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Background Patients with neutropenia resulting from chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome are at high risk for difficult-to-treat and often fatal invasive fungal infections.
Methods In this randomized, multicenter study involving evaluators who were unaware of treatment assignments, we compared the efficacy and safety of posaconazole with those of fluconazole or itraconazole as prophylaxis for patients with prolonged neutropenia. Patients received prophylaxis with each cycle of chemotherapy until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for up to 12 weeks, whichever came first. We compared the incidence of proven or probable invasive fungal infections during treatment (the primary end point) between the posaconazole and fluconazole or itraconazole groups; death from any cause and time to death were secondary end points.
Results A total of 304 patients were randomly assigned to receive posaconazole, and 298 patients were randomly assigned to receive fluconazole (240) or itraconazole (58). Proven or probable invasive fungal infections were reported in 7 patients (2%) in the posaconazole group and 25 patients (8%) in the fluconazole or itraconazole group (absolute reduction in the posaconazole group, –6%; 95% confidence interval, –9.7 to –2.5%; P<0.001), fulfilling statistical criteria for superiority. Significantly fewer patients in the posaconazole group had invasive aspergillosis (2 [1%] vs. 20 [7%], P<0.001). Survival was significantly longer among recipients of posaconazole than among recipients of fluconazole or itraconazole (P=0.04). Serious adverse events possibly or probably related to treatment were reported by 19 patients (6%) in the posaconazole group and 6 patients (2%) in the fluconazole or itraconazole group (P=0.01). The most common treatment-related adverse events in both groups were gastrointestinal tract disturbances.
Conclusions In patients undergoing chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome, posaconazole prevented invasive fungal infections more effectively than did either fluconazole or itraconazole and improved overall survival. There were more serious adverse events possibly or probably related to treatment in the posaconazole group. (ClinicalTrials.gov number, NCT00044486
[ClinicalTrials.gov]
.)
Antifungal prophylaxis with fluconazole reduces morbidity and mortality among recipients of allogeneic hematopoietic stem-cell transplants.12,13 Fluconazole prophylaxis is also used in other patient populations with neutropenia, although fewer data support its efficacy in these patients.14 Fluconazole has an acceptable adverse-event profile but lacks efficacy against filamentous fungi, which have become increasingly frequent causes of infection in patients with neutropenia. Itraconazole has a wider spectrum of activity than fluconazole, including activity against aspergillus species. A meta-analysis of trials involving patients with neutropenia and hematologic cancers showed that prophylaxis with itraconazole is more effective than prophylaxis with fluconazole.15 However, the clinical usefulness of itraconazole is limited by the poor tolerability of the cyclodextrin-containing oral solution and the erratic bioavailability of the oral-capsule formulation. Thus, early-generation oral azole agents have limitations related to the spectrum of antifungal activity and tolerability.
Posaconazole is a new-generation oral azole with in vitro activity against a wide spectrum of medically important fungi, including species of candida, aspergillus, Zygomycetes, and fusarium.16,17 Studies of animals and humans have shown clinical activity of posaconazole in the treatment of invasive infection with molds and yeasts.18,19,20,21 We conducted a randomized trial comparing the efficacy and safety of posaconazole with those of fluconazole or itraconazole for the prevention of invasive fungal infections in patients with neutropenia who were undergoing remission-induction chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome.
Methods
Patients
Patients 13 years of age or older were eligible if they had or were anticipated to have neutropenia, with an absolute neutrophil count of 500 cells per cubic millimeter or less, for 7 days or more, resulting from remission-induction chemotherapy for newly diagnosed, or the first relapse of, acute myelogenous leukemia or the myelodysplastic syndrome. To be eligible, patients also had to be able to take oral medications, although a brief period of intravenous therapy (less than 4 days) was permitted at entry into the trial. Exclusion criteria were an invasive fungal infection within the previous 30 days, clinically significant hepatic or renal dysfunction, an abnormal QT interval corrected for heart rate (QTc interval), a baseline Eastern Cooperative Oncology Group performance status score of more than 2 (in bed more than half of the day), a history of hypersensitivity or idiosyncratic reactions to azoles, or a requirement for medications with a potential for adverse interactions with azoles. Before enrollment, written informed consent was obtained from each patient or the patient's parent or legal guardian, and the study was approved by the institutional review board or ethics committee at each participating center.
Study Design
The study was designed by academic authors and employees of the sponsor, in collaboration with an independent expert panel. The sponsor analyzed the data, and the academic authors and one author who is an employee of the sponsor prepared the manuscript. The academic authors had full access to the primary data and to the results of their analyses and were given full independence in decisions concerning the reporting of results and the content of the manuscript. The academic authors vouch for the accuracy and completeness of the data and data analyses.
In this prospective, randomized trial involving evaluators who were unaware of the treatment assignments, we compared posaconazole with fluconazole or itraconazole for the prevention of invasive fungal infections. On the basis of local practices, investigators selected either fluconazole or itraconazole at the start of the study for use throughout the study. Patients were randomly assigned, in a 1:1 ratio, to receive posaconazole or either fluconazole or itraconazole. Prophylaxis was administered with each chemotherapy cycle, starting either 24 hours after the last anthracycline dose or, in patients not receiving an anthracycline-based regimen, on the first day of chemotherapy. Prophylaxis was continued until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for up to 12 weeks from randomization, whichever came first. Patients were followed for 100 days after randomization and for 30 days after the last dose of the study drug administered during the last chemotherapy cycle. An independent data review committee of infectious disease experts who were unaware of the treatment assignments reviewed and classified all cases of fungal infection as proven, probable, or possible, according to the consensus criteria of the European Organisation for the Research and Treatment of Cancer and the Mycoses Study Group.22
Administration of the Study Drug
Study patients received 200 mg of posaconazole in an oral suspension three times daily, 400 mg of fluconazole (Diflucan, Pfizer) in an oral suspension once daily, or 200 mg of itraconazole (Sporanox, Janssen) in an oral solution twice daily. Patients who were unable to tolerate the oral study drug could receive intravenous prophylaxis at the same dose for 3 days or less per chemotherapy cycle. In the fluconazole or itraconazole group, the intravenous prophylaxis was the assigned study drug; in the posaconazole group, it was amphotericin B deoxycholate (Fungizone [Apothecon Pharmaceuticals] or a generic form, 0.3 to 0.5 mg per kilogram of body weight daily). Patients in either group were permitted to receive amphotericin B or another systemic agent as empirical antifungal therapy for a suspected invasive fungal infection.
Assessment of Efficacy
All patients underwent comprehensive evaluations for the presence of an invasive fungal infection at the beginning and the end of prophylaxis, 30 days after the last dose of the study drug had been administered, and 100 days after randomization. At any time during the treatment phase — defined as the period from randomization to 7 days after the last dose of the study drug had been administered during the last chemotherapy cycle — if a patient had any sign or symptom of infection, including fever, a complete clinical and mycologic evaluation was performed. Surveillance blood specimens were collected twice weekly for the aspergillus galactomannan assay (Platelia aspergillus enzyme-linked immunosorbent assay, Bio-Rad Laboratories). In vitro susceptibility testing of fungal isolates was performed by staff at a central laboratory, according to the methods of the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards).23,24 We measured the steady-state plasma concentrations of the study drug and calculated the arithmetic means using liquid chromatography with a mass-spectrometric detection method for measurements of posaconazole25 and fluconazole26 levels and a high-performance chromatographic method for itraconazole.27
Primary Analysis
The primary efficacy end point was the incidence of proven or probable invasive fungal infection during the treatment phase, as adjudicated by an expert panel whose members were unaware of the treatment assignments, according to consensus criteria of the European Organisation for the Research and Treatment of Cancer and the Mycoses Study Group.
Secondary Analyses
Secondary end points included the incidence of invasive aspergillosis, the incidence of invasive fungal infection within 100 days after randomization, and treatment success (vs. failure) during the treatment phase. Treatment failure was defined as the occurrence of a proven or probable invasive fungal infection; receipt of an intravenous study drug for 4 consecutive days or more or 10 days in total; receipt of any other systemic antifungal agent for 4 days or more for suspected invasive fungal infection; the occurrence of an adverse event possibly or probably related to the study treatment, resulting in the discontinuation of treatment; or withdrawal from the study with no additional follow-up. Survival was evaluated 100 days after randomization, and analyses were conducted for overall survival, time to death from any cause, time to death related to fungal infection, and survival without proven or probable invasive fungal infection. Time to invasive fungal infection and time to first use of empirical antifungal therapy were also assessed.
Assessment of Safety
Adverse events were recorded from randomization until day 30 after the last dose of the study drug had been administered during the last chemotherapy cycle. These events were classified according to the Common Toxicity Criteria grading system of the National Cancer Institute.28
Statistical Analysis
The primary efficacy analysis was based on the intention-to-treat approach, with the use of data from all patients who underwent randomization. First, the noninferiority of posaconazole as compared with fluconazole or itraconazole therapy was assessed. For our study, the incidence of proven or probable invasive fungal infection was assumed to be 8% or less with fluconazole or itraconazole prophylaxis.1 Therefore, using a cutoff level of significance of 4.87% for the final analysis (in order to account for the interim analysis), we calculated that if the upper bound of the 95.13% confidence interval (hereafter called the 95% CI) for the difference between the incidence of proven or probable fungal infection for posaconazole and that for fluconazole or itraconazole was less than 4%, noninferiority would be demonstrated, and the superiority of posaconazole over fluconazole or itraconazole therapy could be assessed. The superiority of posaconazole would be established if the upper bound of the same 95% CI was negative. This two-step analysis allowed for an overall type 1 error rate of 0.05. We used the Kaplan–Meier method to evaluate time to death from any cause, time to death related to fungal infection, time to proven or probable fungal infection, time to first use of empirical antifungal therapy, and survival free from proven or probable invasive fungal infection. The survival benefit was assessed with the chi-square and log-rank tests. All analyses except the noninferiority analysis were based on two-sided P values, with a two-sided P value of less than 0.05 considered to indicate statistical significance. The numbers of patients who would need to be treated to prevent one fungal infection and one death (numbers needed to treat) were calculated as described previously.29
Results
Patient Characteristics
The study was conducted from August 2002 through April 2005 at 89 centers worldwide. A total of 602 patients were randomly assigned to treatment: 304 patients to receive posaconazole and 298 patients to receive fluconazole (240) or itraconazole (58). The two groups had similar characteristics (Table 1).
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Proven or probable invasive fungal infections occurred during the treatment phase in 7 of the 304 patients (2%) in the posaconazole group and in 25 of the 298 patients (8%) in the fluconazole or itraconazole group (absolute reduction in the posaconazole group, –6%; 95% CI, –9.7 to –2.5; P<0.001). The superiority of posaconazole over fluconazole was confirmed in a post hoc analysis limited to centers at which fluconazole was used as the comparison study drug (see the Supplementary Appendix, available with the full text of this article at www.nejm.org). We estimated that 16 patients would need to be treated with posaconazole, as compared with fluconazole or itraconazole, in order to prevent one invasive fungal infection.
During the 100-day period after randomization, 14 of 304 patients (5%) in the posaconazole group had a proven or probable fungal infection, as compared with 33 of 298 patients (11%) in the fluconazole or itraconazole group (P=0.003). The mean (±SD) time to invasive fungal infection was 41±26 days in the posaconazole group and 25±26 days in the fluconazole or itraconazole group. Kaplan–Meier analysis of the time to invasive fungal infection showed a significant difference in favor of posaconazole (P=0.003) (Figure 1A). Table 2 lists the causative pathogens of invasive fungal infections that occurred during the treatment phase; aspergillus was the most common. There were significantly fewer cases of aspergillosis associated with posaconazole prophylaxis than with fluconazole or itraconazole prophylaxis (2 [1%] vs. 20 [7%], P<0.001).
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Rates of clinical success or failure and the reasons for clinical failure are listed in Table 3. Of the 304 patients in the posaconazole group, 81 (27%) received an empirical antifungal agent during the treatment phase, as did 112 of the 298 patients (38%) in the fluconazole or itraconazole group (P=0.004). The analysis of the time to first use of empirical antifungal therapy during the 100-day period revealed a significant difference in favor of posaconazole over fluconazole or itraconazole (P=0.02).
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Of the 304 patients in the posaconazole group, 49 (16%) died during the study period, as did 67 of 298 patients (22%) in the fluconazole or itraconazole group (P=0.048); 44 patients (14%) and 64 patients (21%), respectively, died within 100 days. Kaplan–Meier analysis of the time to death from any cause at the end of the 100-day period after randomization showed a significant survival benefit in favor of posaconazole over fluconazole or itraconazole (P=0.04) (Figure 1B). The relative reduction in mortality at day 100 in the posaconazole group, as compared with the fluconazole or itraconazole group, was 33%. The estimated number needed to treat with posaconazole, as compared with fluconazole or itraconazole, to prevent one death was 14 patients.
Of the 116 deaths that occurred during the study, 21 were considered to be related to fungal infection: 5 (2%) that occurred in the posaconazole group and 16 (5%) in the fluconazole or itraconazole group (P=0.01). Other causes of death were intercurrent illnesses in 20 patients (7%) in the posaconazole group and 30 patients (10%) in the fluconazole or itraconazole group and leukemia-related complications in 24 patients (8%) and 21 patients (7%), respectively. The analysis of the time to invasive fungal infection or death also showed a significant benefit in favor of posaconazole (P=0.01) (Figure 1C).
Safety Analysis
All 602 patients in the intention-to-treat population were included in the safety evaluation. The incidence of treatment-related adverse events was similar among the treatment groups (Table 4 and the Supplementary Appendix). Treatment-related prolongation of the QT or QTc interval was reported in 12 of the 304 patients (4%) receiving posaconazole, 5 of the 240 patients (2%) receiving fluconazole, and 4 of the 58 patients (7%) receiving itraconazole; the prolongation was considered to be serious in 1 patient in the posaconazole group. Other serious treatment-related cardiac events included atrial fibrillation, a decreased ejection fraction, and torsades de pointes, each occurring in one patient receiving posaconazole. Serious adverse events possibly or probably related to treatment were reported by 19 patients (6%) in the posaconazole group and 6 patients (2%) in the fluconazole or itraconazole group (P=0.01).
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Among patients from whom blood was collected for pharmacokinetic analysis, the mean plasma concentration of the study drug was 583±381 ng per milliliter in 215 patients receiving posaconazole, 13,577±7104 ng per milliliter in 172 patients receiving fluconazole, and 785±429 ng per milliliter in 33 patients receiving itraconazole.
Discussion
Our randomized clinical trial involving more than 600 high-risk patients showed that, as compared with fluconazole or itraconazole prophylaxis, posaconazole effectively prevented invasive fungal infections during successive cycles of chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome. Furthermore, mortality from any cause was significantly lower in the posaconazole group than in the fluconazole or itraconazole group, indicating that the survival of patients with acute leukemia can be improved with the use of antifungal prophylaxis during remission-induction chemotherapy.
Before our study, significant reductions in the incidence of invasive fungal infections and in mortality from any cause had been shown with fluconazole prophylaxis only in patients undergoing hematopoietic stem-cell transplantation.13 Fluconazole prophylaxis has become the standard of care in this setting14 and has been used in patients undergoing remission induction for acute leukemia, even though advantages with respect to morbidity or mortality have not been proved and there is no consensus among clinicians regarding its use in these high-risk patients.30 Although the use of itraconazole seems to reduce the incidence of proven invasive fungal infections,31 it does not confer a significant survival benefit over fluconazole in large trials, and it has been associated with greater toxicity.32,33
When we designed our trial, both fluconazole and itraconazole had been shown to be more effective than placebo in preventing fungal infections, so they had been routinely used as the standards of care. However, no benefit of one azole over the other had been clearly established,32,33 nor has one been revealed by more recent data.34 Therefore, given the increased risk of invasive fungal infection among patients undergoing cytotoxic chemotherapy and the benefit seen among those undergoing hematopoietic stem-cell transplantation,13 we believed that a placebo-controlled trial was not feasible. In our study, the investigators used their preferred standard azole as the comparison drug. The different dosing schedules of the three study drugs and the logistics of their intravenous alternatives precluded a double-blind design. To minimize the possibility of bias, an independent data review committee, whose members were unaware of the treatment assignments, examined all suspected potential invasive fungal infections in order to adjudicate them as proven or probable, according to international consensus criteria.22
A patient's ability to swallow is rarely compromised immediately after induction chemotherapy, but oral intake may decrease owing to mucositis later in the course of treatment. Few patients in this trial were unable to tolerate oral medications at entry or during the course of treatment (Table 1). The study is therefore limited in its ability to provide data on the usefulness of azole prophylaxis in patients who have severe mucositis and are unable to eat or take oral medication.
The difference in the incidence of breakthrough fungal infections during the treatment phase resulted predominantly from the significantly lower incidence of invasive aspergillosis in the posaconazole group than in the fluconazole or itraconazole group, which was consistent with the superior antifungal activity of posaconazole against aspergillus species. However, the incidence of aspergillosis among patients who had received itraconazole prophylaxis was unexpectedly high and was similar to that in the fluconazole group.
In our trial, throat and stool surveillance cultures were collected on a weekly basis. The reduction in the incidence of fungal colonization after prophylaxis was similar for the three study drugs. Furthermore, there was no apparent trend toward selection of azole-resistant colonizing yeast strains, although further observation is warranted.
The value of less rigorous end points — such as the time to antifungal treatment or mortality attributable to fungal infection — remains an issue of debate.14 As compared with fluconazole or itraconazole, however, posaconazole prophylaxis resulted in a significant delay of empirical antifungal treatment and a significantly improved rate of survival without proven or probable invasive fungal infection. Since the numbers of patients needed to treat to prevent one invasive fungal infection or one death are low (16 and 14, respectively), the benefit of posaconazole prophylaxis seems to outweigh the risks of toxic effects and selection of resistant organisms, which are inherent in prophylactic drug regimens, and to justify the cost.
Adverse events during treatment were similar with posaconazole and fluconazole. As expected, patients treated with itraconazole had gastrointestinal symptoms more frequently than did patients receiving fluconazole or posaconazole. Although certain serious adverse events — including a decreased ejection fraction, prolongation of the QT or QTc interval, and torsades de pointes — were each reported in one patient receiving posaconazole, the open nature of our study and the prevailing perception of fluconazole as a safe drug cannot be ruled out as an influence in determining any possible relation with posaconazole.
In summary, prophylaxis with posaconazole was superior to prophylaxis with fluconazole or itraconazole in the prevention of proven or probable invasive fungal infection and resulted in lower mortality from any cause and longer survival free from proven or probable invasive fungal infection. Thus, posaconazole prophylaxis may be a useful addition to the standard of care for patients with acute myelogenous leukemia or myelodysplastic syndromes who are undergoing remission-induction chemotherapy.
The study was funded by the Schering-Plough Research Institute.
Dr. Cornely reports receiving grant support from Astellas Pharma, Basilea Pharmaceutica, Gilead, Merck, Pfizer, Schering-Plough, and Vicuron Pharmaceuticals; receiving fees for serving as an adviser to Astellas Pharma, Basilea Pharmaceutica, Gilead, Merck, Nektar Therapeutics, Pfizer, Schering-Plough, Vicuron Pharmaceuticals, and Zeneus Pharma; and serving on a speakers' bureau for Astellas Pharma, Gilead, Merck, Pfizer, and Schering-Plough. Dr. Maertens reports receiving lecture fees and consulting fees or advisory board fees from Astellas Pharma, Biogen, Bio-Rad, Gilead, Merck, Pfizer, Schering-Plough, and Zeneus Pharma. Dr. Winston reports receiving grant support from Astellas Pharma, Schering-Plough, and ViroPharma. Dr. Perfect reports serving as a consultant and receiving honoraria from Astellas Pharma, Enzon, Merck, Pfizer, Pliva, and Schering-Plough and receiving grant support from Schering-Plough and Merck. Dr. Ullmann reports receiving grant support from Schering-Plough; fees for serving as an adviser to Astellas Pharma, Basilea Pharmaceutica, Gilead, Merck, Pfizer, and Schering-Plough; and lecture fees from Astellas Pharma, Gilead, Merck, Pfizer, and Schering-Plough. Dr. Walsh reports having Cooperative Research and Development Agreements with Astellas and with Vicuron (now owned by Pfizer). Drs. Hardalo, Suresh, and Angulo-Gonzalez report being employees of the Schering-Plough Research Institute, and Drs. Hardalo and Angulo-Gonzalez report owning stock options in Schering-Plough. No other potential conflict of interest relevant to this article was reported.
We thank the members of the independent expert panel who helped design the study: Drs. Coleman Rotstein, Eric J. Bow, Jeffrey H. Lipton, Michael Laverdiere, and Jean-Pierre Moquin.
Source Information
From the University of Cologne, Cologne, Germany (O.A.C.); University Hospital Gasthuisberg, Leuven, Belgium (J.M.); University of California, Los Angeles, (D.J.W.); Duke University Medical Center, Durham, NC (J.P.); University of Mainz, Mainz, Germany (A.J.U.); National Cancer Institute, Bethesda, MD (T.J.W.); Weill Cornell Medical College, New York (D.H.); Silesian Medical University, Katowice, Poland (J.H.); Sahlgrenska University Hospital, Göteborg, Sweden (D.S.); Singapore General Hospital, Singapore, Singapore (Y.-T.G.); University of Pisa, Pisa, Italy (M.P.); and Schering-Plough Research Institute, Kenilworth, NJ (C.H., R.S., D.A.-G.).
Address reprint requests to Dr. Cornely at the Klinik I für Innere Medizin, Klinikum der Universität zu Köln, 50924 Cologne, Germany, or at oliver.cornely{at}uni-koeln.de.
References
The following personnel participated in the clinical trial: Investigators — Peripheral General Hospital of Athens "G. Gennimatas," Athens — N. Anagnostopoulos; Robert-Bosch-Krankenhaus, Stuttgart, Germany — W. Aulitzky; Cleveland Clinic Foundation, Cleveland — R. Avery; Hospital das Clinicas da Universidade de Marilia, Marilia, São Paulo — R. Baldissera; University of California, San Diego — A. Bashey; Kansas University Medical Center, Kansas City — D. Bodensteiner; Health Sciences Centre, Winnipeg, MB, Canada — E.J. Bow; Westmead Hospital, Westmead, Sydney — K. Bradstock; HealthONE Presbyterian and St. Luke's Hospital, Denver — M. Brunvand; Hospital Instituto Ecuatoriano de Seguridad Social–Carlos Andrade Marin, Quito, Ecuador — C. Canizares; Instituto Portugues de Oncologia-Lisboa, Lisbon, Portugal — S. Carvalho; Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru — L. Casanova; Sanatorio Parque, Rosario, Sante Fe, Argentina — I. Cerutti; Harper Hospital/Wayne State University, Detroit — P. Chandrasekar; Hackensack University Medical Center, Hackensack, NJ — C. Cicogna; Royal North Shore Hospital, St. Leonards, Sydney — L. Coyle; Oregon Health Sciences University, Portland — P. Curtin; Academisch Ziekenhuis Groningen, Groningen, the Netherlands — S.M.G.J. Daenen; Centre Hospitalier Universitaire de Lille, Hôpital Claude Huriez, Lille, France — S. De Botton; Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands — A.W. Dekker; West Virginia University, Morgantown — S. Ericson; University Hospital Olomouc, Olomouc, Czech Republic — E. Faber; Instituto Oncologico Nacional de Panama, Panama City, Panama — E. Fanilla; University Clinic of Innsbruck, Innsbruck, Austria — G.A. Gastl; Instituto Guatemalteco de Seguridad Social, Guatemala City, Guatemala — F. Godinez; Hospital Universitario Dr. J.E. Gonzalez, Monterrey, Nuevo Leon, Mexico — D. Gomez-Almaguer; University of Kentucky, Lexington — R. Greenberg; University of South Florida, H. Lee Moffitt Cancer Center, Tampa — J. Greene; Tufts–New England Medical Center, Boston — S. Hadley; Hospital Nacional Guillermo Almenara Irigoyen, Lima, Peru — C. Herrera; Medical College of Georgia, Augusta — J. Hiemenz; Akademiska Hospital, Uppsala, Sweden — M. Hoglund; Glasgow Royal Infirmary, Glasgow, United Kingdom — T. Holyoake; Copenhagen University Hospital, Rigshospitalet, Copenhagen East, Denmark — D. Hovgaard; University of Michigan Medical Center, Ann Arbor — A. Jakubowiak; Instituto de Cancerologia Clinica las Americas, Medellin, Colombia — A. Karduss; University Clinic of Vienna, Vienna — P. Knoebl; Bone Marrow Transplant Center–Presidio Ospedaliero R. Binaghi, Cagliari, Italy — G. La Nasa; Hospital 12 de Octubre, Madrid — J.J. Lahuerta; Emory University, Winship Cancer Institute, Atlanta — A. Langston; Hôpital Maisonneuve-Rosemont, Montreal — M. Laverdiere; Princess Margaret Hospital–University Health Network, Toronto — J.H. Lipton; Karolinska University Hospital Huddinge, Stockholm — P. Ljungman; Hospital Universitario Ramón y Cajal, Madrid — J. Lopez; Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico — X. Lopez-Karpovitch; Hospital Solca Guayaquil, Guayaquil, Ecuador — B. Maldonado; Scripps Clinic, La Jolla, CA — J. Mason; Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France — M. Michallet; Ospidaliero Ferrarotto, Catania, Italy — G. Milone; Fundaleu Instituto de Transplante de Medula, Buenos Aires — G. Milone; Instituto de Transplante de Medula Osea, La Plata, Argentina — J. Milone; Hôpital du Sacre-Coeur, Montreal — J.-P. Moquin; Loyola University Medical Center, Maywood, IL — K. Mullane; Ospedale la Maddalena, Palermo, Italy — M. Musso; Ospedale Niguarda-Ca Grande Milano, Milan — A. Nosari; Hospital Universitario Clementino Fraga Filho, Rio de Janeiro — M. Nucci; University Hospital of Wales, Cardiff, United Kingdom — C. Poynton; University of Texas M.D. Anderson Cancer Center, Houston — I. Raad; University of Florida College of Medicine, Gainesville — V. Reddy; Christiana Care Health System, Newark, DE — J. Reinhardt; Hospital Central de las Fuerzas Armadas y Policia Nacional, Santo Domingo, Dominican Republic — C. Rodriguez; Hamilton Health Sciences Corporation–McMaster, Hamilton, ON, Canada — C. Rotstein; Hospital Clinic i Provincial, Barcelona — M. Rovira; Hospital Luis Calvo Mackenna, Santiago, Chile — M.E. Santolaya; University of Pennsylvania, Philadelphia — M. Schuster; Alfred Hospital, Prahran, Victoria, Australia — A. Schwarer; Cruz Roja Ecuatoriana, Quito, Ecuador — J. Sghirla; Pretoria Academic Hospital–Oncology, Pretoria, South Africa — C. Slabber; Hospital Amaral Carvalho, Jau, São Paulo — M. Souza; Hospital de Clinicals da Universidade Federal do Parana, Curitiba, Parana, Brazil — F. Telles; Louisiana State University Medical Center, Shreveport — F. Turturro; Hospital Rosales, San Salvador, El Salvador — H. Valencia; University of Minnesota School of Medicine, Minneapolis — J.-A. van Burik; Baylor University Medical Center, Dallas — E. Vance; Hospital Universitario de Salamanca, Salamanca, Spain — L. Vazquez; Centro Medico Nacional "La Raza" Hospital de Especialidades, Mexico City, Mexico — J. Vela-Ojeda; University District Hospital, San Juan, Puerto Rico — E. Velez-Garcia; Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia — M. Wolf; Peripheral University General Hospital of Patras, Patras, Greece — N. Zoumbos; Data Review Committee — National Cancer Institute, Bethesda, MD — T.J. Walsh, M. Roden; Georgetown University Hospital, Washington, DC — C.E. Gonzales; Dallas Veterans Affairs Medical Center, Dallas — S. Revankar.
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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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