Genotype-Directed Dosing Leads to Optimized Voriconazole Levels in Pediatric Patients Receiving Hematopoietic Stem Cell Transplantation.

Invasive fungal infections are a significant cause of morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT), warranting antifungal prophylaxis as a standard of care in these patients. Voriconazole is commonly used in this setting because of its broad-spectrum activity and available dosage forms. There is wide well-known inter- and intrapatient variability in voriconazole concentrations, in part because concentrations are affected by common CYP2C19 polymorphisms. In 2 successive studies we have optimized voriconazole dosing to achieve target voriconazole serum concentrations using a genotype-specific dosing algorithm for antifungal prophylaxis in the post-HSCT period. In our pilot study all patients undergoing HSCT who received voriconazole antifungal prophylaxis were prospectively followed. Voriconazole concentrations were monitored weekly and doses adjusted until concentrations reached between 1 and 5.5 µg/L. The most common CYP2C19 polymorphisms were determined and correlated with voriconazole dose and time required to reach the target concentration range. In the subsequent study patients receiving voriconazole prophylaxis were dosed based on their CYP2C19 genotype and followed prospectively. In the pilot study 25 patients received voriconazole as antifungal prophylaxis for a median of 49 days (range, 15 to 196 days). The median time to reach the target concentration was 34 days for extensive metabolizers and 11 days for poor metabolizers. Three patients were genotyped as intermediate metabolizers; they reached the target concentration in a median of 56 days. Similarly, 2 patients who were genotyped as ultrarapid metabolizers reached the target range in 18 and 25 days. The time and dose required to reach the adequate concentration showed a trend toward correlation with individual CYP2C19 genotype, although voriconazole concentrations showed large interpatient variability in wild-type patients (extensive metabolizers). In our follow-up study, 20 patients received voriconazole prophylaxis prospectively dosed based on their CYP2C19 genotype. The median times to reach the target concentration using genotype-guided dosing were 9, 6.5, and 4 days for ultrarapid, extensive, and intermediate metabolizers, respectively. Overall, the median time to reach the target concentration with genotype-guided dosing was 6.5 days compared with a median time of 29 days when all patients were started on the same dose regardless of CYP2C19 genotype (P < .001). Our data show that traditional voriconazole dosing does not lead to timely achievement of target levels for fungal prophylaxis. However, a genotype-directed dosing algorithm allows patients to reach the voriconazole target range significantly sooner, providing better prophylaxis against fungal infections in the immediate post-transplant period.

Variable Eculizumab Clearance Requires Pharmacodynamic Monitoring to Optimize Therapy for Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation.

Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with eculizumab. We measured eculizumab serum concentrations, total hemolytic complement activity, and plasma sC5b-9 concentrations. Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined interindividual differences in PK parameters. We also compared transplant survival in patients treated with eculizumab (n = 18) with patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n = 11). In the PK analysis, we found significant interpatient variability in eculizumab clearance, ranging from 16 to 237 mL/hr/70 kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, was a significant determinant of eculizumab clearance and disease response. Sixty-one percent of treated patients had complete resolution of TMA and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared with untreated patients (56% versus 9%, P = .003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Our eculizumab dosing algorithm, including pr-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first eculizumab dose (mg), accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.

Plerixafor is safe and efficacious for mobilization of peripheral blood stem cells in pediatric patients.

BACKGROUND: Chemotherapy followed by filgrastim is the most common strategy used to mobilize autologous peripheral blood stem cells (PBSCs) for high-dose chemotherapy and autologous stem cell transplantation. Unfortunately, this method does not always lead to adequate PBSC collection in heavily treated patients with relapsed malignancies or if multiple transplants are required. Plerixafor, a hematopoietic stem cell mobilizer that inhibits the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1α (SDF-1α), has been shown to be safe and efficacious in the mobilization of autologous PBSC in adults. Despite its use in adults, little evidence exists to support its use in children. STUDY DESIGN AND METHODS: We report a retrospective review of 16 consecutive pediatric patients receiving plerixafor as part of their mobilization regimen at Cincinnati Children's Hospital Medical Center. All patients but one were given 0.24 mg/kg dose of plerixafor and the median number of plerixafor doses received was two (range, one to four doses). One patient received higher doses of plerixafor. RESULTS: An adequate number of CD34+ cells were obtained in 14 of 16 patients (87.5%). The median number of CD34+ cells collected for patients who reached collection goal was 6 × 10(6) CD34+ cells/kg (range, 1.6 × 10(6) -12.4 × 10(6) /kg). No acute adverse events were noted to be attributable to plerixafor administration. CONCLUSION: Our findings suggest that plerixafor use in children is safe and efficacious for the mobilization of autologous PBSCs in subjects with relapsed malignancies or requiring stem cells for multiple transplants.

Vitamin D Deficiency and Survival in Children after Hematopoietic Stem Cell Transplant.

Vitamin D has endocrine function as a key regulator of calcium absorption and bone homeostasis and also has intracrine function as an immunomodulator. Vitamin D deficiency before hematopoietic stem cell transplantation (HSCT) has been variably associated with higher risks of graft-versus-host disease (GVHD) and mortality. Children are at particular risk of growth impairment and bony abnormalities in the face of prolonged deficiency. There are few longitudinal studies of vitamin D deficient children receiving HSCT, and the prevalence and consequences of vitamin D deficiency 100 days after transplant has been poorly studied. Serum samples from 134 consecutive HSCT patients prospectively enrolled into an HSCT sample repository were tested for 25-hydroxy (25 OH) vitamin D levels before starting HSCT (baseline) and at 100 days after transplantation. Ninety-four of 134 patients (70%) had a vitamin D level < 30 ng/mL before HSCT, despite supplemental therapy in 16% of subjects. Post-transplant samples were available in 129 patients who survived to day 100 post-transplant. Vitamin D deficiency persisted in 66 of 87 patients (76%) who were already deficient before HSCT. Moreover, 24 patients with normal vitamin D levels before HSCT were vitamin D deficient by day 100. Overall, 68% of patients were vitamin D deficient (<30 ng/mL) at day 100, and one third of these cases had severe vitamin D deficiency (<20 ng/mL). Low vitamin D levels before HSCT were not associated with subsequent acute or chronic GVHD, contrary to some prior reports. However, severe vitamin D deficiency (<20 ng/mL) at 100 days post-HSCT was associated with decreased overall survival after transplantation (P = .044, 1-year rate of overall survival: 70% versus 84.1%). We conclude that all pediatric transplant recipients should be screened for vitamin D deficiency before HSCT and at day 100 post-transplant and that aggressive supplementation is needed to maintain sufficient levels.

Intravenous pentamidine for Pneumocystis carinii/jiroveci pneumonia prophylaxis in pediatric transplant patients.

SMX/TMP is the current gold standard for prophylaxis against PCP in immunocompromised pediatric patients. Currently, there are several second-line options for prophylaxis but many, including intravenous (IV) pentamidine, have not been reported to be as effective or as safe as SMX/TMP in the pediatric transplant population. This study is to determine the efficacy and safety of IV pentamidine in preventing PCP in pediatric transplant patients. A retrospective chart review was conducted to evaluate all transplant patients that received at least one dose of IV pentamidine from January 2010 to July 2013. The primary outcome, IV pentamidine efficacy, was evaluated by the incidence of PCP diagnosis for 28 days after the last dose of IV pentamidine if patient was transitioned to another agent for PCP prophylaxis. Patients on IV pentamidine for entire course of PCP prophylaxis were followed at least six months after discontinuation of IV pentamidine. The safety of IV pentamidine was assessed by the incidence of adverse events leading to pentamidine discontinuation. All data were analyzed using descriptive statistics. All transplant patients at CCHMC who had received IV pentamidine were reviewed, and 333 patients met inclusion criteria. The overall incidence of PCP was found to be 0.3% for pediatric transplant patients on pentamidine. Pentamidine was found to be safe, and the incidence of adverse events leading to discontinuation was 6% with the most common reason being tachycardia 2.1%. IV pentamidine is safe and effective as PCP prophylaxis in pediatric transplant patients with a PCP breakthrough rate of 0.3% (1 of 333 patients), and only 20 adverse events led to discontinuation. We recommend that IV pentamidine be considered as a second-line option in pediatric transplant patients who cannot tolerate SMX/TMP.

Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy.

We recently observed that dysregulation of the complement system may be involved in the pathogenesis of hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA). These findings suggest that the complement inhibitor eculizumab could be a therapeutic option for this severe HSCT complication with high mortality. However, the efficacy of eculizumab in children with HSCT-TMA and its dosing requirements are not known. We treated 6 children with severe HSCT-TMA using eculizumab and adjusted the dose to achieve a therapeutic level >99 µg/mL. HSCT-TMA resolved over time in 4 of 6 children after achieving therapeutic eculizumab levels and complete complement blockade, as measured by low total hemolytic complement activity (CH50). To achieve therapeutic drug levels and a clinical response, children with HSCT-TMA required higher doses or more frequent eculizumab infusions than currently recommended for children with atypical hemolytic uremic syndrome. Two critically ill patients failed to reach therapeutic eculizumab levels, even after dose escalation, and subsequently died. Our data indicate that eculizumab may be a therapeutic option for HSCT-TMA, but HSCT patients appear to require higher medication dosing than recommended for other conditions. We also observed that a CH50 level ≤ 4 complement activity enzyme units correlated with therapeutic eculizumab levels and clinical response, and therefore CH50 may be useful to guide eculizumab dosing in HSCT patients as drug level monitoring is not readily available.

Potentiation of vincristine toxicity with concomitant fluconazole prophylaxis in children with acute lymphoblastic leukemia.

Use of azole antifungals as prophylaxis is becoming an increasingly common practice in acute lymphoblastic leukemia (ALL). Limited literature in adults heightened the awareness of possible increased vincristine (VCR) toxicity in patients receiving concomitant azole therapy. This is due to inhibition of cytochrome P450 3A4, which may increase overall exposure to VCR, resulting in dose reductions or omissions. The primary objective of this study was to determine whether the use of fluconazole prophylaxis increases vincristine toxicity in children with ALL. The authors retrospectively evaluated children with ALL between January 2004 and December 2009. Patients were subdivided into 2 groups based on whether or not they received fluconazole prophylaxis during induction therapy. Data were collected for up to 3 months following the completion of induction therapy. Thirty-one patients were included for analysis. There was no significant difference in gender, race, steroid use, gastrointestinal (GI) toxicity, VCR dose modification, and the rate of fungal or bacterial infections between these 2 groups. Only advanced age is an independent predictor of neuropathy. Patients receiving fluconazole were 4.5 times more likely to experience neuropathy than those not receiving azole; however, this was not statistically significant. The authors report an increased incidence of VCR toxicity in patients with ALL receiving concomitant fluconazole prophylaxis. Judicious use of azole antifungals is warranted in children with ALL.

Toxicities of gemcitabine in patients with severe hepatic dysfunction.

OBJECTIVE: To determine the relationship between doses of gemcitabine and absolute neutrophil count and thrombocytopenia in patients with severe hepatic dysfunction (total bilirubin > or =4.5 mg/dL), and the relationship between doses of gemcitabine in patients with severe hepatic dysfunction and nonhematologic toxicity. CASE SUMMARY: A retrospective chart review was conducted for patients receiving gemcitabine at the Medical University of South Carolina from October 2006 through October 2008. Seven patients were identified who had an elevated total bilirubin level (> or =4.5 mg/dL) at the time they were receiving gemcitabine. All 7 patients received gemcitabine 1000 mg/m(2) throughout their treatment, regardless of liver function. Six patients did not experience significant hematologic toxicity warranting a dose reduction or a dose being held. One patient developed thrombocytopenia, warranting a dose being held. DISCUSSION: Gemcitabine is a chemotherapy agent frequently used for the treatment of pancreatic cancer as well as metastatic breast, lung, and ovarian cancer. To date there is limited information on dosing of gemcitabine in patients with an elevated total bilirubin. A previous study looking at lower grades of liver dysfunction suggested empiric dose reductions be made in these patients because of increased incidence of toxicity. CONCLUSIONS: These results indicate the possibility that no initial dose reduction is necessary for patients with liver dysfunction receiving gemcitabine; however, close monitoring of these patients is required.

Management of hypertension in renal transplant patients: a comprehensive review of nonpharmacologic and pharmacologic treatment strategies.

OBJECTIVE: To review the guidelines and literature for the treatment of hypertension in renal transplant patients and to provide guidance to practitioners in the selection of appropriate nonpharmacologic and pharmacologic treatment options. DATA SOURCES: A PubMed search (January 1948-March 2010) was performed using the search terms hypertension, antihypertensive agents, blood pressure, and cardiovascular disease, in combination with renal transplant and kidney transplant. The search was limited to articles published in English. All relevant peer-reviewed original studies, meta-analyses, guidelines, consensus statements, and review articles were examined. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All literature found was evaluated for inclusion. Review articles as well as prospective and retrospective original research articles were reviewed. DATA SYNTHESIS: Hypertension after solid organ transplantation is a problem commonly encountered in patients during their posttransplantation clinic visits. Effective management of these patients' hypertension is crucial, as hypertension left untreated may lead to increased morbidity and mortality as well as graft loss. The unique, multifactorial etiology of hypertension in this population makes treatment choices more challenging compared to treatment of a nontransplant patient. Therefore, to guide practitioners in this process, we developed a hypertension management protocol, taking into account the unique considerations faced in the adult renal transplant population. The review guides practitioners from the initial assessment of patients' hypertension through the evaluation and selection of nonpharmacologic and pharmacologic treatment options and provides information about the discontinuation of certain antihypertensive medications. It also provides a concise, but comprehensive review of the major antihypertensive drug classes and economic considerations. CONCLUSIONS: The management of hypertension in posttransplantation patients is challenging and complicated, yet necessary to prevent morbidity, mortality, and graft loss for these patients. Therapy should be individualized based on patient assessment, response to previous therapy, and economic considerations.

Increasing Activities of Daily Living Is as Easy as 1-2-3.

BACKGROUND: Human flora are the most common cause of bacteremia in immunocompromised patients. Activities of daily living (ADL), including oral care and daily chlorhexidine gluconate bathing, can lower the risk of infection. METHODS: To address ADL compliance in our pediatric oncology and bone marrow transplant patients, we adopted the ADL 1-2-3 initiative: daily chlorhexidine gluconate bath and linen change, at least 2 activities per day, and oral care 3 times per day. Using the Model for Improvement we created a standardized ADL process that involved all providers. Interventions included addressing ADL 1-2-3 compliance during rounds, establishing accountability in care delivery, an oral care order set and algorithm, daily text message reminders, and physician intervention with noncompliant and high-risk patients. RESULTS: With our interventions, we increased our median compliance with the all-or-none ADL 1-2-3 initiative from 25% to 66% in 90 days. We have sustained our median compliance to 75% sixteen months after implementation. The greatest impact on compliance was seen with text message reminders to staff to complete and document the ADL 1-2-3 components, designated roles and responsibilities, and physician discussion with noncompliant and high-risk patients. DISCUSSION: Oral care algorithm and order set, daily text message reminders, and physician intervention with noncompliant and high-risk patients has improved our compliance. Units where compliance with ADL participation is low can benefit from incorporating elements from this ADL 1-2-3 initiative.