Johnson, Bradley K.

Abstract Backgrounds: Autologous stem cell transplant (ASCT) has been the standard treatment approach for patients with relapsed or high-risk lymphoma for several decades. Despite the improvement in supportive care, age has remained one of the critical factors that determines transplant eligibility and outcomes. Herein, we explored the transplant-related outcomes of patients with lymphoma aged 70 years or older at our institution and compared to those with younger ages. Methods: In this retrospective single center study, we include all patients with diagnosis of lymphoma who underwent ASCT between January 2000 and February 2021 at Mayo Clinic, Rochester, Minnesota. In addition to data obtained from the transplant database, we abstracted data from electronic medical record. We described relevant clinical characteristics and transplant associated outcomes including engraftment, transplant related mortality, relapse incidence, and survival outcomes. We compared the key transplant related outcomes with patients at the younger age group between 65 and 70 years old. Results: A total of 196 patients with lymphoma aged 70 years or older underwent ASCT between January 2000 and February 2021. The median age of patients at the time of ASCT was 72.4 (70.0-78.7) years with 24 patients (12.2%) being older than 75 years old. Of 196 patients, 76 (38.8%) had Charlson comorbidity index of 3 or higher and 10 (5.1%) had performance status of 2 or higher at the time of ASCT. Table 1 summarizes the relevant baseline clinical characteristics of 196 patients in this cohort including the comparison with younger patients (age 65-70 years old, n=296). The most common transplant indication in this cohort was relapsed diffuse large B cell lymphoma. The majority of patients (91.3%) received peripheral blood graft with a median CD34+ cell dose of 5.14x10 6 cells/kg which was significantly lower than younger patients (P=0.01). The rate of neutrophil and platelet engraftment was 99.0% and 98.8% with corresponding median time to engraftment of 13 days for both cell lineages. The 30- and 100-day non-relapse mortality (NRM) of the entire cohort was 1.5% (95%CI 0-3.2%) and 4.6% (95%CI 1.6-7.5%) not statistically different between 70-75 years old and 75 years or older cohorts. With the median follow-up duration of 48 months, the 2-year event free survival (EFS) and overall survival (OS) was 55.9% (95%CI 49.2-63.5%) and 67.4% (95%CI 61.0-74.5%), respectively. Patients from the 70 years old or older cohort had similar EFS but inferior OS compared to the 65-70 years old cohort. However, there was no difference in EFS and OS between 70-75 and >75 years old cohorts. There was overall an improved trend of 30-day NRM, 2-year EFS and 2-year OS over the 3 different transplant periods (Figures). Although not statistically significant, patients who underwent ASCT between 2000 and 2006 had a trend towards higher 30-day NRM compared to patients who were transplanted at later time points (7.3% vs 0%, P=0.06). The major causes of death included progressive lymphoma, infection, and conditioning regimen related organ toxicities. Conclusion: Outcomes of ASCT in older patients with lymphoma have improved over time with an excellent 30-day NRM (0%) in the past recent years. The major cause of treatment failure after ASCT was progressive disease. With appropriate patient selection, ASCT in older patients is feasible and provides acceptable outcomes comparable to the patients from younger age group. Figure 1 Figure 1. Disclosures Paludo: Karyopharm: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.

Introduction: Cardiorenal dysfunction with impaired cyclic guanosine monophosphate (cGMP) response to volume load is a hallmark of heart failure. Phosphodiesterase V (PDEV) is known to be upregulated and may explain the dysfunction of renal response. Hypothesis: We tested the hypothesis that PDEV inhibition in combination with low dose intravenous (IV) B-type natriuretic peptide (BNP) would improve renal function and potentiate urinary sodium and cGMP excretion in patients with acute heart failure. Methods: Randomized open label study in 67 patients admitted to the hospital with acute heart failure. These patients were randomized to standard care, low dose IV BNP (0.005μg/kg/min), or combination low dose BNP/PDEV inhibition with sildenafil (25 mg q12 hrs) for 48 hours. Plasma and urine studies were obtained at baseline, 24 hours, and 48 hours after study drug initiation to assess renal function. The primary endpoint was the percent change in estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) from baseline to 48 hours. Changes from baseline were summarized with median and quartiles and groups were compared using two-sample t-test. [ClinicalTrials.gov Identifier: NCT00972569] Results: Baseline characteristics were similar between groups. Median age was 78 years and median ejection fraction 39%. Treatment with BNP and BNP/PDEV inhibitor significantly increased plasma cGMP at 24 hr (% increase of 25.6 (8.9, 13.1) and 60.8 (32.3, 103.8) for BNP and BNP/PDEV vs % decrease of 13.5 (-29.1, 14.2) for placebo, p=0.001). BNP levels were significantly higher in both groups at 48 hr compared with placebo. However, there was no significant change in eGFR, BUN, or urinary sodium/cGMP excretion between groups. Hypotension was more common in the BNP/PDEV inhibitor group. Conclusions: Low dose IV BNP and combination BNP/PDEV inhibition increased plasma cGMP in patients with acute heart failure but did not improve renal function or urinary sodium/cGMP excretion. Our study does not support the use of low dose IV BNP with or without PDEV inhibition to enhance renal function in patients admitted with acute heart failure.

Introduction: Atrial natriuretic peptide (ANP) plays an important role in blood pressure (BP) regulation via the second messenger cGMP. ANP also induces lipolysis by increasing plasma levels of non-esterified fatty acids (NEFA). MANP is a new Mayo Clinic designed ANP analog consisting of the native ANP with a novel 12-amino-acid C-terminus extension. In experimental models, MANP is more potent than ANP in reducing BP and inducing natriuresis. These actions are mediated by the activation of the pGC-A receptor and generation of cGMP. To date, the BP pressure lowering, cGMP generating and lipolytic actions of MANP remain unexplored along with its safety and tolerability in subjects with hypertension (HTN) associated with metabolic disease. Hypothesis: In subjects with HTN, obesity and metabolic syndrome (MS), MANP administration is safe, well tolerated, activates cGMP and exerts BP lowering and lipolytic properties. Methods: Double-blind, placebo-control clinical trial in 22 subjects (17 receiving MANP) with HTN, obesity and MS involving a single subcutaneous (SQ) injection of MANP (2.5 μg/Kg) or placebo. Subjects were monitored and cardiovascular, cGMP and metabolic parameters were collected during 24 hours after the injection. Results: In all subjects, MANP was safe and well-tolerated with no serious adverse side effects. MANP increased mean cGMP plasma levels after 30 minutes (delta: 4.8 ± 2.0 pmol/mL, p=0.02) and 1 hour (delta: 2.9 ±1.3 pmol/mL, p=0.03) when compared to baseline. Six hours after MANP injection systolic BP decreased by 5.7 ± 2.9 mmHg (p=0.06) whereas subjects receiving placebo had no decrease in blood pressure values compared to baseline. During fasting period, one hour after the administration of MANP, NEFA plasma levels increased by 108.2 ± 37.4 μM (p=0.01). Conclusions: In subjects with HTN, obesity and MS, SQ MANP is safe, well tolerated and activates the pGC-A receptor as measured by a significant increase in the second messenger cGMP. Subjects receiving MANP showed a borderline significant decrease in systolic BP and a significant increase in NEFA circulating levels supporting anti-hypertensive and lipolytic properties. Our findings support MANP as a potential novel therapy for HTN associated with metabolic disease.

AbstractBackgroundResilience represents the capacity to adapt to adversity. Resilience can improve following behavioral interventions. We examined lung transplant candidates’ resilience as a novel predictor using the Connor‐Davidson Resilience Scale (RISC‐10).MethodsWaitlisted candidates at six centers were mailed questionnaires from 9/16/2015 to 10/1/2019. Follow‐up surveys were collected annually and post‐transplant. Outcomes were recorded through February 17, 2020. Primary outcome was pre‐transplant death/delisting. Analyses included t test or chi‐square for group comparisons, Pearson's correlation coefficients for strength of relationships, and Cox proportional‐hazard models to evaluate associations with outcomes, adjusting for age, sex, and mood.ResultsParticipation was 55.3% (N = 199). Baseline RISC‐10 averaged 32.0 ± 5.6 and did not differ by demographics, primary transplant diagnosis, or disease severity markers. RISC‐10 did not correlate to the commonly utilized Psychosocial Assessment of Candidates for Transplant [PACT] or Stanford Integrated Psychosocial Assessment for Transplantation [SIPAT] tools. Scores < 26.3 (representing > 1 standard deviation below population average) occurred in 16% and were associated with pre‐transplant death or delisting, adjusted Hazard Ratio of 2.60 (95% Confidence Interval 1.23‐5.77; P = .01).ConclusionOne in six lung candidates had low resilience, predicting increased pre‐transplant death/delisting. RISC‐10 did not correlate with PACT or SIPAT; resilience may represent a novel risk factor.