A prospective randomized trial of buffy coat versus CD34-selected autologous bone marrow support in high-risk breast cancer patients receiving high-dose chemotherapy.

High-dose chemotherapy with hematopoietic progenitor cell support is administered increasingly to selected categories of patients with high-risk malignancies. Bone marrow and/or peripheral blood progenitor cells (PBPCs) are commonly cryopreserved with the cryoprotectant dimethyl sulfoxide (DMSO), which can cause a variety of systemic side effects when the graft is thawed and infused. The progenitor cells thought to be responsible for hematopoietic recovery express the CD34 antigen and constitute 1% to 3% of the marrow cells and 0.5% of the PBPC fraction. Transplantation of a CD34(+) graft would markedly reduce the volume and thus the amount of DMSO required, thereby decreasing the infusion-related toxicities. In this study, 89 high-risk breast cancer patients received high-dose therapy and were randomized to receive an autologous CD34(+) marrow graft (Arm A) versus a standard buffy coat fraction (Arm B). After marrow infusion, significant increases in diastolic and systolic blood pressure, as well as significant decreases in heart rate, were documented in Arm B compared to Arm A patients (P < .001). None of the patients in Arm A experienced any clinically serious adverse events associated with the marrow infusion compared to 6% of the Arm B patients. The median time to neutrophil engraftment was 13 days for Arm A and 11 days for Arm B patients (P = .218). The median time to platelet engraftment was 27 days for Arm A and 20 days for Arm B patients (0.051). There were no other significant differences between the two arms of the study with respect to thrombocytopenia-related complications or immune function reconstitution. Additionally, patients on Arm A who received >/=1.2 x 10(6) CD34(+) cells/kg had no delay in platelet recovery (22 days), compared to patients on Arm B, who also received greater than 1.2 x 10(6) CD34(+) cells/kg (20 days) (P = .604). In conclusion, this prospective randomized study demonstrates that breast cancer patients who receive high-dose therapy with autologous CD34(+) marrow support have reduced marrow infusion-related toxicity, comparable time to neutrophil engraftment and immune function recovery posttransplant, and for those who receive <1.2 x 10(6) CD34(+) cells/kg, comparable time to platelet engraftment compared to women who receive buffy coat fractions of marrow.

FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation.

FK506 (Tacrolimus) is an immunosuppressive drug that blocks the activation of antigen-specific T lymphocytes, a major component in the pathogenesis of graft-versus-host disease (GVHD). This study was designed to obtain first estimates of the safety and efficacy of FK506 monotherapy in the prevention of GVHD following HLA-identical sibling marrow transplantation. Additionally, a subset of patients was studied to define the pharmacokinetic profile of FK506. Twenty-seven adult patients with leukemia or myelodysplasia received FK506 starting the day before transplant at a dose of 0.04 mg/kg/d by continuous intravenous infusion. When clinically possible, FK506 was given orally in two divided doses starting at five times the daily intravenous dose. FK506 doses were adjusted to target a steady state or trough blood level between 10 to 30 ng/mL. These patients were followed for 6 months posttransplant. All patients had sustained marrow engraftment. Frequently noted adverse events included reversible renal dysfunction, diarrhea, fever, nausea, vomiting, and headache. Most patients required FK506 dose reductions associated with elevated serum creatinine. Two (7%) patients relapsed, one of whom died of the disease within the 6-month study period. A second patient died due to pulmonary mucor. Whole blood pharmacokinetic parameters indicated a half-life of 18.2 +/- 12.1 hours; volume of distribution of 1.67 +/- 1.02 L/kg; clearance of 71 +/- 34 mL/h/kg; and bioavailability of 32 +/- 24%. Eleven of 27 (41%) patients developed grade II to IV acute GVHD, including 10 grade II and one grade III. Six of 24 (25%) evaluable patients developed chronic GVHD. These data indicate that FK506 monotherapy has activity in preventing GVHD. Further studies of FK506 with lower doses to improve tolerability and in combination with other immunosuppressants to augment efficacy are warranted.

Association of busulfan area under the curve with veno-occlusive disease following BMT.

Busulfan pharmacokinetics, specifically area under the concentration curve (AUC), have been correlated with the occurrence of veno-occlusive disease (VOD) following BMT. To evaluate the risk of VOD, we studied 66 patients who received pharmacotherapeutically monitored busulfan regimens in combination with CY, etoposide (VP16) and/or Ara-C in preparation for BMT. These patients received a total of 16 doses of busulfan dosed as 1 mg/kg/dose q 6 h beginning at 09.00 (n = 39), 18.00 (n = 2), 21.00 (n = 1) or 24.00 (n = 24) h. With the first dose, blood samples were obtained at baseline, every 15-30 min for 2 h, then every 1-2 h for 4 h. Blood was analyzed for busulfan concentration by high performance liquid chromatography and AUC calculated by the trapezoidal rule. Seventeen patients (25.8%) were not evaluable for AUC calculation due to slow absorption and/or elimination: 13 of 27 (48.1%) received the first dose between 18.00-24.00 vs four of 39 (10.2%) patients who received the first dose at 09.00 (P < 0.001). Eighteen of 51 (35.3%) evaluable patients had an AUC > 1500 mumol x min/l; 10 of whom received doses reduced proportionally to achieve an AUC = 1200 mumol x min/l starting with the 10th to 15th dose. Six of 18 (33.3%) patients with an initial AUC > 1500 mumol x min/l developed VOD vs one of 33 (3.0%) patients with an initial AUC < 1500 mumol x min/l (relative risk = 11.1; P = 0.0056). Other pharmacokinetic parameters, age, gender, type of BMT, previous therapy or pre-transplant liver function tests were not predictive of VOD. A higher incidence of VOD occurred in patients receiving BUCY (4 of 10) compared to those receiving BUCYAra-C (1 of 18) or BUCYVP16 (7 of 38), which could not be attributed to increased busulfan exposure in the BUCY patients. Routine pharmacotherapeutic monitoring of busulfan is recommended with further study to evaluate the impact of earlier and greater overall dose reduction in patients with high initial busulfan exposures.

A mathematical model for concentration of blood affecting erythrocyte sedimentation.

The rate at which red blood cells fall in vitro is used as a common clinical test for a number of pathological conditions. But this test becomes unreliable when one finds flaws in the model under consideration and these doubts raise the issue of aggregation of the red blood cells in concentration whose mathematical analysis is relatively unknown. However Huang et al. (Biorheology 8, 157-163, 1971) made some efforts and their model resembles certain moving boundary problems. In the present work the modifications to this model have been suggested so far as the concentration of the blood is concerned, it being one of the important factors to decide ESR (Erythrocyte Sedimentation Rate). In the equation for nutrient concentration, to be more realistic, we have taken account of transfer of nutrient to the tissue from the blood. The exact solution has been obtained using Laplace transform. A finite element technique has been suggested which provides results closer to that of the exact solution. Our results for the blood concentration may be useful for conducting the ESR tests. A special case for an emergent patient when nutrient concentration falls down considerably and glucose is provided to improve the condition, has been shown graphically.

CD34+ progenitor cells from asymptomatic patients are not a major reservoir for human immunodeficiency virus-1.

Controversy exists as to whether hematopoietic progenitor cells are infected by human immunodeficiency virus-1 (HIV-1) in vivo. Most studies have focused on patients with acquired immunodeficiency syndrome (AIDS)/AIDS-related complex, and little data are available on asymptomatic patients with well preserved CD4+ T-cell counts. To determine if CD34+ hematopoietic progenitor cells are infected early in the course of HIV-1 disease, we evaluated 10 asymptomatic HIV-1 seropositive (HIV-1+) patients. The CD34+ cell fraction was purified by a two-step procedure consisting of both affinity chromatography and fluorescence-activated cell sorting that resulted in a median purity of over 99%. Using conventional and nested polymerase chain reaction (PCR) assays, we evaluated the presence and frequency of HIV-1 proviral DNA. Both bone marrow mononuclear cells and CD34- cells from all 10 patients were strongly positive for the HIV-1 pol and/or gag gene sequences. In contrast, sorted CD34+ cells from only two of 10 patients were positive, and the number of copies of proviral DNA in these samples was estimated to be from 2 to 5 per 250,000 cells. To test the in vitro functional capacity of CD34+ progenitors, these cells were assayed in both methylcellulose and long-term stromal culture. We found no significant reduction in the number of colony-forming unit-erythroid (CFU-E), burst-forming unit-erythroid (BFU-E), or colony-forming unit-granulocyte macrophage (CFU-GM) colonies, or in the frequency of cobblestone area forming cells from limit dilution analysis in HIV-1+ asymptomatic patients. Pooled methylcellulose colonies generated from CD34+ cells were HIV-1- in nine of 10 samples. All progeny from long-term cultures of CD34+ cells were HIV-1-. We conclude that the CD34+ hematopoietic progenitor compartment is not infected in the majority of asymptomatic HIV-1+ patients, and that these cells may represent a suitable target for strategies designed to protect developing CD4+ T cells from infection.

Early detection of human cytomegalovirus viremia in bone marrow transplant recipients by DNA amplification.

Surveillance blood cultures for human cytomegalovirus (HCMV) are commonly used to identify the bone marrow transplant (BMT) recipients with the highest risk of serious HCMV disease and for whom early interventional ganciclovir therapy would be beneficial. We monitored 36 allogeneic BMT recipients weekly for the presence of HCMV in the blood from 0 to 100 days posttransplantation. Viable HCMV in leukocytes (WBC) was detected by shell vial and tube culture methods. HCMV DNA in WBC and plasma was detected by PCR and DNA hybridization using primers and a probe from the EcoRI fragment D region of HCMV AD169. A uracil-N-glycosylase-dUTP PCR protocol was used to prevent false-positive results due to amplicon carryover. Seventeen patients had multiple consecutive positive samples containing HCMV DNA in plasma or WBC. In 14 of 17 patients, HCMV was also detected by blood culture. HCMV DNA was detected sporadically in six patients, none of whom had positive cultures. One patient had HCMV viremia detected by WBC culture only. The remaining 12 patients had no positive PCR assays or blood cultures. For the patients with positive blood cultures, PCR detection of HCMV DNA in plasma preceded detection of HCMV in culture by a mean of 8 days and detection in WBC preceded detection in culture by 6 days. HCMV disease (interstitial pneumonia) was documented for two patients with viremia (blood culture and PCR positive) and one patient without viremia (blood culture and PCR negative). The earlier recognition of high-risk patients provided by detection of HCMV DNA in plasma or WBC may improve the efficacy of early interventional antiviral therapy.

Effect of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on hematopoietic regeneration as demonstrated in a nonhuman primate chemotherapy model.

Using a recently developed hepsulfam-induced pancytopenia model in rhesus macaques, we have studied the effects of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on marrow regeneration. Control animals were given hepsulfam (1.5 g/m2 by a single 30-minute intravenous [i.v.] injection, n = 4), while study animals received hepsulfam followed by rhIL-6, rhIL-3, or a combination of rhIL-6 and rhIL-3 (n = 3 per study group). Each cytokine was administered by once-daily subcutaneous (SC) injection (15 micrograms/kg/d) for 3 weeks beginning the day after chemotherapy (days 2 through 22). Mean platelet counts in control animals were < 100,000/microL on days 15 through 24, with 50% of the counts < 50,000/microL and two of four animals requiring platelet transfusion. In the rhIL-6- and rhIL-6/rhIL-3-treated groups, the nadir mean platelet counts were 164,000 +/- 58,700/microL and 162,300 +/- 23,800/microL, respectively, and occurred on day 15. Platelet counts in the rhIL-3-treated group were similar to those in controls. Mean absolute neutrophil counts (ANCs) < 1,000/microL occurred on days 10 through 29 in control animals, days 8 through 15 in rhIL-6-treated animals, and days 6 through 8 and 13 in rhIL-6/rhIL-3-treated animals. The frequency of ANCs < 500/microL was significantly less in the rhIL-6- and rhIL-6/rhIL-3-treated groups versus control groups (2.7 +/- 0.6 and 2.0 +/- 1.0 vs 7.0 +/- 1.4 occurrences, respectively; P < .05). rhIL-3-treated animals had ANCs similar to those in controls; one animal died with septicemia on day 21. Monkeys receiving rhIL-6 were significantly more anemic during the cytokine administration period; however, the anemia resolved by day 24. Coadministration of rhIL-3 and rhIL-6 partially corrected the anemia. The data indicate that rhIL-6 prevents significant thrombocytopenia and shortens the neutropenic period in this chemotherapy model.

Association of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients.

Because the use of fluconazole prophylaxis had been associated with an increased rate of Candida krusei infections at The John Hopkins Oncology Center, early empiric amphotericin B plus flucytosine were given to febrile neutropenic patients colonized by C. krusei. By this practice, the proportion of fungemias attributable to C. krusei was low (12.5%) in patients receiving fluconazole over a 6-month interval. However, Torulopsis (Candida) glabrata assumed a much higher proportion of fungemias (75%) among patients receiving fluconazole. In vitro susceptibility testing combined with this clinical experience suggests that some T. glabrata isolates are not susceptible to fluconazole and can cause breakthrough infections in patients receiving fluconazole.

Cytomegaloviral virus infection in bone marrow transplantation recipients: strategies for prevention and treatment.

Cytomegalovirus is major infectious pathogen following allogeneic bone marrow transplantation. In infected recipients, the virus is generally detected between 4 and 10 weeks after transplantation. Historically, CMV disease developed in 30-40% of seropositive recipients, the predominante manifestation being interstitial pneumonitis, which was generally lethal. Therapeutic interventions are discussed with special reference to the use of antiviral therapy for both treatment and prevention of CMV disease. The strategies developed in the bone marrow transplantation population to treat or prevent the development of CMV disease can be extrapolated to other patients groups who are immunosuppressed and at risk for developing clinical manifestations of CMV infection.

New preparative regimens with diaziquone or cytarabine in combination with busulfan and cyclophosphamide.

Preparative regimens used prior to bone marrow transplantation (BMT) in patients with malignancies must mediate engraftment and eradicate malignant cells without producing significant extramedullary toxicities. The first agents to be tested in BMT preparative regimens, total body irradiation (TBI) and cyclophosphamide (Cy), were ineffective as single agents, but resulted in long-term disease-free survival in some leukemic patients when combined. However, Cy/TBI regimens are associated with significant acute and chronic toxicities as well as technical constraints involving the administration of radiation. Accordingly, a nonradiation-based regimen consisting of Cy and busulfan (Bu) was developed. Regimens using either a 4-day course (BuCy4) or a 2-day course (BuCy2) of Cy have been shown to have significant antileukemic effects. In general, however, BuCy regimens do not appear to result in greater antileukemic activity or lower treatment-related toxicity than Cy/TBI regimens. New preparative regimens are currently being developed to lower the incidence of disease recurrence after BMT. One such regimen consists of BuCy plus etoposide. At our institution, we are currently testing the efficacy and toxicity of regimens in which cytarabine or diaziquone are administered in combination with Bu and Cy. It is hoped that these new preparative regimens will enhance the antileukemic effects of BMT without significantly increasing treatment-related toxicity.

Acyclovir influence on graft versus host disease.

Allogeneic bone marrow transplantation has been used for over two decades as a therapy to treat patients with malignant disease [Thomas et al., 1977; Geller et al., 1989; Clift et al., 1987; Gratwohl et al., 1990; Goldman et al., 1986; Thomas et al., 1986]. High doses of chemotherapy are administered either alone or in combination with total body irradiation in an attempt to eradicate malignant cells. The treatment may be lethal to normal bone marrow function, but this toxicity is overcome by providing bone marrow from an external source. In allogeneic bone marrow transplantation, bone marrow is obtained from an HLA identical family member or unrelated donor. In recent years the use of less well-matched donors has increased, thus expanding the use of this strategy to a larger patient population. The success rate of allogeneic bone marrow transplantation has been greatest in the treatment of haematopoietic malignancies. Patients with acute or chronic leukaemia have a 30-80 percent likelihood of being free of disease at 5 years following transplantation. The success rate depends on the stage of disease at the time of transplantation. Certain nonmalignant diseases have also been treated successfully with allogeneic bone marrow transplantation. These include severe aplastic anaemia, inborn errors of metabolism, and other genetically determined diseases [Storb et al., 1986a, 1991; Lucarelli et al., 1990; Kirkpatrick et al., 1991]. With the availability of effective antiviral therapy, treatment and prophylaxis are available for HSV, CMV, and VZV. Acyclovir has been shown to be effective in treating established infections with HSV and VZV, and in the prophylaxis against HSV, severe CMV infections, and VZV.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits.

PURPOSE: Allogeneic bone marrow transplantation (BMT) is an option for some patients with chronic myelogenous leukemia (CML). We retrospectively evaluated the effect of various risk factors observed at diagnosis and at transplantation on survival, event-free survival (EFS), and relapse after BMT. PATIENTS AND METHODS: Seventy-nine patients with CML in chronic phase (CP) were treated with cyclophosphamide and total body irradiation followed by BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CsA) in most instances or CsA plus the use of lymphocyte-depleted bone marrow (BM). RESULTS: Survival at 4.5 years was 52%. Stratified by age and GVHD prophylaxis, the actuarial survival was 65% (95% confidence interval [CI], 47% to 78%) in patients aged less than 30 years receiving unmanipulated BM, 33% (95% CI, 12% to 56%) in patients greater than or equal to 30 years old receiving unmanipulated BM, and 38% (95% CI, 14% to 63%) in patients greater than or equal to 30 years old receiving lymphocyte-depleted BM. In univariate analysis, patient age (greater than or equal to 30 years) and the use of lymphocyte-depleted BM negatively influenced EFS. When stratified by age and GVHD prophylaxis, however, ABO incompatibility, cytomegalovirus (CMV) seropositivity, and chronic GVHD significantly reduced the probability of EFS. Factors that have been associated with early death in nontransplanted patients (ie, sex, spleen size, blast and platelet counts at presentation) were not predictive of long-term survival outcome after BMT. CONCLUSIONS: The data suggest that (1) BMT should be offered early after diagnosis to all patients with CML in CP who have compatible sibling donors regardless of prognostic factors at presentation, (2) GVHD remains the principal cause of mortality after BMT in patients receiving CsA, and (3) T-cell depletion by the physical separation method of counterflow elutriation (CE) is associated with a significant risk of relapse.

Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole.

BACKGROUND: In early 1990 fluconazole was introduced as a prophylactic antifungal agent after bone marrow transplantation. During the same year Candida krusei emerged as the chief candida pathogen among patients with bone marrow transplants. METHODS: To determine whether there was a correlation between the introduction of fluconazole and the increased incidence of C. krusei, we conducted a retrospective study based on the medical, mycologic, and autopsy records of all adult inpatients who had undergone bone marrow transplantation (n = 296) or who had leukemia (n = 167) at the study center during 1989 and 1990. RESULTS: The 84 patients who received antifungal prophylaxis with fluconazole had a sevenfold greater frequency of C. krusei infection than the 335 patients who did not receive fluconazole (8.3 percent vs. 1.2 percent, P = 0.002), despite having a lower frequency of disseminated C. albicans and C. tropicalis infections (0 vs. 6.0 percent, P = 0.02). Ten of the 11 C. krusei infections were controlled by a combination of amphotericin B and flucytosine. Colonization by C. krusei was found in 40.5 percent of the patients who received fluconazole but in only 16.7 percent of those who did not receive it (P less than 0.0001). Colonization was independently associated with the prophylactic use of both fluconazole (odds ratio, 3.50; P less than 0.001) and norfloxacin (odds ratio, 2.53; P = 0.04). C. krusei was not susceptible to fluconazole in vitro. CONCLUSIONS: In patients at high risk for disseminated candida infections, suppression of bacterial flora and the more common candida pathogens may permit some less pathogenic, but natively resistant candida species, such as C. krusei, to emerge as systemic pathogens.

Oral mucositis after bone marrow transplantation. A marker of treatment toxicity and predictor of hepatic veno-occlusive disease.

Oral mucositis and hepatic veno-occlusive disease (HVOD) are common complications after bone marrow transplantation (BMT). Forty-seven patients were prospectively examined for development of ulcerative oral mucositis (UOM) and HVOD after allogeneic BMT. In 17 patients (36%) UOM developed between 2 days before and 18 days after transplant (median 4 days after BMT). In seven patients (15%) HVOD developed with onset between 3 and 21 days after transplant (median 18 days after BMT). In a time-dependent analysis, in patients given busulfan plus cyclophosphamide or busulfan, etoposide, and cyclophosphamide UOM was 19 times more likely to develop than in patients treated by cyclophosphamide plus total body irradiation or by cyclophosphamide alone (p less than 0.001). Patients in whom UOM developed were 6.5 times more likely to develop HVOD than those in whom UOM did not develop (p less than 0.03). The sensitivity (86%), specificity (73%), and negative predictive value (97%) of UOM to predict HVOD were high, but the positive predictive value (35%) was low. The association of UOM and HVOD support the concept that both are toxic effects of treatment. Patients with hepatic abnormalities but without UOM are unlikely to have HVOD, and other causes of the hepatic dysfunction should be investigated.

The role of immunoglobulin in bone marrow transplantation.

Bone marrow transplantation has proven its value as a therapeutic approach to a variety of human diseases, primarily the hematopoietic malignancies. The major clinical problems preventing successful outcome of marrow transplant have been defined and therapeutic approaches to preventing or treating these complications have led to increased long-term disease survival. Passively administered antibody given as intravenous immunoglobulin has been studied as a therapeutic modality following bone marrow transplantation. Studies have demonstrated the efficacy of immunoglobulin in reducing bacterial infections in the posttransplant period; reducing severe CMV infections in allogeneic marrow transplant recipients who are seronegative for the virus and susceptible to primary infection; reducing mortality from CMV pneumonia in combination with ganciclovir; and reducing acute graft-versus-host disease following allogeneic BMT. In many cases alternate therapeutic strategies offer comparable or greater efficacy (eg, selective CMV-negative blood products for CMV seronegative allogeneic BMT recipients receiving bone marrow from a seronegative donor). However, it is clear that intravenous immunoglobulin has a place in the therapeutic armamentarium of bone marrow transplantation. Future controlled clinical trials are necessary to establish its exact role and to define which preparations and dose schedules provide the greatest therapeutic benefits.

Optic disc edema after bone marrow transplantation. Possible role of cyclosporine toxicity.

Bone marrow transplantation has become widely used in the treatment of aplastic anemia and leukemia. Cyclosporine is used as prophylaxis against graft-versus-host disease. The authors report on eight cases of optic disc edema in patients taking cyclosporine after allogenic bone marrow transplant. Thorough evaluation revealed a possible alternate cause in two cases. In all cases, the optic disc edema resolved after discontinuing or decreasing the cyclosporine. Although cyclosporine has not previously been associated with optic disc edema, it has been implicated as the cause of a variety of neurologic side effects. Bone marrow transplant patients taking cyclosporine should be followed for the development of optic disc edema.

Strategies to prevent or control infections after bone marrow transplants.

Patients receiving bone marrow transplants are at risk of life-threatening infections early post-transplant. This predisposition results from extensive mucosal damage and severe granulocytopenia. Common causes of infection include bacteria and fungi. Infections with opportunistic pathogens occur later and are associated with defects in cellular and/or humoral immunity. The most common sites of infections are the gastrointestinal tract, oropharynx, lung, skin and indwelling vascular catheters. Empiric approaches designed to treat common bacterial and fungal pathogens are generally effective as are measures designed to prevent dissemination of infections. These approaches are also used to prevent fungal infections.

Candida and Aspergillus infections in immunocompromised patients: an overview.

Infection is a major cause of morbidity and mortality in granulocytopenic patients. With the increasing use of aggressive chemotherapy causing prolonged granulocytopenia in patients with cancer, the risk of disseminated fungal infection has increased. Although Candida and Aspergillus species are known to be the most common fungal pathogens responsible for disseminated infection, diagnosis of such infection may be difficult. The use of empiric amphotericin B for presumed disseminated candida infection may reduce morbidity caused by this fungal pathogen; moreover, amphotericin B remains the agent of choice for established candida infection, although fluconazole shows promise. The addition of flucytosine may enhance the efficacy of amphotericin B against Candida. Aspergillus infection is more difficult to treat. Early recognition of invasive aspergillosis and use of high-dose amphotericin B (1.0-1.5 mg/[kg.d]) alone or in combination with flucytosine may reduce associated mortality. More active, less toxic antifungal agents are needed to improve the efficacy of treatment and prophylaxis of disseminated fungal infection.