Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation

Wingard, John R.; Carter, Shelly L.; Walsh, Thomas J.; Kurtzberg, Joanne; Small, Trudy N.; Baden, Lindsey R.; Gersten, Iris D.; Mendizabal, Adam; Leather, Helen; Confer, Dennis L.; Maziarz, Richard T.; Stadtmauer, Edward A.; Bolaños-Meade, Javier; Brown, Janice; DiPersio, John F.; Boeckh, Michael; Marr, Kieren A.

doi:10.1182/blood-2010-02-268151

Cited by 446 publications

(393 citation statements)

References 34 publications

Supporting

Mentioning

373

Contrasting

Unclassified

Order By: Relevance

“…However, despite the knowledge of several post-engraftment risk factors associated with late IFD (for example, corticosteroid therapy and GVHD), considered as a guide for risk-adapted antifungal prophylaxis, the usefulness of such prophylaxis beyond the alloSCT engraftment is still controversial. [8][9][10] There are a few studies specifically analyzing the epidemiology and risk factors for IFD after engraftment in alloSCT adult recipients [3][4][5]11 and the potential impact of antifungal prophylaxis in this setting.…”

Section: Introductionmentioning

confidence: 99%

Incidence and risk factors of post-engraftment invasive fungal disease in adult allogeneic hematopoietic stem cell transplant recipients receiving oral azoles prophylaxis

Montesinos

Rodríguez‐Veiga

Boluda

et al. 2015

Bone Marrow Transplant

View full text Add to dashboard Cite

Studies that analyze the epidemiology and risk factors for invasive fungal disease (IFD) after engraftment in alloSCT are few in number. This single-center retrospective study included 404 alloSCT adult recipients surviving 440 days who engrafted and were discharged without prior IFD. All patients who received ⩾ 20 mg/day of prednisone were assigned to primary oral prophylaxis (itraconazole or low-dose voriconazole). The primary end point was the cumulative incidence (CI) of probable/proven IFD using the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria. The independent prognostic factors after multivariate analyses were used to construct a post-engraftment IFD risk score. The 1-year CI of IFD was 11%. The non-relapse mortality was 40% in those developing IFD and 16% in those who did not. The intent-to-treat analysis showed that 17% of patients abandoned the assigned prophylaxis. Age 440 years, ⩾ 1 previous SCT, pre-engraftment neutropenia 415 days, extensive chronic GVHD and CMV reactivation were independent risk factors. The post-engraftment IFD score stratified patients into low risk (0-1 factor, CI 0.7%), intermediate risk (2 factors, CI 9.9%) and high risk (3-5 factors, CI 24.7%) (P o 0.0001). The antifungal prophylaxis strategy failed to prevent post-engraftment IFD in 11% of alloSCT. Our risk score could be useful to implement risk-adapted strategies using antifungal prophylaxis after engraftment.

show abstract

Section: Introductionmentioning

confidence: 99%

Incidence and risk factors of post-engraftment invasive fungal disease in adult allogeneic hematopoietic stem cell transplant recipients receiving oral azoles prophylaxis

Montesinos

Rodríguez‐Veiga

Boluda

et al. 2015

Bone Marrow Transplant

View full text Add to dashboard Cite

show abstract

“…Low serum levels of posaconazole have been associated with breakthrough aspergillosis. Voriconazole, the drug of choice for treatment of IA, was shown to decrease the frequency of IA but did not improve fungal infection-free survival and overall survival compared with fluconazole (no activity against aspergillus) among allogeneic recipients [13]. Both triazoles, now liberally used for prophylaxis during allogeneic HSCT, are not without potentially serious adverse effects.…”

Section: Chemoprophylaxismentioning

confidence: 99%

Challenges in the management of invasive aspergillosis in hematopoietic stem cell transplantation

Chandrasekar

Ramesh

2009

Expert Review of Anti-infective Therapy

View full text Add to dashboard Cite

“…Fluconazole, itraconazole, posaconazole, voriconazole, and micafungin are recommended for prophylactic use in patients with hematologic malignancies (9,10). Although the results of randomized clinical trials support the prophylactic benefits of these agents (7,8,11), each may be limited in their use: fluconazole has no activity against molds (12); posaconazole demonstrates broad-spectrum activity against both yeasts and molds (13), but optimal absorption of the oral suspension of posaconazole is dependent on administration with a high-fat meal (however, the delayed-release tablets have improved bioavailability) (14); voriconazole is as effective as fluconazole in preventing IFIs (15) but has been associated with breakthrough mucormycosis and a high incidence of side effects (16,17); itraconazole tablets have variable bioavailability, and its oral suspension has poor tolerability (18); and micafungin is available only as an intravenous (i.v.) formulation and has no activity against the Mucorales or Fusarium species (19).…”

mentioning

confidence: 99%

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

Cornely

Böhme²,

Schmitt‐Hoffmann

et al. 2015

Antimicrob Agents Chemother

103

View full text Add to dashboard Cite

Isavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort (n ‫؍‬ 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort (n ‫؍‬ 12). The mean ؎ standard deviation plasma isavuconazole areas under the concentration-time curves for the dosing period on day 7 were 60.1 ؎ 22.3 g · h/ml and 113.1 ؎ 19.6 g · h/ml for the patients in the low-dose and high-dose cohorts, respectively. The adverse events in five patients in the low-dose cohort and in eight patients in the high-dose cohort were considered to be drug related. Most were mild to moderate in severity, and the most common adverse events were headache and rash (n ‫؍‬ 3 each). One patient in the high-dose cohort experienced a serious adverse event (unrelated to isavuconazole treatment), and two patients each in the low-dose and high-dose cohorts discontinued the study due to adverse events. Of the 20 patients who completed the study, 18 were classified as a treatment success. In summary, the results of this analysis support the safety and tolerability of isavuconazole administered at 200 mg and 400 mg once-daily as prophylaxis in immunosuppressed patients at high risk of fungal infections. (This study is registered at ClinicalTrials.gov under registration number NCT00413439.) I nvasive fungal infections (IFIs) are associated with significant morbidity, mortality, and health care costs in patients with hematologic malignancies (1, 2). Allogeneic hematopoietic stem cell transplantation and chemotherapy-associated neutropenia place patients with acute myeloid leukemia (AML) at risk of developing an IFI (3). Aspergillus spp. and Candida spp. are the predominant IFI pathogens in patients with acute leukemia (1, 3, 4). However, other molds, such as the Mucorales, Scedosporium spp., and Fusarium spp., are emerging as pathogens in this setting and are associated with high mortality rates (1).Because IFIs are often difficult to diagnose, and delays in treatment can significantly increase the risk of mortality (5, 6), antifungal prophylaxis has become a commonly used strategy in patients at high risk of IFIs (7, 8). Fluconazole, itraconazole, posaconazole, voriconazole, and micafungin are recommended for prophylactic use in patients with hematologic malignancies (9, 10). Although the results of randomized clinical trials support the prophylactic benefits of these agents (7,8,11), each may be limited in their use: fluconazole has no activity against molds (12); posaconazole demonstrates broad-spectrum activity against both yeasts and mo...

show abstract

Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation

Abstract: Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT).

Cited by 446 publications

References 34 publications

Incidence and risk factors of post-engraftment invasive fungal disease in adult allogeneic hematopoietic stem cell transplant recipients receiving oral azoles prophylaxis

Incidence and risk factors of post-engraftment invasive fungal disease in adult allogeneic hematopoietic stem cell transplant recipients receiving oral azoles prophylaxis

Challenges in the management of invasive aspergillosis in hematopoietic stem cell transplantation

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

Contact Info

Product

Resources

About