•These updated ESMO Clinical Practice Guidelines provide key recommendations on the management of chronic lymphocytic leukaemia (CLL)•Authorship includes a multidisciplinary group of experts from ...different institutions and countries in Europe•Recommendations are provided, including levels of evidence and grades of recommendation where applicable•Prognosis and treatment decisions in CLL depend on genetic and clinical factors including age, stage and comorbidities•Therapies targeting B-cell receptor pathway or defect mechanism of apoptosis induce long lasting remissions
In chronic lymphocytic leukemia (CLL), TP53 gene defects, due to deletion of the 17p13 locus and/or mutation(s) within the TP53 gene, are associated with resistance to chemoimmunotherapy and a ...particularly dismal clinical outcome. On these grounds, analysis of TP53 aberrations has been incorporated into routine clinical diagnostics to improve patient stratification and optimize therapeutic decisions. The predictive implications of TP53 aberrations have increasing significance in the era of novel targeted therapies, i.e., inhibitors of B-cell receptor (BcR) signaling and anti-apoptotic BCL2 family members, owing to their efficacy in patients with TP53 defects. In this report, the TP53 Network of the European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) presents updated recommendations on the methodological approaches for TP53 mutation analysis. Moreover, it provides guidance to ensure that the analysis is performed in a timely manner for all patients requiring treatment and that the data is interpreted and reported in a consistent, standardized, and accurate way. Since next-generation sequencing technologies are gaining prominence within diagnostic laboratories, this report also offers advice and recommendations for the interpretation of TP53 mutation data generated by this methodology.
Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute ...lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further investigation. Here we report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes (LNs), spleen and bone marrow, assessed phenotypic changes of circulating cells and measured whole-blood viscosity. With just one dose of ibrutinib, the average increase in ALC was 66%, and in>40% of patients the ALC peaked within 24 h of initiating treatment. Circulating CLL cells on day 2 showed increased Ki67 and CD38 expression, indicating an efflux of tumor cells from the tissue compartments into the blood. The kinetics and degree of the treatment-induced lymphocytosis was highly variable; interestingly, in patients with a high baseline ALC the relative increase was mild and resolution rapid. After two cycles of treatment the disease burden in the LN, bone marrow and spleen decreased irrespective of the relative change in ALC. Whole-blood viscosity was dependent on both ALC and hemoglobin. No adverse events were attributed to the lymphocytosis.
Sequence analysis of known antibiotic resistance genes of the Mycobacterium tuberculosis complex (MTBC) is increasingly being used to infer phenotypic resistance to a variety of antibiotics. However, ...a clear understanding of the genotype-phenotype relationship is required to interpret genotypic susceptibility results accurately. In this context, it is particularly important to distinguish phylogenetically informative neutral polymorphisms from true resistance-conferring mutations.
Using a collection of 71 strains that encompasses all major MTBC genotypes, we mapped the genetic diversity in 18 genes that are known to be involved or were previously implicated in antibiotic resistance to eight current as well as two novel antibiotics. This included bedaquiline, capreomycin, ethambutol, fluoroquinolones, isoniazid, PA-824, para-aminosalicylic acid, prothionamide, rifampicin and streptomycin. Moreover, we included data from one of our prior studies that focused on two of the three known pyrazinamide resistance genes.
We found 58 phylogenetic polymorphisms that were markers for the genotypes M. tuberculosis Beijing, Haarlem, Latin American-Mediterranean (LAM), East African Indian (EAI), Delhi/Central Asian (CAS), Ghana, Turkey (Tur), Uganda I and II, Ural and X-type, as well as for Mycobacterium africanum genotypes West African I (WA I) and II (WA II), Mycobacterium bovis, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium microti and Mycobacterium canettii.
This study represents one of the most extensive overviews of phylogenetically informative polymorphisms in known resistance genes to date, and will serve as a resource for the design and interpretation of genotypic susceptibility assays.
Both acute and chronic kidney disease are common after liver transplantation and result in significant morbidity and mortality. The introduction of the Model for End‐stage Liver Disease score has ...directly correlated with an increased prevalence of perioperative renal dysfunction and the number of simultaneous liver–kidney transplantations performed. Kidney dysfunction in this population is typically multifactorial and related to preexisting conditions, pretransplantation renal injury, perioperative events, and posttransplantation nephrotoxic immunosuppressive therapies. The management of kidney disease after liver transplantation is challenging, as by the time the serum creatinine level is significantly elevated, few interventions affect the course of progression. Also, immunological factors such as antibody‐mediated kidney rejection have become of greater interest given the rising liver–kidney transplant population. Therefore, this review, assembled by experts in the field and endorsed by the American Society of Transplantation Liver and Intestine Community of Practice, provides a critical assessment of measures of renal function and interventions aimed at preserving renal function early and late after liver and simultaneous liver–kidney transplantation. Key points and practice‐based recommendations for the prevention and management of kidney injury in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.
This review summarizes key data and provides practice‐based guidelines to assess and preserve renal function early and late after liver and liver–kidney transplantation. See page 2516 for the companion review.
Over the last decade the age of liver transplant (LT) recipients and the likelihood of coronary artery disease (CAD) in this population have increased. There are no multicenter studies that have ...examined the impact of CAD on LT outcomes. In this historical cohort study, we identified adult LT recipients who underwent angiography prior to transplantation at seven institutions over a 12‐year period. For each patient we recorded demographic data, recipient and donor risk factors, duration of follow‐up, the presence of angiographically proven obstructive CAD (≥50% stenosis) and post‐LT survival. Obstructive CAD was present in 151 of 630 patients, the CAD(+) group. Nonobstructive CAD was found in 479 patients, the CAD(−) group. Patient survival was similar for the CAD(+) group (adjusted HR 1.13, CI = 0.79, 1.62, p = 0.493) compared to the CAD(−) group. The CAD(+) patients were further stratified into severe (CADsev, >70% stenosis, n = 96), and moderate CAD (CADmod, 50–70% stenosis, n = 55) groups. Survival for the CADsev (adjusted HR = 1.26, CI = 0.83, 1.91, p = 0.277) and CADmod (adjusted HR = 0.93, CI = 0.52, 1.66, p = 0.797) groups were similar to the CAD(−) group. We conclude that when current CAD treatment strategies are employed prior to transplant, post‐LT survival is not significantly different between patients with and without obstructive CAD.
The authors find no significant difference in post‐liver transplant survival between patients with and without angiographically proven obstructive coronary artery disease when current treatment regimens are employed.
We report the 12-year follow-up of the prospective randomized EBMT LYM1 trial to determine whether the benefit of brief duration rituximab maintenance (RM) on progression-free survival (PFS) in ...patients with relapsed follicular lymphoma (FL) receiving an autologous stem cell transplant (ASCT) is sustained. One hundred and thirty-eight patients received RM with or without purging. The median follow-up after random assignment is 12 years (range 10-13) for the whole series. The 10-year PFS after ASCT is 47% (95% CI 40-54) with only 4 patients relapsing after 7.5 years. RM continues to significantly improve 10-year PFS after ASCT in comparison with NM P = 0.002; HR 0.548 (95% CI 0.38-0.80). Ten-year non-relapse mortality (NRM) was not significantly different between treatment groups (7% overall). 10-year overall survival (OS) after ASCT was 75% (69-81) for the whole series, with no significant differences according to treatment sub-groups. 10-year OS for patients who progressed within 24 months (POD24T) was 60%, in comparison with 85% for patients without progression. Thus the benefit of rituximab maintenance after ASCT on relapse prevention is sustained at 12 years, suggesting that RM adds to ASCT-mediated disease eradication and may enhance the curative potential of ASCT.
The combination of the BCL2 inhibitor venetoclax plus obinutuzumab was more effective in the treatment of older medically ill patients with untreated chronic lymphocytic leukemia than was ...chlorambucil plus obinutuzumab. Progression-free survival at 2 years was 88% with venetoclax and 64% with chlorambucil.
Our objective was to evaluate the impact of hydroxyethyl starch (HES) use in organ donors after neurologic determination of death (DNDD) on recipient renal graft outcomes. The following data elements ...were prospectively collected for every DNDD managed by a single organ procurement organization from June 2011 to July 2013: demographics; critical care endpoints; treatments, including the use of HES; graft cold ischemia time (CIT); and the occurrence of recipient delayed graft function (DGF, dialysis in the first week after transplantation). Logistic regression was performed to identify independent predictors of DGF with a p‐value <0.05. The results were then adjusted for each donor's calculated propensity to receive HES. Nine hundred eighty‐six kidneys were transplanted from 529 donors. Forty‐two percent received HES (1217 ± 528 mL) and 35% developed DGF. Kidneys from DNDDs who received HES had a higher crude rate of DGF (41% vs. 31%, p < 0.001). After accounting for the propensity to receive HES, independent predictors of DGF were age (OR 1.02 1.01–1.04 per year), CIT (OR 1.041.02–1.06 per hour), creatinine (OR 1.5 1.32–1.72 per mg/dL) and HES use (OR 1.41 1.02–1.95). HES use during donor management was independently associated with a 41% increase in the risk of DGF in kidney transplant recipients.
To investigate the impact of hydroxyethyl starch (HES) use in deceased organ donors, the authors perform a propensity‐adjusted analysis and find HES use during donor management to be independently associated with an increase in the risk of delayed graft function in kidney transplant recipients.
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