Browsing by Author "Confer, Dennis L"

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    Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation.
    (Blood, 2010-12) Wingard, John R; Carter, Shelly L; Walsh, Thomas J; Kurtzberg, Joanne; Small, Trudy N; Baden, Lindsey R; Gersten, Iris D; Mendizabal, Adam M; Leather, Helen L; Confer, Dennis L; Maziarz, Richard T; Stadtmauer, Edward A; Bolaños-Meade, Javier; Brown, Janice; Dipersio, John F; Boeckh, Michael; Marr, Kieren A; Blood and Marrow Transplant Clinical Trials Network
    Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803.
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    Unlicensed Umbilical Cord Blood Units Provide a Safe and Effective Graft Source for a Diverse Population: A Study of 2456 Umbilical Cord Blood Recipients.
    (Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020-04) Ballen, Karen; Logan, Brent R; Chitphakdithai, Pintip; Kuxhausen, Michelle; Spellman, Stephen R; Adams, Alexia; Drexler, Rebecca J; Duffy, Merry; Kemp, Ann; King, Roberta; Babic, Aleksandar; Delaney, Colleen; Karanes, Chatchada; Kurtzberg, Joanne; Petz, Lawrence; Scaradavou, Andromachi; Shpall, Elizabeth J; Smith, Clayton; Confer, Dennis L; Miller, John P
    Umbilical cord blood (UCB) transplantation (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access to transplantation for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the US Food and Drug Administration required that unrelated UCBT be performed using either licensed UCB or unlicensed UCB under the Investigational New Drug (IND) program. The National Marrow Donor Program manages an IND under which 2456 patients (1499 adults and 957 children, 564 with malignant diseases and 393 with nonmalignant diseases) underwent single or double UCBT between October 2011 and December 2016. The median patient age was 31 years (range, <1 to 81 years), and 50% of children and 36% of adults were non-Caucasian. The median time to neutrophil engraftment (ie, absolute neutrophil count ≥500/mm3) was 22 days for adults, 20 days for pediatric patients with malignant diseases, and 19 days for pediatric patients with nonmalignant diseases, with corresponding rates of engraftment at 42 days of 89%, 88%, and 90%. In these 3 groups of patients, the incidence of acute graft-versus-host disease (GVHD) grade II-IV was 35%, 32%, and 24%; the incidence of chronic GVHD was 24%, 26%, and 24%; and 1-year overall survival (OS) was 57%, 71%, and 79%, respectively. In multivariate analysis, younger age, lower Hematopoietic Cell Transplantation-Specific Comorbidity Index, early-stage chemotherapy-sensitive disease, and higher performance score were predictive of improved OS for adults. In a subset analysis of children with malignancies undergoing single UCBT, the use of either licensed UCB (n = 48) or unlicensed UCB (n = 382) was associated with similar engraftment and survival. The use of unlicensed UCB units is safe and effective and provides an important graft source for a diverse population.
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    Voriconazole pharmacokinetics following HSCT: results from the BMT CTN 0101 trial.
    (The Journal of antimicrobial chemotherapy, 2016-08) Hope, William W; Walsh, Thomas J; Goodwin, Joanne; Peloquin, Charles A; Howard, Alan; Kurtzberg, Joanne; Mendizabal, Alan; Confer, Dennis L; Bulitta, Jürgen; Baden, Lindsey R; Neely, Michael N; Wingard, John R; Blood and Marrow Transplant Clinical Trials Network

    Background

    Voriconazole is a first-line agent for the prevention and treatment of a number of invasive fungal diseases. Relatively little is known about the relationship between drug exposure and the prevention of invasive fungal infections.

    Patients and methods

    A pharmacokinetic-pharmacodynamic substudy was performed as part of the BMT CTN 0101 trial, which was a randomized clinical trial comparing voriconazole with fluconazole for the prevention of invasive fungal infections in HSCT recipients. A previously described population pharmacokinetic model was used to calculate the maximum a posteriori Bayesian estimates for 187 patients. Drug exposure in each patient was quantified in terms of the average AUC and average trough concentrations. The relationship between drug exposure and the probability of breakthrough infection was investigated using logistic regression. AUC and trough concentrations in patients with and without breakthrough infection were compared.

    Results

    Pharmacokinetic data from each patient were readily described using the maximum a posteriori Bayesian estimates. There were only five patients that had a breakthrough infection while receiving voriconazole in the first 100 days post-HSCT. For these patients, there was no statistically significant relationship between the average AUC or average trough concentration and the probability of breakthrough infection [OR (95% CI) 1.026 (0.956-1.102) and 1.108 (0.475-2.581), respectively]. P value for these estimates was 0.474 and 0.813, respectively.

    Conclusions

    Given the very small number of proven/probable infections, it was difficult to identify any differences in drug exposure in HSCT recipients with and without breakthrough fungal infections.