically SSRIs, increased the relative odds of CNS metastasis. We identified cancer patients diagnosed with breast cancer, melanoma, and non-Hodgkin lymphoma (NHL) at one academic cancer center in Rochester, NY between 2005 and 2013. We ascertained 189 patients with CNS metastasis (cases) and 945 patients without CNS metastasis (controls). Cases of CNS metastasis were identified by the ICD-9 code 198.3 secondary malignant neoplasm of brain and spinal cord. Cases and controls were classified with regard to their antidepressant use based on medical chart review. Using multivariable logistic regression, we estimated the relative odds of CNS metastasis associated with ‘any antidepressant use’ (any antidepressant irrespective of class), ‘any SSRI use’ (SSRI use, nonexclusively), and ‘exclusive SSRI use’ (only SSRI use and no other class of antidepressant), all compared to ‘no antidepressant use’. Subset analyses were planned a priori for breast cancer and melanoma; subset analyses could not be conducted for NHL due to the small sample size. Both cases and controls had a median age of 53 years (range: 25-94 years and 15-89 years, respectively). The prevalence of ‘any antidepressant use’ was 28.6% in cases and 25.7% in controls, whereas SSRIs were used in 16.9% of cases and 15.6% of controls. Among all patients, ‘any SSRI use’ was not associated with CNS metastasis (odds ratio (OR) = 1.21; 95% confidence interval (CI) = 0.74, 1.97). However, among breast cancer patients, ‘any SSRI use’ was associated with a 1.73 times greater odds of CNS metastasis (95% CI = 0.75, 4.04). No consistent patterns of association were observed in the analyses of other cancer subsets or exposure measures. This was the first study to examine the association between antidepressant use and CNS metastasis. We did not observe clear patterns of association which may be due in part to the small sample size in many of our analyses. However, we believe that the increased odds in the breast cancer subset warrants further investigation as this is consistent with the animal research. Citation Format: Megan Herr, Nimish Mohile, Edwin van Wijngaarden, Edward Brown, David Q. Rich. Antidepressant use and risk of central nervous system metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3452.

e17587 Background: Pancreatic cancer affects more than 48,000 individuals each year and currently is the fourth leading cause of cancer death in the United States. Dismal outcomes are in large part...

Introduction: For patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), salvage treatment followed by consolidation with high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT) is the standard of care for those with chemosensitive disease, as established by the PARMA and CORAL trials. In the pre-rituximab era, patients with DLBCL experiencing disease progression following HD-ASCT had a dismal prognosis with a median overall survival of 3 months. These early studies demonstrate that early progression following HD-ASCT is the most important predictor of poor outcome. In the rituximab era, there is very little data examining incidence and outcomes of patients with late relapses following HD-ASCT for relapsed/refractory DLCBCL. Therefore, we sought to evaluate survival outcomes in a cohort population of patients relapsing late after HD-ASCT for DLBCL. Methods: We reviewed consecutive patients who underwent HD-ASCT for biopsy confirmed relapsed or refractory DLBCL between 2001 and 2010 at the University of Rochester James P. Wilmot Cancer Institute. Eligible patients were required to have received rituximab as part of their therapeutic regimen. Survival probability was estimated by the Kaplan-Meier method. Comparisons were made using the X2 test and Fisher's exact test, where appropriate. Results: A total of 88 patients were identified. Median age was 55 (range 20-74). Eighty percent of patients received a BEAM – like conditioning regimen (Carmustine, Etoposide, Cytarabine, and Melphalan). Thirty-five patients were in complete remission at the time of transplant. Median follow up for surviving patient was 5.8 years (range 139 days -12.5 years). The median overall survival for all patients was 5.2 years (range of 15 days-12.5 years). In total, 51 patients died (58%); 31 of these deaths were related to DLBCL (61%). Median progression free survival was not reached. Thirty-five patients relapsed following ASCT. Of these, 89% relapsed < 3 years from ASCT (early relapse), 2 of whom remain alive. Only 4 patients (11%) relapsed ≥ 3 years from ASCT (late relapse), 2 of whom died, and 2 of whom remain alive. Of the deaths, 1 was lymphoma-related, and 1 was death from graft versus host disease in a patient undergoing subsequent allogeneic transplant. Median time to progression in the entire cohort was 167 days. Consistent with early studies, the presence of disease status prior to ASCT was associated with shorter time to progression, p=0.0028 by Fisher's exact test. Conclusions: Ours is one of few series examining late relapses following ASCT performed for relapsed and refractory DLBCL in the rituximab era. In this cohort, late relapses following ASCT for relapsed and refractory DLBCL occurred infrequently. Our data indicate that for the few patients relapsing beyond 3 years, there is a suggestion of long-term disease control. Figure 1: Figure 1:. Progression Free Survival of Patients Relapsing After ASCT for Relapsed/Refractory DLBCL Based on Time to Progression Disclosures No relevant conflicts of interest to declare.

Background Imexon is a 1-carboxamido-2-cyan-aziridine isomer investigated as an anti-cancer agent given its pro-oxidant properties. By binding reduced sulfhydryls leading to the accumulation of reactive oxygen species, imexon interferes with the endoplasmic reticulum and mitochondrial reduction-oxidation (redox) balance, inhibiting protein translation and cell growth and inducing apoptosis. Pre-clinical studies demonstrated activity across an array of tumor cells in vitro and increased activity amongst B-cell non-Hodgkin lymphomas (NHL). A partial response in a follicular lymphoma (FL) patient was observed in a previous phase I study. This phase II trial was initiated to further investigate the clinical activity of imexon in patients with relapsed or refractory NHL. Methods Histologically confirmed NHL, > 1 prior therapy, age≥18, ECOG performance status 0–2, measurable disease, signed informed consent, creatinine and bilirubin < 2.0 x IULN as well as G6PD > IULN were required. Patients were treated with imexon 1000 mg/m2 IV daily on days 1-5 of a 21 day cycle for up to 1 year. Messenger RNA analysis was performed on pre-treatment tumor specimens, evaluating 22 genes important for antioxidant enzyme expression, 16 genes previously associated with outcome in NHL as well as 4 immune cell surface markers. Included were 13 genes used to generate a redox signature score, previously demonstrated to correlate with NHL prognosis (Tome, Blood 2005). Results Twenty-two NHL patients [9 FL, 5 diffuse large B cell (DLBCL), 3 mantle cell, 2 transformed follicular, 2 chronic lymphocytic leukemia and 1 Burkitt] with a median age of 64 (range 43-92) completed a median of 2.5 (range 1-13) cycles of therapy. With a median number of 4 prior therapies, 9 patients had undergone a prior stem cell transplant, 10 had stage IV disease and 6 were refractory to prior therapy. Twenty patients were evaluable for response, 2 pts discontinued therapy during cycle 1 due to progressive disease and grade 5 sepsis respectively. Of the 20 evaluable patients, the overall response rate was 30% (6/20) with another 35% achieving stable disease. Responses were observed in 4 FL and 2 DLBCL pts. After a median follow-up of 7 months, the median progression free survival (PFS) was 2.4 mos (range, 0.6 to 19.1 mos) with a median PFS of 6.7 mos (range, 1.2 to 9.0 mos) in FL patients. The median overall survival has not been reached. Grade 3 and 4 toxicities consisted of anemia (7 pts), thrombocytopenia (2 pts), neutropenia (2 pts), sepsis (2 pts), vomiting (2 pts), pneumonia (2 pts), fatigue (2 pts), dehydration (2 pts) as well as hypokalemia, hyperuricemia, transient ischemic attack, increased creatinine, rash and urinary tract infection in 1 pt each. 13 pts had available pre-treatment tumor biopsies, 2 of which attained a partial response with therapy. Patients with a higher redox score were more likely to achieve an objective response (p=0.03). Further, individual genes most predictive of response included CD68, GPX1 and SOD2. Conclusions This is the first trial to demonstrate that targeting the cellular redox environment is a viable therapeutic strategy in NHL and may be particularly effective in FL. The side effect profile may lend imexon to rational combination studies. Lymphomas reliant on antioxidant defense enzymes for proliferation and survival may be more susceptible to redox directed therapy. Evaluation of antioxidant related gene expression as a predictive biomarker is warranted in future investigations of imexon and similar targeted agents. (NCT01314014) Disclosures: Barr: Seattle Genetics: Consultancy; Celgene: Consultancy. Off Label Use: Imexon; being investigated for use in Non-Hodgkin lymphoma. Schwartz:HTG Molecular Diagnostics: Employment. Dorr:Amplimed Corporation: Employment.

Histone deacetylase (e.g., vorinostat) and proteasome inhibitors interact synergistically to promote cell death in various cancer cells, including malignant human hematopoietic cells. The novel, proteasome inhibitor carfilzomib is an attractive candidate for combination regimens due to diminished neurotoxicity, irreversible proteasome inhibition, favorable tolerability profile relative to bortezomib, and preclinical and clinical evidence of activity in bortezomib-resistant cells and patients. Preclinical studies demonstrated synergistic interactions between carfilzomib and vorinostat in human diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells both in vitro and in vivo as well as in bortezomib-resistant cells (Dasmahapatra et al., Blood 115:4478; 2010; Mol Cancer Ther 10:1686, 2001). These preclinical findings prompted a phase 1 trial, using a 3+3 design, with the goal of determining the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for the combination of carfilzomib and vorinostat in patients with recurrent or refractory B-cell lymphomas. Eligible patients included those with recurrent or refractory non-Hodgkin’s lymphoma. The schedule of administration was vorinostat orally twice-daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Initial dose levels were 20/27 mg/m2 (carfilzomib) and 200 mg (vorinostat). To date, 20 patients have been treated at 4 dose levels. Patient characteristics included the following disease types: DLBCL, n = 6; follicular lymphoma, n = 2; MCL, n = 10; and transformed lymphoma, n = 2. The male to female ratio was 14:6, the median age was 67 years (range: 36-79), ECOG performance scores ranged from 0 to 2, and the median number of prior therapies was 3.5 (range: 1-13). Dose-limiting toxicities (DLTs) and adverse events were determined using CTCAE version 4. Grade 3 and 4 AEs possibly, probably, or definitely related to study treatment occurring in ≥ 5% of patients included anemia (grade 3, 15%), leukopenia (grade 4, 10%; grade 3, 15%), lymphopenia (grade 3, 10%), neutropenia (grade 4, 5%; grade 3, 25%), thrombocytopenia (grade 3, 10%), catheter-related infection (grade 3, 5%), dyspnea (grade 3, 5%), fatigue (grade 3, 5%), febrile neutropenia (grade 3, 5%), hypokalemia (grade 3, 5%), hyponatremia (grade 3, 5%), lymph node pain (grade 3, 5%), and pneumonitis (grade 3, 5%). Two grade 5 events were observed; 1 was attributed to disease progression and not related to study treatment; 1 was attributed to pneumonia possibly related to treatment. Common grade 2 AEs possibly, probably or definitely related to treatment in ≥ 15% of patients included anemia (25%), diarrhea (15%), fatigue (20%), hyperglycemia (15%), hypokalemia (15%), nausea (15%), neutropenia (15%), thrombocytopenia (20%), and vomiting (15%). There were 2 DLTs at dose level 1, grade 3 pneumonitis and febrile neutropenia, and there were no DLTs at dose level -1 (carfilzomib 20/20 mg/m2 and vorinostat 100 mg twice daily). Two intermediate dose levels (-1a and -1b) were added between dose-levels 1 and -1. No DLTs or significant differences in toxicities were observed at dose levels -1a and -1b. Consequently, two MTD/RP2D levels have been identified: carfilzomib 20/20 mg/m2 and vorinostat 200 mg twice daily (level -1a) and carfilzomib 20/27 mg/m2 and vorinostat 100 mg twice daily (level -1b). All 20 patients treated were evaluable for response. The best response on this phase 1 study was 1 partial response; 2 patients had stable disease. Correlative studies evaluating pre- and post-treatment plasma levels of IL-10 and TNF are currently undergoing analysis. Collectively, these findings indicate that the combination of carfilzomib and vorinostat is reasonably tolerable in this patient population. Two dose levels have been identified for the MTD/RP2D. The regimen appears to have modest activity in heavily pre-treated patients with relapsed and/or refractory B-cell lymphomas. Disclosures: Friedberg: Merck & Co.: Research Funding.