Long-term management of chronic immune thrombocytopenic purpura in adults

Chronic immune thrombocytopenic purpura (ITP) is generally a more benign disease than previously thought. Currently it is recommended that only those patients with severe and/or symptomatic thrombocytopenia definitely require treatment. Additional factors, such as age, lifestyle, and uremia can also influence the hemorrhagic risk and should be carefully assessed before decision-making on the appropriate management of patients with less severe forms of ITP. The recent introduction of new classes of therapeutic agents such as rituximab and the thrombopoietic growth factors has had a major impact on the management of ITP. Updated treatment guidelines have recently been made available but they are based largely on expert opinion rather than on high-quality clinical trial evidence. This structured review is focused on the management of adults with chronic ITP, including the use of new classes of agents

PARASITIC INFECTIONS IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However, they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients

Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays?

Tauopathies are a group of neurodegenerative diseases characterized by the hyperphosphorylation and deposition of tau proteins in the brain. In Alzheimer's disease, and other related tauopathies, the pattern of tau deposition follows a stereotypical progression between anatomically connected brain regions. Increasing evidence suggests that tau behaves in a prion-like manner, and that seeding and spreading of pathological tau drive progressive neurodegeneration. Although several advances have been made in recent years, the exact cellular and molecular mechanisms involved remain largely unknown. Since there are no effective therapies for any tauopathy, there is a growing need for reliable experimental models that would provide us with better knowledge and understanding of their etiology and identify novel molecular targets. In this review, we will summarize the development of cellular models for modeling tau pathology. We will discuss their different applications and contributions to our current understanding of the prion-like nature of pathological tau

Capacity for seeding and spreading of argyrophilic grain disease in a wild-type murine model; comparisons with primary age-related tauopathy

Argyrophilic grain disease (AGD) is a common 4R-tauopathy, causing or contributing to cognitive impairment in the elderly. AGD is characterized neuropathologically by pre-tangles in neurons, dendritic swellings called grains, threads, thorn-shaped astrocytes, and coiled bodies in oligodendrocytes in the limbic system. AGD has a characteristic pattern progressively involving the entorhinal cortex, amygdala, hippocampus, dentate gyrus, presubiculum, subiculum, hypothalamic nuclei, temporal cortex, and neocortex and brainstem, thus suggesting that argyrophilic grain pathology is a natural model of tau propagation. One series of WT mice was unilaterally inoculated in the hippocampus with sarkosyl-insoluble and sarkosyl-soluble fractions from 'pure' AGD at the age of 3 or 7/12 months and killed 3 or 7 months later. Abnormal hyper-phosphorylated tau deposits were found in ipsilateral hippocampal neurons, grains (dots) in the hippocampus, and threads, dots and coiled bodies in the fimbria, as well as the ipsilateral and contralateral corpus callosum. The extension of lesions was wider in animals surviving 7 months compared with those surviving 3 months. Astrocytic inclusions were not observed at any time. Tau deposits were mainly composed of 4Rtau, but also 3Rtau. For comparative purposes, another series of WT mice was inoculated with sarkosyl-insoluble fractions from primary age-related tauopathy (PART), a pure neuronal neurofibrillary tangle 3Rtau + 4Rtau tauopathy involving the deep temporal cortex and limbic system. Abnormal hyper-phosphorylated tau deposits were found in neurons in the ipsilateral hippocampus, coiled bodies and threads in the fimbria, and the ipsilateral and contralateral corpus callosum, which extended with time along the anterior-posterior axis and distant regions such as hypothalamic nuclei and nuclei of the septum when comparing mice surviving 7 months with mice surviving 3 months. Astrocytic inclusions were not observed. Tau deposits were mainly composed of 4Rtau and 3Rtau. These results show the capacity for seeding and spreading of AGD tau and PART tau in the brain of WT mouse, and suggest that characteristics of host tau, in addition to those of inoculated tau, are key to identifying commonalities and differences between human tauopathies and corresponding murine models

Geriatric assessment in hematology scale predicts treatment tolerability in older patients diagnosed with hematological malignancies: The RETROGAH study

Chemotherapy; Geriatric assessment; ToxicityQuimioterapia; Evaluación geriátrica; ToxicidadQuimioteràpia; Avaluació geriàtrica; ToxicitatIntroduction The GAH (Geriatric Assessment in Hematology) scale is a psychometrically valid tool aimed at identifying older patients with hematological malignancies at higher risk of treatment-related toxicity. Our objective in this study was to determine the weights for each dimension of the GAH scale and the cut-off point to reliably predict treatment tolerability in this population, estimated by a weighted receiver operating characteristic (ROC) analysis and quantified by the area under the curve (AUC). Material and Methods The RETROGAH was a retrospective cohort study including 126 patients who had previously participated in the GAH study. Patients were ≥ 65 years old with newly diagnosed myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), multiple myeloma (MM), or chronic lymphoid leukemia (CLL) and treated with standard front-line therapy within three months after having completed the GAH scale. Results The optimal cut-off value of the GAH total score to discriminate patients at higher risk of treatment toxicity was 42, with 68.5% sensitivity and 55.8% specificity. Using this value, 66.1% of patients evaluated were found to develop some type of toxicity. The AUC was 0.6259 (95% CI: 0.512–0.739; p = 0.035). Discussion The GAH scale not only would enable clinicians to individualize therapy based on individual risk of toxicity but also discriminate patients that will benefit most from intensive treatments from those requiring an adapted approach. While futures studies in clinical practice may improve the model and overcome its limitations, the GAH scale should not be used alone when making treatment decisions.This study was supported by Celgene España S.L

Deciphering predictive factors for choice of thrombopoietin receptor agonist, treatment free responses, and thrombotic events in immune thrombocytopenia

Malalties hematològiques; Trastorns immunològicsEnfermedades hematológicas; Trastornos inmunológicosHaematological diseases; Immunological disordersVery few data exist on when a particular thrombopoietin-receptor agonist (TPO-RA) is favored in clinical practice for the treatment of patients with immune thrombocytopenia (ITP), about novel risk factors for vascular events (VE) with these drugs, nor about predictive factors for therapy free responses (TFR). We conducted an observational, retrospective, long-term follow-up multicenter study from November 2016 to January 2018 of 121 adult ITP patients initiating TPO-RA between January 2012 to December 2014. Data reflected that a platelet count ≤25 × 109/l at the time when the TPO-RA was initiated was associated with a 2.8 higher probability of receiving romiplostim vs. eltrombopag (P = 0.010). VE on TPO-RA was related to previous neoplasia in patients over 65 years (50% vs. 2.2%, P < 0.001), and to previous splenectomy in younger patients (100% vs. 33%, P = 0.001). Receiving romiplostim as first TPO-RA with no subsequent TPO-RA switching was associated with a 50% likelihood of TFR after 2.9 years of therapy (3.3 years in chronic ITP patients). These real-world data help deciphering some areas of uncertainty, and offer insight into some of the most relevant challenges of ITP which may help clinicians make appropriate treatment decisions in the management of adult ITP patients with TPO-RA

Cost analysis of voriconazole versus liposomal amphotericin B for primary therapy of invasive aspergillosis among patients with haematological disorders in Germany and Spain

Background: The current healthcare climate demands pharmacoeconomic evaluations for different treatment strategies incorporating drug acquisition costs, costs incurred for hospitalisation, drug administration and preparation, diagnostic and laboratory testing and drug-related adverse events (AEs). Here we evaluate the pharmacoeconomics of voriconazole versus liposomal amphotericin B as first-line therapies for invasive aspergillosis (IA) in patients with haematological malignancy and prolonged neutropenia or who were undergoing haematopoietic stem-cell transplantation in Germany or Spain. Methods: A decision analytic model based on a decision tree was constructed to estimate the potential treatment costs of voriconazole versus liposomal amphotericin B. Each model pathway was defined by the probability of an event occurring and the costs of clinical outcomes. Outcome probabilities and cost inputs were derived from the published literature, clinical trials, expert panels and local database costs. In the base case, patients who failed to respond to first-line therapy were assumed to experience a single switch between comparator drugs or the other drug was added as second-line treatment. Base-case evaluation included only drug-management costs and additional hospitalisation costs due to severe AEs associated with first-and second-line therapies. Sensitivity analyses were conducted to assess the robustness of the results. Cost estimates were inflated to 2011 euros ((sic)). Results: Based on clinical trial success rates of 52.8% (voriconazole) and 50.0% (liposomal amphotericin B), voriconazole had lower total treatment costs compared with liposomal amphotericin B in both Germany ((sic)12,256 versus (sic)18,133; length of therapy [LOT] = 10-day intravenous [IV] + 5-day oral voriconazole and 15-day IV liposomal amphotericin B) and Spain ((sic)8,032 versus (sic)10,516; LOT = 7-day IV + 8-day oral voriconazole and 15-day IV liposomal amphotericin B). Assuming the same efficacy (50.0%) in first-line therapy, voriconazole maintained a lower total treatment cost compared with liposomal amphotericin B. Cost savings were primarily due to the lower drug acquisition costs and shorter IV LOT associated with voriconazole. Sensitivity analyses showed that the results were sensitive to drug price, particularly the cost of liposomal amphotericin B. Conclusions: Voriconazole is likely to be cost-saving compared with liposomal amphotericin B when used as a first-line treatment for IA in Germany and Spain