Days Of Infusion Research Articles

Outcomes for central venous catheter repair in patients receiving long-term home parenteral support: A descriptive cohort study.

Central venous catheter (CVC) complications are frequently reported in patients receiving home parenteral support (HPS). Compromised CVC integrity or breakage is one such issue. Repairing such breakages can potentially avoid costly and risky catheter replacements. We completed a retrospective descriptive cohort study using a prospectively maintained data set, in a national UK intestinal failure reference center. Repair success, CVC longevity, and catheter-related bloodstream infection (CRBSI) rates after repair were the primary outcome measures. A total of 763 patients received HPS. There were 137 CVC repairs: 115 (84%) tunneled CVCs and 22 peripherally inserted central catheters (PICCs) attempted in 72 patients. Of the 137 attempts at CVC repair, 120 (88%) were deemed to be successful, allowing a median duration of subsequent CVC use of 336 days following repair (range 3-1696 days), which equates to 99,602 catheter days of HPS infusion. Three patients had a CRBSI within 90 days of repair, and patients required admission to the hospital for refeeding on 14 occasions following repair, such that hospitalization was avoided in 103/120 (86%) occasions following successful CVC repair. There was no increase in the recorded rate of CRBSIs in patients undergoing CVC repair compared with the CRBSI rates of all HPS-dependent patients under our care during the study period (0.03 vs 0.344/1000 catheter days, respectively). This is the largest single-center experience to demonstrate that CVCs, including PICCs, used for the administration of HPS can be safely repaired, prolonging CVC longevity without leading to an increased risk of CRBSI.

Practice pattern for the use of intravenous iloprost for the treatment of peripheral vasculopathy in systemic sclerosis: A case-control study from the Italian national multicenter "SPRING" (Systemic Sclerosis Progression InvestiGation) Registry.

Intravenous iloprost has been widely used for the treatment of systemic sclerosis peripheral vasculopathy. No agreement has been found on the regimen and the dosage of intravenous iloprost in different scleroderma subset conditions. This study aimed to evaluate the modalities of intravenous iloprost administration within a large cohort of systemic sclerosis patients from the SPRING Registry and to identify any associated clinical-demographic, instrumental or therapeutic data. Data of systemic sclerosis patients treated with intravenous iloprost for at least 1 year (case group) were retrospectively analyzed, including different timing and duration of intravenous iloprost session, and compared with those of untreated patients (control group). Out of 1895 analyzed patients, 937 (49%) received intravenous iloprost treatment, while 958 (51%) were assigned to the control group. Among cases, about 70% were treated every 4 weeks, 24% with an interval of more than 4 weeks, and only 6% of less than 4 weeks. Most patients receiving the treatment every 4 weeks, or less, underwent infusion cycle for 1 day only, while if it was scheduled with an interval of more than 4 weeks, a total number of 5 consecutive days of infusions was the preferred regimen. The comparison between the two groups revealed that patients treated with intravenous iloprost had a higher frequency of DUs (p < 0.001), pitting scars (p < 0.001), diffuse cutaneous involvement (p < 0.001), interstitial lung disease (p < 0.002), as well as higher rates of anti-topoisomerase I, "late" scleroderma pattern at nailfold videocapillaroscopy. These findings were confirmed by multivariate analysis. Our data provide a picture on the Italian use of intravenous iloprost among systemic sclerosis patients and showed that it was usually employed in patients with a more aggressive spectrum of the disease. The disparity of intravenous iloprost treatment strategies in the different centers suggests the need of a rational therapeutical approach based on the clinical characteristics of different patients' subsets.

Clinical Efficacy of Imdevimab/Casirivimab for Persistent Omicron SARS-CoV-2 Infection in Patients with Hematological Malignancies.

Objective Prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been reported in immunocompromised patients, as they poorly develop antibodies against SARS-CoV-2. We conducted a clinical trial to determine the efficacy of Imdevimab/Casirivimab (Imde/Casiri), an anti-viral monoclonal antibody (mAb), for prolonged infection at our institution. Methods Nine patients with hematological malignancies (six with malignant lymphoma and three with multiple myeloma) in our institution presented with coronavirus disease 2019 caused by SARS-CoV-2 omicron variants (one, five, and one with BA.2, BA.5, and BF.7, respectively; two undetermined). Although not all nine patients developed severe disease, viral mRNA was detected in all patients after treatment with remdesivir or molnupiravir. Imde/casiri was infused 11-49 days after the disease onset. Results Within seven days of infusion, viral RNA was undetectable in five of the nine cases. Because all seven viruses isolated from patients whose viral RNA became undetectable showed low or no sensitivity to this monoclonal antibody cocktail, the disappearance of viral RNA in these cases may not be attributable to the antibody cocktail. Conclusion It may be worth considering the use of monoclonal antibodies that show some activity against these virus variants to treat persistent SARS-CoV-2 infection in immunocompromised patients.

Impact of Tolvaptan Combined with Low-Dose Dopamine in Heart Failure Patients with Acute Kidney Injury.

The impact of tolvaptan and low-dose dopamine on heart failure (HF) patients with acute kidney injury (AKI) remains uncertain from a clinical standpoint.HF patients with AKI were selected and divided in a 1:1 fashion into the dopamine combined with the tolvaptan group (DTG), the tolvaptan group (TG), and the control group (CG). According to the standard of care, TG received tolvaptan 15 mg orally daily for a week. DTG received combination treatment, including 7 consecutive days of dopamine infusion (2 μg/kg・minutes) and oral tolvaptan 15 mg. Venous blood and urine samples were taken before and after therapy. The primary endpoint was the cardiorenal serological index after 7 days of treatment.Sixty-five patients were chosen randomly for the DTG (22 patients), TG (20 patients), and CG (23 patients), which were similar before the treatment. The serum indexes related to cardiac function (N-terminal probrain natriuretic peptide and cardiac troponin I) in DTG were decreased, compared with TG and CG (P < 0.05). Furthermore, the serological markers of renal function (serum cystatin C, serum creatinine, and neutrophil gelatinase-associated lipocalin) in DTG were lower than those in TG and CG (P < 0.05). There was no significant difference in the incidence of adverse reactions among groups.Low-dose dopamine combined with tolvaptan can markedly improve patients' cardiac and renal function. This may be considered a new therapeutic method for HF patients with AKI.

Risk Factors for Bloodstream Infection in Patients Receiving Peripheral Parenteral Nutrition.

Background Intravenous fluid therapy, including peripheral parenteral nutrition (PPN), administered via a peripheral intravenous catheter (PVC) can occasionally lead to bloodstream infections (BSIs). PPN may thus be a risk factor for PVC-related BSI (PVC-BSI). However, the risk factors and incidence of PVC-BSI have not been previously reported, and evidence for these conditions remains unclear. Methods We retrospectively collected data from 391 patients who underwent PPN therapy with PVC at the Fukujuji Hospital from August 2022 to November 2023. We compared 20 patients who developed BSI during PPN therapy (BSI group) with 371 who did not develop BSI during PPN therapy (no-infection group). Results The incidence rate of PVC-BSI during PPN therapy was 5.1%. The BSI group had a significantly longer average daily infusion time of PPNs (median 24.0 [range 6.0-24.0] h vs. 6.0 [2.0-24.0] h, p<0.001) and of all intravenous fluids (median 24.0 [range 8.8-24.0] h vs. 10.3 [2.0-24.0] h, p<0.001) than the no infection group. An average daily infusion time of PPNs ≥12.0 h and an average daily infusion time of intravenous fluids ≥18.0 h were identified as predictive risk factors for BSI. When both risk factors were present, the sensitivity, specificity, and odds ratio for the development of BSI were 85.0%, 83.2%, and 27.9, respectively. Conclusion This study identified the incidence of and risk factors for developing BSI, such as a longer average daily infusion time of PPNs and all intravenous fluids, in patients receiving PPN therapy.

ADAMTS13 in pediatric sepsis: a prognostic biomarker with potential therapeutic implications

BackgroundGrowing evidence implicates a pro-thrombotic state, caused by ADAMTS13 deficiency, in sepsis-associated organ dysfunction, but pediatric data is limited. Our purpose was to evaluate association of ADAMTS13 with prognosis of pediatric sepsis.ResultsThis was prospective observational study, conducted on 70 children with sepsis and 18 healthy controls. Patients were classified upon Pediatric Intensive Care Unit (PICU) admission into sepsis, severe sepsis, and septic shock groups. Serum ADAMTS13 was measured within 24 h of admission. The primary outcome was all-cause PICU mortality. ADAMTS13 was lower among patients than controls [median and interquartile range (IQR): 1.30 (0.88–3.13ng/mL) vs. 6.00 (5.55–6.50 ng/mL); p < 0.001]. ADAMTS13 was lower in both severe sepsis and septic shock than sepsis [median (IQR): 0.90 (0.80–1.75 ng/mL); 1.0 ng/ml (0.90–1.20); and 2.80 (1.00–3.85ng/mL), p = 0.026 and 0.006 respectively]. ADAMTS13 was lower among non-survivors compared with survivors [median (IQR): 0.9 (0.80–1.18 ng/mL) vs. 2.45 (0.98–3.50 ng/mL); p < 0.001]. ADAMTS13 had area under Receiver Operating Characteristic Curve (AUC) of 0.77 for mortality prediction. Lower ADAMTS13 level was associated with mechanical ventilation; vasoactive medications; acute respiratory distress syndrome; and multiple organ dysfunction syndrome. ADAMTS13 correlated with pediatric Sequential Organ Failure Assessment (pSOFA) score (rs = -0.46, p < 0.001); vasoactive infusion days ((rs = -0.48, p < 0.001); and vasoactive-inotropic score on day1 (rs = -0.43, p < 0.001) and day2 ((rs = -0.41; p < 0.001).ConclusionIn pediatric sepsis, lower ADAMTS13 level is a risk factor for organ dysfunction and mortality, lending theoretical foundations to therapeutic interventions aiming at reversing the pro-thrombotic state in sepsis.

Intravenous infusion of 5-hydroxytryptophan to mid-lactation Holstein cows transiently affects milk production and circulating amino acid concentrations

In dairy cows, the lactating mammary glands synthesize serotonin, which acts in an autocrine-paracrine manner in the glands and is secreted into the periphery. Serotonin signaling during lactation modulates nutrient metabolism in peripheral tissues such as adipose and liver. We hypothesized that the elevation of circulating serotonin during lactation would increase nutrient partitioning to the mammary glands, thereby promoting milk production. Our objective was to elevate circulating serotonin via intravenous infusion of the serotonin precursor 5-hydroxytryptophan (5-HTP) to determine its effects on mammary supply and extraction efficiency of AA, and milk components production. Twenty-two multiparous mid-lactation Holstein cows were intravenously infused with 5-HTP (1 mg/kg body weight) or saline, in a crossover design with two 21-d periods. Treatments were infused via jugular catheters for 1 h/d, on d 1 to 3, 8 to 10, and 15 to 17 of each period, to maintain consistent elevation of peripheral serotonin throughout the period. Milk and blood samples were collected in the last 96 h of each period. Whole-blood serotonin concentration was elevated above saline control for 96 h after the last 5-HTP infusion. Dry matter intake was decreased for cows receiving 5-HTP, and on average they lost body weight over the 21-d period, in contrast to saline cows who gained body weight. Milk production and milk protein yield were lower in cows receiving 5-HTP during the 3 infusion days, but both recovered to saline cow yields in the days after. Although milk fat yield exhibited a day-by-treatment interaction, no significant difference occurred on any given day. Milk urea nitrogen concentration was lower in 5-HTP cows on the days following the end of infusions, but not different from saline cows on infusion days. Meanwhile, plasma urea nitrogen was not affected by 5-HTP infusion. Circulating concentrations of AA were overall transiently decreased by 5-HTP, with concentrations mostly returning to baseline within 7 h after the end of 5-HTP infusion. Mammary extraction efficiency of AA was unaffected by 5-HTP infusion. Overall, both lactation performance and circulating AA were transiently reduced in cows infused with 5-HTP, despite sustained elevation of circulating serotonin concentration.

Successful Treatment of Massive Pulmonary Embolism with Rescue Fibrinolysis in Young Patient with Homocystinemia - Case Report

Abstract Pulmonary embolism (PE) is the most frequently missed diagnosis in the urgent clinical department with serious consequences. Patients with unprovoked PE have increased risk of recurrent PE. Approximately 5 to 8% of PE patients have inherited thrombophilias. A solated homocystinemia is a rare cause of unprovoked acute pulmonary embolism. Timely diagnosis and proper treatment can prevent complications, costs and mortality and provide patient better quality of life. We are presenting a 42-year-old woman was admitted to our emergency department with the first episode of severe dyspnea and chest pain. She had no history of previous cardiovascular or respiratory disease and no history of previous pulmonary embolism (PE) or deep vein thrombosis (DVT). Urgent echocardiography showed indirect signs of pulmonary embolism which was confirmed by the pulmonary artery CT angiography performed one day after the patient’s admission. After two days of heparin infusion, she developed a hemodynamic instability with cardiogenic shock and was treated successfully with fibrinolysis. After the clinical stabilization, she was put on the rivaroxaban therapy, which was recommended for additional six months. The thrombophilia profile was done two weeks after stopping the therapy with rivaroxaban. The thrombophilia panel came back positive for high levels of homocysteine (67 μmol/L), with other thrombophilia results within normal limits. The patient was stable during the follow-up period. Pulmonary embolism should be always suspected in younger patients with acute severe dyspnea even without provocable risk factors. High suspicion level and fast diagnosis are lifesaving. In younger patients presented with unprovoked pulmonary embolism, clinicians should consider inherited prothrombotic factors and homocystinemia as a potential cause. Rescue fibrinolysis is a lifesaving therapy in hemodynamic worsening in intermediate high-risk PE patients. A longer anticoagulation therapy should be considered in these cases with novel oral anticoagulants that are recommended as safer and superior therapy.

Effect of delayed cell infusion in patients with large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy.

Complications occurring after lymphodepleting chemotherapy (LDC) may delay chimeric antigen receptor (CAR) T-cell infusion. The effect of these delays on clinical outcomes is unclear. We performed a retrospective analysis of 240 patients with relapsed/refractory large B-cell lymphoma treated with standard-of-care axicabtagene ciloleucel (axi-cel) and identified 40 patients (16.7%) who had delay in axi-cel infusion. Of these, 85% had delay due to infection. At time of LDC initiation, patients with delayed infusion had lower absolute neutrophil count (P=0.006), lower platelets (P=0.004), lower hemoglobin (P<0.001) and higher C-reactive protein (P=0.001) than those with on-time infusion. Patients with delayed infusion had lower day 30 overall response rates (59.0% vs. 79.4%; P=0.008) and shorter median progression-free survival (PFS) (3.5 vs. 8.2 months; P=0.002) and overall survival (7.8 vs. 26.4 months; P=0.046) than those with on-time infusion. The association with PFS was maintained on multivariate analysis. There was also an association between extent of delay and survival, with shorter median PFS in patients who had delays of 2-5 days (1.8 vs. 8.2 months; P=0.001) and >5 days (4.6 vs. 8.2 months; P=0.036), but not 1 day (5.7 vs. 8.2 months; P=0.238). Following propensity score matching, patients with delayed infusion continued to have shorter median PFS (3.5 vs. 6.0 months; P=0.015). Levels of pro-inflammatory cytokines on day of infusion were significantly higher in patients with delayed infusion. Together, these findings suggest that delays in CAR T-cell administration after initiation of LDC are associated with inferior outcomes. Further studies are needed to guide strategies to improve efficacy in such patients.

Axicabtagene Ciloleucel in Patients Aged 75 and Older: A Retrospective Cohort Study

Background The treatment of older patients with relapsed/refractory (R/R) aggressive non-Hodgkin B-cell lymphomas (NHL) remains a significant clinical challenge. Chimeric antigen receptor T-cell (CAR-T) therapy represents a potentially curative option, but elderly patients remain underrepresented in relevant clinical trials, and less is known about the safety of CAR-T among patients older than 75 years. Toxicities including cytokine release syndrome (CRS), neurotoxicity (ICANS), arrhythmias, renal failure, and cytopenias may pose higher risk in elderly patients with comorbidities and decreased physiologic reserve compared to younger CAR-T recipients. We sought to characterize outcomes and toxicities of axicabtagene ciloleucel (axi-cel) in a cohort of patients aged ≥ 75 years. Methods This was a retrospective analysis of consecutive patients aged ≥ 75 years with R/R NHL who received axi-cel at New York-Presbyterian/Weill Cornell Medical Center. Data collected included patient characteristics and outcomes including response rates, event-free and overall survival, rates of CRS, ICANS, arrhythmias and severe cytopenias, and length of hospital stay. CRS and ICANS severity were graded following the ASTCT consensus criteria. Cytopenias were graded as per NCI-CTCAE v5.0. Event free survival (EFS) was defined as time to disease progression or death. Results We identified 15 patients with a median age of 78 (range 75-87) years; 6 (40%) were ≥ 80 years of age. 14 patients had a diagnosis of large B-cell lymphoma and 1 had multiply relapsed follicular lymphoma. Ten patients (67%) had received 3 or more prior lines of therapy. Additional baseline characteristics are summarized in Table 1. Among 10 patients (67%) who developed CRS of any grade, only 1 (7%) experienced grade ≥3 CRS; this CRS event was fatal. Five (33%) patients developed ICANS with only 1 patient (7%) developing grade ≥3 ICANS. Two (13%) patients and 10 (67%) patients developed grades 3 and 4 cytopenias within 30 days of infusion, respectively. Four (27%) patients required blood or platelet transfusions within 100 days of infusion. Febrile neutropenia was seen in 8 (53%) patients, and 8 patients had culture or PCR-verified bacterial (33%), viral (40%), or fungal (7%) infections. Only 1 (7%) patient developed a new abnormality on EKG within 30 days of infusion (right ventricular conduction delay). Median length of inpatient stay was 17 days (range 13-35), and 2 (13%) required re-hospitalization within 100 days of infusion. Overall and complete response rates at 100 days post-infusion were 13 (86%) and 11 (73%), respectively. At one year, overall and event-free survival were 72.2% (95% CI: 54.4-99.6%) and 53.3% (95% CI: 33.2%-85.6%), respectively. The median overall survival was 30.8 months with a median follow-up of 21.4 months. One patient experienced treatment-related mortality due to CRS, and 5 (33%) had subsequent disease relapse. Conclusion These results suggest that axi-cel is an effective and well-tolerated treatment for patients age ≥ 75 with R/R NHL. Only 1/15 patients developed grade ≥3 CRS or ICANS which is comparable to reported rates of toxicities in younger patients. Although multiple studies have identified cytopenias and cardiac arrhythmias as major CAR-T toxicities, a minority of our cohort required transfusions, and none developed life-threatening arrhythmias. OS and EFS were also comparable to real-world experience seen in younger patients. This study may be limited by the selection of a relatively fit population of elderly patients; however, the median Karnofsky Performance Score was 80 and ranged as low as 60. Overall, these findings show that axi-cel may be an appropriate strategy for relapsed aggressive NHL in carefully selected patients in their eighth and even ninth decades of life.

Bisantrene in Combination with Fludarabine and Clofarabine As Salvage Therapy for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)- an Open-Label, Phase II, Study

Background: Bisantrene (Bis), is a topoisomerase-II inhibitor with anthracycline-like activity, lower cardiotoxicity, and activity in patients (pts) with relapsed (rel)/primary refractory (PR) acute myeloid leukemia (AML) (Am J Hematol, 2021). Bis was also found to synergize with the cytotoxic purine nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in vitro (J Clin Exp Oncol, 2021). We now conducted a phase II study combining Bis with Clo and Flu in pts with Rel/PR AML (NCT04989335). Methods: This was a phase II open-label single-center study with 2 stages: a stage with 3+3 dose escalation to assess the safety and provide phase 2 dose (RP2D, 4 vs 5 days) of infusion (i.v.) with up to 12 pts and an expansion phase with up to 17 pts (Simon 2-stage design 9+8) to assess the primary efficacy and confirm the safety of f Bis/Clo/Flu combination pts with Rel/PR AML. Flu (10 mg/m 2) was administered i.v. over 1 hour (h), followed by a 1-h infusion of Clo (30 mg/m 2), and then a 2-h infusion of Bis at 250 mg/m 2, with a 1-hour break for 4 days. The primary endpoint was achieving a partial response (PR). Efficacy was assessed by bone marrow (BM) examination 21 - 30 days post-therapy. Safety included treatment-emergent adverse events (TEAEs), all-cause mortality, and cardiac monitoring with ECG and troponins Toxicity was assessed as per Common Terminology Criteria for Adverse Events (CTCAE v5.0). Interim analysis was planned after the first 12 pts. Results: 20 pts were included from August 2021. The median age was 48 (19-69) years and 55% were male.14 pts had de novo AML and 5 had secondary AML, 11 pts were in rel, while 9 had PR disease. Median lines of therapy were 4(3-9), 12 with ≤ 4 and 8 &amp;gt;4 lines of therapy. All pts were refractory to the last line of therapy.15 pts (75%) were in relapse post allogeneic transplantation (HSCT). 5 (25%) pts had active extramedullary disease (EMD, 1 with CNS involvement). Median bone marrow blasts pre-Bis/Clo/Flu treatment was 50%. Cytogenetic was normal in 10 (50%) of the pts, 5 had a complex karyotype, 2 MLL rearrangements, 1 t8; 21 and 2 pts had other chromosomal abnormalities. The maximum tolerated dose of the Bis/Clo/Flu combination was 4 days of infusion due to grade 3 liver toxicity in 2 pts and 1 pt that died from sepsis in the first stage of the study. Overall 10 pts developed liver toxicity with elevated liver enzymes and bilirubin in 9 of them (grade 1-4 pts; grade 2-3 pts and grade 3-3 pts). Liver toxicity was transient and resolved in all pts. Two pts had treatment interruption due to liver toxicity. 4 pts had grade I renal toxicity, 7 had mild fluid retention, and 18 developed neutropenic fever of which 10 pts had verified bacteremia. Five pts had pneumonia, 4 invasive fungal infections, and 2 sepsis (1/2 died).1 additional pt died from cerebral venous sinus thrombosis. Overall 5 pts died early and could not be evaluated for response. Clinical-relevant cardiac toxicity was not observed in any of the pts and no one developed ECG changes Transient grade 1 elevation of troponin levels was observed in 4 pts. Six pts responded (CR-5, PR-1) 3 with EMD, however, responses were short-lived and lasted up to 3 months. Five pts (responding-4, active disease-1, being the second transplant in 4) underwent HSCT 1-3 months post-Bis/Clo/Flu with reduced /intermediate intensity conditioning. Stem cell donors were haploidentical-2, matched unrelated -1, and matched sibling-2, respectively. Three pts died: one from graft versus host disease and the other from relapse within 4 months post-transplant and the third from sepsis 2 years post-HSCT. Two of the transplanted pts are in complete remission with a 2-month follow-up. Conclusions : In this Phase II study in a very advanced group of relapsed refractory AML ptsresistant to multiple previous lines of chemotherapy including transplantation and with a median of 50% blasts at study initiation, Bis/Clo/Flu combination therapy was found to be safe and well tolerated without cardiac toxicity or tumor lysis syndrome. The maximum length of Bis/Clo/Flu administration was 4 days due to rapidly reversible liver toxicity, and transaminitis. As expected in this highly pretreated population, the infection rates were high. Six /15 evaluable pts (40%) respond, enabling an HSCT in 5 of them. These rather impressive results in such a heavily pretreated population support further studies of Bisantrene-based combinations, including those with venetoclax or hypomethylating agents.

Rationale for and Design of Papilio-1: A Phase 1/2, Multicenter, Open-Label Study to Evaluate the Feasibility, Safety, and Efficacy of Point-of-Care-Manufactured Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells (GLPG5301) in Relapsed/Refractory Multiple Myeloma

Background and Significance Despite improvements in treatment, patients with multiple myeloma (MM) ultimately relapse or become refractory to available regimens. Triple-refractory (refractory to CD38 monoclonal antibodies [mAbs], 1 proteasome inhibitor [PI] and 1 immunomodulatory drug [IMiD]) or penta-refractory (refractory to CD38 mAbs, 2 PIs and 2 IMiDs) patients have a poor prognosis and are in urgent need of novel treatment options. Chimeric antigen receptor (CAR) T-cell therapies have been used to target B-cell maturation antigen (BCMA) and have shown good clinical activity in patients with relapsed/refractory MM (RRMM). Faster manufacturing procedures may improve clinical outcomes by lowering discontinuation rates and reducing the need for bridging therapy. GLPG5301, a BCMA-directed CAR T-cell therapy, is produced using a novel decentralized and automated point-of-care manufacturing model. This allows administration of a fresh product within 7 days of apheresis. The objective of Papilio-1 is to evaluate the feasibility, safety and efficacy of GLPG5301, manufactured at the point-of-care, in adult patients with RRMM. Study Design and Methods Papilio-1 (CTIS: 2022-500782-27-00) is a Phase 1/2, multicenter, open-label study of GLPG5301 in patients with RRMM after ≥2 prior lines of therapy. Key eligibility criteria are presented ( Table). The study will be conducted in centers across Europe. The Phase 1 primary objective is to evaluate the safety of GLPG5301 and determine the recommended Phase 2 dose (RP2D). The Phase 1 primary endpoint is incidence of serious adverse events, including dose-limiting toxicities (DLTs), until 14 days post-infusion. The Phase 2 primary objective is to evaluate GLPG5301 efficacy. The Phase 2 primary endpoint is best objective response until 2 years post-infusion. Secondary endpoints include: type, frequency and severity of adverse events; duration of response; progression-free survival (PFS); overall survival (OS); minimal residual disease; soluble BCMA levels; time to response; time to progression; GLPG5301 levels in blood and bone marrow; serum levels of chemokines and cytokines; and number of successfully manufactured GLPG5301 products. Exploratory assessments include additional GLPG5301 pharmacokinetics (PK) and pharmacodynamics (PD). Patients will undergo leukapheresis of mononuclear cells for point-of-care manufacturing of GLPG5301 after screening ( Figure). Prior to infusion of GLPG5301, patients will receive fludarabine/cyclophosphamide lymphodepleting chemotherapy, followed by a resting period of at least 2 days. GLPG5301 will be administered as a fresh product, followed by in-hospital monitoring for 7 days. Safety, efficacy, PK and PD will be assessed until end of treatment (100 days post-infusion), and monthly until study completion (2 years). Patients will be enrolled in a long-term follow-up for up to 15 years. In Phase 1, dose escalation will be based on the occurrence of DLTs occurring within 14 days of infusion, according to predefined criteria. Three dose levels (DLs) will be assessed (DL1, DL2 and DL3). Six patients will receive the lowest dose level (DL1) and be evaluated for DLTs and efficacy. The appropriate dose for the following cohort will be then determined by the Safety Review Committee. This will be repeated until RP2D is determined. Approximately 30 patients will be treated with the RP2D in Phase 2. Safety and efficacy data will be analyzed using descriptive statistics. Response status will be summarized as best response (number, percentage, 95% confidence interval) and graphically displayed using swimmer plots by dose. Other binary endpoints will be described using a similar method. PFS and OS will be assessed using the Kaplan‒Meier method and calculated from the median survival time. Summary In Papilio-1, the feasibility, safety and efficacy of GLPG5301, a point-of-care-manufactured BCMA-directed CAR T-cell therapy, will be evaluated in adult patients with RRMM.

Cellular Dynamics Following CAR T Cell Therapy Are Associated with Response, Resistance and Cytokine Release Syndrome in Relapsed/Refractory Multiple Myeloma

Introduction The introduction of B cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). While long-term follow-up of CD19 CAR T cells demonstrated a connection between CAR T cell expansion and persistence with outcome, very little is known about persistence and effects on bystander cells of BCMA-targeting CAR T cells. Methods We analyzed 27 RRMM patients (pts) treated with Idecabtagene vicleucel (Ide-cel) at our center. Pts were grouped based on their remission evaluated 100 days after infusion into responders (partial response or better, n=16) or non-responders (progressive disease, n=11). Peripheral blood (pb) was drawn at day of leukapheresis, at day of infusion/after lymphodepletion (LD, d0) and at several time points following Ide-cel infusion (d7, d14, d30 and d100). In order to reflect a comprehensive picture of the longitudinal dynamics of CAR and non-CAR T cells, we subjected pb mononuclear cells to advanced flow cytometry. Additionally, we assessed the impact of cellular dynamics on the occurrence of cytokine release syndrome (CRS), tocilizumab application and the incidence of cytopenia. Results The median number of infused CAR T cells was 430x10 6 (range: 248.8 - 489.1x10 6) with one exception (25.7x10 6). There was no correlation between the median number of infused cells and in vivo expansion of CAR T cells after infusion as well as response or the development of CRS or cytopenia. Significant differences between responders and non-responders were already detected on day of leukapheresis: While non-responders showed similar numbers of CD4+ and CD8+ T cells, responders had significantly higher CD8+ T cell counts as compared to CD4+ T cells (p&amp;lt;0.05, Figure 1). Additionally, significantly reduced percentages of effector memory CD8+ T cells were detected in responders as compared to non-responders. The latter group showed significantly increased numbers of CD3+CD8+ T cells at the day of infusion indicating a less effective LD in non-responders. Following CAR T cell infusion, peak expansion occurred two weeks after infusion and was significantly higher in responders as compared to non-responders (p&amp;lt;0.001, Figure 2). CD3+ CAR T cell compartment predominantly comprised of CD8+ T cells regardless of response (median: 85%). Analysis of the distribution of CAR and non-CAR T cells after infusion revealed that the majority of CD4+ T cells in responders and non-responders were untransfected. Similar results were detected for CD8+ T cells in non-responders. However, in responders CD8+ CAR T cells approximated CD8+ non-CAR T cells with no significant differences on d7 and d14. With regard to T cell differentiation, almost the entire CD4+ T cells exhibited either a central memory or effector memory phenotype after CAR T cell infusion. Shortly after CAR T cell infusion, effector memory CD8+ T cells outbalanced all other CD8+ T cell subtypes. Most pts had no detectable CAR T cells 100 days after infusion, regardless of remission. Overall, 22 pts (81%) developed CRS shortly after CAR T cell infusion and 7 of these (32%) required tocilizumab treatment. Whereas percentages of CD3+ CAR T cells were significantly elevated in both CRS positive groups (p&amp;lt;0.05) shortly after infusion, absolute numbers were significantly increased only in CRS positive pts without tocilizumab. Analysis of blood counts following CAR T cell infusion revealed that cytopenias persisted longer in CRS pts treated with tocilizumab, which was also reflected by significantly increased numbers of days below thresholds for all cell lines (anemia, thrombocytopenia and leukopenia, p&amp;lt;0.01). Even though the occurrence of CRS and especially the treatment with tocilizumab affected blood cell composition, it did not correlate to response. Conclusion We demonstrate that BCMA-targeting CAR T cells only transiently persist in pb after infusion. Still, initial CAR T cell expansion, predominantly caused by effector memory CD8+ CAR T cells, was linked to response and CRS in RRMM pts. A correlation between CRS and tocilizumab administration with prolonged cytopenias following CAR T cell infusion was also observed. Our data provide first evidence that responders and non-responders can early be distinguished by differential cellular composition in CAR and non-CAR T cell compartments with distinct features already present at day of apheresis.

Determinants of Response to Anti CD-19 CAR-T Cells for Diffuse Large B-Cell Lymphoma in Pre-Treatment Peripheral Blood Mononuclear Cells Using Single-Cell RNA-Seq

Background: Chimeric antigen receptor T (CAR-T) cell therapy has become the standard of care in patients with relapsed/refractory diffuse large cell lymphoma (R/R DLBCL), providing durable remission in 40% of patients. Lack of response is likely to be attributed to inter- and intra-patient variability, including PBMC heterogeneity and apheresis material composition, CAR-T infusion product, in-vivo expansion and activity of CAR-T cells and the development of tumor-intrinsic mechanisms. Current methods for evaluating CAR-T cell activation and potency have limited predictive value for clinical outcomes. To address this challenge, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) obtained from patients with R/R LBCL patients at the time of apheresis for the manufacturing of anti-CD19 CAR-T cell therapy. Methods: Between 10/2020 and 03/2022, 31 patients who underwent lymphopheresis were enrolled. Samples were obtained - 1) At day of lymphopheresis from peripheral blood; 2) On the day of infusion of CAR-T from the product; and 3) On day +7 after infusion from peripheral blood. All patients had day +30 PET-CT. In addition, PBMCs samples from healthy donors were used as control to analyze baseline characteristics compared to the DLBCL patients. PBMCs from patients of healthy donors were purified from frozen blood samples by density gradient separation, stained using human CD45 antibody and loaded onto a 10x Chromium system. libraries were generated using the 10X Genomics Chromium Single Cell 3' Kit. The data was processed and analyzed using the Seurat R package. The study was approved by the local Ethic committee. Results: Patient characteristics: 31 RR DLBCL patients (42% females; median age 72, range 47-81 years), all treated with CAR-T cells therapy as third line of therapy, participated in the study. All patients underwent lymphopheresis, followed by CAR-T production. Disease status at lymphodepletion was complete remission (CR, n=4, 13%), partial remission (n=6, 19%), and progressive disease (n=21, 68%) and patients received either tisagenlecleucel (n=20, 65%) or axicabtagene ciloleucel (n=11, 35%) . PET scan performed on day 30 post treatment revealed that 68% and 32% obtained CR, and PD, respectively. scRNA analysis revealed differences in PBMC composition between healthy donors and LBCL patients (Figure 1A), with lower levels of naïve and memory T cells and elevated levels of activated monocytes in LBCL patients, suggesting a shift towards an inflamed and pre-dysfunctional immune state. Categorization of LBCL patients into responders (PR/CR on day +30 PET-CT) and non-responders (PD on day +30 PET-CT) revealed differences in immune cell subsets between responders and non-responders (Figure 2A), with enriched inflammation-related pathways in non-responders, In contrast, responders exhibited a distinct healthy-like immune profiles, particularly high levels of naive T cells, similar to that obtained in their age matched healthy controls. Of note, non-responders showed alterations in immune cell subsets, including increased levels of T regulatory cells and effector NK cells. Furthermore, non-responders demonstrated a prominent inflammatory immune profile, characterized by gene pathways related to inflammation and activation, such as type I and III IFN-G, and TNFb response (Figure 1B). Notably, an IFN-G score was significantly higher in non-responder's monocytes subpopulations, compared to responders. Conclusions: These findings indicate that the success of CAR-T therapy could be determined by the molecular characteristics and subpopulation distribution of each patient's PBMC. The diverse immune profiles of DLBCL patients might impact the effectiveness of their immune cells in generating successful CAR-T products or providing a conducive environment for CAR T cells to combat cancer. Furthermore, these findings emphasize the potential of scRNA-seq in evaluating PBMC from CAR-T patients prior to treatment, allowing the potential calculation of an “immune potency score” associated with the probability of a positive outcome from CAR-T treatment of DLBCL patients. This score could potentially be used by oncologists in decision-making processes to determine the appropriate candidates for CAR-T therapy.

Detection of CAR-T Cell Persistence with Digital Droplet PCR: Correlation of In Vivo Expansion with Clinical Outcomes in a Cohort of B-Cell Lymphoma Patients

Introduction: In vivo CAR-T cell expansion is of central importance to clinical response and toxicity in patients with hematologic malignancies. In clinical trials, the area under the curve (AUC) within the first 28 days of infusion was considered a valid tool to describe the concentration-time profile of CAR-T cells in peripheral blood (PB). However, several longitudinal assessments performed by either flow cytometry or quantitative real-time polymerase chain reaction (qPCR) were required. This study evaluates the clinical utility of assessing CAR-T concentration by digital droplet PCR (ddPCR) in patients with non-Hodgkin lymphoma (B-NHL). Methods: Patients with B-NHL ddPCR test collected on day 28 ± 7 post-commercial CD19 CAR T infusion, and clinical outcome data was extracted retrospectively. In this ddPCR assay, the PCR primers target the mammalian expression vector present in the CAR constructs as well as the ATP2B4 reference gene. The CAR-T and reference gene signals are segregated by differential fluorescence signals of tagged probes. The number of CAR constructs and reference gene signals per microliter (uL) are calculated from sample droplets and data fitting to a Poisson distribution. The assay sensitivity is ~0.003% of CAR construct per reference gene. Results: Between October 2020 and February 2022, 66 patients (62% male) with diffuse large B cell lymphoma (DLBCL, 73%), Burkitt lymphoma (1%), mantle cell lymphoma (MCL, 24%) and follicular lymphoma (FL, 12%) received axicabtagene ciloleucel (83%), brexucabtagene autoleucel (12%), or tisagenlecleucel (5%), with fludarabine/cyclophosphamide (49%) or bendamustine (51%) lymphodepletion and had testing within the timeframe. Bridging therapy was administered in 82%, and elevated serum LDH prior to CAR T was present in 31%. With a median follow-up of 4.5 months (IQR 3.1-6.2 mo), the day 28 overall response rate was 80%, complete remission 57%, and progressive disease 18%. Median CAR copies/microL was 2.3 (range 0-474); of those with a detectable value, the median was 3.57 copies/microL. Excluding the 7 patients who had progression at the same time the sample was drawn, day 28 landmarked 3- and 6-month progression-free survival (PFS) for patients with non-detectable (22%) vs. detectable (78%) ddPCR construct was 31% vs 81% and 31% vs 73%, respectively (p=0.012, Figure 1B). Three- and 6-month PFS for non-detectable (22%), detectable &amp;lt;= 3.57 (41%), and detectable &amp;gt;3.57 (37%) was 31%, 77%, 86% and 31%, 62%, and 86%, respectively (p=0.039, Figure 1A). Univariable analysis of factors predicting detection of CAR T construct by ddPCR at Day 28, including age, sex, gender, elevated LDH, lines of therapy, bridging, CAR T construct, grade 2+ cytokine release syndrome (CRS), and grade 2+ ICANS was significant only for grade 2+ CRS. Patients with grade 0-1 CRS (44%) vs grade 2+ CRS (56%) had a median of 0 (range 0 - 474) vs 4 (0 - 307) CAR copies/microL (p&amp;lt;0.001). Conclusion: Assessment of PB CAR-T concentration performed by ddPCR at a single timepoint reliably predicted CD19 CAR-T cell efficacy in patients with B-NHL, with detectable CAR construct at day 28 predicting better 6-month PFS. Further research is needed to define the best timepoint for testing and the impact of using strategies to mitigate CRS and/or ICANS.

Severe Reaction to Rituximab in Children

Background: Rituximab is a chimeric monoclonal antibody used in various pathologies involving CD20-positive cells. While it is usually well tolerated, infusion-related reactions are frequent but usually mild. Severe reactions such as anaphylaxis and serum sickness nevertheless can occur. Rituximab-induced serum sickness (RISS) is a rare delayed hypersensitivity reaction that may be unrecognized, as it can be confused with severe infection or in some circumstances with primary disease flare-up. We aim to extend our knowledge about severe infusion related reactions to rituximab in children, focusing on RISS and anaphylaxis. Objectives: Our study objective was to study severe reactions to rituximab by evaluating all children and adolescents who received rituximab in our center. Methods: Children and adolescents who received rituximab between 2014 and 2021 at CHU Sainte-Justine, a tertiary and leading pediatric center in Quebec, Canada, were included in the study. Data was collected retrospectively from our electronic medical records in CHU Ste-Justine. The diagnostic criteria proposed by the World Allergy Organization in 2020 were used to classify patients in the anaphylaxis subgroup. Patients with RISS were included if they developed fever and at least rash and/or arthralgia, starting 1 to 30 days following rituximab infusion, and if no other confirmed diagnosis explained symptoms. The study was approved by local Institutional Review Board. Results and discussion: 1534 rituximab infusions in 391 patients were analyzed. A severe infusion reaction to rituximab occurred in 14 patients (3.6%); none resulted in death. Rituximab was prescribed for an auto-immune disease in 61% of cases. Seven patients presented with RISS (1.8%); all were treated for an auto-immune disease including 4 for immune thrombocytopenia (ITP). Mean time from rituximab to RISS was 9 days (ranging from 6 to 12 days). All RISS patients but one presented with the classical triad of fever, rash and arthralgia. Increased C-reactive protein or sedimentation rate was documented in all patients, and decreased complement in 83%. Three patients required admission to intensive care unit due to hemodynamic instability. Patients received corticosteroids and/or intravenous immunoglobulins; mean duration of RISS was 4 days (ranging from 3 to 6 days). Rituximab was reinfused after RISS in one patient; she presented an immediate anaphylactoid reaction after which rituximab was permanently discontinued. Patients who received lower doses of rituximab were less likely to present RISS compared to patients who received higher doses (risk ratio 0.14, CI 0.03-0.74, p=0.016). Although few ITP patients developed RISS, RISS was associated with a greater chance of achieving partial or complete ITP remission (risk ratio 3, CI 1.47-6.14, p=0.033). Such possible association was not observed in other diseases. Seven patients developed severe anaphylaxis (1.8%), 3 of them reacted after the first dose (42.8%). Five of them were able to receive further rituximab infusion, using desensitization protocols. Conclusion: RISS is a rare hypersensitivity reaction in children. To this day, our study is the first to report more than 3 patients in a pediatric setting. RISS in children seems to be more frequent when rituximab is administered for an autoimmune condition, especially ITP. Although the classic triad of fever, rash and arthralgia appears more frequent in children than in adults, RISS should be considered in the differential diagnosis of any suggestive symptom developing within 30 days of infusion. Presence of biological inflammation and/or low serum complement can further support the diagnosis. In all patients, evolution was favorable within a few days with steroids. However, in contrast with anaphylaxis, RISS should be considered as a contraindication for further rituximab therapy.

Gene Therapy Expressing Platelet-Derived Factor VIII for Correction of Hemophilia Α with a History of Inhibitors

Introduction: Platelet targeted gene therapy with human factor VIII has established hemostasis in murine and canine models with severe hemophilia A withouteliciting inhibitory antibodies. Here-in we describe feasibility, safety and efficacy of the first subject treated on a first-in-human phase 1 trial that targets factor FVIII synthesis and storage within platelet α-granules for delivery at the site of vascular injury for hemophilia A (NCT03818763). Method: Eligible are severe hemophilia A patients ≥18 years with a history of inhibitors to factor VIII (≥0.6 Bethesda Units [BU]/ml). Following mobilization, autologous CD 34+ cells (≥6 x 10 6/kg) are collected and transduced with a lentiviral vector encoding the ITGA2B gene promoter for ectopic expression of human B-domain-deleted factor VIII within the megakaryocyte lineage. The transduced cells are infused after reduced intensity cytoreduction with fludarabine (120 mg/m 2) and melphalan (120 mg/m 2) followed by a washout period of ≥24 hours. The primary endpoints of feasibility and safety are defined as: 1) feasibility of the cell manufacturing procedure by the availability of ≥4 x 10 6/kg transduced clinical grade CD34+cells, cell viability ≥70% and undetectable microbial contamination and 2) safety defined as hematopoietic recovery ≤28 days of infusion and absence of ≥ grade 3 toxicity (CTCAE version 5.0). Outcome: Subject 1 is a 29-year-old male with severe hemophilia A who developed inhibitors to factor VIII (2.6 BU/ml) in his first year of life. Immune tolerance to factor VIII had been established with a non-detectable inhibitor titer at enrollment. Hemostatic prophylaxis was maintained with emicizumab weekly and recombinant factor VIII for breakthrough bleeding. His annualized bleeding rate was 16 in the 12-month period preceding infusion. The cell product was the result of 1 day of collection yielding 6.73 x 10 6 /kg total viable CD34+ cells post-transduction and vector copy number by qPCR of 1.16 copies/cell. Megakaryocyte factor VIII:C levels were 0.00 mU/10 6 before transduction and 101.32 mU/10 6 after transduction. The cell product satisfied release criteria. Neutrophil recovery (≥0.5 x 10 9/L) and platelet transfusion independence (≥50 x 10 9/L) was achieved 15 days post-infusion and sustained for &amp;gt;12 months. The duration of hospitalization was 21 days with no re-admissions. There was no breakthrough bleeding during collection and hospitalization. During and post-infusion there was no unexpected toxicity ≥ grade 1. He has not required immune suppression. Emicizumab was discontinued 3.6 months post-infusion after demonstration of whole blood vector copy number at 1 and 3-months. There has been no spontaneous bleeding or a need for “on demand” factor VIII after discontinuing emicizumab. Secondary outcomes are summarized in Table 1. No replication competent lentivirus was detected through month 12 post-infusion. Integration site analysis was carried out, and none of the samples tested through 12 months contained cell clones which exceeded 20% relative abundance. Transduced cells were highly polyclonal. Integration site analysis showed no enrichment of integration near cancer-associated genes in the cell product nor in whole blood cell lineages post-infusion. Conclusion: We report feasibility, safety and efficacy in the first subject with severe hemophilia A and a history of inhibitors who received lentiviral vector gene therapy directed to induce megakaryocytes to synthesize and store factor VIII within platelets. These findings extend the potential to treat severe hemophilia A patients who are not eligible for valoctcogene roxaoarvovec (AAV5-hFVIII-SQ).

First Fever between Lymphodepletion and Day 30 after CAR-T Cell Therapy: Patterns, Origins, and Implications in Lymphoma Patients

Introduction: Fever is a common adverse event associated with chimeric antigen receptor-T cell (CAR-T cell) therapy and serves as the hallmark of cytokine release syndrome (CRS). However, limited data are available on competing and contributing etiologies of fever. Thus, we aimed to investigate the causes, risk factors, and implications of fever in CAR-T cell recipients in the period with the most profound immunosuppression: between lymphodepletion (LD) and day 30 after infusion. Methods: In this single-center retrospective analysis, we studied 304 non-Hodgkin lymphoma patients (80% large B-cell lymphoma, 11% mantle cell lymphoma, 4% follicular lymphoma) treated with CD19-CAR-T cells (48% axi-cel, 23% tisa-cel, 23% liso-cel, 6% brexu-cel) between 2016 and 2023. First fever was defined as a temperature of 38°C or higher between LD and day 30 after CD19-CAR-T cells. Patients experiencing fever were routinely cultured, following institutional guidelines. Additional workup, including respiratory virus PCR panel, stool gastrointestinal PCR panel, Clostridioides difficile PCR, urine culture, chest x-ray, and fungal infection assessment, was done at the medical team's discretion. A contributing infectious source for the fever was considered if there was a positive test in the workup within 72 hours of the initial fever. Results: Fever occurred in 232/304 (76%) of patients between LD and day 30 after CAR-T cell infusion. The median time from LD to first fever was 5 days (range 2-13) and from CAR-T infusion to first fever was 2 days (range: LD initiation to 16). Of patients who had not developed a fever up to the day of infusion (n=271), 199 (73%) experienced a fever between infusion (day 0) and day 30. The primary etiology of fever between LD and day 30 was CRS (n=159/232, 68.5%), with 54% experiencing grade 2 or higher. An infectious source was identified in 52/232 (22%) of all patients and 35/194 (18%) of the subgroup developing CRS. Leading infectious etiologies were gastrointestinal (GI), bloodstream, and respiratory infections in 20 (38%), 14 (27%), and 11 (21%) of patients, respectively (Figure A). The most frequent pathogens identified were Clostridioides difficile for GI tract infections (10/20), Enterobacteriaceae for bloodstream infections (8/14), and common upper respiratory viruses, such as Rhinovirus and Parainfluenzavirus (10/16). Importantly, in patients developing fever after infusion, an infectious source was identified in 42/199 (21%). Among them, 12/42 (29%) were bloodstream infections, and 10/42 (24%) were Clostridioides difficile infections requiring rapid antibiotic management. Of an array of potential risk factors, only pre-apheresis metabolic tumor volume was associated with an increased risk for an infectious cause of fever in a univariable logistic-regression model (p=0.029). Furthermore, an infectious source of fever, compared to a non-infectious cause, was associated with an increased risk of mortality (HR 1.60, 95%CI 1.02-2.51, p=0.039) in a multivariable Cox regression model adjusted for LDH range before lymphodepletion, age and CAR-T construct type (Figure B). Conclusions: This study represents one of the first and largest investigations into fever patterns and origins in CAR-T cell therapy recipients. Although fever is common, treatable infectious sources are infrequent. Our findings may have implications for antibiotic stewardship and fever management in CAR-T patients. Finally, the association between infectious fever and inferior survival warrants further investigation on the biological processes driving mortality.

Extravascular Factor IX Pool Fed By Prophylaxis Is a True Hemostatic Barrier Against Bleeding

Factor IX (FIX) can bind to type-IV collagen in the endothelial basement membrane and diffuse into extravascular spaces. Previous studies in rodents have reported a large biodistribution of FIX. However, the potential hemostatic activity of extravascular FIX and its role in protecting against joint bleeds have not been demonstrated. The capacity of 4 different FIX molecules (plasma derived [pd] and recombinants) to bind type I and type IV collagen was studied here. FIX molecules were also administered intravenously at doses of 50 to 3000 IU/kg in FIX knock-out (KO) mice. A specific FIX signal was detected in immunohistochemistry in the liver as well as in muscles and knee joints with recombinant FIX molecules injected at 1000 and 3000 IU/kg but not at the usual clinical doses of 50-100 IU/kg, while pdFIX generated a FIX signal at all doses including 50 IU/kg. After five 100 IU/kg daily infusions of rFIX, a clear accumulation of FIX was seen in the liver and joints of animals having received 5-day daily FIX infusions with all FIX molecules, with a higher FIX labelling intensity compared to that observed after a single infusion of FIX 100 IU/kg or a single infusion of FIX 500 IU/kg. The extravascular procoagulant activity of FIX was assessed in saphenous vein bleeding assays performed 7 days after a single infusion of FIX 100 IU/kg. An additional group of FIX KO mice received intravenously for 5 days a single daily dose of 100 IU/Kg of one the four types of FIX concentrate in order to mimic prophylaxis. The number of clots formed in 15 minutes was significantly greater in mice having received prophylaxis during 5 days with 100 IU/kg FIX compared to untreated FIX KO mice (p=0.009) and to mice having received a single infusion of FIX 100 IU/kg (p&amp;lt;0.0001) (Figure 1). Taken together, these results show that in individuals with severe hemophilia B receiving regular prophylaxis with FIX, extravascular accumulation of FIX over time may have a significant impact on the coagulation capacity and protection towards bleeding.

No Place like Home: Home-Based Intravenous Arsenic Trioxide for the Treatment of Acute Promyelocytic Leukemia (APL)

Introduction: APL has transitioned from a highly fatal malignancy to a disease that is curable with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Intravenous (IV) administration of ATO remains the standard of care for consolidation, however, its use is associated with long infusion times, electrolyte disturbances, and QTc prolongation that has historically required frequent outpatient infusion center administration and monitoring. Following induction, patients receive a cumbersome schedule of ATO through daily infusions 5 days each week (typically Monday-Friday) 4 weeks on 4 weeks off for 4 cycles. Oral formulations of ATO are poorly water soluble, have not demonstrated adequate absorption in the gastrointestinal (GI) tract leading to significant GI upset and are not approved for use in the United States. Beginning in 2020, patients treated at our institution were given the option of receiving ATO at home through a partnership via Qualitas Specialty Pharmacy of RWJBarnabas Health. This retrospective review evaluates the feasibility, safety, and efficacy of administration of ATO in the home infusion setting for patients with APL receiving ATO consolidation. Methods: Through retrospective chart review, we evaluated patients who received consolidation therapy of ATO through home infusion from 2020-2023. Eligible patients included those with an ECOG of &amp;lt;2, absence of baseline QTc prolongation (defined as &amp;gt;500ms), and patients without significant kidney dysfunction or hepatotoxicity at baseline. We evaluated each patient for adverse effects such as QTc prolongation, electrolyte disturbances, liver function test (LFT) abnormalities, neutropenic fever, bacteremia, unplanned Emergency Room (ER) or urgent care visits, and unexpected hospitalizations (via Common Terminology Criteria for Adverse Events version 5). Results: Fifteen patients aged 19-79 (median = 43) were reviewed with 60% being male and 40% female. Sixty percent had a baseline ECOG 1 and 40% had an ECOG 0. Twenty percent of patients had a prior malignancy (n=3). Eighty percent of the patients experienced grade (gd) 1-3 electrolyte abnormalities (47% gd 1 hyperphosphatemia, 13% gd 1 hyperkalemia, 7% gd 2 hyperkalemia, 7% gd 3 hyperkalemia, 13% gd 1 hypokalemia, 13% gd 1 hypermagnesemia, 7% gd 3 hypermagnesemia, 7% gd 1 hypomagnesemia, 33% gd 1 hypernatremia, 33% gd 1 hyponatremia, &amp; 7% gd 2 hyponatremia). Of the 15 patients receiving treatment, 27% experienced gd 1 alanine aminotransferase (ALT) increase, 13% of patients experienced gd 1 aspartate aminotransferase (AST) increase, and 7% of patients experienced gd 2 hyperbilirubinemia. For QTc prolongation, 53% of patients experienced gd 1 prolongation, 7% of patients experienced gd 2 prolongation, and 13% of patients experienced gd 3 prolongation. One out of the 15 patients experienced treatment delays due to QTc prolongation. While forty percent of patients visited either the ER and/or urgent care during consolidation therapy, no visits were deemed therapy related. Reasons for urgent evaluation included infections (n=3), vertigo (n=1), low back pain (n=1), facial numbness (n=1), fall (n=1), abdominal pain (n=1), and hemorrhoidal bleeding (n=1). Two patients were hospitalized, due to a renal infarct (n=1) and a subdural hematoma after a fall (n=1). None of the 15 patients experienced febrile neutropenia/bacteremia while receiving consolidation therapy. Of the 11 patients who completed consolidation at the time of this abstraction, all (100%) had complete remission demonstrated on post-consolidation bone marrow. One of the 11 patients relapsed within 6 months of consolidation; however, is now in remission following two additional consolidation courses and a bone marrow transplant. Four patients have not yet completed four cycles of ATO consolidation. One patient was transitioned from home infusion to clinic treatment due to out-of-pocket cost. Conclusions: Our study demonstrates that home infusion of ATO is both safe and highly effective for patients. Therapy was well tolerated with predictable and manageable toxicity. Prospective studies are needed to evaluate the efficacy and safety in comparison to patients receiving ATO in the infusion center as well as to assess patient-reported and cost outcomes. Given the safety profile of home-based ATO, we have implemented at home ATO consolidation as standard therapy for all eligible patients.