Key Points Overall, no benefit of granulocyte transfusion therapy was observed, but the power of the study was reduced due to low accrual. Post hoc secondary analysis suggested that patients receiving higher doses tended to have better outcomes than those receiving lower ones.

Key Points Laboratory parameters associated with increased bleeding were platelet counts ≤5 × 109/L, hematocrits ≤25%, INR >1.2, and aPTT >30 seconds. Platelet and RBC transfusions on days with bleeding are often not sufficient to change bleeding outcomes on the following day.

Bacterial and fungal infections continue to be a major problem in patients with prolonged severe neutropenia. Early controlled trials suggested that granulocyte transfusions were modestly effective in this setting, but the doses provided were later considered inadequate. Recent studies have shown that the dose can be increased substantially by administering G-CSF ± dexamethasone to granulocyte donors. Although these cells circulate in neutropenic recipients and appear to function normally, the evidence for clinical efficacy has been inconclusive. We report here the result of the RING study, a recently completed randomized controlled trial on the efficacy of high-dose granulocyte transfusion therapy, carried out as part of the NHLBI Transfusion Medicine/Hemostasis Clinical Trials Network. Fourteen clinical sites participated. Eligible subjects were those with neutropenia (ANC<500) and proven/probable/presumed bacterial or fungal infection. Subjects were randomized to receive either 1) standard antimicrobial therapy or 2) standard antimicrobial therapy plus daily granulocyte transfusions from normal donors stimulated with G-CSF (450µg) and dexamethasone (8mg). The primary end point was a composite one; survival plus a microbial response, both evaluated 42 days after randomization. Microbial response was determined by a blinded adjudication panel. The target sample size was 236 subjects, designed to provide 80% power to detect a 20% difference in success rates between treatment and control groups; however, only 114 subjects could be enrolled. Patient infections were 36% invasive fungal, 27% invasive bacterial, 11% fungemia, and 26% bacteremia. Subjects in both arms were well matched in terms of demographics, underlying disease, types and sites of infection, and severity of illness. Fifty six subjects were randomized to the granulocyte arm; 51 received at least one transfusion; the mean time from eligibility to the first transfusion was 2.3 +/- 1.2 days. Among these 51 subjects, the median number of transfusions was 5 (quartiles 3 and 9), given over a median of 6 days (quartiles 4 and 11). The median number of granulocytes administered per transfusion was 54.9 x109 (quartiles 26.1 x109, 72.5 x109). Fourteen percent of these patients had > Grade 3 hypoxemia develop during or within six hours after a granulocyte transfusion, requiring ventilation in one patient (2%). No deaths were attributed to adverse effects associated with the transfusions. Among subjects with sufficient data to determine the primary outcome, success rates were 42% (20/48) and 43% (21/49) for the granulocyte and control groups, respectively (p> 0.99) on Intention to Treat (ITT) analysis, and 49% (17/35) and 41% (16/39), respectively, for subjects who adhered to their assigned treatments (Per Protocol (PP) analysis)(p=0.64). There was also no significant difference between treatment groups in a model of the primary outcome that adjusted for baseline prognostic factors (e.g. ventilator use, high Zubrod score). Differences in primary end point success rates for granulocyte and control arms did not differ significantly for any infection type whether analyzed by ITT or PP. Outcomes for patients who received the first transfusion within 2 days of eligibility were similar to outcomes for patients who received the first transfusion later. For patients who received at least three granulocyte transfusions, those who received an average dose per transfusion of >50x109 granulocytes had a higher success rate (57.7%)(n=26) than those receiving <5x109 cells per transfusion (11.1%)(n=9)(p = 0.04); while supporting the hypothesis that dose is critical to the outcome, this result needs be interpreted with caution because of the low numbers and poor outcome of the low dose group. There was no significant difference between the granulocyte and control arms on overall survival to either 42 or 90 days after randomization. Because of incomplete patient enrollment, the power of this study to detect a 20% difference in overall success rates was reduced to approximately 40%. Thus it is possible that a true convincing favorable effect was missed, particularly, as suggested, in the subset of patients who received daily transfusions containing at least 50x109 granulocytes per transfusion. Disclosures Off Label Use: In the study being discussed, G-CSF is administered to normal blood donors. This is an off-label use of G-CSF. McCullough:Fresenius/Kabe: Membership on an entity's Board of Directors or advisory committees. Ness:Terumo BCT: Consultancy.

To compare drug survival of ixekizumab to other IL-17 inhibitors (IL-17i) and TNF inhibitors (TNFi) among patients with psoriasis (PsO) in a real-world setting. Participants included adult PsO patients enrolled in the Corrona Psoriasis Registry who initiated ixekizumab, TNFi, or other IL-17i between 16 March 2016 to 10 August 2019 and completed ≥1 follow-up visit. Multivariable adjusted hazard ratios (HR) were calculated to estimate the risk for drug discontinuation in the ixekizumab group relative to the other drugs. Among the 1604 drug initiations, 552 initiated ixekizumab, 450 initiated TNFi, and 602 initiated other IL-17i. Mean age was 51 years, 49% were women, and 52% were obese (BMI > 30). Ixekizumab patients had a higher proportion of patients with PASI >12 at drug initiation (24%) than TNFi (15%) and other IL-17i (19%). Over a median of 11 months of follow-up, 723/1604 (45%) drug discontinuations occurred. Persistence of ixekizumab, TNFi, and other IL-17i at 24-months were 68%, 33%, and 46%, among biologic-naïve patients (n = 543), and 46%, 23%, and 36%, for biologic-experienced patients (n = 1061), respectively. Ixekizumab patients had a 64% lower risk of discontinuation vs TNFi (HR = 0.36; 95% CI 0.27-0.47) and a 31% lower risk vs other IL-17i (HR = 0.69, 95% CI 0.55-0.87) after adjustment for biologic experience and other covariates. HRs were similar when limited to patients with moderate-to-severe PsO (BSA > 3, PASI > 3, and IGA > 1, n = 1076) at initiation. In our study of real-world patients with PsO, initiators of ixekizumab had more prolonged drug survival than both initiators of TNFi and other IL-17i up to 2 years of follow-up.

SUMMARYWe compared a novel 5% testosterone (T) cream (AndroForte 5, Lawley Pharmaceuticals, Australia) with a 1% T gel (Testogel, Besins Healthcare, Australia). Using an open-label crossover design, subjects were randomized to one of two treatment sequences using either the T gel or T cream first in a 1 : 1 ratio. Each treatment period was 30 days with a 7-14 days washout period between them. On Days 1 and 30 of each treatment period blood was sampled at À15, À5 min, 0, 2, 4, 5, 6, 7, 8, 9, 10, 12 and 16 h post study drug administration. Sixteen men with established androgen deficiency aged between 29 and 73 years, who had undertaken a washout from prior testosterone therapy participated in the study. One subject failed to complete both arms and another was excluded post-completion because of a major protocol violation. Bioequivalence was established based on key pharmacokinetic (PK) variables: AUC, C avg , C max , T max , % fluctuation (with and without baseline correction) for the two formulations of testosterone on Day 1 and Day 30. The ratio and 90% CI of AUC 0.99 (0.86-1.14), C max 1.02 (0.84-1.24) and C avg 0.99 (0.86-1.14) for T cream/T gel were within the predetermined bio-equivalence criteria of 80% to 125% at Day 30. There were no statistically significant differences between secondary biochemical markers: serum dihydrotestosterone (DHT), oestradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH) and (FSH). The two testosterone formulations were shown to be bioequivalent.

No abstract

Malnutrition is associated with increased mortality and other unfavorable echocardiographic and clinical outcomes compared with those of NB. The same effect of obesity on survival was not observed. Further studies are needed investigating the long-term impact of abnormal anthropometric measurements on outcomes in pediatric DCM. (Pediatric Cardiomyopathy Registry; NCT00005391).

The presence or development of WBC antibodies had no demonstrable effect on any clinical aspect of granulocyte transfusion therapy. It appears that, at least in the patient population studied, there is no evidence suggesting need for concern about recipient WBC alloimmunization when prescribing granulocyte transfusions.