Heinz body hemolysis following extended use phenazopyridine in a post-HCT patient with hemorrhagic cystitis: An old problem for a new generation.

Hemorrhagic cystitis is a common complication following the use of cyclophosphamide. Associated dysuria can be painful and there are few good options to relieve pain. Phenazopyridine has historically been utilized for dysuria and is available over the counter. However, it is associated with hematologic side effects with prolonged use. Here we present a case of a patient who developed Heinz body hemolysis following prolonged administration of phenazopyridine to treat cyclophosphamide-induced hemorrhagic cystitis following hematopoietic stem cell transplant.

Evaluation of Children with Malignancies for Blood and Marrow Transplantation: A Report from the ASTCT Committee on Practice Guidelines.

Evaluation of a candidate for hematopoietic cell transplantation (HCT) is a complex process with substantial intercenter variability. Although literature providing guidance for evaluating the eligibility of adults is well established, similar guidance for children is lacking. To address gaps between adult recommendations and the specific needs of children, we convened a panel of pediatric HCT experts from a wide geographic range of American Society of Transplantation and Cellular Therapy (ASTCT) member institutions to offer recommendations for pediatric-focused pre-HCT evaluation. In this report from the ASTCT Committee on Practice Guidelines, we present a practical framework for evaluating children with malignancies who are candidates for HCT. We also highlight key differences from adults and emphasize areas of unmet need that require additional research to delineate best practices.

Prospective Validation and Refinement of a Population Pharmacokinetic Model of Fludarabine in Children and Young Adults Undergoing Hematopoietic Cell Transplantation.

Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models have not been validated in a prospective cohort of patients. In this multicenter pharmacokinetic study, fludarabine plasma concentrations were collected via a sparse-sampling strategy. A fludarabine popPK model was evaluated and refined using standard nonlinear mixed effects modelling techniques. The previously described fludarabine popPK model well-predicted the prospective fludarabine plasma concentrations. Individuals who received model-based dosing (MBD) of fludarabine achieved significantly more precise overall exposure of fludarabine. The fludarabine popPK model was further improved by both the inclusion of fat-free mass instead of total body weight and a maturation function on fludarabine clearance. The refined popPK model is expected to improve dosing recommendations for children younger than 2 years and patients with higher body mass index. Given the consistency of fludarabine clearance and exposure across its multiple days of administration, therapeutic drug monitoring is not likely to improve targeted exposure attainment.

A Guidance for Concomitant Drug Reconciliation Prior to Allogeneic Hematopoietic Cell Transplantation in Children and Young Adults.

Pediatric diseases treated by allogeneic hematopoietic stem cell transplantation (alloHCT) are complex and associated with significant comorbidities and medication requirements that can complicate the transplant process. It is critical to reconcile pre-transplant concomitant medications (pcon-meds) in the weeks prior to alloHCT and to consider the potential for pcon-meds to cause harmful drug-drug interactions (DDIs) or overlapping toxicities with conditioning agents. In this perspective, we describe a systematic process to review pcon-meds and determine the drug modifications needed to avoid DDIs with conditioning regimens. We provide an extensive appendix with timelines for discontinuation or modification of common pcon-meds that patients are taking when presenting to the HCT medical team. The timelines are based on the pharmacokinetic (PK) properties of both the pcon-meds and the planned conditioning medications, as well as anticipated DDIs. They also account for the ages seen at pediatric transplant centers (0-30 years old). Common scenarios, such as when pcon-med discontinuation is not an option, are discussed. Since alloHCT patients are often dependent upon psychiatric medications with problematic DDIs, a table of alternative, non-interacting psychiatric medications is also presented. The appendix provides details regarding how to adjust pcon-meds prior to the start of chemotherapy for children and young adults undergoing alloHCT, however patient-specific circumstances always need to be taken into account. Careful attentiveness to pcon-meds at the time the decision is made to pursue transplant will result in more consistent HCT outcomes, with lower toxicity and increased efficacy of conditioning agents.

Pharmacogenomics education, research and clinical implementation in the state of Minnesota.

Several healthcare organizations across Minnesota have developed formal pharmacogenomic (PGx) clinical programs to increase drug safety and effectiveness. Healthcare professional and student education is strong and there are multiple opportunities in the state for learners to gain workforce skills and develop advanced competency in PGx. Implementation planning is occurring at several organizations and others have incorporated structured utilization of PGx into routine workflows. Laboratory-based and translational PGx research in Minnesota has driven important discoveries in several therapeutic areas. This article reviews the state of PGx activities in Minnesota including educational programs, research, national consortia involvement, technology, clinical implementation and utilization and reimbursement, and outlines the challenges and opportunities in equitable implementation of these advances.

A phase I dose finding study of intravenous voriconazole in pediatric patients undergoing hematopoietic cell transplantation.

To optimize voriconazole dosing in pediatric hematopoietic cell transplantation (HCT), we conducted a phase I study with a modified 3 + 3 dose-escalation followed by an expansion cohort at the maximum tolerated, minimum efficacious dose (MTD/MED). Patients ≤21 years who required voriconazole for prevention or treatment of an invasive fungal infection were assigned to three age groups. Of the 59 evaluable patients, 13 were <2 years, 23 were 2-11, and 23 were 12-21. Therapeutic serum voriconazole troughs (1.5-5 µg/mL) drawn at 7 days after initiation determined efficacy. The MTD/MED was 12 mg/kg/dose q12 h × 2 loading doses, then 10 mg/kg/dose q12 h in patients <2, and was 10 mg/kg/dose q12 h in patients 2-11. The 12-21 age group had no dose-limiting toxicity at 8 mg/kg/dose q12 h; however, the MED was not reached. Drug-related AEs ≥grade 3 included increased bilirubin, transaminases, and creatinine, all occurring in <10%. There was no significant association between supra-therapeutic troughs and AEs. Five of 17 patients who had supra-therapeutic troughs (29%) had an AE, compared to 8 of 42 who did not (19%, p = 0.38). Observational population pharmacokinetic analysis demonstrated that inter-individual variability on voriconazole clearance was >100% CV, and clearance increased with age.