Poor absorption of high-dose posaconazole in pediatric bone marrow transplant patients.

OBJECTIVE: To describe the use of high-dose posaconazole in 2 pediatric patients who received bone marrow transplant (BMT) and highlight concerns regarding posaconazole absorption. CASE SUMMARY: We present 2 pediatric BMT patients in whom prescribed high doses of posaconazole (120-300 mg/kg/day for >3 months) provided serum concentrations less than 1 µg/mL. Both patients received posaconazole with other antifungal therapy and surgical debridement for Rhizopus spp. infections after allogeneic BMTs. Various alternative dosing strategies to potentially enhance posaconazole absorption to increase serum concentrations were attempted, including higher daily doses, frequent or continuous oral administration via feeding tube, use of enteral nutrition, and limiting use of acid-blocking agents. During high-dose therapy, frequent posaconazole serum concentration measurement and other monitoring techniques, such as continuous telemetry, were used. While the fungal infections resolved in both patients and no serious adverse effects could be attributed to high-dose posaconazole administration, posaconazole therapy may have contributed to nausea and vomiting in 1 of the patients. DISCUSSION: These 2 cases describe complex circumstances, with several reasons that may have affected the patients' posaconazole serum concentrations. Both patients received significantly higher doses than those recommended in the posaconazole prescribing information, but potentially serious adverse events were not observed since serum concentration measurements were rarely more than 0.5 µg/mL. CONCLUSIONS: The safety of high-dose posaconazole therapy was not determined in these 2 patients. However, given that limited alternative therapy options are available for severely ill patients with suspected posaconazole malabsorption, research regarding dosing strategies should be considered.

Safety and efficacy of CMX001 as salvage therapy for severe adenovirus infections in immunocompromised patients.

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/µL (range, 7-1500 cells/µL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.

Analysis of 120 pediatric patients with nonmalignant disorders transplanted using unrelated plasma-depleted or -reduced cord blood.

BACKGROUND: Unrelated cord blood (CB) is an important stem cell source for unrelated hematopoietic cell transplantation (HCT) of patients with nonmalignant disorders. Processing methods to prepare red blood cell-reduced CB units incur significant nucleated cell loss. In contrast, plasma depletion or reduction (PDR) processing of CB units entails the removal of only a portion of the plasma with minimal nucleated cell loss. However, there are relatively limited data regarding outcomes of CB transplants using units processed by PDR. STUDY DESIGN AND METHODS: A Center for International Blood and Marrow Transplant Research (CIBMTR)-audited analysis was performed on 120 pediatric patients with nonmalignant disorders transplanted between November 2001 and January 2008 at 29 US and 17 international centers using PDR CB units from two CB banks. RESULTS: Transplant characteristics were as follows: median age, 3.5 years (range, 0.1-14 years); median patient weight, 15 kg (range, 4-61 kg); 58% male; HLA matches (intermediate-resolution HLA-A and HLA-B and high-resolution HLA-DRB1) of the units used in these patients six of six in 26, five of six in 48, four of six in 47, and three of six or two of six in 6; median prefreeze total nucleated cell dose, 10.5×10(7)/kg; median prefreeze CD34+ dose, 3.7×10(5)/kg; and nonmyeloablative regimen in 24%. The median times to myeloid and platelet engraftment were 21 and 49 days, respectively. The cumulative incidence of reported Grade II to IV acute graft-versus-host disease (aGVHD) was 38±5%, and 19±4% had Grade III to IV aGVHD. The Kaplan-Meier estimates of 3-year transplant-related mortality, overall survival, and disease-free survival were 20±4, 79±4, and 70±6%, respectively. CONCLUSION: These data demonstrate the effectiveness of PDR CB units for HCT.

Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised children and healthy adults.

Voriconazole pharmacokinetics are not well characterized in children despite prior studies. To assess the appropriate pediatric dosing, a study was conducted in 40 immunocompromised children aged 2 to <12 years to evaluate the pharmacokinetics and safety of voriconazole following intravenous (IV)-to-oral (PO) switch regimens based on a previous population pharmacokinetic modeling: 7 mg/kg IV every 12 h (q12h) and 200 mg PO q12h. Area under the curve over the 12-h dosing interval (AUC(0-12)) was calculated using the noncompartmental method and compared to that for adults receiving approved dosing regimens (6 → 4 mg/kg IV q12h, 200 mg PO q12h). On average, the AUC(0-12) in children receiving 7 mg/kg IV q12h on day 1 and at IV steady state were 7.85 and 21.4 µg · h/ml, respectively, and approximately 44% and 40% lower, respectively, than those for adults at 6 → 4 mg/kg IV q12h. Large intersubject variability was observed. At steady state during oral treatment (200 mg q12h), children had higher average exposure than adults, with much larger intersubject variability. The exposure achieved with oral dosing in children tended to decrease as weight and age increased. The most common treatment-related adverse events were transient elevated liver function tests. No clear threshold of voriconazole exposure was identified that would predict the occurrence of treatment-related hepatic events. Overall, voriconazole IV doses higher than 7 mg/kg are needed in children to closely match adult exposures, and a weight-based oral dose may be more appropriate for children than a fixed dose. Safety of voriconazole in children was consistent with the known safety profile of voriconazole.

Analysis of hematopoietic cell transplants using plasma-depleted cord blood products that are not red blood cell reduced.

Limited cell dose hampers wider use of cord blood transplantation (CBT). By depleting plasma but not RBC during processing, nucleated cell (NC) loss is reduced to <0.1% which increases significantly the proportion of high cell dose products-3-fold for products with NC >or=200 x 10(7). Clinical outcome for plasma depleted (PD) CBT was previously unavailable. A retrospective audited analysis was performed on 118 PD CBT, with mean and median NC doses of 7.6 x 10(7)/kg and 5.6 x 10(7)/kg, respectively, for this mostly pediatric population. The median times to engraftment and engraftment rates for ANC 500 and platelet 20K were 22 and 50 days, respectively, and 90% +/- 3% and 77% +/- 5%, respectively. The incidences of grade III-IV acute graft-versus-host disease (aGVHD) and extensive chronic GVHD (cGVHD) were 13% +/- 4% and 17% +/- 6%, respectively. Relapse rate for malignancies was 25% +/- 6% and 100-day treatment-related mortality (TRM) was 16% +/- 3%. With a median follow-up of 557 days, the 1-year overall survival and relapse-free survival are 65% +/- 5% and 51% +/- 6%, respectively. These results demonstrate that PD CBT is safe and effective, and that eliminating RBC reduction or depletion improves cell recovery during CB processing, resulting in a larger proportion of the inventory with high NC number.

Granulocyte-Stimulating Factor-Induced Bone Marrow Reconversion Simulating Neuroblastoma Metastases on MRI: Case Report and Literature Review.

Granulocyte colony-stimulating factor (GCSF), often used as an adjunct to chemotherapy, can pose a dilemma in differentiating the associated bone marrow changes from metastatic disease on magnetic resonance imaging. The phenomenon has been previously reported in children undergoing treatment for primary musculoskeletal malignancies [1, 2]. We present a case of GCSF-induced marrow reconversion simulating neuroblastoma metastases on MR imaging. An interesting observation in our case was intense abnormal signal in a pattern of metaphyseal bands, which, to our knowledge, was not previously reported in the English literature to be associated with GCSF-induced marrow reconversion.

Application of fibrin glue to damaged bladder mucosa in a case of BK viral hemorrhagic cystitis.

BK virus is a common cause of severe hemorrhagic cystitis refractory to standard treatment. We describe a technique to achieve hemostasis after failed conservative therapy using fibrin glue applied suprapubically while visualizing and insufflating the bladder through a cystoscope. Long-term hemostasis was achieved using this novel procedure.

Acute lymphoblastic leukemia of the skin and subcutaneous tissues; the first manifestation of disease in a 6-month-old infant: a case report with literature review.

Leukemic infiltrate involving the skin and subcutaneous tissue was the first manifestation of disease in a 6-month-old female infant. Knowledge of age-related distribution patterns of the red (cellular) and yellow (fatty) marrow is crucial for the interpretation of magnetic resonance imaging (MRI) studies. Diffusely decreased signal intensity throughout the bone marrow on the T1-weighted images specifically involving the epiphyseal ossification centers in infants 6 months after their appearance should be suggestive of a marrow infiltrative/replacement process. Correlation with the peripheral blood smear and bone marrow aspirate are necessary for the diagnosis of leukemia.

Pegaspargase: a review of clinical studies.

The chemotherapy agent L-asparaginase has been an important part of acute lymphoblastic leukemia therapy for over 30 years. Two of the main disadvantages of the drug are (1) the need for frequent intramuscular injection and (2) a very high rate of allergic reactions. Because of this, L-asparaginase seemed like an ideal target for pegylation and PEG-L-asparaginase was developed in the 1970s and 1980s. The drug has undergone extensive testing and appears to retain its antileukemic effectiveness while allowing less frequent administration than the native compound. While the actual cost to patients for PEG-L-asparaginase is greater than that of multiple injections of other L-asparaginases, the reduced need for physician visits and treatment of complications of therapy may make overall treatment costs considerably less than that of the conventional L-asparaginases. In the review below, we outline the history of therapy with L-asparaginase, the development of PEG-L-asparaginase, and clinical trials in which it has been administered.

Economic comparison of home-care-based versus hospital-based treatment of chemotherapy-induced febrile neutropenia in children.

OBJECTIVE: The purpose of this study was to compare health-care resource utilization and outcomes among children treated for low-risk febrile neutropenia (FN) in a hospital-based setting with those treated in a home-care-based setting. METHODS: The perspective of this retrospective, cohort study was the health payer. We collected health-care utilization and treatment outcome data from medical records of 63 children (26 boys and 37 girls) with low-risk, chemotherapy-induced FN who were treated at the University of Arizona (27 children, the hospital-based group) and University of New Mexico (36 children, the home-care-based group). We identified 144 FN episodes (72 episodes in each group). Health-care utilization included physician visits, home-care visits, laboratory visits, outpatient visits, hospital days, intensive care unit days, medical tests and studies, and medications used to manage FN (e.g., filgrastim, antimicrobials, and ancilliary drugs and supplies). We applied uniform charges, based on those used at the University of New Mexico in 1998. We collected outcomes of the FN treatment (success vs. failure and time to resolution, defined as number of days of antibiotic therapy). Rates of positive blood cultures during treatment were also compared. Data were analyzed using nonparametric Mann-Whitney U tests for continuous data and chi-square analysis for categorical data. Sensitivity analyses were conducted by varying the amount of total resource utilization, as well as utilization of specific health-care resources. RESULTS: There was no difference in outcome; all episodes of treatment in both groups resulted in successful recovery from FN. Time to resolution of FN was 8.3 +/- 2.7 days for home-care FN episodes versus 7.3 +/- 3.6 days for hospital FN episodes (P =.064). Median charge per FN episode was significantly (P<.001) greater when managed in the hospital compared to home care (9392 US dollars vs. 5893 US dollars). There was greater use of laboratory and radiographic studies in the hospital-based patients (P <.01). However, children in the home-care-based group were more often treated with granulocyte colony-stimulating factor (filgrastim, median charge 1085 US dollars vs. 451 US dollars, P <.001), and median antibiotic charges were higher (2523 US dollars vs. 1526 US dollars, P <.001). Positive blood cultures were more common among the hospital-based FN treatments (30.6 vs. 11.1%, P=.012). CONCLUSIONS: We found that management of low-risk FN in a home-care-based setting was associated with significantly lower median total charges with no differences in outcome.