Oren, I., Rowe, J. M., Sprecher, H., Tamir, A., Benyamini, N., Akria, L., . . . Dann, E. J. (2006). A prospective randomized trial of itraconazole vs fluconazole for the prevention of fungal infections in patients with acute leukemia and hematopoietic stem cell transplant recipients. Bone Marrow Transplantation, 38, 127–134.

To determine whether itraconazole is superior to fluconazole in the prevention of invasive fungal infections, particularly invasive aspergillosis, in hematopoietic stem cell transplant (HSCT) recipients and patients with acute leukemia (AL).

Patients were stratified to either high or low risk based on type of therapy or disease.  High risk included patients undergoing allogeneic HSCT or patients with relapsed/resistant AL.  Low risk included patients undergoing autologous HSCT or newly diagnosed patients with AL receiving induction.  Patients were then randomized to receive either itraconazole or fluconazole prophylaxis in each risk stratum, using a random number generator, in blocks of four.  Intravenous (IV) preparations were used only if the patient could not tolerate oral medications and was switched back to oral as soon as the patient tolerated oral medications.  Antifungal prophylaxis was continued until the resolution of neutropenia, for a maximum of eight weeks. Antibacterial prophylaxis was not administered.  Fluconazole was given in a dose of 400 mg once daily, and itraconazole was given at 200 mg twice daily.

• One hundred ninety-five patients were included.
• Median patient age was 49 (range 18–73) in the fluconazole arm and 50 (range 17–75) in the itraconazole arm.
• In the fluconazole arm, 56% of patients were male and 43% were female.  In the intraconazole arm, 63% of patients were male and 33% were female.
• Patients received autologous HSCT (56% in the fluconazole group, 52% in the itraconazole group), allogeneic HSCT (19% in the fluconazole group, 18% in the itraconazole group), haploidentical HSCT (3% in the fluconazole group, 4% in the itraconazole group), or no transplant (21% in the fluconazole group, 22% in the itraconazole group).  Per the above criteria, patients were considered low-risk (74% in the fluconazole group, 72% in the itraconazole group) or high-risk (25% in the fluconazole group, 24% in the itraconazole group).  Mean duration of neutropenia for high-risk patients was 13.4 days (SD = 6.1) in the fluconazole arm and 15.4 days (SD = 9.7) in the itraconazole arm.  Mean duration of neutropenia in low-risk patients was 10.7 days (SD = 6.4) in the fluconazole arm and 10.8 days (SD = 7.0) in the itraconazole arm.  Patients receiving group 1 chemotherapy (consisting of standard induction and consolidation regimens for AL and chemotherapy-based conditioning regimens for autologous bone marrow transplant [BMT]) included 77% in the fluconazole arm and 76% in the itraconazole arm.  Patients receiving group 2 chemotherapy (consisting of total body irradiation-based conditioning regimens for autologous or allogeneic BMT) included 10% in the fluconazole arm and 8% in the itraconazole arm.  Patients receiving group 3 chemotherapy (consisting of reduced intensity or T cell depleted conditioning regimens, which included anti-thymocyte globulin and/or fludarabine for allogeneic or haploidentical BMT) included 12% in both groups.

• Single site  
• Inpatient 
• This study was conducted at a single hematology and BMT center, comprising a 15-bed BMT unit and an 11-bed hematology unit, on hospitalized patients in these two units, in a protected environment using a high-efficiency particulate absorption filtration system.

Patients were undergoing the active treatment phase of care.

This was a randomized trial comparing oral and IV itraconazole with oral and IV fluconazole.

Toxicity was graded from 0 to 4 according to the National Cancer Institute Common Toxicity Criteria.

Itraconazole was not found to be more effective than fluconazole in preventing invasive fungal infections (IFIs) in neutropenic patients after chemotherapy for AL or after HSCT.  Both drugs were successful in preventing invasive candidal infections.  Invasive aspergillosis (IA) was not as decreased in the itraconazole arm as expected, although the mortality from IA  was lower in the itraconazole arm.

Fungal prophylaxis is important in patients with AL and those undergoing HSCT.  Both itraconazole and fluconazole seem to be effective in preventing IFIs and IA, but neither appeared to be superior to the other in this study.  Itraconazole seems to be less well tolerated in the oral form due to gastrointestinal side effects, although none were significant.  Neither drug completely prevented IA, which causes significant morbidity and mortality; therefore, more research is needed for drugs that have better prophylaxis against IA.

This was a nonblinded study leading to bias in the assessment of efficacy and adverse events, as well as the evaluation of response and causes for adverse events.  There was a lack of itraconazole blood measurement.  Antifungal prophylaxis was only used during the early period at risk (during the neutropenic period), the high-risk patients, especially, are at risk for significantly more time than just the neutropenic period.  Antifungal prophylaxis should be continued for an extended period after engraftment, especially in patients undergoing allogeneic HSCT.  This information is useful for most hematologic malignancy but may not be generalizable for patients with solid tumors.

Education related to antifungal prophylaxis and the necessity of taking these medications is important.  Nurses can educate about the expected side effects, especially the GI side effects of itraconazole when given orally.