Hathcock, Matthew

Congenital heart diseases, including single ventricle circulations, are clinically challenging due to chronic pressure overload and the inability of the myocardium to compensate for lifelong physiological demands. To determine the clinical relevance of autologous umbilical cord blood–derived mononuclear cells (UCB-MNCs) as a therapy to augment cardiac adaptation following surgical management of congenital heart disease, a validated model system of right ventricular pressure overload due to pulmonary artery banding (PAB) in juvenile pigs has been employed. PAB in a juvenile porcine model and intramyocardial delivery of UCB-MNCs was evaluated in three distinct 12-week studies utilizing serial cardiac imaging and end-of-study pathology evaluations. PAB reproducibly induced pressure overload leading to chronic right ventricular remodeling including significant myocardial fibrosis and elevation of heart failure biomarkers. High-dose UCB-MNCs (3 million/kg) delivered into the right ventricular myocardium did not cause any detectable safety issues in the context of arrhythmias or abnormal cardiac physiology. In addition, this high-dose treatment compared with placebo controls demonstrated that UCB-MNCs promoted a significant increase in Ki-67-positive cardiomyocytes coupled with an increase in the number of CD31+ endothelium. Furthermore, the incorporation of BrdU-labeled cells within the myocardium confirmed the biological potency of the high-dose UCB-MNC treatment. Finally, the cell-based treatment augmented the physiological adaptation compared with controls with a trend toward increased right ventricular mass within the 12 weeks of the follow-up period. Despite these adaptations, functional changes as measured by echocardiography and magnetic resonance imaging did not demonstrate differences between cohorts in this surgical model system. Therefore, this randomized, double-blinded, placebo-controlled pre-clinical trial establishes the safety of UCB-MNCs delivered via intramyocardial injections in a dysfunctional right ventricle and validates the induction of cardiac proliferation and angiogenesis as transient paracrine mechanisms that may be important to optimize long-term outcomes for surgically repaired congenital heart diseases.

8022 Background: Bone marrow (BM) assessment of minimal residual disease (MRD) is being considered as a surrogate endpoint in clinical trials and is prognostic for survival in multiple myeloma (MM). Timing of BM assessment is variable across Chimeric Antigen Receptor T cell (CART) therapy trials and differs from standard of care practice. BM myeloma cell clearance can be detected by month 1 post CART, even before serum immunofixation becomes negative. BM is still hypocellular at month 1, thus prognostic value of MRD negative (MRDneg) at this timepoint is unclear. We examined impact of Day 30 MRD status in patients (pts) who received CART at Mayo Clinic. Methods: Medical records were reviewed retrospectively for MM pts who received CART between 8/2016 and 6/2021. PFS and OS were plotted by Kaplan-Meier method. Results: Sixty MM pts received CART and had BM biopsy at month 1. Median age was 62 yrs, 53% were male, and 78% were BM MRDneg by flow cytometry. Baseline demographics were similar between MRDneg and MRD+ (Table). Overall, 85% (40/47) who were month 1 BM MRDneg had i/u FLC<normal. Patients who achieved CR/sCR had higher rates of BM MRDneg (100% vs 61%, p<0.001) and i/u FLC< normal (89% vs 58%, p<0.001). At month 1, 24/60 (40%) pts had hypocellular BM. Serial BM samples at month 3 (n=35), 6 (n=28) and 12 (n=23) showed MRDneg rate of 93% (25/27), 56% (9/16) 58% (7/12), respectively.. Rate of hypocellularity was 54% (19/35), 32% (9/28) and 30% (7/23), respectively. Among the MRDneg/hypocellular pts at month 1, hypocellular BM was seen in 8/11 (73%) pts at month 3 and 2/4 (50%) pts at month 6 and 12. Compared to MRD+, pts who had BM MRDneg at months1 had longer PFS (Table). PFS was not statistically significantly different between pts who had BM MRDneg and were either hypocellular or not. MRDneg pts with i/u FLC<normal at months1 had better median PFS compared to those who did not. (MRD+:2.9 months (1.2-NR). MRDneg/FLC>normal: 4.9 months (2.3-NR). vs MRDneg/FLC<normal:17.9 months (11.8-NR), p<0.0001). Conclusions: Hypocellular BM is common in the 3 months post CART. Regardless of BM cellularity, BM MRDneg at month 1 correlates with deep response and prolonged PFS. Majority of BM MRDneg pts at month 1 also had FLC<normal. BM MRDneg status and FLC normalization were associated with longer survival. Our data support the continued evaluation of BM early post CART infusion as a prognostic tool. [Table: see text]

e19049 Background: Prognosis of COVID-19 is poor in the setting of immunosuppression. Casirivimab/imdevimab (REGEN-COV), bamlanivimab, and sotrovimab are investigational monoclonal antibodies (MoAbs) authorized for treatment of mild/moderate COVID-19 for patients (pts) 12 years or older and who are at high-risk for progression to severe COVID-19. These neutralizing antibodies, against SARS-CoV-2 spike proteins, have been shown to decrease risk of progression to severe disease. Recipients of allogeneic stem cell transplants (allo-SCT) or chimeric antigen T cell therapy (CAR T cell) represent a high risk population. However, treatment outcomes with these MoAbs in these pts are not well described. Methods: This retrospective study included 33 consecutive adult pts who developed mild/moderate COVID-19 and received anti-spike SARS-CoV-2 MoAbs between December 2020 and November 2021. Allo-SCT (N=27) or CAR T cell (N=6) recipients were included, and outcomes were analyzed separately. Pts received REGEN-COV (N=19), bamlanivimab (N=11), or sotrovimab (N=1), missing (N=2). Results: In the allo-SCT cohort (N=27), median age at time of COVID-19 was 55 (23-76) years. Median time from allo-SCT to COVID-19 was 31 (22-64) months. Two pts received CAR T-cell therapy prior to allo-SCT. Diagnoses included leukemia or myeloid diseases (82%), lymphoma (11%), or myeloma (7%). Transplant characteristics are summarized (Table). Thirteen pts were vaccinated against SARS-CoV-2 prior to breakthrough COVID-19. Events considered included hospitalization due to COVID-19, disease progression, or death from any cause. The 6-month event-free and overall survivals were 81% and 91%, respectively. In the CAR T cell recipients cohort (N=6), 4 pts received axicabtagene ciloleucel for diffuse large B-cell or follicular lymphoma and 2 received brexucabtagene autoleucel for mantle cell lymphoma. The median follow-up was 8 (1-11) months. Two pts received autologous SCT prior to COVID-19. Median time from CAR T cell therapy to COVID-19 was 10 (3-24) months. Three pts were vaccinated prior to COVID-19. Only 1 pt was hospitalized due to severe COVID-19 requiring mechanical ventilation leading to death. Conclusions: These results show a potential benefit of MoAbs in high-risk pts, namely allo-SCT or CAR T cell recipients. Future studies should evaluate the role of prophylactic use MoAbs in these populations. A comparative analysis with a matched control cohort (who did not receive MoAbs) will be provided at the meeting. [Table: see text]

Background: Ovarian cancer has the highest mortality of all gynecologic malignancies, howeverthere is no proven effective screening for ovarian cancer. Evidence suggests that epithelial ovarian cancer begins in the fallopian tubes. Prophylactic bilateral total salpingectomy has been shown to reduce the risk of epithelial ovarian cancer and is now recommended to be considered at the time of sterilization procedures. There are limited well designed clinical trials that compare the safety and feasibility of total salpingectomy to that of traditional partial salpingectomy for tubal sterilization in obstetrics. We thus conducted a randomized controlled trial to assess the safety of bilateral total salpingectomy at the time of cesarean delivery. Methods: We conducted a non-inferiority randomized controlled trial at the Mayo Clinic, Rochester, Minnesota. Women age 21 years and older who were undergoing cesarean delivery and desired concomitant sterilization were enrolled between May 17, 2017 and July 16, 2018. Stratified randomization was performed based on number of previous cesarean deliveries and their Basal Metabolic Index, into a bilateral total salpingectomy (BTS) group and bilateral partial salpingectomy (BPS) group. All salpingectomies were performed using clamps and suture. The primary outcome was to compare the mean peri-operative hemoglobin change for both groups. Secondary objectives included sterilization completion time, postoperative length of stay, estimated blood loss, postoperative pain and adverse events. Results: Of the 111 women screened, 40 were enrolled and randomized. Of these, 38 underwent the assigned procedure (18 BTS, 20 BPS). No difference in Mean ± SD hemoglobin drop between groups (1.4 ± 0.7 g/dL for the BPS group and 1.8 ± 1.0 g/dL for the BTS group, p = 0.08), however the point estimate of –0.4 is very close to the non-inferiority margin of –0.5, and the CI widely exceeds the non-inferiority margin (95% CI –0.99, 0.17). Therefore non-inferiority was not shown. Mean time to completion of sterilization procedure was significantly longer in the BTS group (16.3 ± 5.6 minutes for the BTS group vs 5.1 ± 1.6 minutes for the BPS group, p < 0.01). No significant differences for other outcome measures. Conclusions: Bilateral total salpingectomy is not non-inferior to tradiational bilateral partial salpingectomy with regards to postoperative hemoglobin drop, and is associated with a small increase in operative time. There, however, was no difference in adverse events, postoperative length of stay and postoperative pain between the two groups. This information may be helpful when counseling patients.