Implementing pharmacogenetics in clinical trials: considerations about current methodological, ethical, and regulatory challenges.

INTRODUCTION: The implementation of pharmacogenetic analysis within clinical trials faces methodological, ethical, and regulatory challenges, as well as tackling the difficulty in obtaining actionable information with a sufficient level of evidence to enable its integration into routine clinical practice. AREAS COVERED: We discuss the current status of pharmacogenetics integration in clinical trials, underscore the associated challenges, and make some suggestions on the aspects to address in any clinical trial including a pharmacogenetic evaluation. We conducted a literature review, thoroughly reviewed the applicable regulations and available guidelines, and assessed the application dossiers submitted for evaluation to the Ethics committee of Hospital La Paz (Madrid, Spain) to extract information related to inclusion of pharmacogenetics evaluations. EXPERT OPINION: The integration of pharmacogenetics into clinical trials is becoming increasingly common. However, several regulatory, methodological and ethical aspects involved are insufficiently addressed. There is a need for specific and transparent guidelines that establish unified and compliant criteria for methodology, proper handling of samples in compliance with regulations, and the protection of data privacy and confidentiality. Participants should receive complete and appropriate information regarding the purpose, handling, storage, and transfer of their samples and data, and should have the right to decide about their processing.

Advancing pharmacogenetic testing in a tertiary hospital: a retrospective analysis after 10 years of activity.

The field of pharmacogenetics (PGx) holds great promise in advancing personalized medicine by adapting treatments based on individual genetic profiles. Despite its benefits, there are still economic, ethical and institutional barriers that hinder its implementation in our healthcare environment. A retrospective analysis approach of anonymized data sourced from electronic health records was performed, encompassing a diverse patient population and evaluating key parameters such as prescribing patterns and test results, to assess the impact of pharmacogenetic testing. A head-to-head comparison with previously published activity results within the same pharmacogenetic laboratory was also conducted to contrast the progress made after 10 years. The analysis revealed significant utilization of pharmacogenetic testing in daily clinical practice, with 1,145 pharmacogenetic tests performed over a 1-year period and showing a 35% growth rate increase over time. Of the 17 different medical departments that sought PGx tests, the Oncology department accounted for the highest number, representing 58.47% of all genotyped patients. A total of 1,000 PGx tests were requested for individuals susceptible to receive a dose modification based on genotype, and 76 individuals received a genotype-guided dose adjustment. This study presents a comprehensive descriptive analysis of real-world data obtained from a public tertiary hospital laboratory specialized in pharmacogenetic testing, and presents data that strongly endorse the integration of pharmacogenetic testing into everyday clinical practice.

Identifying biomarkers of treatment response to ciclosporin in atopic dermatitis through multiomic predictive modelling: DERMATOMICS study protocol.

INTRODUCTION: There is a need to optimise the management of atopic dermatitis (AD), improving the efficacy of treatments and reducing the toxicity associated with them. Although the efficacy of ciclosporine (CsA) in the treatment of AD has been thoroughly documented in the literature, the optimal dose has not been yet established. The use of multiomic predictive models of treatment response could optimise CsA therapy in AD. METHODS AND ANALYSIS: The study is a low-intervention phase 4 trial to optimise the treatment of patients with moderate-severe AD requiring systemic treatment. The primary objectives are to identify biomarkers that could allow for the selection of responders and non-responders to first-line treatment with CsA and to develop a response prediction model to optimise the CsA dose and treatment regimen in responding patients based on these biomarkers. The study is divided into two cohorts: the first comprised of patients starting treatment with CsA (cohort 1), and the second, of patients already receiving or who have received CsA therapy (cohort 2). ETHICS AND DISSEMINATION: The study activities began following authorisation by the Spanish Regulatory Agency (AEMPS) and the Clinical Research Ethics Committee of La Paz University Hospital approval. Trial results will be submitted for publication in an open access peer-reviewed medical speciality-specific publication.Trial registration of this study can be located at the EU Clinical Trials Register, available from https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en. Our clinical trial was registered in the website before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according the WHO. Once our trial was included in a primary and official registry, in order to extend the accessibility to our research, we also registered it retrospectively in clinicaltrials.gov; however, this is not mandatory as per our regulation. TRIAL REGISTRATION NUMBER: NCT05692843.

Prediction of blood volume to be processed to achieve a target number of CD34+ cells: Development, validation and implementation of a formula.

BACKGROUND AND OBJECTIVES: Calculation of blood volume (BV) to be processed to achieve the target number of CD34+ cells can be accomplished by using collection efficiency 2 (CE2) formula. Our aim was to develop a BV web formula. MATERIALS AND METHODS: We calculated CE2 from aphereses performed between January 2015 and March 2020 in allogeneic donors and patients. From May 2020 to May 2021, we validated a formula: BV = ((Target CD34+ cells in the product)/(CD34+ pre-apheresis cells × CE2)) × 100. Subsequently, we compared the outcome of the procedures carried out before formula implementation (pre-formula), when standard three total BV collection was performed. RESULTS: CE2 was assessed in 384 apheresis procedures before formula implementation. CE2 was higher in allogeneic donors than in patients (53% ± 17% vs. 48% ± 15%, p = 0.008). CE2 was higher in multiple myeloma and non-Hodgkin lymphoma than Hodgkin's lymphoma (48% ± 15%, 48% ± 15% and 42% ± 13%, respectively; p = 0.008). Our formula (available on a website: Publisheet) was prospectively used in 54 individuals. The formula was very accurate: predicted versus observed CD34 + cells/kg collected had an r-value of 0.89 (p < 0.0001). We compared their results with 78 pre-formula individuals. In the post-formula group, a greater BV was processed in patients and less BV in allogeneic donors. Among individuals under 60 years of age, it was significantly less frequent than the need for more than one apheresis in the post-formula group. CONCLUSION: Formula calculations were accurate. Formula implementation allowed the optimization of the procedures and reduced the rate of individuals in need of apheresis for more than 1 day.

Comparison Between Standard and High Dose of G-CSF for Mobilization of Hematopoietic Progenitors Cells in Patients and Healthy Donors.

A standard dose of 10 µg/kg/day granulocyte colony stimulating factors (G-CSF) is currently recommended for hematopoietic progenitor cells (HPCs) mobilization. Our aim was to analyze whether certain patients or healthy donors could benefit from high dose of G-CSF.We performed a retrospective multicenter analysis of HPCs mobilization procedures (2015-2020) in patients and healthy donors. Those who received standard dose of G-CSF (10 µg/Kg/day for 4 days to patients and healthy donors) and those that received higher dose (24 µg/Kg/day for 4 days to patients and 16 µg/Kg/day for 4 days to healthy donors) were compared.496 individuals were included (201 standard dose and 295 higher dose). Between standard or higher dose, we did not find significant differences in median number of mobilized CD34+ cells/mL, neither among healthy donors (77 100 vs 75 500 respectively, P = .895), nor in patients (34 270 vs 33 704 respectively, P = .584). Additionally, among those with the same underlaying pathology the comparison between standard and higher dose did not showed differences. High G-CSF dose was not associated with a less frequent incidence of poor mobilizers (<20 000 CD34+ cells/mL) neither in healthy donors (1 [1.3%] vs 0; P = .218) nor patients (30 [24.4%] vs 32 [18.1%]; P = .165). Multivariate analysis showed that age, gender, and G-CSF dose did not influence median number of mobilized CD34+ cells/mL in healthy donors or patients. However, the underlying pathology among patients significantly influenced the CD34+ cells mobilization. In healthy donors, cellular blood count showed significantly higher leukocytes and platelets count with G-CSF high-dose, while in patients just a higher platelets count was found. To conclude, high dose of G-CSF compared to standard dose did not show significant benefit in terms of mobilization of CD34+ cells in healthy donors or in patients, also without a decrease in the incidence of poor mobilizers.

Real-world effectiveness of caplacizumab vs the standard of care in immune thrombotic thrombocytopenic purpura.

Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by anti-ADAMTS13 antibodies. Caplacizumab is approved for adults with an acute episode of iTTP in conjunction with plasma exchange (PEX) and immunosuppression. The objective of this study was to analyze and compare the safety and efficacy of caplacizumab vs the standard of care and assess the effect of the concomitant use of rituximab. A retrospective study from the Spanish TTP Registry of patients treated with caplacizumab vs those who did not receive it was conducted. A total of 155 patients with iTTP (77 caplacizumab, 78 no caplacizumab) were included. Patients initially treated with caplacizumab had fewer exacerbations (4.5% vs 20.5%; P < .05) and less refractoriness (4.5% vs 14.1%; P < .05) than those who were not treated. Time to clinical response was shorter when caplacizumab was used as initial treatment vs caplacizumab used after refractoriness or exacerbation. The multivariate analysis showed that its use in the first 3 days after PEX was associated with a lower number of PEX (odds ratio, 7.5; CI, 2.3-12.7; P < .05) and days of hospitalization (odds ratio, 11.2; CI, 5.6-16.9; P < .001) compared with standard therapy. There was no difference in time to clinical remission in patients treated with caplacizumab compared with the use of rituximab. No severe adverse event was described in the caplacizumab group. In summary, caplacizumab reduced exacerbations and refractoriness compared with standard of care regimens. When administered within the first 3 days after PEX, it also provided a faster clinical response, reducing hospitalization time and the need for PEX.

Utility of Lymphocyte Transformation Test for Assisting Updated Roussel Uclaf Causality Assessment Method in Drug-Induced Liver Injury: A Case-Control Study.

Background: The Roussel Uclaf Causality Assessment Method (RUCAM) is a validated tool for assessing causality in cases of suspected drug-induced liver injury (DILI). However, RUCAM cannot discriminate between concomitant hepatotoxic drugs with the same temporal sequence. Objective: To analyse the utility of the lymphocyte transformation test (LTT) for assisting updated RUCAM in 45 patients and 40 controls with a clinical diagnosis of DILI. Methods: Suspected DILI cases were detected through the Prospective Pharmacovigilance Program from Laboratory Signals in Hospital (PPLSH) or by consultations. The controls completed the drug therapy with no adverse reactions during the study period. A receiver operating characteristics (ROC) curve analysis was performed to calculate the optimal cut-off value for the stimulation index (SI), corresponding to the largest sum for the specificity and sensitivity values of LTT for true DILI cases. Results: Out of 45 patients diagnosed with DILI, 42 cases were detected by the PPLSH, two cases by consultation and one case by both methods. Most DILI cases (64.4%) arose during hospitalization. According to the biochemical parameters, 24 cases (53.3%) had the hepatocellular phenotype, 14 (31.1%) had the cholestatic phenotype, and 7 cases (15.6%) had the mixed phenotype. Considering the severity criteria, 7 (15.5%) cases were classified as moderate DILI, and 4 (8.9%) were severe DILI; there were no fatal cases. A total of 149 drugs (median/case, 3; IQR, 2-5) were suspected to be involved in the DILI cases (RUCAM score ≥3). In 8 cases, only one drug was suspected, and polypharmacy (≥5 drugs) was identified in 29% of the cases. Of all DILI cases, 46 (30.9%) of the 149 suspected drugs produced positive LTT results, and the LTT was positive in 34 (75.5%) of the 45 patients. No exposed controls produced positive LTT results. The optimal cut-off of 1.95 for the SI was obtained with a sensitivity of 77% and specificity of 100% (area under the curve, 0.91; 95% asymptotic confidence interval 0.84-0.97; p < 0.001). The sensitivity of the hepatocellular phenotype was 92%. Conclusion: Our results demonstrate that LTT is an add on strengthening causality in cases of suspected idiosyncratic DILI, especially for patients with several suspected drugs and a hepatocellular phenotype.

Melatonin in the Prophylaxis of SARS-CoV-2 Infection in Healthcare Workers (MeCOVID): A Randomised Clinical Trial.

We evaluated in this randomised, double-blind clinical trial the efficacy of melatonin as a prophylactic treatment for prevention of SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. Healthcare workers fulfilling inclusion criteria were recruited in five hospitals in Spain and were randomised 1:1 to receive melatonin 2 mg administered orally for 12 weeks or placebo. The main outcome was the number of SARS-CoV-2 infections. A total of 344 volunteers were screened, and 314 were randomised: 151 to placebo and 163 to melatonin; 308 received the study treatment (148 placebo; 160 melatonin). We detected 13 SARS-CoV-2 infections, 2.6% in the placebo arm and 5.5% in the melatonin arm (p = 0.200). A total of 294 adverse events were detected in 127 participants (139 in placebo; 155 in melatonin). We found a statistically significant difference in the incidence of adverse events related to treatment: 43 in the placebo arm and 67 in the melatonin arm (p = 0.040), and in the number of participants suffering from somnolence related to treatment: 8.8% (n = 14) in the melatonin versus 1.4% (n = 2) in the placebo arm (p = 0.008). No severe adverse events related to treatment were reported. We cannot confirm our hypothesis that administration of melatonin prevents the development of SARS-CoV-2 infection in healthcare workers.

Recurrence Rate and Morbidity after Ultrasound-guided Transvaginal Aspiration of Ultrasound Benign-appearing Adnexal Cystic Masses with and without Sclerotherapy: A Systematic Review and Meta-analysis.

OBJECTIVE: To determine the pooled recurrence rate of benign adnexal masses/cysts (namely simple cyst, endometrioma, hydrosalpinx, peritoneal cyst) after transvaginal ultrasound-guided aspiration, with or without sclerotherapy. DATA SOURCES: Search of studies published in PubMed and Web of Science databases between January 1990 and December 2020. METHODS OF STUDY SELECTION: A systematic search strategy was done using Medical Subject Heading terms. Only randomized trials and prospective studies published in English language were included. TABULATION, INTEGRATION, AND RESULTS: A total of 395 articles were screened. After applying inclusion and exclusion criteria, 20 studies were included in this review comprising data from 1386 patients with a mean follow-up of 11.4 months (range 0.5-26.5 months). The overall pooled rate of recurrence of adnexal masses was 27%, (95% confidence interval [CI], 18%-39%). Recurrence rate was significantly higher after only aspiration than after sclerotherapy (53%; 95% CI, 46%-60% vs 14%; 95% CI, 8%-22%; p <.001). However, a high heterogeneity across the studies was found. A total of 10 major complications were recorded in the different publications. CONCLUSION: In a selected population, aspiration with sclerotherapy had a lower recurrence rate than aspiration without sclerotherapy. However, these results should be interpreted with caution given the heterogeneity of the studies and the paucity of randomized controlled trials. Regarding the adoption of this procedure in routine clinical practice, we believe that aspiration should be considered an experimental procedure as there are few studies addressing long-term recurrence rate, and data comparing this technique with surgical cystectomy are lacking.

Experience of a Strategy Including CYP2C19 Preemptive Genotyping Followed by Therapeutic Drug Monitoring of Voriconazole in Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation.

Many factors have been described to contribute to voriconazole (VCZ) interpatient variability in plasma concentrations, especially CYP2C19 genetic variability. In 2014, Hicks et al. presented data describing the correlation between VCZ plasma concentrations and CYP2C19 diplotypes in immunocompromised pediatric patients and utilized pharmacokinetic modeling to extrapolate a more suitable VCZ dose for each CYP2C19 diplotype. In 2017, in our hospital, a clinical protocol was developed for individualization of VCZ in immunocompromised patients based on preemptive genotyping of CYP2C19 and dosing proposed by Hicks et al., Clinical Pharmacogenetics Implementation Consortium (CPIC) clinical guidelines, and routine therapeutic drug monitoring (TDM). We made a retrospective review of a cohort of 28 immunocompromised pediatric patients receiving VCZ according to our protocol. CYP2C19 gene molecular analysis was preemptively performed using PharmArray®. Plasma trough concentrations were measured by immunoassay analysis until target concentrations (1-5.5 µg/ml) were reached. Sixteen patients (57.14%) achieved VCZ trough target concentrations in the first measure after the initial dose based on PGx. This figure is similar to estimations made by Hicks et al. in their simulation (60%). Subdividing by phenotype, our genotyping and TDM-combined strategy allow us to achieve target concentrations during treatment/prophylaxis in 90% of the CYP2C19 Normal Metabolizers (NM)/Intermediate Metabolizers (IM) and 100% of the Rapid Metabolizers (RM) and Ultrarapid Metabolizers (UM) of our cohort. We recommended modifications of the initial dose in 29% (n = 8) of the patients. In RM ≥12 years old, an increase of the initial dose resulted in 50% of these patients achieving target concentrations in the first measure after initial dose adjustment based only on PGx information. Our experience highlights the need to improve VCZ dose predictions in children and the potential of preemptive genotyping and TDM to this aim. We are conducting a multicenter, randomized clinical trial in patients with risk of aspergillosis in order to evaluate the effectiveness and efficiency of VCZ individualization: VORIGENIPHARM (EudraCT: 2019-000376-41).

Piometra secundario a estenosis cervical en una adolescente / Pyometra secondary to cervical stenosis in an adolescent

INTRODUCCIÓN: El piometra es una afección infrecuente, pero grave, que en general se diagnostica en mujeres posmenopáusicas. En adolescentes es sumamente raro, y si se acompaña de amenorrea primaria hay que tener en mente las anomalías congénitas. CASO CLÍNICO: Adolescente de 13 años, sin antecedentes personales de interés salvo amenorrea primaria, que acude con abdomen agudo y es intervenida por una peritonitis difusa causada por un piometra secundario a disgenesia (estenosis) cervical congénita. Se realizó dilatación cervical y se dejó una sonda vesical intrauterina para prevenir la reestenosis. CONCLUSIONES: Un diagnóstico precoz y un tratamiento conservador con dilatación cervical y colocación temporal de un catéter urinario son esenciales para un manejo seguro y efectivo de la estenosis cervical en adolescentes.

INTRODUCTION: Pyometra is an uncommon but serious condition that is generally diagnosed in postmenopausal women. In adolescents it is extremely rare; if accompanied by primary amenorrhea, consider congenital abnormalities. CASE REPORT: A 13-year-old adolescent, with no relevant personal history except primary amenorrhea, who presented with an acute abdomen and was operated on for diffuse peritonitis caused by pyometra secondary to congenital cervical dysgenesis (stenosis). Cervical dilation was performed and a urinary catheter was temporarily placed inside the uterus to prevent restenosis. CONLUSIONS: An early diagnosis and conservative treatment with cervical dilation and temporary placement of a urinary catheter are essential for the safe and effective management of cervical stenosis in adolescents.

Age-Adjusted Endothelial Activation and Stress Index for Coronavirus Disease 2019 at Admission Is a Reliable Predictor for 28-Day Mortality in Hospitalized Patients With Coronavirus Disease 2019.

Background: Endothelial Activation and Stress Index (EASIX) predict death in patients undergoing allogeneic hematopoietic stem cell transplantation who develop endothelial complications. Because coronavirus disease 2019 (COVID-19) patients also have coagulopathy and endotheliitis, we aimed to assess whether EASIX predicts death within 28 days in hospitalized COVID-19 patients. Methods: We performed a retrospective study on COVID-19 patients from two different cohorts [derivation (n = 1,200 patients) and validation (n = 1,830 patients)]. The endpoint was death within 28 days. The main factors were EASIX [(lactate dehydrogenase * creatinine)/thrombocytes] and aEASIX-COVID (EASIX * age), which were log2-transformed for analysis. Results: Log2-EASIX and log2-aEASIX-COVID were independently associated with an increased risk of death in both cohorts (p < 0.001). Log2-aEASIX-COVID showed a good predictive performance for 28-day mortality both in the derivation cohort (area under the receiver-operating characteristic = 0.827) and in the validation cohort (area under the receiver-operating characteristic = 0.820), with better predictive performance than log2-EASIX (p < 0.001). For log2 aEASIX-COVID, patients with low/moderate risk (<6) had a 28-day mortality probability of 5.3% [95% confidence interval (95% CI) = 4-6.5%], high (6-7) of 17.2% (95% CI = 14.7-19.6%), and very high (>7) of 47.6% (95% CI = 44.2-50.9%). The cutoff of log2 aEASIX-COVID = 6 showed a positive predictive value of 31.7% and negative predictive value of 94.7%, and log2 aEASIX-COVID = 7 showed a positive predictive value of 47.6% and negative predictive value of 89.8%. Conclusion: Both EASIX and aEASIX-COVID were associated with death within 28 days in hospitalized COVID-19 patients. However, aEASIX-COVID had significantly better predictive performance than EASIX, particularly for discarding death. Thus, aEASIX-COVID could be a reliable predictor of death that could help to manage COVID-19 patients.

Health Care Workers' Reasons for Choosing Between Two Different COVID-19 Prophylaxis Trials in an Acute Pandemic Context: Single-Center Questionnaire Study.

BACKGROUND: In April 2020, two independent clinical trials to assess SARS-CoV-2 prophylaxis strategies among health care workers were initiated at our hospital: MeCOVID (melatonin vs placebo) and EPICOS (tenofovir disoproxil/emtricitabine vs hydroxychloroquine vs combination therapy vs placebo). OBJECTIVE: This study aimed to evaluate the reasons why health care workers chose to participate in the MeCOVID and EPICOS trials, as well as why they chose one over the other. METHODS: Both trials were offered to health care workers through an internal news bulletin. After an initial screening visit, all subjects were asked to respond to a web-based survey. RESULTS: In the first month, 206 health care workers were screened and 160 were randomized. The survey participation was high at 73.3%. Health care workers cited "to contribute to scientific knowledge" (n=80, 53.0%), followed by "to avoid SARS-CoV-2 infection" (n=33, 21.9%) and "the interest to be tested for SARS-CoV-2" (n=28, 18.5%), as their primary reasons to participate in the trials. We observed significant differences in the expected personal benefits across physicians and nurses (P=.01). The vast majority of volunteers (n=202, 98.0%) selected the MeCOVID trial, their primary reason being their concern regarding adverse reactions to treatments in the EPICOS trial (n=102, 69.4%). CONCLUSIONS: Health care workers' reasons to participate in prophylaxis trials in an acute pandemic context appear to be driven largely by their desire to contribute to science and to gain health benefits. Safety outweighed efficacy when choosing between the two clinical trials.

Transfusion support in COVID-19 patients: Impact on hospital blood component supply during the outbreak.

BACKGROUND: During the COVID-19 outbreak, most hospitals deferred elective surgical procedures to allow space for the overwhelming number of COVID-19 patient admissions, expecting a decrease in routine blood component requirements. However, because transfusion support needs of COVID-19 patients are not well known, its impact on hospital blood supply is uncertain. The objective of this study was to assess the effect of the COVID-19 pandemic on transfusion demand. STUDY DESIGN AND METHODS: Transfusion records during the peak of the COVID-19 pandemic (March 1-April 30, 2020) were reviewed in our center to assess changes in blood requirements. RESULTS: During this period 636 patients received a total of 2934 blood components, which reflects a 17.6% reduction in transfusion requirements with regard to the same period of 2019, and blood donations in Madrid dropped by 45%. The surgical blood demand decreased significantly during the outbreak (50.2%). Blood usage in the hematology and oncology departments remained unchanged, while the day ward demand halved, and intensive care unit transfusion needs increased by 116%. A total of 6.2% of all COVID inpatients required transfusion support. COVID-19 inpatients consumed 19% of all blood components, which counterbalanced the savings owed to the reduction in elective procedures. CONCLUSION: Although only a minority of COVID-19 inpatients required transfusion, the expected reduction in transfusion needs caused by the lack of elective surgical procedures is partially offset by the large number of admitted patients during the peak of the pandemic. This fact must be taken into account when planning hospital blood supply.

Randomised multicentre clinical trial to evaluate voriconazole pre-emptive genotyping strategy in patients with risk of aspergillosis: vorigenipharm study protocol.

INTRODUCTION: Invasive aspergillosis is the most important cause of morbidity and mortality in patients with haematological diseases. At present, voriconazole is the first-line treatment for invasive fungal disease. The pharmacokinetic interindividual variability of voriconazole depends on genetic factors. CYP450 is involved in 70%-75% of total metabolism of voriconazole, mainly CYP3A4 and CYP2C19, with the remaining 25%-30% of metabolism conducted by monooxygenase flavins. CYP2C19 single nucleotide polymorphisms could explain 50%-55% of variability in voriconazole metabolism. MATERIALS AND METHODS: The main objective is to compare efficiency of pre-emptive voriconazole genotyping with routine practice. The primary outcome is serum voriconazole on the fifth day within the therapeutic range. The secondary outcome is the combined variables of therapeutic failure and adverse events within 90 days of first administration, associated with voriconazole. A total of 146 patients at risk of invasive aspergillosis who will potentially receive voriconazole will be recruited, and CYP2C19 will be genotyped. If the patient ultimately receives voriconazole, they will be randomised (1:1 experimental/control). In the experimental arm, patients will receive a dose according to a pharmacogenetic algorithm, including CYP2C19 genotype and clinical and demographic information. In the control arm, patients will receive a dose according to clinical practice guidelines. In addition, a Spanish National Healthcare System (NHS) point-of-view cost-effectiveness evaluation will be performed. Direct cost calculations for each arm will be performed. CONCLUSION: This trial will provide information about the viability and cost-effectiveness of the implementation of a pre-emptive voriconazole genotyping strategy in the Spanish NHS. ETHICS AND DISSEMINATION: A Spanish version of this protocol has been evaluated and approved by the La Paz University Hospital Ethics Committee and the Spanish Agency of Medicines and Medical Devices. Trial results will be submitted for publication in an open peer-reviewed medical speciality-specific publication. TRIAL REGISTRATION NUMBER: Eudra-CT: 2019-000376-41 and NCT04238884; Pre-results.

Role of therapeutic plasma exchanges in refractory severe warm autoimmune hemolytic anemia: Presentation of two case reports.

BACKGROUND: Warm autoimmune hemolytic anemia (WAIHA) is a disorder with a usually good response to corticosteroid treatment, whereas in some cases first-line treatment's response is poor and other therapies such as intravenous immunoglobulins (IVIGs), rituximab, or splenectomy must be applied. STUDY DESIGN AND METHODS: Herein, we describe two patients with severe WAIHA treated at our center, who obtained a response after therapeutic plasma exchanges (TPEs) combined with low doses of IVIG. RESULTS: The first patient was an 18-year-old man with no relevant past medical history who was diagnosed with WAIHA. The patient presented a progressive clinical worsening despite treatment with prednisone, IVIG, and rituximab. After starting TPEs, signs of hemolysis rapidly improved and hemoglobin started to recover. The second patient was a 38-year-old man with a past history of immune thrombocytopenia and WAIHA. The patient presented a new flare of WAIHA, with no response after 2 weeks of treatment with corticosteroids, IVIG, and rituximab. After initiation of TPEs, the patient had an improvement in hemolysis biomarkers and recovery of hemoglobin concentration. CONCLUSION: Combination of TPEs with rituximab and IVIG might be considered as a therapeutic option in patients with severe WAIHA without response to corticosteroid and IVIG treatment.

Risk factors and outcome of COVID-19 in patients with hematological malignancies.

BACKGROUND: Prognostic factors of poor outcome in patients with hematological malignancies and COVID-19 are poorly defined. PATIENTS AND METHODS: This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory-confirmed SARS-CoV-2 infection through PCR assays from March 1st 2020 to May 15th 2020. RESULTS: We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n = 58) or allogeneic stem cell transplantation (allo-SCT) (n = 65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1-93.8). Recipients of ASCT and allo-SCT showed lower mortality rates (17% and 18%, respectively) compared to non-SCT patients (31%) (p = 0.02). Prognostic factors identified for day 45 overall mortality (OM) by logistic regression multivariate analysis included age > 70 years [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.2-3.8, p = 0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6-5.2, p < 0.0001); ECOG 3-4 (OR, 2.56, 95% CI 1.4-4.7, p = 0.003); neutropenia (< 0.5 × 109/L) (OR 2.8, 95% CI 1.3-6.1, p = 0.01); and a C-reactive protein (CRP) > 20 mg/dL (OR 3.3, 95% CI 1.7-6.4, p < 0.0001). In multivariate analysis of 216 patients with very severe COVID-19, treatment with azithromycin or low dose corticosteroids was associated with lower OM (OR 0.42, 95% CI 0.2-0.89 and OR 0.31, 95% CI 0.11-0.87, respectively, p = 0.02) whereas the use of hidroxycloroquine did not show significant improvement in OM (OR 0.64, 95% CI 0.37-1.1, P = 0.1). CONCLUSIONS: In most patients with hematological malignancies COVID-19 mortality was directly driven by older age, disease status, performance status, as well as by immune (neutropenia) parameters and level of inflammation (high CRP). Use of azithromycin and low dose corticosteroids may be of value in very severe COVID-19.

Potential Survival Benefit for Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation after Nivolumab Therapy for Relapse/Refractory Hodgkin Lymphoma: Real-Life Experience in Spain.

Clinical trials have shown that nivolumab has remarkable activity against relapsed/refractory classical Hodgkin lymphoma (cHL). However, the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) as consolidation therapy in these patients remains controversial. We performed a retrospective analysis of data from 74 patients treated with nivolumab. The overall response rate was 58% (including 30.6% with complete responses). Treatment-related adverse events were reported in 56.8% of patients (grade ≥3 in 9.4%). The main reasons for nivolumab discontinuation were referral for transplantation (41.7% patients) and disease progression (37.5%). The 2-year overall survival (OS) rate was 52% for the entire series. Ultimately, 39 patients underwent allo-HSCT. The cumulative incidence of grade II-IV acute graft-versus-host disease was 33.3% (grade III-IV in 2 patients). The cumulative incidence of nonrelapse mortality was 13.2%. Among the patients who responded to nivolumab, the 2-year OS and progression-free survival (PFS) were higher in patients who underwent consolidation with allo-HSCT (77.5% versus 42.6% [P = .126] and 73.9% versus 27.2% [P = .025], respectively). Thus, the efficacy and safety of nivolumab were comparable to values reported in previous clinical trials. The percentage of patients who bridged to transplantation was high, indicating a preference for Spanish physicians. These results suggest that consolidation allo-HSCT increases OS and PFS.

Prolapso uretral: imagen diagnóstica de una enfermedad poco frecuente / Urethral prolapse: Diagnostic image of a rare pathology

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