Clinical management, monitoring, and prophylaxis of adverse events of special interest associated with datopotamab deruxtecan.

Antibody drug conjugates (ADCs) are an emerging class of treatments designed to improve efficacy and decrease toxicity compared with other systemic therapies through the selective delivery of cytotoxic agents to tumor cells. Datopotamab deruxtecan (Dato-DXd) is a novel ADC comprising a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2 (TROP2), a protein that is broadly expressed in several types of solid tumors. Dato-DXd is being investigated across multiple solid tumor indications. In the ongoing, first-in-human TROPION-PanTumor01 phase I study (ClinicalTrials.gov: NCT03401385), encouraging and durable antitumor activity and a manageable safety profile was demonstrated in patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor2-negative breast cancer (HR+/HER2- BC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC). Improved understanding of the adverse events (AEs) that are associated with Dato-DXd and their optimal management is essential to ensure safe and successful administration. Interstitial lung disease/pneumonitis, infusion-related reactions, oral mucositis/stomatitis, and ocular surface events have been identified as AEs of special interest (AESIs) for which appropriate prevention, monitoring, and management is essential. This article summarizes the incidence of AESIs among patients with HR+/HER2- BC, TNBC, and NSCLC reported in TROPION-PanTumor01. We report our recommendations for AESI prophylaxis, early detection, and management, using experience gained from treating AESIs that occur with Dato-DXd in clinical trials.

Longitudinal adherence to surveillance for late effects of cancer treatment: a population-based study of adult survivors of childhood cancer.

BACKGROUND: Adult survivors of childhood cancer are at elevated risk of morbidity and mortality compared to the general population, but their adherence to lifelong periodic surveillance is suboptimal. We aimed to examine adherence to surveillance guidelines for high-yield tests and identify risk factors for nonadherence in adult survivors of childhood cancer. METHODS: In this retrospective, population-based cohort study, we used health care administrative data from Ontario, Canada, to identify adult survivors of childhood cancer diagnosed between 1986 and 2014 who were at elevated risk of therapy-related colorectal cancer, breast cancer, or cardiomyopathy. Using a Poisson regression framework, we assessed longitudinal adherence and predictors of adherence to the Children's Oncology Group surveillance guideline. RESULTS: Among 3241 survivors, 327 (10%), 234 (7%), and 3205 (99%) were at elevated risk for colorectal cancer, breast cancer, and cardiomyopathy, respectively. Within these cohorts, only 13%, 6%, and 53% were adherent to recommended surveillance as of February 2020. During a median follow-up of 7.8 years, the proportion of time spent adherent was 14% among survivors at elevated risk for colorectal cancer, 10% for breast cancer, and 43% for cardiomyopathy. Significant predictors of adherence varied across the risk groups, but higher comorbidity was associated with adherence to recommended surveillance. INTERPRETATION: Survivors of childhood cancer in Ontario are rarely up to date for recommended surveillance tests. Tailored interventions beyond specialized clinics are needed to improve surveillance adherence.

Morbidity and healthcare use among mothers of children with cancer: A population-based study.

BACKGROUND: The impact of a child's cancer diagnosis on subsequent maternal physical health is unclear. METHODS: We identified all Ontario children diagnosed less than 18 years with cancer between 1992 and 2017. Linkage to administrative databases identified mothers who were matched to population controls. We identified physical health conditions, acute healthcare use, and preventive healthcare use through validated algorithms using healthcare data, and compared them between exposed (child with cancer) and unexposed mothers. Predictors of health outcomes were assessed among exposed mothers. RESULTS: We identified 5311 exposed mothers and 19,516 matched unexposed mothers. For exposed mothers, median age at last follow-up was 48 years, (interquartile range: 42-53). Exposed mothers had an increased risk of cancer (hazard ratio [HR] 1.2, 95% confidence interval [95% CI]: 1.0-1.5, p = .03), but not of any other adverse physical outcomes or of increased acute healthcare use. Exposed mothers were more likely to receive influenza vaccinations (odds ratio 1.4, 95% CI: 1.3-1.5, p < .0001), and underwent cancer screening at the same rate as unexposed mothers. Among exposed mothers, bereavement was associated with a subsequent increased risk of cancer (HR 1.7, 95% CI: 1.2-2.5, p = .004) and death (HR 2.2, 95% CI: 1.2-4.1, p = .01). CONCLUSION: Mothers of children with cancer are at increased risk of developing cancer, but not of other adverse physical health outcomes, and were equally or more likely to be adherent to preventive healthcare practices. Bereaved mothers were at increased risk of subsequent cancer and death. Interventions targeting specific subpopulations of mothers of children with cancer or focused on screening for specific cancers may be warranted.

Ceftazidime Plasma Concentrations and Neurotoxicity: The Importance of Therapeutic Drug Monitoring in Patients Undergoing Different Modalities of Renal Replacement Therapy. A Grand Round.

ABSTRACT: Ceftazidime-avibactam (CTZ-AVM) is a novel cephalosporin/beta-lactamase inhibitor with broad-spectrum activity against multidrug-resistant Pseudomonas aeruginosa . Ceftazidime-induced neurotoxicity is a well-described adverse effect, particularly in patients with renal insufficiency. However, appropriate dosing of ceftazidime-avibactam in patients undergoing renal replacement therapy (RRT) is sparsely investigated, and therapeutic drug monitoring to guide dosing remains lacking. Furthermore, when dose adjustment for impaired renal function is based on CTZ-AVM product information, inferior cure rates have been obtained compared with those with the standard therapy for intra-abdominal infections. Maintaining an effective dose while avoiding toxicity in these patients is challenging. Here, the authors describe the case of a critically ill patient, undergoing 2 modalities of RRT, who developed ceftazidime-induced neurotoxicity as confirmed using ceftazidime therapeutic drug monitoring. This case illustrates a therapeutic drug monitoring-based approach for guiding ceftazidime-avibactam dosing in this context and in diagnosing the cause of neurological symptoms and signs.

Treatment patterns and outcomes in adolescents and young adults with nodular lymphocyte-predominant Hodgkin lymphoma: an IMPACT cohort study.

We leveraged population-based clinical and healthcare data to identify treatment patterns and long-term outcomes among adolescents and young adults (AYA) with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). All Ontario, Canada, AYA aged 15-21 years at diagnosis with NLPHL between 1992 and 2012 were identified, and their detailed clinical data were collected. Linkage to healthcare databases identified additional events (subsequent malignant neoplasms [SMN], relapses and deaths). Event-free survival (EFS) and overall survival (OS) were compared by locus of care (adult vs. paediatric) and predictors of outcomes determined. Of 1014 AYA with Hodgkin lymphoma, 54 (5.3%) had NLPHL; 15 (27.8%) were treated at a paediatric centre. No paediatric centre patient received radiation only versus 16 (41.0%) of adult centre patients. Excision only was more common in paediatric centres (p < 0.001). The 20-year EFS and OS rates were 82.9% ± 5.2% and 100% respectively. Advanced stage (hazard ratio: 4.9, 95% CI: 1.3-18.4; p = 0.02) was associated with inferior EFS. Although the 25-year cumulative incidence of SMN was 19.3% ± 9.6% for the entire cohort, there were no SMN among the patients treated with excision only. AYA with NLPHL have outstanding long-term survival. Resection alone was rare outside of paediatric institutions but associated with excellent outcomes. Given substantial SMN risks, chemotherapy-sparing and radiation-sparing strategies for appropriate subsets of patients are warranted.

LInezolid Monitoring to MInimise Toxicity (LIMMIT1): A multicentre retrospective review of patients receiving linezolid therapy and the impact of therapeutic drug monitoring.

BACKGROUND: Linezolid is a broad-spectrum antimicrobial with limited use due to toxicity. This study aimed to evaluate linezolid toxicity in a large multicentre cohort. Secondary objectives were to identify factors contributing to toxicity, including the impact of therapeutic drug monitoring (TDM). METHODS: Patients administered linezolid between January 2017 and December 2019 were retrospectively reviewed. Data were collected on patient characteristics, linezolid therapy and outcomes. Descriptive statistics were performed on all patients, and statistical comparisons were undertaken between those who did and did not experience linezolid toxicity. A multivariable logistic regression model was constructed to identify any covariates that correlated with toxicity. RESULTS: Linezolid was administered to 1050 patients; of these, 381 did not meet the inclusion criteria and 47 were excluded as therapy ceased for non-toxicity reasons. There were 105 of 622 (16.9%) patients assessed to have linezolid toxicity. Patients who experienced toxicity displayed a higher baseline creatinine (96.5 µmol/L vs. 79 µmol/L; P = 0.025), lower baseline platelet count (225 × 109/L vs. 278.5 × 109/L; P = 0.002) and received a longer course (median 21 vs. 14 days; P < 0.001) than those who did not. Linezolid TDM was performed in 144 patients (23%). Multivariable logistic regression demonstrated that TDM-guided appropriate dose adjustment significantly reduced the odds of linezolid toxicity (aOR = 0.45; 95% CI 0.21-0.96; P = 0.038) and a treatment duration > 28 days was no longer significantly associated with toxicity. CONCLUSIONS: This study confirmed that linezolid treatment-limiting toxicity remains a problem and suggests that TDM-guided dose optimisation may reduce the risk of toxicity and facilitate prolonged courses beyond 28 days.

Multispecies Outbreak of Nocardia Infections in Heart Transplant Recipients and Association with Climate Conditions, Australia.

A multispecies outbreak of Nocardia occurred among heart transplant recipients (HTR), but not lung transplant recipients (LTR), in Sydney, New South Wales, Australia, during 2018-2019. We performed a retrospective review of 23 HTR and LTR who had Nocardia spp. infections during June 2015-March 2021, compared risk factors for Nocardia infection, and evaluated climate conditions before, during, and after the period of the 2018-2019 outbreak. Compared with LTR, HTR had a shorter median time from transplant to Nocardia diagnosis, higher prevalence of diabetes, greater use of induction immunosuppression with basiliximab, and increased rates of cellular rejection before Nocardia diagnosis. During the outbreak, Sydney experienced the lowest monthly precipitation and driest surface levels compared with time periods directly before and after the outbreak. Increased immunosuppression of HTR compared with LTR, coupled with extreme weather conditions during 2018-2019, may explain this outbreak of Nocardia infections in HTR.

Disseminated Aspergillus lentulus Infection in a Heart Transplant Recipient: A Case Report.

We present the first published case of successfully treated disseminated Aspergillus lentulus infection in a solid organ transplant recipient with invasive pulmonary disease, endophthalmitis, and a cerebral abscess. This case highlights important challenges associated with treating A. lentulus, particularly regarding antifungal resistance and toxicities associated with long-term antifungal therapy.

Risk of COVID-19 Infections and of Severe Complications Among Survivors of Childhood, Adolescent, and Young Adult Cancer: A Population-Based Study in Ontario, Canada.

PURPOSE: Survivors of childhood, adolescent, and young adult cancer are at risk of late effects, including pulmonary and infectious complications. Whether survivors are at increased risk of COVID-19 infection and severe complications is unknown. METHODS: Population-based registries in Ontario, Canada, identified all 5-year survivors of childhood cancer diagnosed age 0-17 years between 1985 and 2014, and of six common adolescent and young adult cancers diagnosed age 15-21 years between 1992 and 2012. Each survivor alive on January 1, 2020, was randomly matched by birth year, sex, and residence to 10 cancer-free population controls. Individuals were linked to population-based laboratory and health care databases to identify COVID-19 tests, vaccinations, infections, and severe outcomes (emergency department [ED] visits, hospitalizations, intensive care unit admissions, and death within 60 days). Demographic, disease, and treatment-related variables were examined as possible predictors of outcomes. RESULTS: Twelve thousand four hundred ten survivors were matched to 124,100 controls. Survivors were not at increased risk of receiving a positive COVID-19 test (386 [3.1%] v 3,946 [3.2%]; P = .68) and were more likely to be fully vaccinated (hazard ratio, 1.23; 95 CI, 1.20 to 1.37). No increase in risk among survivors was seen in emergency department visits (adjusted odds ratio, 1.2; 95 CI, 0.9 to 1.6; P = .19) or hospitalization (adjusted odds ratio, 1.8; 95 CI, 1.0 to 3.5; P = .07). No survivor experienced intensive care unit admission or died after COVID-19 infection. Pulmonary radiation or chemotherapies associated with pulmonary toxicity were not associated with increased risk. CONCLUSION: Cancer survivors were not at increased risk of COVID-19 infections or severe sequelae. These results can inform risk-counseling of survivors and their caregivers. Further study is warranted to determine risk in older survivors, specific subsets of survivors, and that associated with novel COVID-19 variants.

Impact of locus of care on outcomes in adolescents and young adults with osteosarcoma and Ewing sarcoma treated at pediatric versus adult cancer centers: An IMPACT cohort study.

BACKGROUND: Location of cancer care (LOC; pediatric vs. adult center) impacts outcomes in adolescents and young adults (AYA) with some cancer types. Data on the impact of LOC on survival in AYA with osteosarcoma (OSS) and Ewing sarcoma (EWS) are limited OBJECTIVES: To compare differences in demographics, disease/treatment characteristics, and survival in a population-based cohort of AYA with OSS or EWS treated at pediatric versus adult centers METHODS: The Initiative to Maximize Progress in Adolescent Cancer Therapy (IMPACT) cohort captured demographic, disease, and treatment data for all AYA (15-21 years old) diagnosed with OSS and EWS in Ontario, Canada between 1992 and 2012. Patients were linked to provincial administrative health care databases. Outcomes were compared between patients treated in pediatric versus adult centers. RESULTS: One hundred thirty-seven AYA were diagnosed with OSS (LOC: 47 pediatric, 90 adult) and 84 with EWS (38 pediatric, 46 adult). AYA treated at pediatric centers were more likely to be enrolled in a clinical trial (OSS 55% vs. 1%, p < .001; EWS 53% vs. 2%, p < .001) and received higher cumulative chemotherapy doses. Five-year event-free survival (EFS ± standard error) in OSS and EWS were 47% ± 4% and 43% ± 5%, respectively. In multivariable analysis, the impact of LOC (pediatric vs. adult center) on EFS in OSS (adjusted hazard ratio [HR] 1.15, 95% confidence interval [CI]: 0.58-2.27, p = .69) and EWS (adjusted HR 1.82, 95% CI: 0.97-3.43, p = .06) was not statistically significant. CONCLUSION: Despite disparities in trial participation and chemotherapy doses, outcomes did not differ by LOC suggesting that AYA with bone tumors can be treated at either pediatric or adult centers.

Emerging therapeutic drug monitoring of anti-infective agents in Australian hospitals: Availability, performance and barriers to implementation.

AIMS: The purpose of the study was to assess the status of emerging therapeutic drug monitoring (TDM) of anti-infective agents in Australian hospitals. METHODS: A nationwide cross-sectional survey of all Australian hospitals operating in the public and private health sector was conducted between August and September 2019. The survey consisted of questions regarding institutional TDM practice for anti-infective agents and clinical vignettes specific to ß-lactam antibiotics. RESULTS: Responses were received from 82 unique institutions, representing all Australian states and territories. All 29 (100%) of principal referral (major) hospitals in Australia participated. Five surveys were partially complete. Only 25% (20/80) of hospitals had TDM testing available on-site for any of the eight emerging TDM candidates considered: ß-lactam antibiotics, anti-tuberculous agents, flucytosine, fluoroquinolones, ganciclovir, human immunodeficiency virus (HIV) drugs, linezolid and teicoplanin. A considerable time lag was noted between TDM sampling and reporting of results. With respect to ß-lactam antibiotic TDM, variable indications, pharmacodynamic targets and sampling times were identified. The three greatest barriers to local TDM performance were found to be (1) lack of timely assays/results, (2) lack of institutional-wide expertise and/or training and (3) lack of guidelines to inform ordering of TDM and interpretation of results. The majority of respondents favoured establishing national TDM guidelines and increasing access to dose prediction software, at rates of 89% and 96%, respectively. CONCLUSION: Translating emerging TDM evidence into daily clinical practice is slow. Concerted efforts are required to address the barriers identified and facilitate the implementation of standardised practice.

Morbidity and health care use among siblings of children with cancer: A population-based study.

BACKGROUND: Childhood cancer impacts the entire family unit. We sought to investigate its impact on the long-term physical health outcomes of siblings of children with cancer. PROCEDURE: Pediatric cancer patients diagnosed in Ontario, Canada between 1988 and 2016 were linked to biological siblings. Sibling cases were matched to population controls based on sex, age, geographic location, and number of other children in the family. After individual linkage to health services data, we compared several outcomes between sibling cases and controls: (a) physical health conditions (such as diabetes, hypertension, and death); (b) acute health care use (hospitalization, low- and high-acuity emergency department [ED] visits); and (c) preventive health care use (periodic health checkups, influenza vaccinations). Cox proportional hazards, recurrent event, or logistic regression models were used as appropriate. RESULTS: We identified 8529 sibling cases and 30,364 matched controls (median age at index: 6 years, median age at last follow-up 17 years). Compared to controls, siblings were at increased risk of hypertension (hazard ratio [HR] 1.8; 95% confidence interval [CI] 1.1-2.9; p = .01), had higher rates of low- and high-acuity ED visits (rate ratio 1.1; 95% CI 1.1-1.2; p < .001), and increased risk of hospitalization (HR 1.1; 95% CI 1.1-1.2; p < .001). Sibling cases were also more likely to receive preventive health care (p < .05). CONCLUSION: Increased risk of hypertension, high-acuity ED visits, and hospitalizations suggest that siblings may experience poorer health compared to controls. Counseling families about this potential increased risk and long-term follow-up of siblings to monitor their physical health may be justified.

Assessment of cefepime toxicodynamics: comprehensive examination of pharmacokinetic/pharmacodynamic targets for cefepime-induced neurotoxicity and evaluation of current dosing guidelines.

BACKGROUND: Cefepime-induced neurotoxicity (CIN) is an increasingly reported adverse event; however, the toxicity threshold remains unclear. This study was conducted to provide a comprehensive examination of the most appropriate threshold for CIN, and evaluate the ability of current dosing regimens to attain therapeutic targets. METHODS: Data of the incidence of CIN and cefepime plasma concentrations were collected retrospectively from patients administered cefepime. Population pharmacokinetic modelling was used to determine daily cefepime trough concentration (Cmin), maximum serum concentration and area under the concentration-time curve. The ability of each pharmacokinetic parameter to predict CIN was evaluated using receiver operating characteristic (ROC) curves, from which optimal toxicity thresholds were determined. Pharmacokinetic simulation was used to evaluate the ability of cefepime dosing guidelines to meet established efficacy targets, whilst maintaining exposure below the determined CIN threshold. RESULTS: In total, 102 cefepime courses were evaluated, with CIN reported in 10. ROC analyses showed that all cefepime pharmacokinetic parameters were strongly predictive of CIN. Cmin of 49 mg/L was identified as the optimal toxicity target, based on its predictive ability (0.88, 95% confidence interval 0.758-0.999, P<0.001) and ease of clinical use. Assessment of cefepime dosing regimens predicted that only 29% of simulated patients achieve therapeutic targets, with patients with impaired renal function more likely to exhibit subtherapeutic concentrations (89%), and patients with normal renal function likely to have potentially toxic exposure (64%). CONCLUSIONS: The findings from this study provide evidence that cefepime exposure is highly predictive of CIN, with Cmin of 49 mg/L being the most appropriate toxicity threshold. Further research is required to optimize cefepime dosing in the context of this therapeutic target.

Impact of the model of long-term follow-up care on adherence to guideline-recommended surveillance among survivors of adolescent and young adult cancers.

PURPOSE: Adolescent and young adult cancer survivors require lifelong healthcare to address the late effects of therapy. We examined the impact of different provider models of long-term follow-up (LTFU) care on adherence to recommended surveillance. METHODS: We conducted a retrospective cohort study using administrative health databases in Ontario, Canada. Five-year survivors were identified from IMPACT, a database of patients aged 15-20.9 years at diagnosis of six cancers between 1992 and 2010. We defined three models of LTFU care hierarchically: specialized survivor clinics (SCCs), general cancer clinics (GCCs), and family physician (FP). We assessed adherence to the Children's Oncology Group surveillance guidelines for cardiomyopathy and breast cancer. Multistate models assessed adherence transitions and impacts of LTFU attendance. RESULTS: A total of 1574 survivors were followed for a mean of 9.2 years (range 4.3-13.9 years) from index (5-year survival). The highest level of LTFU attended in the first 2-years post-index was a GCC (47%); only 16.7% attended a SCC. By the end of study, 72% no longer attended any of the models of care and only 2% still attended an SCC. Among 188 survivors requiring breast cancer surveillance, 6.9% were adherent to their first required surveillance testing. Attendance at a SCC in the previous year and higher cumulative FP or GCC visits increased the rate of subsequently becoming adherent. Among 857 survivors requiring cardiomyopathy surveillance, 11% were adherent at study entry. Each subsequent SCC visit led to an 11.3% (95% CI: 1.05-1.18) increase in the rate of becoming adherent. CONCLUSION: LTFU attendance and surveillance adherence are sub-optimal. SCC follow-up is associated with greater adherence, but few survivors receive such care, and this proportion diminished over time. Interventions are needed to improve LTFU attendance and promote surveillance adherence.

Long-term medical imaging use in children with central nervous system tumors.

BACKGROUND: Children with central nervous system (CNS) tumors undergo frequent imaging for diagnosis and follow-up, but few studies have characterized longitudinal imaging patterns. We described medical imaging in children before and after malignant CNS tumor diagnosis. PROCEDURE: We conducted a retrospective cohort study of children aged 0-20 years diagnosed with CNS tumors between 1996-2016 at six U.S. integrated healthcare systems and Ontario, Canada. We collected computed topography (CT), magnetic resonance imaging (MRI), radiography, ultrasound, nuclear medicine examinations from 12 months before through 10 years after CNS diagnosis censoring six months before death or a subsequent cancer diagnosis, disenrollment from the health system, age 21 years, or December 31, 2016. We calculated imaging rates per child per month stratified by modality, country, diagnosis age, calendar year, time since diagnosis, and tumor grade. RESULTS: We observed 1,879 children with median four years follow-up post-diagnosis in the U.S. and seven years in Ontario, Canada. During the diagnosis period (±15 days of diagnosis), children averaged 1.10 CTs (95% confidence interval [CI] 1.09-1.13) and 2.14 MRIs (95%CI 2.12-2.16) in the U.S., and 1.67 CTs (95%CI 1.65-1.68) and 1.86 MRIs (95%CI 1.85-1.88) in Ontario. Within one year after diagnosis, 19% of children had ≥5 CTs and 45% had ≥5 MRIs. By nine years after diagnosis, children averaged one MRI and one radiograph per year with little use of other imaging modalities. CONCLUSIONS: MRI and CT are commonly used for CNS tumor diagnosis, whereas MRI is the primary modality used during surveillance of children with CNS tumors.

Influence of chronic comorbidities on periodic colorectal cancer screening participation: A population-based cohort study.

Guidelines recommend regular screening for colorectal cancer (CRC). We examined the effects of chronic comorbidities on periodic CRC testing. Using linked healthcare databases from Ontario, Canada, we assembled a population-based cohort of 50-74-year olds overdue for guideline-recommended CRC screening between April 1, 2004 and March 31, 2016. We implemented multivariable recurrent events models to determine the association between comorbidities and the rate of becoming up-to-date with periodic CRC tests. The cohort included 4,642,422 individuals. CRC testing rates were significantly lower in persons with renal disease on dialysis (hazard ratio, HR 0.66, 95% confidence interval, CI 0.63 to 0.68), heart failure (HR 0.75, CI 0.75 to 0.76), respiratory disease (HR 0.84, CI 0.83 to 0.84), cardiovascular disease (HR 0.85, CI 0.84 to 0.85), diabetes (HR 0.86, 95% CI 0.86 to 0.87) and mental illness (HR 0.88, CI 0.87 to 0.88). There was an inverse association between the number of medical conditions and the rate of CRC testing (5 vs. none: HR 0.30, CI 0.25 to 0.36; 4 vs. none: HR 0.48, CI 0.47 to 0.50; 3 vs. none: HR 0.59, CI 0.58 to 0.60; 2 vs. none: HR 0.72, CI 0.71 to 0.72; 1 vs. none: HR 0.85, CI 0.84 to 0.85). Having both medical and mental comorbidities was associated with lower testing rates than either type of comorbidity alone (HR 0.72, CI 0.71 to 0.72). In summary, chronic comorbidities present a barrier to periodic guideline-recommended CRC testing. Exploration of cancer prevention gaps in these populations is warranted.

Adolescents and young adult acute myeloid leukemia outcomes at pediatric versus adult centers: A population-based study.

BACKGROUND: Adolescents and young adult (AYA) acute myeloid leukemia (AML) outcomes remain poor. The impact of locus of care (LOC; adult vs pediatric) in this population is unknown. PROCEDURE: The IMPACT cohort comprises detailed data for all Ontario, Canada, AYA aged 15-21 years diagnosed with AML between 1992 and 2012, linked to population-based health administrative data. We determined the impact of LOC on event-free survival (EFS) and overall survival (OS), treatment-related mortality (TRM), and relapse/progression. RESULTS: Among 140 AYA, 51 (36.4%) received therapy at pediatric centers. The five-year EFS and OS for the whole cohort were 35.0% ± 4.0% and 53.6% ± 4.2%. Cumulative doses of anthracycline were higher among pediatric center AYA [median 355 mg/m2 , interquartile range (IQR) 135-492 vs 202 mg/m2 , IQR 140-364; P = 0.003]. In multivariable analyses, LOC was not predictive of either EFS [adult vs pediatric center hazard ratio (HR) 1.3, 95% confidence interval (CI) 0.8-2.2, P = 0.27] or OS (HR 1.0, CI 0.6-1.6, P = 0.97). However, patterns of treatment failure varied; higher two-year incidence of TRM in pediatric centers (23.5% ± 6.0% vs.10.1% ± 3.2%; P = 0.046) was balanced by lower five-year incidence of relapse/progression (33.3% ± 6.7% vs 56.2% ± 5.3%; P = 0.002). CONCLUSIONS: AYA AML survival outcomes did not vary between pediatric and adult settings. Causes of treatment failure were different, with higher intensity pediatric protocols associated with higher TRM but lower relapse/progression. Careful risk stratification and enhanced supportive care may be of substantial benefit to AYA with AML by allocating maximal treatment intensity to patients who most benefit while minimizing the risk of TRM.

Evaluation of amikacin use and comparison of the models implemented in two Bayesian forecasting software packages to guide dosing.

AIMS: Bayesian forecasting software can assist in guiding therapeutic drug monitoring (TDM)-based dose adjustments for amikacin to achieve therapeutic targets. This study aimed to evaluate amikacin prescribing and TDM practices, and to determine the suitability of the amikacin model incorporated into the DoseMeRx® software as a replacement for the previously available software (Abbottbase®). METHODS: Patient demographics, pathology, amikacin dosing history, amikacin concentrations and Abbottbase® predicted TDM targets (area under the curve up to 24 hours, maximum concentration and trough concentration) were collected for adults receiving intravenous amikacin (2012-2017). Concordance with the Australian Therapeutic Guidelines was assessed. Observed and predicted amikacin concentrations were compared to determine the predictive performance (bias and precision) of DoseMeRx®. Amikacin TDM targets were predicted by DoseMeRx® and compared to those predicted by Abbottbase®. RESULTS: Overall, guideline compliance for 63 courses of amikacin in 47 patients was suboptimal. Doses were often lower than recommended. For therapy >48 h, TDM sample collection timing was commonly discordant with recommendations, therapeutic target attainment low and 34% of dose adjustments inappropriate. DoseMeRx® under-predicted amikacin concentrations by 0.9 mg/L (95% confidence interval [CI] -1.4 to -0.5) compared with observed concentrations. However, maximum concentration values (n = 19) were unbiased (-1.7 mg/L 95%CI -5.8 to 0.8) and precise (8.6% 95%CI 5.4-18.1). Predicted trough concentration values (n = 7) were, at most, 1 mg/L higher than observed. Amikacin area under the curve values estimated using Abbottbase® (181 mg h/L 95%CI 161-202) and DoseMeRx® (176 mg h/L 95%CI 152-199) were similar (P = .59). CONCLUSION: Amikacin dosing and TDM practice was suboptimal compared with guidelines. The model implemented by DoseMeRx® is satisfactory to guide amikacin dosing.

Evaluation of a Pilot Vancomycin Precision Dosing Advisory Service on Target Exposure Attainment Using an Interrupted Time Series Analysis.

This study evaluated the ability of a pilot therapeutic drug monitoring (TDM) Advisory Service to facilitate vancomycin therapeutic target attainment within a real-world clinical setting. The Service provided area under the concentration-time curve (AUC)-guided vancomycin dose recommendations, using Bayesian forecasting software and clinical expertise, to prescribers at an Australian hospital. A retrospective audit of intravenous vancomycin therapy (> 48 hours) in adults (≥ 18 years old) was undertaken over a 54-month period to evaluate attainment of established vancomycin pharmacokinetic/pharmacodynamic targets (AUC over 24 hours / minimum inhibitory concentration: 400-600) before (36-month period) and after (18-month period) Service implementation. Interrupted time series analysis was employed to evaluate monthly measures of the median proportion of therapy spent within the target range. Indices of time to target attainment were also assessed before and after Service implementation. The final cohort comprised 1,142 courses of vancomycin (816 patients); 835 courses (596 patients) and 307 courses (220 patients) administered before and after Service implementation, respectively. Prior to piloting the Service, the median proportion of time in the target range was 40.1% (95% CI, 34.3-46.0%); this increased by 10.4% (95% CI, 1.2-19.6%, P = 0.03) after the Service, and was sustained throughout the post-Service evaluation period. Post-Service target attainment at 48-72 hours after initiation of therapy was increased (7.8%, 95% CI, 1.3-14.3%, P = 0.02). The findings of this study provide evidence that a consultative TDM Service can facilitate attainment of vancomycin therapeutic targets; however, optimization of the Service may further improve the use of vancomycin.