Effects of CYP3A5 Genotype on Tacrolimus Pharmacokinetics and Graft-versus-Host Disease Incidence in Allogeneic Hematopoietic Stem Cell Transplantation.

Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including CYP3A5*3 and CYP3A4*22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac C0/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C0/dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower C0 at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.

At-Home Foscarnet Administration in Patients with Cytomegalovirus Infection Post-Allogeneic Stem Cell Transplantation: A Unicentric, Safe, and Feasible Program.

Cytomegalovirus (CMV) infection is a relevant cause of morbimortality in patients receiving allogeneic stem cell transplantation (allo-HCT). Foscarnet (FCN) is an effective drug against CMV administered intravenously and usually on an inpatient basis. The Home Care Unit (HCU) for hematologic patients at our hospital designed an at-home FCN administration model to avoid the hospitalization of patients requiring FCN treatment. This study analyzes whether the at-home administration of FCN is as safe and effective as its hospital administration. We collected and compared demographic, clinical, analytical, and economic data of patients with CMV infection post-allo-HCT who received FCN in the hospital (n = 16, 17 episodes) vs. at-home (n = 67, 88 episodes). The proportions of patients with cured CMV infections were comparable between the two groups (65.9% vs. 76.5%, p = 0.395). The median duration of FCN treatment was 15 (interquartile range [IQR] 9-23) and 14 (IQR 11-19) days in the HCU and inpatient cohorts, respectively (p = 0.692). There were no significant differences in the FCN toxicities between groups except for hypocalcemia (26.1% vs. 58.8%, p = 0.007), which was more prevalent in the inpatient cohort. A significant cost-effectiveness was found in the HCU cohort, with a median savings per episode of EUR 5270. It may be concluded that home administration of FCN is a safe, effective, and cost-efficient therapeutic option for patients with CMV infection and disease.

Assessment of the change of antiemetic prophylaxis from double to triple combination in patients with high dose carboplatin chemotherapy.

INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) is one of the adverse events that most affects oncologic patients' quality of life. Carboplatin AUC ≥ 4 belongs to agents with high emetic risk (moderate risk in ASCO guidelines). We aimed to compare the effectiveness of netupitant/palonosetron and dexamethasone triple combination (TC) therapy versus ondansetron and dexamethasone double combination (DC) therapy as antiemetic prophylaxis in patients with carboplatin AUC ≥ 4. As a secondary endpoint, in TC group we evaluated the effectiveness of changing NEPA administration timing from 1 h to 15 min before chemotherapy. METHODS: Open-label prospective study conducted in a tertiary-care hospital in patients receiving carboplatin AUC ≥ 4. CINV was evaluated using MASCC antiemetic tool, in acute (<24 h) and delayed phase (24-120 h). Results were analyzed using χ2 test. RESULTS: Two-hundred four completed questionnaires (CQ) were analyzed (76 in DC and 128 in TC). The proportion of patients who remained emesis-free was superior for TC-treated group compared to DC, either in acute (99.2% vs 92.1%, p = 0.0115) and delayed phase (97.6% vs 90.7%, p = 0.043). Likewise, a higher proportion of TC-treated patients compared to DC remained nausea-free for the first 24 h after treatment (90.6% vs 71%, p = 0.0004) and between 24 and 120 h (82.3% vs 62.7%, p = 0.0025). The change of NEPA administration time showed similar effectiveness in terms of CINV control (81.6% vs 74.5%, p = 0.70). CONCLUSIONS: TC showed superiority in early and delayed CINV control in carboplatin AUC ≥ 4 regimens, with no significant differences among cancer types. Change in NEPA administration timing has beneficial implications; it allows NEPA to be administered at hospitals before chemotherapy session.

Real-world data of the use and experience of caplacizumab for the treatment of acquired thrombotic thrombocytopenic purpura: Case series.

PURPOSE: Caplacizumab was licensed for acquired thrombotic thrombocytopenic purpura (aTTP) based on prospective controlled trials. Real-world evidence is crucial in rare diseases. We aim to describe a patient population with aTTP, receiving caplacizumab in a real-world setting, reporting their outcomes, including safety and tolerability, and contrasting them with a historical cohort from our center. METHODS: We describe data collected retrospectively from 2012 to 2022 for 16 patients with aTTP (8 received caplacizumab and 8 the historical standard-of-care). Patients' characteristics and outcomes were compared between groups. RESULTS: Patients' demographic and baseline characteristics were similar in both groups. Caplacizumab led to a rapid normalization of the platelet count of 3.5 (IQR, 2-6) versus 16 (IQR, 9.5-23.5) days in the historical cohort: (p = .002). The median number of plasma exchanges and the length of days requiring them, between the caplacizumab group versus the historical cohort, was 6 (IQR, 6-10) versus 19.5 (IQR, 12.5-29.5) plasma exchanges (p = .006); and 9 (IQR, 8.5-13.5) versus 22 (15-31) days (p = .049), respectively. There were no refractory cases in the caplacizumab group in comparison with 37.5 % in the historical cohort. None of patients treated with caplacizumab experienced a recurrence after 1081 (IQR, 511-3125) days of follow-up. Safety was in line with data reported in clinical trials, with mild adverse events (mostly grade≤2). CONCLUSION: We provided real-world evidence in the treatment of aTTP, confirming the results obtained in clinical trials. Caplacizumab reduced the time to platelet count recovery and the number and length of plasma exchanges.

Drug interactions with oral antineoplastic drugs: The role of the pharmacist.

The main objective of the study is to determine the pharmacist detection of drug-drug and drug-food interactions in patients receiving oral antineoplastic drugs (OADs). Descriptive, prospective study in a tertiary-care teaching hospital. The study population included patients who received OADs from the Outpatient Pharmacy of the hospital. The study population was attended by a pharmacist who checked potential interactions. The severity of interactions was evaluated using the summary of product characteristics of each drug and three different databases. We included 219 patients with a total of 736 concomitant medications. A total of 34 drug-drug or food-drug interactions were recorded. The most common interaction detected was between erlotinib and ranitidine (major interaction). In 19 of the 34 interactions detected in the experimental group, the pharmacist prevented them from reaching the patient. Interactions were resolved by drug suspensions, drug changes, or changes in schedules always according to the attending physician or the patient. In the remaining 15 interactions, the doctor was not contacted because the interactions were considered to be of little relevance or because they only required surveillance. Hospital pharmacist can improve the patient's safety and the efficiency of oral cytostatic treatment by detecting and preventing drug-drug and drug-food interactions.

Dosing of chemotherapy in obese and cachectic patients: results of a national survey.

BACKGROUND: It is not unusual to find obese and cachectic patients in the hematology oncology setting. However, information on dosage in these groups is scarce. OBJECTIVE: The objectives of our study were to explore the dosing strategies applied in the treatment of obese and cachectic cancer patients and to determine whether these strategies are applied in clinical trials. SETTING: Members of the Spanish Group for the Development of Hematology-Oncology Pharmacy (GEDEFO). METHODS: We invited all cancer hospital pharmacists to participate in a survey. MAIN OUTCOME MEASURE: Descriptive statistics of the dosing strategies approaches. RESULTS: We invited 159 eligible hospitals to participate, and 38 responded to the survey. A total of 50 surveys were received: different strategies were applied by different physicians from the same hospital and by hematology and oncology departments. Body mass index was used to define obesity and cachexia in 40 and 30 % of the cases, respectively. Capping the body surface area (BSA) was the approach most commonly followed (64.1 %) in obese patients, whereas no specific approach was adopted in cachectic patients. In hematology patients, the BSA calculation was based on ideal body weight or adjusted body weight in 16.0 % of cases (n = 2) and 50.0 % of cases (n = 6), respectively; in oncology patients, use of adjusted or ideal body weight was negligible. Actual body weight was the main approach in obese patients (35 surveys) and cachectic patients (48 surveys). Creatinine clearance was assessed mainly using the Cockcroft and Gault equation (around 76.0 % of responses). As for clinical trials, 64.1 % of the respondents (n = 25 hospitals) considered the criteria from each clinical trial individually. CONCLUSIONS: Dose adjustments are more frequent in obese patients than in cachectic patients. In cancer oncology patients, dose is adjusted mainly by hematology and hematopoietic cell transplant teams. Capping BSA is the most frequent strategy, followed by calculating actual body weight.

Interstitial pneumonitis as an adverse reaction to mTOR inhibitors.

INTRODUCTION: mTOR (mammalian target of rapamycin) inhibitors sirolimus and everolimus, used as immunosuppressants in solid organ transplantation, may cause severe adverse effects, such as interstitial pneumonitis. INCIDENCE AND CLINICAL PRESENTATION: The estimated incidence of interstitial pneumonitis is 4-11% although it may be higher. Most reported cases have occurred in renal transplant recipients treated with sirolimus. Clinical presentation is heterogeneous, which makes diagnosis difficult. Abnormalities, such as ground glass opacities, are often found in computerised axial tomography scans of the chest. Physiopathology is not well-known. However, patients with abnormal renal function and those with previous calcineurin inhibitor treatment display a higher incidence. The relationship between pneumonitis and mTOR inhibitor plasma concentrations is not well defined. TREATMENT: Drug discontinuation and administration of high doses of corticosteroids seems to be an effective treatment. mTOR inhibitor dose reduction and replacing sirolimus with everolimus are other alternatives, but they are still under discussion. CONCLUSION: Iatrogenic pneumonitis must be suspected when a transplant recipient being treated with mTOR inhibitors presents respiratory symptoms. There is lack of conclusive data on treatment strategies. It appears that everolimus may be tolerated better than sirolimus.

Prescribing of zoledronic acid in a tertiary outpatient hospital setting.

BACKGROUND: Zoledronic acid (ZA) is an intravenous bisphosphonate approved for the prevention and treatment of cancer skeletal-related events. OBJECTIVE: Our aim was to analyze the prescription patterns of ZA in the cancer outpatient clinic. METHOD: We performed a retrospective chart review of all patients who received at least 1 dose of ZA from January 2009 until December 2010 in our institution. The patients' follow-up period was defined from the administration of the first dose until February 2011. RESULTS: The sample comprised 345 patients: 31.9 % had breast cancer, 14.5 % prostate cancer, 29.0 % multiple myeloma, and 24.6 % other solid tumors. A total of 4,546 doses were administered; 2,749 (60.5 %) without intravenous chemotherapy. 71.1 % of patients with breast cancer, 86 % with prostate cancer, 60 % with multiple myeloma and 44.6 % with other solid tumors, received ZA without intravenous chemotherapy throughout bisphosphonate treatment. Doses were adjusted in one-third of cases. Administration every 4-weeks was the most frequent schedule. Median duration of treatment varied between 15.0 months for breast cancer and 4.2 months for other solid tumors. CONCLUSION: Most of ZA prescriptions in cancer outpatients followed the labeled indications. The percentage of ZA doses administered without intravenous chemotherapy was 60.5 %.