Expanding the scope of the infectious diseases pharmacist in HCT: Beyond antimicrobial stewardship.

BACKGROUND: Infectious disease (ID) pharmacists and antimicrobial stewardship (AMS) programs are integral to the infection management of hematopoietic cell transplant (HCT) recipients demonstrating effective implementation of clinical pathways, de-escalation of empirical antibiotics for febrile neutropenia (FN), allergy assessments, and use of rapid diagnostic testing. The HCT procedure is complex, dynamic, and a high risk for infectious complications. Therefore, there is an important role for an ID and AMS pharmacist to collaborate with the primary treating team, with ongoing care, involving the optimal individual patient prophylactic, pre-emptive and treatment management of infections in this high-risk population. CONCLUSION: This review highlights key factors for consideration of ID/AMS Pharmacists in relation to HCT, including important aspects in the evaluation of infection risk prior to transplant, risk from donor sources, length of, and changes in immunosuppression, and potential drug-drug interactions from other essential supportive care therapies.

Antimicrobials in patients with hematologic malignancies and recipients of hematopoietic cell transplantation and other cellular therapies.

BACKGROUND: Appropriate use of antimicrobials for hematologic malignancy, hematopoietic stem cell transplant recipients, and other cellular therapies is vital, with infection causing significant morbidity and mortality in this unique population of immunocompromised hosts. However, often in this population the choice and management of antimicrobial therapy is complex. When selecting an antimicrobial agent, key considerations include the need for dose adjustments due to renal or hepatic impairment, managing drug interactions, the potential for additive drug toxicity among those receiving polypharmacy and therapeutic drug monitoring. Other factors include leveraging pharmacodynamic principles to enable optimization of directed therapy against challenging pathogens, as well as judicious use of antimicrobials to limit drug resistance and adverse drug reactions. SUMMARY: This review summarizes the clinical considerations for commonly used antimicrobials in this setting, including antibacterial, antiviral, and antifungal agents.

Epstein-Barr virus posttransplant lymphoproliferative disorder: update on management and outcomes.

PURPOSE OF REVIEW: Management of Epstein-Barr virus posttransplant lymphoproliferative disorder (EBV PTLD) is complex, involving risk stratification, prevention and/or preemptive measures involving monitoring EBV DNAemia and balancing treatment options, using a combination of reduction of immune suppression, anti-B cell therapy, and cytotoxic T lymphocytes (CTLs). RECENT FINDINGS: The highest risk factor for the development of EBV PTLD in hematopoietic cell transplant (HCT) remains T cell depletion, with increasing use of antithymocyte globulin (ATG) or alemtuzumab in conditioning. In solid organ transplantation (SOT), the incidence of PTLD is highest among EBV seronegative recipients who are at risk for primary EBV infection following transplant in the first 12 months. Prevention is a critical component of the management of EBV PTLD. Although preemptive therapy remains standard of care, there continues to be heterogenicity and debate over the optimal choice of EBV DNA quantification and the threshold to use. Novel therapies such as donor-derived multipathogen and EBV specific CTLs for the prevention and third party CTLs for the treatment of EBV PTLD are promising, with rapidly expanding evidence, including large scale Phase III trials currently underway. SUMMARY: With an increasing number of risk groups for developing EBV PTLD in HCT and SOT, management strategies using prophylaxis or preemptive therapy remain standard of care, however the use of prophylactic or preemptive EBV specific or multipathogen CTLs show promising results and safety profiles.

Choice and duration of antifungal prophylaxis and treatment in high-risk haematology patients.

PURPOSE OF REVIEW: This review aims to summarize available guidelines as well as the emerging evidence for the prevention and treatment of invasive fungal diseases in high-risk haematology patients. RECENT FINDINGS: Primary mould-active prophylaxis is the strategy used in many centres to manage the risk of invasive fungal disease in high-risk haematology patients, and posaconazole remains the antifungal of choice for most of these patients. Data on the use of other antifungals for primary prophylaxis, including isavuconazole, are limited. There is considerable interest in identifying a strategy that would limit the use of mould-active agents to the patients who are the most likely to benefit from them. In this regard, a recent trial demonstrated that the preemptive strategy is noninferior to the empiric strategy. For primary treatment of invasive aspergillosis, two randomized trials found isavuconazole and posaconazole to be noninferior to voriconazole. Isavuconazole does not appear to require therapeutic drug monitoring. SUMMARY: Prophylaxis and treatment of invasive fungal diseases in high-risk haematology patients is a rapidly evolving field. Critical clinical questions remain unanswered, especially regarding the management of suspected invasive fungal diseases breaking through mould-active prophylaxis, and the duration of antifungal therapy for invasive mould infections.

Epstein-Barr virus related post-transplant lymphoproliferative disorder prevention strategies in allogeneic hematopoietic stem cell transplantation.

Epstein-Barr virus associated post-transplant lymphoproliferative disorders (EBV PTLD) are recognized as a significant cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). The number of patients at risk of developing EBV PTLD is increasing, partly as a result of highly immunosuppressive regimens, including the use of anti-thymocyte globulin (ATG). Importantly, there is heterogeneity in PTLD management strategies between alloHSCT centers worldwide. This review summarizes the different EBV PTLD prevention strategies being utilized including the alloHSCT and T-cell depletion regimes and the risk they confer; monitoring programs, including the timing and analytes used for EBV virus detection, as well as pre-emptive thresholds and therapy with rituximab. In the absence of an institution-specific policy, it is suggested that the optimal pre-emptive strategy in HSCT recipients with T-cell depleting treatments, acute graft vs host disease (GVHD) and a mismatched donor for PTLD prevention is (a) monitoring of EBV DNA post-transplant weekly using plasma or WB as analyte and (b) pre-emptively reducing immune suppression (if possible) at an EBV DNA threshold of >1000 copies/mL (plasma or WB), and treating with rituximab at a threshold of >1000 copies/mL (plasma) or >5000 copies/mL (WB). There is emerging evidence for prophylactic rituximab as a feasible and safe strategy for PTLD, particularly if pre-emptive monitoring is problematic. Future management strategies such as prophylactic EBV specific CTLs have shown promising results and as this procedure becomes less expensive and more accessible, it may become the strategy of choice for EBV PTLD prevention.

Cytomegalovirus (CMV) management in allogeneic hematopoietic cell transplantation: Pre-transplant predictors of survival, reactivation, and spontaneous clearance.

BACKGROUND: Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplant (alloHCT). METHOD: We analyzed 159 alloHCT recipients with 4409 quantitative CMV viral loads to determine pre-transplant predictors of CMV reactivation, clinically significant CMV infection (cs-CMVi, defined as CMV viral load >1000 IU/mL), CMV disease, kinetics of spontaneous clearance of CMV, and survival using a standardized pre-emptive therapy approach to identify at-risk groups to target prevention strategies. RESULTS: Cs-CMVi was most common in D-/R+ unrelated donor transplants (URD). Spontaneous CMV clearance occurred in 26% of patients who reached a viral load of 56-137 IU/mL, 6% at 138-250 IU/mL and in one patient >250 IU/mL. Median time between the first CMV reactivation (>56 IU/mL) and a viral load >250 IU/mL was 13 days, whereas the time from the first viral load >250 IU/mL to reach a vial load >1000 IU/mL was 4 days. Cs-CMVi was associated with a significant increase in non-relapse mortality (NRM) on multivariate analysis. CONCLUSIONS: Overall, this study indicates that D-/R+ URD recipients are at high-risk for cs-CMVi- and CMV-related mortality, and are potential candidates for targeted CMV prophylaxis. Spontaneous clearance of CMV beyond a viral load of 250 IU/mL is uncommon, suggesting that this could be used as an appropriate threshold to initiate pre-emptive therapy.

Dynamics of Epstein-Barr virus on post-transplant lymphoproliferative disorders after antithymocyte globulin-conditioned allogeneic hematopoietic cell transplant.

BACKGROUND: The use of antithymocyte globulin (ATG) in allogeneic hematopoietic cell transplant (HCT) is associated with an increased risk of Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorders (PTLD). The dynamics and outcomes of EBV-DNAemia are not well described in this population. METHODS: We retrospectively assessed the kinetics of EBV-DNAemia after ATG conditioning of HCT recipients. Receiver operating characteristic (ROC) curves were used to assess EBV-DNAemia to predict EBV-PTLD in this group. RESULTS: A total of 174/405 (43%) consecutive HCT recipients from two centers met inclusion criteria of ATG conditioned, non-B-cell lymphoma patients. Of these with EBV-DNA measured using standardized IU/ml, 78.6% (92/117) developed EBV-DNAemia: 62% spontaneously resolved; 19% cleared after preemptive rituximab, and 13% developed EBV-PTLD. ROC curve analysis using maximum pre-EBV-PTLD EBV-DNAemia, demonstrated an AUC of 0.912 with EBV-DNAemia of 9782 IU/ml, associated with 82.6% sensitivity and 94.4% specificity for development of EBV-PTLD. Median time for EBV-DNAemia to increase from initial detection to >1000 IU/ml was 7 days; to >10 000 IU/ml, 12 days; and to >100 000 IU/ml, 18 days. Median EBV-DNAemia level prior to administration of rituximab was significantly lower in patients with successful preemptive treatment, compared with those who developed EBV-PTLD (3.41 log10  IU/ml [3.30-3.67] vs. 4.34 log10  IU/ml [3.85-5.13], p = .002; i.e., 2628 IU/ml vs. 21 965 IU/ml, respectively). CONCLUSIONS: EBV-DNAemia >10 000 IU/ml was the strongest predictor of the development of EBV-PTLD, and progression to this level was rapid in ATG-conditioned HCT recipients. This information may guide EBV-PTLD management strategies in these high-risk patients.

Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2021.

Antifungal prophylaxis can reduce morbidity and mortality from invasive fungal disease (IFD). However, its use needs to be optimised and appropriately targeted to patients at highest risk to derive the most benefit. In addition to established risks for IFD, considerable recent progress in the treatment of malignancies has resulted in the development of new 'at-risk' groups. The changing epidemiology of IFD and emergence of drug resistance continue to impact choice of prophylaxis, highlighting the importance of active surveillance and knowledge of local epidemiology. These guidelines aim to highlight emerging risk groups and review the evidence and limitations around new formulations of established agents and new antifungal drugs. It provides recommendations around use and choice of antifungal prophylaxis, discusses the potential impact of the changing epidemiology of IFD and emergence of drug resistance, and future directions for risk stratification to assist optimal management of highly vulnerable patients.

New advances in the management of cytomegalovirus in allogeneic haemopoietic stem cell transplantation.

Cytomegalovirus (CMV) viraemia continues to be a frequent complication in the post-haemopoietic stem cell transplantation period despite a low incidence of CMV end-organ disease. Several significant advances in the understanding and management of CMV infection have occurred in the last few years including improved diagnostics, monitoring of CMV immunity, availability of novel anti-CMV drugs, and emerging use of immunotherapies including CMV-specific T-cell infusions. In addition to reviewing these advances we also explore some of the more practical prescribing issues of the older and newer CMV drugs including cost, toxicity and drug interactions to help clinicians navigate this new era of CMV management.

Azole antifungals and new targeted therapies for hematological malignancy.

PURPOSE OF REVIEW: With the introduction of new targeted therapies for hematological malignancies comes the challenges of both assessing the risk of developing an IFD while being treated with these agents, as well as managing the drug--drug interactions between azole antifungals and the agents. RECENT FINDINGS: New targeted therapies for hematological malignancy include chimeric antigen receptor T cells (CAR T cells), Bi-specific T-cell Engager (BiTE) blinatumomab, and the antibody-drug conjugate (ADC) of calicheamicin inotuzumab ozogamicin for acute lymphoblasic leukemia (ALL) and lymphoma; the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and phosphatidylinositol 3-kinase (PI3Kδ) inhibitor idelalisib for lymphoma and graft-versus-host disease (GVHD); FMS-like tyrosine kinase 3 (FLT3) inhibitors, such as midostaurin, sorafenib and gilteritinib for acute myeloid leukemia (AML); and the BCL-2 inhibitor venetoclax for a range of hematological malignancies including lymphoma and leukemia. This review summarizes recommendations for IFD prophylaxis using these therapies and evidence for managing concomitant azole administration. SUMMARY: Whilst some evidence exists to guide IFD prophylaxis using new targeted therapies for hematological malignancies, there is an overall lack of descriptive, robust studies specifically describing IFD risk and management. With the emergence of novel agents, clinical judgment must be used to assess the risk of developing an IFD. Care must also be taken when administering azoles with drug--drug interactions, often requiring dose adjustment of the cancer therapies.

Adherence to Antifungal Guidelines in Malignant Hematology Patients: A Review of the Literature.

Objective: To review the published literature assessing adherence rates to antifungal guidelines and reasons for nonadherence in the adult malignant hematology inpatient setting. Data sources: The databases Embase, MEDLINE, and PubMed (from data inception to May 2019) were searched using the terms hematology, oncology, antifungal, guidelines, adherence, and stewardship with the search limited to adult human subjects and published in English. This yielded 123 articles. From this list, studies that were published in peer-reviewed journals were extracted, leaving 10 citations that met the final inclusion criteria. Study Selection and Data Extraction: Ten studies were selected assessing adherence to consensus antifungal guidelines in the malignant hematology setting. These included studies investigating the introduction of antifungal stewardship programs in tertiary hospitals. Data Synthesis: Although the studies were heterogeneous, all focused on appropriateness of antifungal therapy in the inpatient setting. Adherence to antifungal guidelines for optimal antifungal prophylaxis and treatment was low in most studies, with rates of inappropriate antifungal therapy ranging from 25% to 70% of fungal prescriptions. Relevance to Patient Care and Clinical Practice: Adherence rates with guidelines for antifungal therapy are low in the hematology inpatient setting. This may affect infection rates influencing morbidity and mortality in this high-risk population. Conclusion: Given the prevalence of invasive fungal infections in malignant hematology inpatients, suboptimal adherence with antifungal guidelines is concerning. This demands a focus on education, antifungal stewardship, and updating guidelines to meet real-world scenarios. Adherence with antifungal guidelines in the outpatient hematology setting is unknown and requires further research.

Effects of Food and Omeprazole on a Novel Formulation of Super Bioavailability Itraconazole in Healthy Subjects.

To address the limited bioavailability and intolerance of the conventional itraconazole (ITZ) formulations, a new formulation labeled super bioavailability (SUBA) itraconazole has been developed; however, the specific effects of food and gastric pH are unknown. This study evaluated the pharmacokinetic profile of SUBA itraconazole under fasting and fed conditions, as well as with the concomitant administration of a proton pump inhibitor. First, the effect of food was assessed in an open-label, randomized, crossover bioavailability study of 65-mg SUBA itraconazole capsules (2 65-mg capsules twice a day) in healthy adults (n = 20) under fasting and fed conditions to steady-state levels. Second, an open-label, two-treatment, fixed-sequence comparative bioavailability study in healthy adults (n = 28) under fasted conditions compared the pharmacokinetics of a single oral dose of SUBA itraconazole capsules (2 65-mg capsules/day) with and without coadministration of daily omeprazole delayed-release capsules (1 40-mg capsule/day) under steady-state conditions. In the fed and fasted states, SUBA itraconazole demonstrated similar concentrations at the end of the dosing interval, with modestly lower total and peak ITZ exposure being shown when it was administered under fed conditions than when it was administered in the fasted state, with fed state/fasted state ratios of 78.09% (90% confidence interval [CI], 74.49 to 81.86%) for the area under the concentration-time curve over the dosing interval (14,183.2 versus 18,479.8 ng · h/ml), 73.05% (90% CI, 69.01 to 77.33%) for the maximum concentration at steady state (1,519.1 versus 2,085.2 ng/ml), and 91.53% (90% CI, 86.41 to 96.96%) for the trough concentration (1,071.5 versus 1,218.5 ng/ml) being found. When dosed concomitantly with omeprazole, there was a 22% increase in the total plasma exposure of ITZ, as measured by the area under the concentration-time curve from time zero to infinity (P = 0.0069), and a 31% increase in the peak plasma exposure of ITZ, as measured by the maximum concentration (P = 0.0083).

Serum levels, safety and tolerability of new formulation SUBA-itraconazole prophylaxis in patients with haematological malignancy or undergoing allogeneic stem cell transplantation.

OBJECTIVES: To assess therapeutic levels, safety and tolerability of a novel formulation SUBA-itraconazole (where SUBA stands for SUper BioAvailability) when compared with conventional itraconazole liquid when used as antifungal prophylaxis in patients undergoing allogeneic HSCT or in haematological malignancy patients with an intermediate/high risk of invasive fungal infection (IFI). METHODS: This was a single-institution, prospective cohort study using a historical control group as the comparator. RESULTS: A total of 57 patients were assessed: 27 in the SUBA-itraconazole cohort and 30 in the liquid itraconazole cohort. Therapeutic concentrations were achieved significantly more quickly in the SUBA-itraconazole group: median of 6 (95% CI 5-11) days versus 14 (95% CI 12-21) days in the liquid itraconazole group (P < 0.0001). At day 10, therapeutic concentrations were achieved in 69% (95% CI 44%-81%) of the SUBA-itraconazole group versus 21% (95% CI 7%-33%) of the liquid itraconazole group (P < 0.0001). The mean trough serum concentrations at steady-state of SUBA-itraconazole were significantly higher, with less interpatient variability [1577 ng/mL, coefficient of variation (CV) 35%] versus liquid itraconazole (1218 ng/mL, CV 60%) (P < 0.001). There were two (7.4%) treatment failures in the SUBA-itraconazole group, both due to cessation of therapy for mucositis, compared with seven (23.3%) treatment failures in the liquid itraconazole group, due to subtherapeutic levels (five), mucositis (one) and gastrointestinal intolerance (one) (P = 0.096). CONCLUSIONS: The use of the SUBA-itraconazole formulation was associated with more rapid attainment of therapeutic levels with less interpatient variability compared with conventional liquid itraconazole when used as IFI prophylaxis in allogeneic HSCT or intermediate-/high-IFI risk haematological malignancy patients.

Safety, clinical effectiveness and trough plasma concentrations of intravenous posaconazole in patients with haematological malignancies and/or undergoing allogeneic haematopoietic stem cell transplantation: off-trial experience.

OBJECTIVES: This study describes the safety, clinical effectiveness and trough plasma concentration (Cmin) of intravenous (iv) posaconazole, provided as part of Merck Sharp and Dohme Australia's Named Patient Programme (NPP) in non-clinical trial settings. METHODS: A multicentre, retrospective study on the NPP use of iv posaconazole between July 2014 and March 2015 across seven Australian hospitals. RESULTS: Seventy courses of iv posaconazole were prescribed and evaluated in 61 patients receiving treatment for haematological malignancy. Sixty-one courses were prescribed for prophylaxis against invasive fungal disease (IFD), the majority of which (59) were initiated in patients with gastrointestinal disturbances and/or intolerance to previous antifungals. The median (IQR) duration for prophylaxis was 10 (6-15) days. No breakthrough IFD was observed during or at cessation of iv posaconazole. Nine courses of iv posaconazole were prescribed for treatment of IFD with a median (IQR) duration of 19 (7-30) days. Improvement in signs and symptoms of IFD was observed in five cases at cessation of, and six cases at 30 days post-iv posaconazole. Cmin was measured in 39 courses of iv posaconazole, with the initial level taken [median (IQR)] 4 (3-7) days after commencing iv posaconazole. The median (IQR) of initial Cmin was 1.16 (0.69-2.06) mg/L. No severe adverse events specifically attributed to iv posaconazole were documented, although six courses were curtailed due to potential toxicity. CONCLUSIONS: This non-clinical trial experience suggests that iv posaconazole appeared to be safe and clinically effective for prophylaxis or treatment of IFD in patients receiving treatment for haematological malignancies.

The development and evaluation of an oncological palliative care deprescribing guideline: the 'OncPal deprescribing guideline'.

PURPOSE: Current data suggests that potentially inappropriate medicines (PIMs) are common in palliative cancer patients; however, there is a lack of criteria to assist clinicians in identifying PIMs in these patients. The aims of this study were to design and validate a deprescribing guideline for palliative cancer patients and to undertake a descriptive analysis of the identified PIMs. METHODS: This prospective, non-interventional cohort study consisted of four major stages: developing an 'OncPal Deprescribing Guideline' from current evidence, the prospective recruitment of consecutive palliative cancer inpatients with an estimated <6-month prognosis, the assessment of all medications to identify PIMs using both a panel of medical experts without access to the guideline as well as a Clinical Pharmacist independently using the OncPal Deprescribing Guideline and the evaluation of the guideline by testing concordance. Descriptive data on the incidence of PIMs identified were also assessed. RESULTS: A total of 61 patients were recruited. The OncPal Deprescribing Guideline matched 94% of 617 medicines to the expert panel with a Kappa value of 0.83 [95% CI (0.76, 0.89)] demonstrating an 'outstanding' concordance. Forty-three (70%) patients were taking at least one PIM, with 21.4% of the total medicines assessed identified as PIMs. The medication-associated cost per patient/month was AUD$26.71. CONCLUSION: A guideline to assist in the de-escalation of inappropriate medications in palliative cancer patients was developed from current literature. The OncPal Deprescribing Guideline was successfully validated, demonstrating statistically significant concordance with an expert panel. We found that the incidence of PIMs was high in our patient group, demonstrating the potential benefits for the OncPal Deprescribing Guideline in clinical practice.

Facing the challenges of new melanoma-targeted therapies: Treatment of severe fevers associated with dabrafenib/trametinib combination therapy.

With the emergence of new oral therapies for metastatic melanoma to the market, as well as ongoing pre-marketing trials and special access schemes, it is important to keep up to date with the side effect profiles of these medications. A common side effect associated with the BRAF inhibitor dabrafenib is severe fever symptoms such as pyrexia and rigors/chills; however, treatment options are limited. We report a patient who was debilitated by severe pyrexia and rigors caused by dabrafenib used in combination with trametinib to treat metastatic melanoma, who was treated with low-dose steroids. To our knowledge, the use of prednisolone for the treatment and prevention of further dabrafenib-associated pyrexia is not published; however, it is a low risk and low cost option that was very effective in this case.

Reducing potentially inappropriate medications in palliative cancer patients: evidence to support deprescribing approaches.

OBJECTIVES: Cancer patients who have transitioned from curative intent chemotherapy or radiotherapy to palliative therapy have limited life expectancies. Due to this, medications for primary and secondary prevention or those with no short-term benefit are potentially inappropriate medicines in this patient group. These medications often have potentially harmful profiles, increasing the patient's adverse drug events, pill burden, and medication costs. This review evaluates the most current evidence to assess the outcomes and potential methods used for identifying and ceasing potentially inappropriate medications (PIMs) in palliative cancer patients. METHODS: A systematic review of the literature was conducted using the databases Ovid MEDLINE, PubMed, EMBASE, IPA, and CINAHL. RESULTS: Of the 51 articles examined in detail, three studies relating to cancer have been evaluated. In these retrospective and cross-sectional studies, the incidence of PIMs was shown in approximately 20% of patients, although the studies were inconsistent. In addition, six studies were identified that demonstrated the evidence in other population groups; these studies have been selected to establish the evidence in large-scale retrospective studies, prospective cross-sectional studies, both demonstrating the prevalence of PIMs, as well as the outcomes of ceasing PIMs. CONCLUSION: There is evidence that PIMs are commonly prescribed in palliative care patients. There are no studies that have identified the impact of ceasing PIMS in this setting. Published tools and implemented strategies have focused on the elderly populations. Further research is warranted in establishing clear guidelines for the identification of PIMs in palliative cancer patients as well as interventional studies assessing the outcomes of ceasing PIMs in these patients.

Rituximab for posttransplant lymphoproliferative disorder - therapeutic, preemptive, or prophylactic?

To minimize mortality due to posttransplant lymphoproliferative disorder (PTLD), the following strategies have been used: (1) Therapy without EBV Monitoring, i.e., administration of rituximab after PTLD diagnosis, usually by biopsy, in the absence of routine Epstein-Barr virus (EBV) DNAemia monitoring, (2) Prompt Therapy, i.e., monitoring EBV DNAemia, searching for PTLD by imaging when the DNAemia has exceeded a pre-specified threshold, and administration of rituximab if the imaging is consistent with PTLD, (3) Preemptive Therapy, i.e., monitoring EBV DNAemia and administration of rituximab when the DNAemia has exceeded a pre-specified threshold, and (4) Prophylaxis, i.e., administration of rituximab to all transplant recipients. The superiority of one of these strategies over the other strategies has not been established. Here we review the pros and cons of each strategy. Preemptive therapy or prophylaxis may currently be preferred for patients who are at a high risk of dying due to PTLD. However, Therapy without EBV Monitoring may be used for both high- and low-risk patients in the future, if effective and relatively non-toxic therapies for rituximab-refractory PTLD (e.g., EBV-specific T cells) have become easily available.

Subtherapeutic concentrations of posaconazole tablet: determining risk factors and effectiveness of a standardized dose adjustment in hematology inpatients.

Posaconazole is indicated for antifungal prophylaxis in hematology patients at high-risk of invasive fungal infections (IFI). Consensus guidelines recommend maintaining steady-state trough concentrations above 0.7 mg/L; however, upto one-third of patients return subtherapeutic concentrations which is associated with breakthrough IFI. This retrospective observational study of 496 concentrations from 90 hematology inpatients prescribed posaconazole tablet (PCZ-tab) between May 2017 and May 2019 identified 24% (n = 121) of posaconazole concentrations were subtherapeutic after the dosage of 300 mg daily. On multivariable analyses, diarrhea (p = 0.002), male gender (p = 0.018), and concurrent regular metoclopramide (p = 0.002) were significantly associated with subtherapeutic posaconazole concentrations. Eighty-nine percent of patients (n = 16) who underwent dose adjustment to 200 mg twice daily successfully achieved target posaconazole concentrations at first steady-state measurement. This study confirms that therapeutic drug monitoring of posaconazole remains necessary as subtherapeutic posaconazole concentrations are relatively common, and that dose adjustment of 200 mg twice daily, safely enabled achievement of therapeutic concentrations.