Michael. L. Grossbard

Patients with hematologic malignancies are a high priority for SARS-CoV-2 vaccination, yet the benefit they will derive is uncertain. We investigated the humoral response to vaccination in 53 non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or CLL patients. Peripheral blood was obtained 2 weeks after first vaccination and 6 weeks after second vaccination for antibody profiling using the multiplex bead-binding assay. Serum IgG, IgA, and IgM antibody levels to the spike specific receptor binding domain (RBD) were evaluated as a measure of response. Subsequently, antibody-positive serum were assayed for neutralization capacity against authentic SARS-CoV-2. Histology was 68% lymphoma and 32% CLL; groups were: patients receiving anti-CD20-based therapy (45%), monitored with disease (28%), receiving BTK inhibitors (19%), or chemotherapy (all HL) (8%). SARS-CoV-2 specific RBD IgG antibody response was decreased across all NHL and CLL groups: 25%, 73%, and 40%, respectively. Antibody IgG titers were significantly reduced (p < 0.001) for CD20 treated and targeted therapy patients, and (p = 0.003) for monitored patients. In 94% of patients evaluated after first and second vaccination, antibody titers did not significantly boost after second vaccination. Only 13% of CD20 treated and 13% of monitored patients generated neutralizing antibodies to SARS-CoV-2 with ICD50s 135 to 1767, and 445 and > 10240. This data has profound implications given the current guidance relaxing masking restrictions and for timing of vaccinations. Unless immunity is confirmed with laboratory testing, these patients should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals. Statement of Translational Relevance Non Hodgkin lymphoma (NHL) and Chronic Lymphocytic leukemia (CLL) patients who are treated with anti-CD20 antibody therapy, BTK inhibitor therapy, or who are monitored with active disease, have decreased antibody response to SARS-CoV-2 vaccination and decreased antibody titers compared to healthy controls. Antibody titers do not boost following second vaccination, and very few patients generate neutralizing antibodies against SARS-CoV-2. This data is of particular importance, given the recent guidance from the CDC that vaccinated patients no longer need to be masked indoors as well as outdoors. Patients with NHL or CLL who fall into these categories should not consider their immunity from vaccination to be assured. If infected with SARS-CoV-2, they should be a high priority for monoclonal antibody directed therapy. Unless immune response to vaccination is confirmed with laboratory testing, they should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.

10039 Background: Survival outcomes for older patients with aggressive NHL are disproportionally inferior to those of younger patients. While differences in tumor biology may play a role, older patients are often frail with comorbidities, polypharmacy, and use potentially inappropriate medications (PIM) such as anticholinergics and benzodiazepines. Methods: Using Cox proportional hazard and logistic regression models, we analyzed all aggressive NHL patients age ≥60 treated at our two affiliated hospitals from 2009-2014 to examine the association of polypharmacy and PIM use with progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Results: In this updated and final analysis, we included 171 patients with complete records from these two hospitals. They share similar demographic, clinical, and laboratory characteristics except for higher International Prognostic Index (IPI) in patients from one hospital. The median age was 70 years (range 65-77). At the time of diagnosis, 46% of patients used more than 4 medications (polypharmacy) and 47% used at least one PIM. Only 43% of patients received first-line chemotherapy of adequate relative dose intensity (>85% dosage), and 65% experienced ≥grade 3 toxicities. Polypharmacy and PIM use were associated with shortened PFS and OS by log-rank test. Most importantly, PIM use remained an independent predictor of PFS, OS, and ≥ grade 3 toxicities in multivariable analyses (Table). Conclusions: This is the first report of significantly adverse survival impacts of polypharmacy and PIM use in older patients with aggressive NHL, presumably from drug-drug interactions that increase toxicities and impair the delivery of adequate chemotherapy dosage. Our findings support the use of evidence-based geriatric principles to guide meticulous medication management to improve outcome disparity for these patients. [Table: see text]

129 Background: Survival outcomes for older patients with aggressive non-Hodgkin’s lymphoma (NHL) are disproportionally inferior to those of younger patients. While differences in tumor biology may play a role, older patients are often frail with comorbidities, polypharmacy, and use potentially inappropriate medications (PIM). Methods: Using Cox proportional hazard and logistic regression models, we retrospectively analyzed all aggressive NHL patients age 60 and older diagnosed and treated at our institution from 2009-2014 to examine the effect of polypharmacy and PIM use on progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Results: We included 141 patients with evaluable data after excluding patients with incomplete record. The median age was 71 years. At the time of diagnosis, 44% of patients used more than 4 medications and 47% used at least one PIM. During first-line treatment, only 43% of patients received chemotherapy of adequate relative dose intensity (>85% scheduled dose), and 63% experienced grade 3 or greater toxicities. Age, International Prognostic Index, and PIM use correlated with each other. Number of medications (p = 0.005) and PIM use (p < 0.001) were associated with shortened PFS by log-rank test, and PIM use remained a strong independent predictor of PFS in multivariable analysis (HR 1.84, p = 0.005). Number of medications (p = 0.003) and PIM use (p = 0.009) were also associated with shortened OS by log-rank test, although only albumin level predicted OS in multivariable analysis. Most importantly, PIM use was strongly associated with grade 3 or greater toxicities in multivariable analysis (OR 7.4, p = 0.001). Conclusions: We report here for the first time adverse impacts of polypharmacy and PIM use in older patients with aggressive lymphoma. We suggest that drug-drug interactions may significantly impair the delivery of adequate chemotherapy dosage and increase toxicities thus resulting in inferior survival outcome. Our findings support the use of evidence-based geriatric and palliative care principles to guide meticulous medication management to eliminate outcome disparity in older lymphoma patients.

Background: In Hodgkin lymphoma (HL) the malignant Hodgkin Reed-Sternberg (HRS) cells comprise only a small fraction of the total cellular tumor population, which orchestrate an inflammatory microenvironment of reactive cells that propagate a permissive milieu for HL growth. This HL-mediated immune suppression may have effects that extend beyond the tumor microenvironment. Previously we have shown that the circulating T cells of HL patients show high expression of the receptor programmed death-1 (PD-1). Here wecharacterize the systemic immune profile of 20 HL patients with newly diagnosed (ND) or relapsed (R) disease. Methods: Informed consent obtained from patients with ND (n = 14) or R (n = 6) HL treated since January of 2013. Blood samples were drawn pre-treatment, and at sequential time-points during therapy. Cryopreserved PBMCs were thawed then evaluated with multi-color flow cytometry. Cells were stained with fixable viability dye (eBioscence); then stained with fluorescent-conjugated antibodies. For intracellular staining, cells were fixed and permeabilized using FOXP3 staining kit (eBioscience) then stained with intracellular antibodies. Stained cells were analyzed using LSRII flow cytometer (BD Bioscience) and FlowJo software (Tree Star). The following anti-human antibodies were used: CD3, CD4, CD8, CD25, CD160, CD45RO, CD27, HLA-DR, PD-1,FOXP3 and Helios, (Biolegend). Singlet lymphocytes were gated based on forward and side scatter properties. Dead cells were excluded based on viability dye. Patient samples were compared to normal controls matched for age and sex (n = 20). Results: The median HL patient age was 38 (range: 20-90 years). Twelve of the HL subjects were male and 8 were female. All but 1 ND patient were treated with upfront ABVD. Two out of 6 R patients had prior stem cell transplant (SCT), but were not on immunosuppression. Thirteen patients (12 ND, 1 R) responded to therapy (11 CR and 2 PR); 4 patients (1 ND, 3 R) progressed on therapy or had stable disease, 2 patients do not have disease status confirmed. HL patients displayed distinct circulating immune profile compared to normal age matched controls, with increased circulating CD4 and CD8 effector cells and a decrease in CD8 central memory cells. The proportion of CD4 or CD8 effector memory T cells expressing CD160+ and PD1+ CD4 effector memory cells, were also highly significantly increased in HL patients. In contrast, a decreased percent of bona fide CD4+ regulatory T cell subset (Foxp3+Helios) was found in HL patients. Together these findings suggest that the systemic immune profile in HL patients is perturbed towards severe chronic activation/exhaustion of T cells. Conclusion: HL patients have evidence of chronic activation/exhaustion in their central memory T cells, suggesting that ineffective immune clearance of the HRS cells may be a systemic phenomenon. This underscores the rationale for immune targeted therapy in HL patients. Citation Format: Catherine S. Diefenbach, Bruce Raphael, Kenneth Hymes, Michael Grossbard, Tibor Moskovits, David Kaminetzky, Meghan Mcshea, Peter Martin, Jia Ruan, Lina Kozhaya, Maryam Bonakdar, Cem Abidoglu, John Leonard, Derya Unutmaz. Hodgkin lymphoma patients demonstrate evidence of chronic activation/exhaustion in circulating T cell subsets. [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 4895.

6562 Background: Survival outcomes for elderly non-Hodgkin’s lymphoma (NHL) patients are disproportionally inferior to those of younger patients. While their tumor biology may differ, elderly patients are often frail with comorbidities and polypharmacy, and use potentially inappropriate medications (PIM) as defined by the Beers Criteria. Methods: Using Cox proportional hazard and logistic regression models, we retrospectively analyzed all NHL patients age 60 and above diagnosed at our institution from 2009-2014 to examine the impact of polypharmacy and PIM use on primary end-points of progression-free survival (PFS) and overall survival (OS), and the secondary end-point of treatment-related toxicities. Results: We included 246 patients with evaluable data after excluding patients with incomplete record or treated elsewhere. The median age was 71 years. Aggressive lymphoma accounted for 57% of patients. At the time of diagnosis, 49% of patients had more than 4 medications and 48% used at least one PIM. During first-line treatment 45% of patients experienced grade 3 or greater toxicities (CTCAE v4). Charlson Comorbidity Index (CCI), polypharmacy, and PIM use correlated with each other. Number of medications (p = 0.004) and PIM use (p < 0.001) were associated with shortened PFS by log-rank test, and PIM use remained an independent predictor of PFS in multivariable analysis (HR 1.62, p = 0.001). Number of medications (p = 0.004) and PIM use (p = 0.002) were also associated with shortened OS by log-rank test. However, only CCI and lymphoma grade predicted OS in multivariable analysis. Finally, PIM use was strongly associated with grade 3 or greater toxicities in multivariable analysis (OR 3.1, p = 0.002). Conclusions: We report here for the first time adverse impact of geriatric polypharmacy and PIM use in elderly lymphoma patients. It seems plausible that the reduced survival is due to drug-drug interactions during intensive chemotherapy that lead to increased toxicities or impair delivery of full dose chemotherapeutics. Our findings support the use of geriatric principles to guide meticulous medication management to improve outcomes for elderly lymphoma patients during active treatment.