Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Infection Rates and Rapid Immune Cell Reconstitution Following Familial Haploidentical (FHI) CD34 Enriched Peripheral Blood (PB) Stem Cell Transplantation (HISCT) with PB Mononuclear Cell Addback in Patients with High-Risk Sickle Cell Disease (SCD)

Background:We previously reported the results of a phase II multicenter transplant trial using haploidentical parental donors for children and adolescents with high-risk Sickle Cell Disease (SCD) achieving excellent survival with exceptionally low rates of graft-versus-host disease (GVHD) and resolution of SCD symptoms. Objective: To investigate the rates of infections and immune reconstitution in 20 patients with high risk sickle cell disease who have undergone haploidentical transplantation. Methods: Comprehensive assessment of immune reconstitution included lymphocyte subsets, plasma cytokines, complement levels, and activation markers were obtained. Incidence of viral, bacterial and fungal infections were recorded. Results: Myeloid engraftment was robust (100%) at a median of 9 days. NK cell levels were rapidly restored by 30 days. By 60 days, CD19 B cells were normal. CD8 and CD4 T cells levels were normal by 279 and 365 days, respectively. Activated CD4 and CD8 T cells were elevated 100-365 days post-transplant while naïve cells renewal was below baseline. Tregs were elevated 100-270 days post-transplant, returning to baseline levels at one year. At one year, C3 and C4 levels were above baseline and CH50 levels were similar to baseline. The incidence of viral reactivation was CMV = 5, EBV = 5, HHV6 = 3, and Adenovirus = 2. Three fungal infections occurred (Candida = 2, Aspergillus fumigatus = 1). There were 10 bacterial infections-, Enterobacter cloacae = 4, Bacillus = 2, Staph coag neg = 2, Elizabethkingia menignoseptica = 1, and Strep slavarius = 1. The cumulative incidence of grades 2 to 4 acute GVHD and late acute GVHD was 6.2% and moderate and/or severe chronic GVHD was 6.7%. The probability of 1-year EFS or overall survival was 90% (95% CI, 64.1%-97.3%) and of 2-year EFS or overall survival was 84% (95% CI, 57.0%-94.4%), and no patient had residual SCD symptoms. Conclusion: These results suggest that haploidentical transplantation utilizing CD34 enrichment and PB MNC addback resulted in rapid and 100% engraftment with excellent OS and EFS. The fixed T cell addback was protective against significant viral infections but reactivations did occur. There were no primary deaths attributable to infection. The 50% incidence of bacterial infections is significant and should warrant future studies. Extended bacterial prophylaxis may be warranted for this population

Haploidentical Viral Specific Cytotoxic T-Lymphocytes (Vctls) for the Treatment of Refractory Viral Infections in Primary Immunodeficiency (Pid), Solid Organ (Sot) or Allogeneic Bmt Patients

Background and Aims: Viral infections cause significant mortality in patients with immunodeficiencies. Due to limitations of antiviral therapies, adoptive immune therapy has been developed to provide T-cell immunity. Ex-vivo production of vCTLs is limited by time and quantities for infusion. Miltenyi Biotec developed the CliniMACS Prodigy which isolates virus specific CD4+/CD8+ T cells from donors after incubation with viral antigen peptides. The Multicenter Viral CTL Consortium was created to treat immunocompromised patients. To demonstrate vCTLs manufactured using the CliniMACS Prodigy for CMV, EBV, AdV, and BK virus is safe and effective for immunocompromised patients with refractory viral infections. Methods: Patients 0.1-30 years with PID or following SOT or alloHSCT with refractory viral illnesses were eligible. Unmobilized PBMCs were obtained via apheresis. vCTLs were manufactured using the CliniMACS® Prodigy. HLA mismatched related donor cells were infused at 0.5x104 CD3/kg per dose. Infusions of vCTLs Q2 weeks based on response and toxicity (maximum of 5 infusions). CR=PCR negative and PR=PCR ≥1 log decrease. Results: Thirty-three patients met eligibility with two PID and 31 alloHSCT/SOT. Donors were screened. Four patients became ineligible; n=1 due to death from a viral infection, n=1 parental refusal and n=2 subjects with decreasing viral titers. Seventeen patients received vCTLs from their original haplo BMT donor and 12 received third party haplo-related donor vCTL infusions. Seven patients received CMV CTLs, 15 ADV CTLs, 5 BK CTLs, and 2 EBV vCTLs. Of the evaluable patients, responses were 17-CR, five-PR, three-SD, and one-PD with an ORR 85%. Two of the patients developed grade II-III aGVHD of the skin. There was no extensive cGVHD, infusion reactions, or CRS related to vCTLs. Conclusions: The manufacturing of vCTLS using the CliniMACS Prodigy for patients with PID or following SOT or alloHSCT is efficient and the treatment appears safe and effective. Supported by FDA R01006363

The impacts of total body irradiation on umbilical cord blood hematopoietic stem cell transplantation

Background: Umbilical cord blood hematopoietic stem cells are commonly used for hematopoietic system reconstitution in recipients after umbilical cord blood transplantation (UCBT). However, the optimal conditioning regimen for UCBT remains a topic of debate. The exact impact of total body irradiation (TBI) as a part of conditioning regimens remains unknown. Objectives: The aim of this study was to evaluate the impacts of TBI on UCBT outcomes. Design: This was a multi-institution retrospective study. Methods: A retrospective analysis was conducted on the outcomes of 136 patients receiving UCBT. Sixty-nine patients received myeloablative conditioning (MAC), in which 33 underwent TBI and 36 did not, and 67 patients received reduced-intensity conditioning (RIC), in which 43 underwent TBI and 24 did not. Univariate and multivariate analyses were conducted to compare the outcomes and the post-transplant complications between patients who did and did not undergo TBI in the MAC subgroup and RIC subgroup, respectively. Results: In the RIC subgroup, patients who underwent TBI had superior overall survival (adjusted hazard ratio [aHR] = 0.25, 95% confidence interval [CI]: 0.09–0.66, p = 0.005) and progression-free survival (aHR = 0.26, 95% CI: 0.10–0.66, p = 0.005). However, in the MAC subgroup, there were no statistically significant differences between those receiving and not receiving TBI. Conclusion: In the setting of RIC in UCBT, TBI utilization can improve overall survival and progression-free survival. However, TBI does not show superiority in the MAC setting. © The Author(s), 2023.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Treating Children, Adolescents, and Young Adults (CAYA) with Refractory Viral Infections in Primary Immunodeficiencies (PID), or Post Solid Organ Transplant (SOT) or Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) with Virus Specific TLymphocytes (vCTLs)

Background: Patients with PID and secondary immunodeficiency (SID) following SOT or AlloHSCT have compromised T-cell mediated viral immunity leading to increase in morbidity and mortality due to viral reactivation. Due to limitations of antiviral therapy, further research has gone into the development of virus-specific cytotoxic T-lymphocytes (vCTLs) (Bollard Blood 2016). Multiple studies have demonstrated efficacy and safety utilizing the IFN-γ Cytokine Capture System (CCS) using the fully automated CliniMACS Prodigy® device (Miltenyi Biotec) for isolating vCTLs as prophylactic/preemptive treatment or for treating refractory infections (Feuchtinger Blood 2010). We created a multicenter viral CTL consortium (VIRCTLC) to treat immunodeficiency patients with vCTLs and have previously demonstrated the safety and efficacy of vCTLs in this population (Flower/Cairo et al, ASTCT 2020). Objective: To demonstrate the use of Cytomeglovirus (CMV), Epstein Barr virus (EBV), adenovirus (AdV), and BK virus CTLs manufactured utilizing the CliniMACS Prodigy will be safe and effective in decreasing viral loads in CAYA PID or SID patients with refractory viral infections. Design/Methods:A phase II prospective, multicenter, multidisciplinary clinical trial under IND 17449. CAYA patients with refractory viral infections (CMV, AdV, EBV, or BK virus) who met eligibility were consented onto study. Parental donors\u27 peripheral blood mononuclear cells were collected via non-stimulated apheresis. The vCTLs were isolated in the fully-automated IFN-γ CCS by the CliniMACS® Prodigy after incubation with MACS GMP PepTivator® peptide pools. Cell doses were limited to 0.5x104 CD3/kg in HLA mismatched related donors. vCTLs infusions were given every 2 weeks based on responses, for a maximum of 5 infusions. Results: Twenty-six patients received vCTLs. Two patients had PID, three patients were SOT recipients, and twenty-one were alloHSCT recipients. Six patients received CMV CTL infusions, 14 received ADV CTLs, three received EBV virus CTLs, and five patients received BK vCTLs. Median number of vCTL infusions was 2 (1-5). Sixteen patients (62%) achieved complete remission (CR) (PCR negative), five achieved partial response (PR) (PCR ≥1 log decrease), three had stable disease (SD), one had progressive disease (PD), one patient died prior to evaluation secondary to multiorgan system failure. No patient has developed grade III/IV acute GVHD, extensive chronic GVHD, an infusion reaction, cytokine release syndrome, or immune effector cell-associated neurotoxicity syndrome secondary to vCTLs. Conclusion: Viral specific CTLs are safe in CAYA patients with refractory viral reactivation and manufacturing via the automated CliniMACS Prodigy is reproducible in a timely manner. Accrual is ongoing