Ashley Teusink

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 anitfungals is warranted in children with ALL.

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.

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.

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.

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.

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

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.

RSV infection without ribavirin treatment in pediatric hematopoietic stem cell transplantation

RSV infection without ribavirin treatment in pediatric hematopoietic stem cell transplantation

Rapid rituximab infusion is safe in paediatric and young adult patients with non-malignant indications

Rituximab, a chimeric monoclonal anti CD20-antibody, is used to treat indications, such as Epstein–Barr virus (EBV) viraemia, autoimmune cytopenias and graft-versus-host disease (GVHD), in haematopoietic stem cell transplant recipients (Cutler et al, 2006; Au et al, 2007; Rao et al, 2008; Khellaf et al, 2014). It is recommended to administer rituximab using a drug titration protocol due to a high risk of infusion reactions. The first infusion is usually takes 4–6 h and subsequent infusions are given over 2–4 h if tolerated. Adult studies reported that rapid rituximab infusions (RRI) given over 60–90 min are safe with a low infusion-associated reaction rate of 0·9–2·6%, but there are no safety data of RRI in children (Sehn et al, 2007; Tuthill et al, 2009; Lang et al, 2011; Swan et al, 2014). Based on our experience in adults, we implemented uniform clinical practice using RRI for second and subsequent doses in children and young adults who received rituximab for non-malignant indications and were not at risk for tumour lysis syndrome from 1 June 2013 (Al Zahrani et al, 2009). Patients who previously received at least one rituximab infusion (375 mg/m2 per dose) using a standard drug titration protocol without any adverse reactions received subsequent infusions given over 1 h using the RRI protocol. Patients were observed for infusion-related reactions during and 30 min after RRI. Any new clinical symptoms, administration of steroids, diphenhydramine or acetaminophen were recorded for 24 h before and after each infusion. After 6 months of prospective safety monitoring of each infusion, the Pharmacy and Therapeutics committee at our centre approved RRI as acceptable clinical practice. Our study goal was to report RRI safety in children and young adults after Institutional Review Board approval of this retrospective review. Over the study period of 18 months, 22 patients received 80 doses of rituximab using RRI. Study cohort characteristics are summarized in Table I. Indications for rituximab were autoimmune cytopenias (50%), EBV viraemia (36%) and GVHD (14%). Table I Study cohort characteristics. Eighty per cent of all infusions (64/80) were given to children (<18 years) and 20% to young adults (16/80). The median number of RRI administered was 4 (range 1–10). Overall, 78/80 (97·5%) infusions were tolerated without any adverse events. There were no adverse events reported in young adults. Out of 64 RRI given to children, one infusion resulted in transient rash that resolved in 24 h without interventions. At the time of infusion the patient was receiving 1 mg/kg/d of methylprednisolone for GVHD and was not treated with any additional premedications. This patient subsequently received four additional RRI without incident. Another child developed nausea with the fourth RRI that resolved with ondansetron and pausing infusion. He was given 1 mg/kg per dose of hydrocortisone as premedication prior to re-starting rituximab as he was not on any steroids. Infusion was resumed after 15 min using the manufacturers recommended titration protocol, but the patient developed shortness of breath. Infusion was discontinued. Symptoms resolved with administration of 1 mg/kg per dose of hydrocortisone and he was discharged home. This patient was listed as having rituximab allergy and did not receive any further doses. At the time of RRI, 10 of 22 patients (45·5%) were receiving steroid therapy at a median dose of 1 mg/kg/d methylprednisolone equivalent (range 0·14–2 mg/kg/d). Eight of 12 (66·7%) patients were not on steroids and were administered 1 mg/kg per dose hydrocortisone as premedication for each RRI without any events, with the exception of the one patient listed above. Premedication with hydrocortisone was given based on primary treating physician preference. Four patients did not receive any steroids and had no adverse events. Each outpatient stay for RRI was about 2 h. All patients receiving RRI in the outpatient setting were discharged after observation for 30 min. There were no re-admissions to the hospital within 24 h after infusions. A total of 160 clinical care hours were saved using RRI. Rapid rituximab infusions given over 1 h was safe and well tolerated in children and young adults when administered as the second and subsequent doses. Only 1 of all 80 (1·25%) infusions resulted in an adverse event warranting discontinuation of the therapy. Out of 64 infusions given to children, 2 (3%) resulted in adverse events that resolved without long-term sequelae. There were no severe life-threatening events. Overall, infusion-associated reaction rate was low and similar to that reported in adults receiving RRI (Lang et al, 2011). The need to use hydrocortisone premedication for patients not receiving steroids should be further studied. We conclude that RRI is a safe option in children and young adults with non-malignant indications, such as EBV viremia, GVHD or autoimmune cytopenias. This regimen should not be considered for subjects with active B-cell malignancies or post-transplant lymphoproliferative disorder due to the risk of tumour lysis syndrome. RRI will probably have a positive impact on patient satisfaction and resource utilization for busy paediatric practices where these medications are commonly used.