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A correction has been published: N Engl J Med 2007;357(4):428.
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Background Invasive fungal infections are an important cause of morbidity and mortality after allogeneic hematopoietic stem-cell transplantation.
Methods In an international, randomized, double-blind trial, we compared oral posaconazole with oral fluconazole for prophylaxis against invasive fungal infections in patients with graft-versus-host disease (GVHD) who were receiving immunosuppressive therapy. The primary end point was the incidence of proven or probable invasive fungal infections from randomization to day 112 of the fixed treatment period of the study.
Results Of a total of 600 patients, 301 were assigned to posaconazole and 299 to fluconazole. At the end of the fixed 112-day treatment period, posaconazole was found to be as effective as fluconazole in preventing all invasive fungal infections (incidence, 5.3% and 9.0%, respectively; odds ratio, 0.56; 95 percent confidence interval [CI], 0.30 to 1.07; P=0.07) and was superior to fluconazole in preventing proven or probable invasive aspergillosis (2.3% vs. 7.0%; odds ratio, 0.31; 95% CI, 0.13 to 0.75; P=0.006). While patients were receiving study medications (exposure period), in the posaconazole group, as compared with the fluconazole group, there were fewer breakthrough invasive fungal infections (2.4% vs. 7.6%, P=0.004), particularly invasive aspergillosis (1.0% vs. 5.9%, P=0.001). Overall mortality was similar in the two groups, but the number of deaths from invasive fungal infections was lower in the posaconazole group (1%, vs. 4% in the fluconazole group; P=0.046). The incidence of treatment-related adverse events was similar in the two groups (36% in the posaconazole group and 38% in the fluconazole group), and the rates of treatment-related serious adverse events were 13% and 10%, respectively.
Conclusions Posaconazole was similar to fluconazole for prophylaxis against fungal infections among patients with GVHD. It was superior in preventing invasive aspergillosis and reducing the rate of deaths related to fungal infections. (ClinicalTrials.gov number, NCT00034645
[ClinicalTrials.gov]
.)
Randomized, controlled trials have shown the superiority of fluconazole over placebo for the prevention of fungal infections, primarily those caused by candida species, after hematopoietic stem-cell transplantation. Fluconazole prophylaxis reduces both fungal-infection–related and overall mortality7,8 and has become a standard of care for antifungal prophylaxis after the first 100 days of the post-transplantation period in recipients of hematopoietic stem-cell transplants.7,8,9
The incidence of infections caused by aspergillus species among recipients of hematopoietic stem-cell transplants ranges from 3 to 14%,1,10,11,12,13,14 with the peak occurrence after hematopoietic recovery associated with GVHD and immunosuppressive therapy.1,4,10,11,12,13,14,15 So far, no prophylactic strategies for the prevention of mold infections during this period of risk have been validated in randomized, controlled trials. The lack of established prophylactic measures for these patients underscores the need for options for broad-spectrum, well-tolerated antifungal prophylaxis for this population.
Posaconazole is an extended-spectrum triazole with in vitro activity against a broad spectrum of fungi16,17,18 and clinical activity against various fungal pathogens, including aspergillus species, candida species, zygomycetes, and fusarium species.19,20,21 On the basis of this broad spectrum of antifungal activity, we compared posaconazole with fluconazole for efficacy, safety, and tolerability in the prevention of invasive fungal infections among recipients of allogeneic hematopoietic stem-cell transplants with GVHD who were receiving immunosuppressive therapy.
Methods
Study Design
The study was a phase 3, randomized, multicenter, double-blind and double-dummy, parallel-group, multinational trial comparing posaconazole with fluconazole for prophylaxis against invasive fungal infections in high-risk patients with GVHD after allogeneic hematopoietic stem-cell transplantation. The trial was conducted from March 1999 through February 2003. The study protocol and informed-consent form were reviewed and approved by an independent ethics committee or institutional review board at each study site. Written informed consent was obtained from all participants before the initiation of any study-related activities. An independent data review committee of eight physicians with expertise in opportunistic infections in transplant recipients reviewed all suspected and documented fungal infections in a blinded fashion and classified the infections according to consensus criteria.22
The study was designed in part by the academic authors and in part by a clinical team of employees of the sponsor. All authors, except those employed by the sponsor, gathered the clinical data. The sponsor was responsible for the analysis of the data. All authors contributed to the writing of the manuscript. All authors also had full access to the primary data and to the analysis, and all vouch for the accuracy and completeness of the reported data.
Patients
Male and female patients 13 years of age or older and weighing more than 34 kg (75 lb) who had undergone allogeneic hematopoietic stem-cell transplantation were eligible to participate in the study if they had either acute GVHD, grade II to IV, or chronic extensive GVHD,23,24 or if they were being treated with intensive immunosuppressive therapy consisting of either high-dose corticosteroids (
1 mg per kilogram of body weight per day for patients with acute GVHD or 0.8 mg per kilogram every other day for patients with chronic GVHD), antithymocyte globulin, or a combination of two or more immunosuppressive agents or types of treatment. Patients were excluded if they had a history of proven or probable mold infections or a suspected invasive fungal infection at baseline, clinically significant hepatic dysfunction as indicated by elevated alanine aminotransferase or aspartate aminotransferase levels or both (>10 times the upper limit of the normal range), or renal dysfunction. Patients were also excluded if they required medications known to interact with azoles.25 For a detailed description of the inclusion and exclusion criteria, see the Supplementary Appendix (available with the full text of this article at www.nejm.org).
Stratification and Randomization
Patients were stratified according to GVHD status at baseline and were randomly assigned to receive posaconazole oral suspension (Noxafil, Schering-Plough), at a dose of 200 mg three times daily plus placebo capsules once daily, or fluconazole capsules (Diflucan, Pfizer), at a dose of one 400-mg encapsulated tablet orally once daily plus placebo oral suspension three times daily, for the expected 112-day fixed treatment period of the study. After randomization, patients were treated for up to 112 days or until a protocol-specified end point (a breakthrough invasive fungal infection, an adverse event requiring discontinuation of the study medication, or death) was reached. Patients who discontinued treatment for reasons other than death were followed for the full 112 days. The period from the first dose of the study drug to 7 days after receipt of the last dose was defined as the exposure period. Patients or physicians could interrupt the study medication for up to 5 consecutive days.
Efficacy End Points
The primary efficacy end point was the incidence of proven or probable invasive fungal infections,22 as adjudicated by the data review committee in a blinded fashion, during the period from randomization to day 112 (the treatment period) in the intention-to-treat population (patients who had given informed consent and undergone randomization). For the primary end point, failure of prophylaxis was defined as the development of an invasive fungal infection during the fixed treatment period.
Other end points were based on cases adjudicated by the data review committee and included the following: the incidence of proven or probable aspergillosis during the treatment period in the intention-to-treat population, the incidence of breakthrough proven or probable invasive fungal infections during the exposure period, the time to the occurrence of an invasive fungal infection, the overall mortality in the intention-to-treat population, and mortality attributable to fungal infection in the intention-to-treat population. Deaths occurring at any time during the study were included in the mortality analysis. The cause of death was assessed by the investigators and was attributed to intercurrent illness, drug-related adverse events, GVHD progression, complications of an invasive fungal infection, or other causes that could not be categorized. If a patient was unable to continue taking the assigned study medication or had a probable or proven invasive fungal infection,22 treatment with the study drug was discontinued, and the patient was treated according to the local standard of care for antifungal therapy.
Laboratory evaluations for susceptibility to fungal isolates and testing for colonization were performed every 2 weeks by a designated laboratory.26,27 Immunoassays for the detection of aspergillus galactomannan antigen in serum (Platelia Aspergillus EIA, Bio-Rad Laboratories) were performed at the central laboratory.28 Fungal colonization at baseline and colonization at the end of therapy were compared. An increase of more than 4 times the minimum inhibitory concentration was considered a clinically significant change in susceptibility. Plasma concentrations of posaconazole were determined with the use of a validated method of liquid chromatography–tandem mass spectrometry.29
Safety Assessment
The safety and tolerability of the study drugs were assessed in all patients who underwent randomization. The assessment was based on paired electrocardiographic and laboratory evaluations and evaluation for changes in clinical signs and symptoms. Patients were monitored for 16 weeks (the fixed 112-day treatment period) and were followed for an additional 8 weeks; the total of 24 weeks was considered the observation period. Adverse events were characterized according to the National Cancer Institute's Common Toxicity Criteria (version 2.0, revised March 23, 1998). Reasons for early discontinuation of the study treatment were recorded.
Statistical Analysis
At the time of the initiation of the study, the incidence of invasive fungal infections among patients with GVHD who were receiving fluconazole was not known. The study was designed with 90% power at a significance level of 0.05 to detect a risk ratio of 2 or more, assuming an overall incidence of invasive fungal infection of 15%. The design required 93 invasive fungal infections and a total of approximately 600 patients.
The primary analysis was a comparison of the incidence rates of proven or probable invasive fungal infections during the period from randomization to day 112 in the two treatment groups. As stated in the protocol, the evaluation of efficacy occurred in two stages. First, the noninferiority of posaconazole to fluconazole was assessed. If noninferiority was demonstrated, then the superiority of posaconazole to fluconazole was assessed. This two-stage process allowed for control of the type I error rate. Furthermore, adjustment for the two prespecified, unequally spaced interim analyses resulted in 95.01% confidence intervals (CIs, hereafter called 95% CI) in the final analysis.
Posaconazole was considered to be noninferior to fluconazole, with respect to the primary efficacy end point, on the basis of evaluations of all patients if the upper limit of the 95% CI for the adjusted odds ratio did not exceed a maximum value corresponding to a relative difference of 15 percentage points from the observed incidence rates in the fluconazole group. The 95% CI of Mantel–Haenszel odds ratios, adjusted for the stratification factor (acute vs. chronic GVHD), were computed for the effect of treatment on the incidence of proven or probable invasive fungal infections.
The incidence of proven or probable aspergillosis during the fixed treatment period in the intention-to-treat population and the incidence of breakthrough proven or probable invasive fungal infections during the exposure period were evaluated in a similar manner, with the use of the Mantel–Haenszel method. The time to invasive fungal infection, the time to death, and the time to death related to invasive fungal infection were evaluated with the use of the Kaplan–Meier method, and between-group comparisons were performed with the use of the log-rank test.
Results
Study Population
Patients were enrolled during the 4-year study period at 90 centers worldwide. A total of 600 patients underwent randomization (301 patients assigned to posaconazole, and 299 to fluconazole) and were included in the intention-to-treat population. Approximately 40% of the patients underwent randomization in the United States. Of the 600 patients, 291 received at least one dose of posaconazole, and 288 received at least one dose of fluconazole. The duration of treatment was similar in the two groups. Patients in the posaconazole group were treated for a mean of 80 days (median, 111; range, 1 to 138), and those in the fluconazole group were treated for a mean of 77 days (median, 108; range, 1 to 130).
The demographic characteristics and the selected risk factors for invasive fungal infections were similar in the two groups (Table 1). The majority of patients had two or more known risk factors for invasive fungal infections; the two groups appeared to be balanced with respect to these risk factors. Few patients (
5%) had a history of invasive yeast or mold infection, and none were considered to have evidence of proven or probable invasive fungal infections at baseline or were receiving secondary prophylaxis.
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A total of 175 cases of suggestive invasive fungal infections were submitted to the independent data review committee for adjudication. Of these 175 cases, 62 were judged to be proven or probable infections occurring during the 24-week observation period (overall incidence, 10%); 43 of the cases occurred during the treatment period from randomization to day 112, and 19 occurred after day 112.
The incidence of invasive fungal infections during the fixed treatment period (the primary end point) was 5.3% in the posaconazole group and 9.0% in the fluconazole group (odds ratio for invasive fungal infection in the posaconazole group, 0.56; 95% CI, 0.30 to 1.07). Given the total number of events, ruling out a 15% relative difference between the two groups resulted in an odds ratio of 1.16. Since the upper limit of the CI (1.07) was less than 1.16, the noninferiority of posaconazole, as compared with fluconazole, was established; superiority was not demonstrated (P=0.07).
The majority of the invasive fungal infections occurring during the fixed treatment period were invasive aspergillosis (Table 2). In other analyses, posaconazole was superior to fluconazole in reducing the incidence of proven or probable aspergillosis (odds ratio, 0.31; 95% CI, 0.13 to 0.75; P=0.006) during the treatment period and was superior to fluconazole in reducing the incidence of breakthrough proven or probable invasive fungal infections (odds ratio, 0.30; 95% CI, 0.12 to 0.71; P=0.004) and invasive aspergillosis during the exposure period (odds ratio, 0.17; 95% CI, 0.05 to 0.57; P=0.001). Rates of invasive fungal infections in the two groups during the fixed treatment period, according to selected risk factors considered to be predictive of such infections, are shown in Table 3. In general, the results of this subgroup analysis were consistent with the overall results.
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In both the posaconazole group and the fluconazole group, the principal pathogens were Candida albicans and C. glabrata. C. krusei was detected in only four patients treated with fluconazole. The development of resistance to the study drug occurred more frequently among patients taking fluconazole (17%, 4 of 24 patients) than among those taking posaconazole (5%, 1 of 21 patients).
Safety Evaluation
The safety evaluation included all 600 patients. The majority of the adverse events were considered by the investigators to be unrelated to the study treatment. The incidence of adverse events judged to be related to the study drugs was similar in the two groups (36% in the posaconazole group and 38% in the fluconazole group) (Table 4).
The frequency of discontinuation of a study drug because of an adverse event was similar in the two groups (103 patients [34%] in the posaconazole group and 114 patients [38%] in the fluconazole group). For detailed information on discontinuation of a study drug prematurely, see the Supplementary Appendix. The most common treatment-related adverse events that led to discontinuation of the study drug were those associated with gastrointestinal disorders. Overall, the frequency of treatment-related serious adverse events was similar in the two groups (Table 4). No single serious, treatment-related adverse event occurred at a rate higher than 2% in either group. A high rate of treatment discontinuation occurred in this study because of the severity of the underlying disease; only 46% of the patients in the posaconazole group and 41% of those in the fluconazole group completed the full 16 weeks of treatment.
Discussion
This large, randomized, multicenter, double-blind trial showed that posaconazole was as effective as fluconazole in preventing all invasive fungal diseases in recipients of hematopoietic stem-cell transplants with severe GVHD who were receiving immunosuppressive agents during a 16-week period. Posaconazole was superior to fluconazole in the prevention of invasive aspergillosis. Rates of invasive fungal infections among patients with chronic GVHD are reported to be as high as 39%.30 Previous trials of prophylaxis focused on the efficacy of primary prophylaxis only during the early period (up to day 100) after hematopoietic stem-cell transplantation.7,8,31,32,33,34 The advantage of our study design is that the patients enrolled were at high risk for invasive fungal infections as well as at increased risk for disorders related to the underlying disease. Therefore, any potential shortcoming in safety would be readily identified in this population with complicated conditions.
Although a previous study of itraconazole prophylaxis followed patients for up to 180 days, itraconazole was associated with greater toxic effects and poorer tolerability than fluconazole, thus limiting its success.35 In contrast, in our study, the discontinuation rates in the two groups were similar. Fluconazole was considered in the past to be a benchmark for safe antifungal prophylaxis acceptable to patients in the setting of hematopoietic stem-cell transplantation. In our study, posaconazole was shown to be as safe and as acceptable as fluconazole. This finding confirms the results of previous studies involving patients with neutropenia.36 The high incidence of gastrointestinal abnormalities in both treatment groups was expected, and most of these events were considered to be related to GVHD.
As in other trials, efficacy was analyzed in the group of patients who had received at least one dose of the study medication.7,35,37 Not all patients continued taking the study drug for the planned duration of 112 days; however, posaconazole was significantly more effective in preventing invasive fungal infections during the exposure period than was fluconazole. How long prophylaxis is required at this stage of disease is not established. Although previous studies used longer periods of prophylaxis, the prophylactic regimen was initiated earlier in the disease in these studies than it was in our study.7,8,31,33
The study was powered under the assumption that there would be 93 invasive fungal infections. However, only 43 cases were observed at the time of the final analysis, making it difficult to show significant differences. Given this outcome, the finding of noninferiority can be considered strengthened. The overall incidence of invasive fungal infections in the study was lower than incidences reported in other studies.3,30 This low incidence may be explained, in part, by the relatively short duration of prophylaxis and by the fact that all study patients received prophylaxis. Many patients with GVHD remain at risk for much longer periods, depending on the extent of the GVHD and the duration of immunosuppressive therapy needed. After the onset of GVHD, invasive fungal infections developed later among patients receiving posaconazole at any time after transplantation than among those receiving fluconazole, underscoring the prophylactic effect of this agent. The superiority of posaconazole in preventing invasive aspergillosis reflects the lack of activity of fluconazole against filamentous fungi, which are the major fungal pathogens affecting patients with GVHD.1,3,4 The demographic and clinical characteristics of the patients, including baseline risk factors for infection, did not differ significantly between the two groups; the results were therefore not influenced by differences in the baseline risk of infection.
The effects of factors such as the environment or compliance with other strategies for fungal prevention could have played an additional role in the incidence of invasive fungal infections in our study. In addition, patients discontinuing participation in the study for any reason were evaluated for the efficacy of treatment; however, these patients usually received fluconazole during the observation period, a fact that explains the similarity between the two groups in the intention-to-treat population. It would have been unethical to withhold prophylaxis as standard care.
Although posaconazole provided no advantage over fluconazole with respect to overall mortality, a difference in mortality due to invasive fungal infections was observed, and this finding has been reported in only a few trials conducted in different settings.7,8,32 Some suggest that survival free of invasive fungal infections should be included as a primary end point in a prophylaxis trial,35,38 but our trial was not powered to demonstrate differences in mortality.
In the majority of the patients in our study, plasma levels of posaconazole were above the minimum inhibitory concentration for most fungal pathogens.16,18 The low number of breakthrough invasive fungal infections in the posaconazole group confirms the bioavailability of oral posaconazole in this patient population. Though the emergence of fungi with reduced susceptibility to posaconazole was not detected during the study period, the development of resistance remains a concern with prophylaxis and warrants further investigation.
Our study showed that although posaconazole was as effective as fluconazole in preventing all invasive fungal infections, it was superior in preventing invasive aspergillosis in a high-risk population of patients who had undergone hematopoietic stem-cell transplantation and in reducing the rate of death attributable to invasive fungal infections. Posaconazole should be considered an option for prophylaxis in patients with severe GVHD.
Supported by Schering-Plough Research Institute.
Dr. Ullmann reports receiving grant support from Schering-Plough, advisory-board fees from Astellas Pharma, Basilea Pharmaceutica, Gilead, Merck Sharp & Dohme, Pfizer, and Schering-Plough (including Essex Pharma), and speaking fees from Astellas Pharma, Gilead, Merck Sharp & Dohme, Pfizer, and Schering-Plough (including Essex Pharma); Dr. Lipton, consulting fees or advisory-board fees from Astellas Pharma, Merck, and Pfizer and lecture fees from Merck and Pfizer; Dr. Chandrasekar, lecture fees from Pfizer and Schering-Plough; Dr. Langston, fees for attending a Schering-Plough Research Institute advisory board and support for clinical trials through research support (by contract) to his institution from Schering-Plough; Dr. Greinix, research grants from the European Commission (QLK-CT-2002-01936 from Transeurope and MCRTN-CT-2004-512252 from Transnet), and speaking fees from Therakos; Dr. de Azevedo, lecture fees from Roche and Pfizer; Dr. Reddy, consulting fees or fees for attending an advisory board from Pfizer and Schering-Plough, and lecture fees from Pfizer; Dr. Durrant, consulting fees or fees for attending an advisory board from Amgen, Novartis, and Roche; and Ms. Boparai, Dr. Pedicone, and Dr. Patino, holding stock options in Schering-Plough. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Johannes Gutenberg University, Mainz, Germany (A.J.U.); Princess Margaret Hospital, Toronto (J.H.L.); the Medical College of Wisconsin, Milwaukee (D.H.V.); Harper Hospital, Detroit (P.C.); Emory University, Atlanta (A.L.); University of Nebraska Medical Center, Omaha (S.R.T.); Medical University of Vienna, Vienna (H.G.); Hospital das Clinicas da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil (W.M.A.); University of Florida, Gainesville (V.R.); Schering-Plough Research Institute, Kenilworth, NJ (N.B., L.P., H.P.); and Royal Brisbane Hospital, Brisbane, Australia (S.D.).
Address reprint requests to Dr. Ullmann at the Johannes Gutenberg University, III Medizinische Klinik und Poliklinik, Langenbeckstr. 1, 55101 Mainz, Germany, or at ullmann{at}uni-mainz.de.
References
In addition to the authors, the following persons participated in the Posaconazole Prophylaxis study: Investigators, subinvestigators, and coordinators: King Faisal Specialist Hospital, Riyadh, Saudi Arabia — H. Al-Abdely; Unidade de Transplantacao de Medula ossea-Instituto Portugues de Oncologia Lisbon, Lisbon, Portugal — M. Abecassis; Baylor University Medical Center, Dallas — J. Aguanno; Southwest Texas Methodist Hospital, San Antonio — C. Bachier; Azienda Ospedaliera San Martino, Genoa, Italy — A. Bacigalupo; Ospedale Civile, Pescara, Italy — P. di Bartolomeo; Institut Paoli-Calmettes–Centre de Lutte contre le Cancer, Marseille, France — D. Blaise; University Hospitals of Cleveland, Cleveland — J. Blumer; Institut Gustave Roussy, Villejuif, France — J.-H. Bourhis; Jewish Hospital, Cincinnati — E.R. Broun; HealthONE Presbyterian/St. Luke's Hospital, Denver — M. Brunvard; University of Texas, San Antonio — N. Callander; Hospital Universitario de la Princesa, Madrid — R. de la Camara; Blood and Marrow Transplant Group of Georgia, Atlanta — G. Connaghan; Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada — S. Couban; Oregon Health Sciences University, Portland — P. Curtin; Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands — A.W. Dekker; St. Vincent's Hospital, Darlinghurst, Sydney, Australia — A. Dodds; Hospital das Clinicas de Faculdade de Medicina da Universidade de São Paulo, São Paulo — F.L. Dulley; West Virginia University, Morgantown — S. Ericson; University of South Florida, Tampa — T. Field; Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France — D. Fiere; University of Maryland, Baltimore — M.H. Fox; Liberty Hematology/Oncology, Columbia, SC — K. Godder; Singapore General Hospital, Singapore — Y.-T. Goh; Instituto Mexicano del Seguro Social Hospital de Especialidades, Piso, Mexico — J. González-Llaven; Centre Hospitalier Universitaire Hôpital de la Miletrie, Poitiers, France — F. Guilhot; Tufts–New England Medical Center, Boston — S. Hadley; University of Louisville, Louisville, KY — R. Herzig; Centre Hospitalier Universitaire de Strasbourg, Hôpital de Hautepierre, Strasbourg, France — R. Herbrecht; Massachusetts General Hospital, Boston — P. Hibberd; Medical College of Georgia, Augusta — J. Hiemenz; Akademiska Hospital, Uppsala, Sweden — M. Hoglund; Silesian Medical Academy, Katowice, Poland — J. Holowiecki; Azienda Ospedaliera, Calabria, Italy — P. Iacopino; City of Hope National Medical Center, Duarte, CA — J.I. Ito; Henry Ford Hospital, Detroit — N. Janakiraman; Instituto Alexander Fleming, Buenos Aires — G. Kusminsky; Hospital Maisonneuve-Rosemont, Montreal — M. Laverdiere; University Clinic of Graz, Graz, Austria — W. Linkesch; Karolinska University Hospital Huddinge, Stockholm — P. Ljungman; Centro Medico Nacional, Cuevas, Mexico — M. Lopez-Hernandez; Friends Hall Physician's Office, Philadelphia — K. Mangan; Kansas City Cancer Center, Kansas City, MO — J. McGuirk; Johannes Gutenberg University, Mainz, Germany — P. Meinhardt; Comite Independiente de Etica para Ensayos en Farmacologia Clinica, Buenos Aires — G. Milone; Ospedale la Maddalena, Palermo, Italy — M. Musso; Hospital Nacional Edgardo Rebagliati Matins, Lima, Peru — J. Navarro; Royal London Hospital, London — A. Newland; Children's Hospital of Orange County, Orange, CA — S. Neudorf; Southern Cross Hospital, Cape Town, South Africa — N. Novitzky; National Institute for Hematology and Immunology, Budapest, Hungary — K. Paloczy; Comite de Etica em Pesquisa em Seres Humanos da Universidade Federal do Paraná, Curitiba, Brazil — R. Pasquini; Unidade Transplante de Medula Ossea do Instituto Portugues Oncologia, Ameida, Portugal — P. Pimental; University of Pennsylvania, Philadelphia — D. Porter; University Hospital of Wales, Cardiff — C.H. Poynton; University of Texas M.D. Anderson Cancer Center, Houston — I. Raad; Christiana Care Health System, Newark, DE — J. Reinhardt; Hospital Clinic i Provincial, Barcelona — M. Rovira; Tom Baker Cancer Centre, Calgary, AB, Canada — J. Russell; Universitätsklinik Carl Gustav Carus, Dresden, Germany — U.S. Schuler; Alfred Hospital, Prahran, Australia — A. Schwarer; University Hospital, Oklahoma City — G. Selby; Yale University, New Haven, CT — S. Seropian; University of California, Los Angeles — G. Schiller; Deutsche Klinik für Diagnostik, Wiesbaden, Germany — R. Schwerdtfeger; Rush–Presbyterian–St. Luke's Medical Center, Chicago — D.R. Simpson; Evangelismos General Hospital of Athens, Athens — A. Skandalis; Hamilton Health Services–McMaster Campus, Toronto — F. Smaill; University Hospital Motol, Prague, Czech Republic — J. Stary; Sahlgrenska University Hospital, Göteborg, Sweden — D. Stockelberg; Comite de Etica em Pesquisa do Instituto Nacional do Cancer, Rio de Janeiro — D. Tabak; Hospital Universitario Reina Sofia, Cordova, Spain — A. Torres; University of Minnesota School of Medicine, Minneapolis — J. van Burik; Hospital Universitario de Salamanca, Salamanca, Spain — L. Vazquez; Copenhagen University Hospital, Denmark — L. Vindelov; Institute of Hematology and Blood Transfusion, Prague, Czech Republic — A. Vitek; Helsingin Yliopistollinen Keskussairaala, Meilahden sairaala, Hematologian klinikka, Helsinki — L. Volin; Louisiana State University, Baton Rouge — B.B. Weinberger; Centre Hospitalier Régional et Universitaire de Lille, Hôpital Claude Huriez, Lille, France — I. Yakoub-Agha. Data review committee: CancerCare Manitoba Health Sciences Centre, Winnipeg, Canada — E.J. Bow; University of Arkansas for Medical Sciences, Little Rock — R. Bradsher; University of Virginia, Charlottesville — G. Donowitz; Veterans Affairs Medical Center, Minneapolis — V. Morrison; University of Texas Health Science Center at San Antonio, San Antonio — T.F. Patterson; Veterans Affairs Medical Center, Dallas — S.G. Revankar; Roswell Park Cancer Institute, Buffalo, NY — B.H. Segal; Memorial Sloan-Kettering Cancer Center, New York — K.A. Sepkowitz. Other investigators: Schering-Plough Research Institute, Kenilworth, NJ — T. Brundage, J. Gogate.
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Related Letters:
Posaconazole Prophylaxis in Hematologic Cancer
Weiler S., Bellmann R., Kontoyiannis D. P., Lewis R. E., Krause D. S., van Nieuwkoop C., van Dissel J. T., Ullmann A. J., Chandrasekar P., Patino H., Cornely O. A., Ullmann A. J., Hardalo C.
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N Engl J Med 2007;
356:2214-2218, May 24, 2007.
Correspondence
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