High Graft-versus-Host Disease-Free,Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study

Allogeneic stem cell transplantation (SCT) as primary treatment for aplastic anemia (AA) is being increasingly used. Yet, age, stem cell source, and donor type are important outcome factors. We have recently performed a nationwide cohort study of all patients with AA in Sweden diagnosed from 2000 to 2011 and now present outcome data on SCT patients. In total, 68 patients underwent SCT, and 63% of them had failed immunosuppressive therapy. We found that, with a median follow-up of 109 months (range, 35 to 192 months), 5-year overall survival (OS) for all patients was 86.8%, whereas graft-versus-host disease-free, relapse/rejection-free survival (GRFS) at 5 years was 69.1%. There was no survival impact regarding the donor type or stem cell source. Patients aged ≥40 years had a higher transplant-related mortality (29.4% versus 7.8%; P = .023), which translated into a lower 5-year OS: 70.6% versus 92.2% (P = .022) and a trend of lower GRFS (52.9% versus 74.5%; P = .069). In conclusion, we found in this real-world setting that both OS and GRFS were high, but SCT for patients with AA aged ≥40 years is problematic, and clinical trials addressing this issue are warranted.     

CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials

Small molecule pharmacological inhibition of dominant human genetic disease is a feasible treatment that does not rely on the development of individual, patient‐specific gene therapy vectors. However, the consequences of protein inhibition as a clinical therapeutic are not well‐studied. In advance of human therapeutic trials for CAPN5 vitreoretinopathy, genetic inactivation can be used to infer the effect of protein inhibition in vivo. We created a photoreceptor‐specific knockout (KO) mouse for Capn5 and compared the retinal phenotype to both wild‐type and an existing Capn5 KO mouse model. In humans, CAPN5 loss‐of‐function (LOF) gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes. Ocular examination of the retina of Capn5 KO mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 LOF CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these LOF variants were nearby known disease‐causing variants within the proteolytic core and in regions of high homology between human CAPN5 and 150 homologs, yet the LOF of CAPN5 was tolerated as opposed to gain‐of‐function disease‐causing variants. These results indicate that localized inhibition of CAPN5 is a viable strategy for hyperactivating disease alleles.     

Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation

Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients’ abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P?=?.01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE⁺) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n?=?21). For patients who underwent HSCT with GdE⁺ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n?=?27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE⁺ status is a strong predictor of disease progression in untreated patients.? This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.     

Fidaxomicin versus oral vancomycin for severe Clostridium difficile infection: a retrospective cohort study

ObjectivesThis study was conducted to compare clinical outcomes of fidaxomicin versus oral vancomycin in the management of severe Clostridium difficile infection (CDI).MethodsThe investigation was a retrospective, multicentre, propensity score-matched analysis using a national clinical administrative database. Veterans treated for severe CDI from any Veterans Affairs Medical Center between 1 June 2011 and 30 June 2017 were included if they received fidaxomicin or an oral vancomycin regimen for treatment. The two groups were matched by the nearest-neighbour method from a propensity score derived from independent variables associated with the selection of a fidaxomicin course.ResultsPropensity score matching resulted in two well-matched cohorts consisting of 213 fidaxomicin and 639 oral vancomycin courses. No statistically-significant difference was found for the primary outcome of combined clinical failure or recurrence (68/213 (31.9%) versus 163/639 (25.5%), respectively, p 0.071). Additionally, no statistically significant differences were found for the secondary outcomes of 30-day (23/213 (10.8%) versus 75/639 (11.7%), respectively, p 0.71), 90-day (48/213 (22.5%) versus 140/639 (21.9%), respectively, p 0.85), and 180-day mortality (62/213 (29.1%) versus 186/639 (29.1%), respectively, p 1.0) between the two treatment groups.ConclusionsCourses of fidaxomicin or oral vancomycin for severe CDI resulted in similar treatment outcomes. Study findings are consistent with current treatment guideline recommendations for the use of either agent in the management of severe CDI.     

Combining VITEK® 2 with colistin agar dilution screening assist timely reporting of colistin susceptibility

ObjectivesThe rise in carbapenem resistance among Gram-negative bacteria has renewed interest in colistin. Recently, the EUCAST-CLSI Polymyxin Breakpoints Working Group declared that broth microdilution (BMD) is the only valid method for colistin susceptibility testing. BMD is not easily incorporated into the routine work of clinical laboratories, and usually this test is incorporated serially, resulting in delayed susceptibility reporting. We tested a strategy of combining VITEK^® 2 with a 2 μg/mL colistin agar dilution (VITEK^® 2/AD) screening plate to improve performance and time to reporting of colistin susceptibility.MethodsColistin susceptibility for 364 clinical isolates was determined by VITEK^® 2/AD and compared with the reference standard BMD according to the ISO 20776-1:2007 and CLSI guidelines. The EUCAST colistin susceptibility breakpoint of ≤2 μg/mL was used. Escherichia coli NCTC 13846 served as quality control strain. Agreement, very major error (VME) and major error rates were determined using ISO 20776-2:2007.ResultsThe VME rate for VITEK^® 2 alone was 30.6% (15/49, 95% CI 18.3–45.4%), and was reduced to 10.2% (5/49, 95% CI 3.4–22.2%) using the VITEK^® 2/AD combined testing. The combined testing had categorical agreement with BMD of 97% (354/364, 95% CI 95.0–98.7%), and a major error (ME) rate of 1.6% (5/315, 95% CI 0.5–3.7%). Using the combined testing, even against challenging strains, 349 (95.8%, 95% CI 93.3–97.7%) colistin susceptibility results could be reported, and only 15 isolates required further analysis by BMD.DiscussionOur method is simple to apply and allows rapid reporting of colistin susceptibility.