Practice guidelines for lipid-based amphotericin B in stem cell transplant recipients.

OBJECTIVE: To provide clinicians who practice in the stem cell transplantation (SCT) setting with practical guidelines for the use of lipid-based amphotericin B (AmB) formulations in SCT patients who have documented or probable invasive fungal infections, are experiencing neutropenic fever, or require secondary prophylaxis for fungal infections. DATA SOURCES: Recommendations are based on the results of a two-day consensus meeting that convened clinicians versed in the management of infectious complications in patients undergoing SCT. This meeting, which was held October 21-23, 1998, in Orlando, Florida, was sponsored by an educational grant from The Liposome Company. In addition, primary articles were identified by MEDLINE search (1980-December 1999) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS: Immunocompromised patients, particularly patients undergoing high-dose chemotherapy with SCT, experience a high degree of morbidity and mortality from invasive fungal infections. Historically, treatment for such infections with conventional AmB had been limited primarily by its associated nephrotoxicity. Lipid-based formulations of AmB have helped to advance the management of invasive fungal infections in the SCT population by offering a treatment alternative that allows for administration of adequate amounts of active drug to produce clinical and mycologic responses, compared with conventional AmB, in a delivery system that is less nephrotoxic. Unfortunately, these agents are relatively expensive. Therefore, patients who are candidates for lipid-based products must be selected carefully. CONCLUSIONS: Practical guidelines are provided for the use of lipid-based AmB formulations in SCT patients who have documented or probable invasive fungal infections, are experiencing neutropenic fever, or require secondary prophylaxis for fungal infections.

Lipid formulations of amphotericin B.

The incidence of systemic fungal infections, especially in immunocompromised patients, has continued to increase during the past few decades. Treatment with conventional amphotericin B has been the standard care for the majority of patients with invasive fungal infections, despite its associated toxicity. Three lipid formulations of amphotericin B have now been approved for use in the United States. The pharmacology, pharmacokinetics, clinical experience, toxicity, dosing strategies, and cost of these three preparations--amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B--were reviewed in detail in this chapter. The clinical data indicate that lipid formulations of amphotericin B represent an important therapeutic modality in the management of invasive fungal infections.

A randomized, double-blind trial of filgrastim (granulocyte colony-stimulating factor) versus placebo following allogeneic blood stem cell transplantation.

Blood stem cell transplantation (BSCT) results in rapid hematopoietic recovery in both the allogeneic and autologous transplant settings. Because of the large numbers of progenitor cells in mobilized blood, the administration of growth factors after transplantation may not provide further acceleration of hematopoietic recovery. A randomized, double-blind, placebo-controlled study was performed to determine the effects of filgrastim (granulocyte colony-stimulating factor; G-CSF) administration on hematopoietic recovery after allogeneic BSCT. Fifty-four patients with hematologic malignancies undergoing a related, HLA-matched allogeneic BSCT were randomly assigned to receive daily filgrastim at 10 microg/kg or placebo starting on the day of transplantation. A minimum of 3 x 10(6) CD34(+) cells/kg in the allograft was required for transplantation. All patients received a standard preparative regimen and a standard regimen for the prevention of graft-versus-host disease (GVHD). The median time to achieve an absolute neutrophil count greater than 0.5 x 10(9)/L was 11 days (range, 9-20 days) for patients who received filgrastim compared with 15 days (range, 10-22 days) for patients who received placebo (P =.0082). The median time to achieve a platelet count greater than 20 x 10(9)/L was 13 days (range, 8-35 days) for patients who received filgrastim compared with 15.5 days (range, 8-42 days) for patients who received placebo (P =.79). There were no significant differences for red blood cell transfusion independence, the incidence of acute GVHD, or 100-day mortality between the groups. The administration of filgrastim appears to be a safe and effective supportive-care measure following allogeneic BSCT.

High-dose chemotherapy with autologous stem cell rescue in the outpatient setting.

Intensive outpatient care is rapidly becoming the primary mode of care for selected patients undergoing high-dose chemotherapy with autologous peripheral blood stem cell (PBSC) transplantation. Although the traditional inpatient model of care may still be necessary for high-risk patients, published data suggest that outpatient care is safe and feasible during or after administration of high-dose chemotherapy and autologous PBSC transplant. Blood and marrow transplant (BMT) centers have developed programs to provide more outpatient care under three basic models: an early discharge model, a delayed admission model, and a comprehensive, or total, outpatient model. This review will describe these models of care and address the elements necessary for the development of an outpatient BMT program, including patient selection, staff development, and patient and caregiver education. Available supportive care strategies to facilitate outpatient care will also be highlighted. Clinical outcome data and pharmacoeconomic analyses evaluating various outpatient BMT programs, as well as limited quality-of-life evaluations, will be reviewed.

Oral chemotherapy agents in the treatment of leukaemia.

Oral chemotherapy agents have been an important component of the treatment of leukaemia for many years. Obstacles such as poor or erratic bioavailability and noncompliance have often limited the utility of oral agents in the treatment of leukaemia. However, recent evaluations of new or existing oral agents have expanded the clinician's options and understanding of the use of these drugs in the treatment of leukaemia. One major advance is the use of tretinoin (all-trans retinoic acid) in the treatment of acute promyelocytic leukaemia (APL). Tretinoin, an oral vitamin A derivative that reverses abnormal differentiation in APL is now an essential component of first-line therapy for APL, replacing standard intravenous chemotherapy induction regimens. Other advances include an increased understanding of the pharmacokinetic and pharmacodynamic profile of oral chemotherapy agents such as etoposide and high dose busulfan, allowing for modifications or individualisation of administration regimens to enhance efficacy or minimise toxicity. Evaluations of noncompliance with oral agents in the treatment of leukaemia have also provided the clinician with important information on how this obstacle to oral therapy may be overcome or minimised.

Efficacy of low-dose dopamine in preventing amphotericin B nephrotoxicity in bone marrow transplant patients and leukemia patients.

This study evaluated the efficacy of low-dose dopamine for prevention of amphotericin B-induced nephrotoxicity in autologous bone marrow transplant and leukemia patients. Seventy-one patients undergoing cytoreductive therapy who required amphotericin B were randomly assigned in an unblinded fashion to a group receiving continuous-infusion low-dose dopamine (3 microgram/kg/min) or a group receiving no dopamine. Amphotericin B was dosed at 0.5 or 1.0 mg/kg/day based on computerized tomography scan results or presence of positive blood cultures. No patient received saline boluses. The rate of nephrotoxicity, severity as graded by Southwest Oncology Group toxicity criteria, and time to each grade of nephrotoxicity were compared between the two groups. Eighty percent of the no-dopamine group and 66.7% of the dopamine group developed nephrotoxicity, defined as a 1.5-fold or greater increase in baseline serum creatinine level (P = 0.20). No statistical difference was noted at any grade of nephrotoxicity between the two groups. Thirty-four percent of patients in the no-dopamine group versus 17.6% in the dopamine group had a 2.5-fold or greater increase in serum creatinine level, which was not statistically significant (P = 0.0888). Ten patients developed grade IV nephrotoxicity and were withdrawn from the study, 7 in the no-dopamine group and 3 in the dopamine group (P = 0.19). The time to each grade of nephrotoxicity was also not significantly different for the two groups. Eleven adverse drug reactions were reported in the dopamine group in comparison to one in the no-dopamine group. Thus, dopamine offers little in the way of prevention of nephrotoxicity associated with amphotericin B therapy. Although the significance of drug reactions in the dopamine group is not clearly established due to lack of cardiac monitoring in the no-dopamine group, dopamine therapy is not without complications.

An open-label dose comparison study of ondansetron for the prevention of emesis associated with chemotherapy prior to bone marrow transplantation.

Nausea and vomiting are significant side effects in bone marrow transplant (BMT) patients who receive high-dose preparative regimens. Higher than conventional ondansetron doses and continuous infusion might improve emetic control, because of the high doses and combinations of chemotherapy (CT) used in this setting. Our objective was to conduct a prospective, randomized study comparing two different administration methods of high-dose ondansetron during a BMT preparative regimen in breast cancer patients. Patients were eligible if they were nonpregnant women over 18 but under 65 years of age, undergoing highly emetogenic CT in preparation for autologous BMT. All patients received ondansetron as an intermittent (INT = 24 mg i.v. q 12 h/day) or continuous intravenous infusion (CIV = 8 mg i.v. loading dose followed by a continuous infusion of 2 mg/h per day). A total of 66 patients were enrolled in the study (n = 34, INT; n = 32, CIV). There was no statistical difference between treatment groups in the worst grade of emesis for the entire study period (P = 0.49). Greater than 90% of all patients were graded as failures (> or = 5 emetic episodes or need for rescue antiemetics). Complete control (no vomiting episodes) and complete plus major control (1-2 emetic episodes) per day ranged from 8% to 85% and 11% to 91%, respectively. There was no significant difference between the treatment arms in: grade of emesis, episodes of vomiting and retching, nausea scores, and mean number of rescue medications administered. There were no differences in efficacy when high-dose ondansetron was given as CIV or INT for the control of nausea and vomiting in breast cancer patients undergoing high-dose CT for autologous BMT. Ondansetron alone was not adequate to provide sustained control of CT-induced nausea and vomiting over the entire 5-day study period. A combination of antiemetics targeting various mechanisms of CT-induced nausea and vomiting may be necessary to improve response rates.

Allogeneic bone marrow transplantation with matched unrelated donors for patients with hematologic malignancies using a preparative regimen of high-dose cyclophosphamide and fractionated total body irradiation.

Allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling donor is effective therapy for patients with bone marrow failure states and those with hematologic malignancies. However, only a minority of them will have an HLA-identical sibling donor; unrelated donors, matched or partially mismatched, have been used successfully for patients lacking a related donor. Even though results with allogeneic transplants using unrelated donors are encouraging, the incidence of complications including graft-versus-host disease (GVHD) and graft rejection or late graft failure is increased compared to identical sibling transplants. The combination of cyclophosphamide and total body irradiation (TBI) has been used as an effective preparative regimen for allogeneic transplants, however, the total dosage and dosing schedule of both the cyclophosphamide and TBI has varied significantly among studies. To decrease the rate of graft rejection and late graft failure with volunteer donors, we evaluated a preparative regimen of high-dose cyclophosphamide (200 mg/kg over 4 consecutive days, days -8, -7, -6, -5) followed by fractionated TBI (1400 cGy administered in eight fractions over 4 days, days -4, -3, -2, -1). GVHD prophylaxis included FK506 and methotrexate. From July 1993 to January 1996, 43 adult patients, median age 38 years (range 18-58 years), were treated with this preparative regimen. Seventeen patients had low-risk disease and 26 had high-risk disease. Thirty-one donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Seven additional pairs were minor mismatched at the HLA-A or HLA-B loci. Four other donor/recipient pairs were HLA-A,-B, and -DR identical by serology but allele mismatched at either DRB1 or DQB. Forty patients were evaluable for myeloid engraftment. Engraftment occurred in all 40 patients at a median of 19 days. There were no cases of graft rejection or late graft failure. Nephrotoxicity was the primary adverse event with 26 patients (60%) experiencing a doubling of their creatinine. Hepatic veno-occlusive disease occurred in seven patients, six of whom had high-risk disease. All patients who had relapsed or refractory disease prior to BMT achieved a complete remission following BMT. Six patients transplanted for high-risk disease relapsed a median of 377 days post-BMT. None of the patients with low-risk disease have relapsed following transplant; the Kaplan-Meier survival for those patients with low-risk disease is 62% and 37% for those patients transplanted with high-risk disease (P = 0.0129). The median Karnofsky performance status is 100% (range 70-100%). Therefore, a preparative regimen of high-dose cyclophosphamide and fractionated TBI is an acceptable regimen for patients receiving an allograft from unrelated donors.

The outcome of unrelated donor bone marrow transplantation in patients with hematologic malignancies using tacrolimus (FK506) and low dose methotrexate for graft-versus-host disease prophylaxis.

Initial studies of FK506 combined with methotrexate (MTX) in patients receiving unrelated donor BMT have demonstrated a possible-decrease in the incidence of severe GVHD but high rates of severe stomatitis and nephrotoxicity. With this background, we undertook a pilot study evaluating FK506 in combination with a lower than usual dose of MTX in an attempt to improve the tolerability of this immunoprophylaxis regimen. Between July 1993 and October 1994, 26 consecutive adults receiving unrelated donor BMT at Emory University Hospital were enrolled on this study. All patients received FK506 intravenously at an initial dose of 0.03 mg/kg/day beginning day -1 and continuing until oral FK506 was tolerated. Patients also received MTX intravenously at 5 mg/m2 on days 1, 3, 6, and 11. The preparative regimen administered to all but one patient included cyclophosphamide at 200 mg/kg over 4 days followed by total body irradiation (TBI) at 1400 cGy in twice daily fractions over 4 days. The median age of patients was 31 years (range: 19 to 52). Sixteen donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Ten paris were minor mismatches at either class I or class II. Twenty-two of 26 patients (85%) completed four doses of MTX on schedule. Nephrotoxicity was the most common adverse event associated with the administration of FK506: 88% of patients experienced a doubling of their serum creatinine. One patient died of central nervous system hemorrhage prior to engraftment. Twenty-four of the remaining 25 patients (96%) engrafted. Fourteen of 24 patients (50%) evaluable developed grades 2-4 acute GVHD. The rate of severe (grades 3-4) acute GVHD was 25%. Chronic GVHD developed in 11 of 20 (55%) evaluable patients. At a median follow-up of 461 days, 14 patients (54%) are alive. All are relapse-free with a median Karnofsky performance status of 90% (range: 70-100%). The cumulative probability of 2-year disease-free survival is 50% (95% confidence interval [CI]: 0.33 to 0.77); for low risk patients 67% (95% CI: 0.47 to 0.95) and for high risk patients 23% (95% CI: 0.049 to 1.00). These preliminary data indicate that FK506-based immunosuppression following unrelated donor BMT is effective in preventing severe acute GVHD and warrants comparison to CSA-based regimens.

Cytokine therapy after bone marrow transplantation.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) have an important yet controversial role in the care of patients undergoing bone marrow transplantation (BMT). Numerous studies have documented acceleration of neutrophil recovery by the agents. Because of the differences and lack of published clinical outcomes and of direct comparisons of the two CSFs, coupled with limited data from phase III trials, it is difficult to draw conclusions from the literature on the use of the agents after BMT. Issues that must be critically evaluated are toxicity profile, dose, initiation and duration of administration, route of administration, and cost.

Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients.

The purpose of this open-label, prospective study was to compare steady state concentrations and clearances of intravenously administered cyclosporine or tacrolimus with and without concomitant high-dose (400 mg/day) fluconazole in allogeneic BMT patients. Twenty-one patients were evaluable. The mean steady state cyclosporine and tacrolimus concentrations without fluconazole were 320.3 and 18.2 ng/ml and increased to 389.2 and 21.2 ng/ml, respectively, after the addition of fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) increase. The mean steady state clearance of cyclosporine and tacrolimus without fluconazole was 6.82 and 1.28 ml/min/kg, which decreased to 5.57 and 1.10 ml/min/kg with fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) decrease, respectively. The 21% difference in the cyclosporine concentration and clearance was not thought to be clinically significant. These results suggest that fluconazole's interaction with cyclosporine or tacrolimus may be a result of fluconazole's inhibition of gut metabolism, resulting in a greater extent of absorption.

Minimal toxicity and mortality in high-risk breast cancer patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin plus autologous marrow/stem-cell transplantation and comprehensive supportive care.

PURPOSE: To assess the clinical toxicity and outcome associated with a comprehensive supportive care approach in poor-risk breast cancer (BrCA) patients with high-dose chemotherapy (HDC). PATIENTS AND METHODS: One hundred twenty-five consecutive patients with stages II, III or metastatic breast cancer received HDC between February 1992 and June 1994. Recipients received 4 days of continuous infusion of cyclophosphamide 1.5 g/m2/d, thiotepa 125 mg/m2/d, and carboplatin 200 mg/m2/d followed by infusion of bone marrow or peripheral-blood stem cells (PBSC) and recombinant human growth factor (rhu-GF) support. Patients received similar supportive care that included administration of prophylactic antibiotics, management of neutropenic fevers, and transfusion support. RESULTS: There were 38 women with stage II or III (27 patients with > or = 10 lymph nodes), four with stage IIIB, and 83 with metastatic breast cancer. The median age was 44 years (range, 27 to 61). Grade II or greater nonhematologic toxicities included diarrhea (66%), stomatitis (33%), hepatic venoocclusive disease (VOD) (5%), and pulmonary toxicity (4%). Myeloid and platelet engraftment was comparable between bone marrow and PBSC recipients (P > .1). Infectious complications were rare and consisted of gram-negative bacteremia (1.6%), gram-positive bacteremia (1.6%), fungemia (1.6%), and documented or suspected aspergillosis infection (3%). There was one treatment-related death secondary to severe VOD. CONCLUSION: A comprehensive supportive care approach was associated with a low treatment-related mortality rate of less than 1%. With the observed reduction in treatment-related mortality, it is reasonable to evaluate the efficacy of HDC in women with less than 10 positive nodes and stage II disease in well-designed clinical trials.

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.

Randomized trial of loperamide versus dose escalation of octreotide acetate for chemotherapy-induced diarrhea in bone marrow transplant and leukemia patients.

This study compares maximal daily doses of loperamide to escalating doses of continuous intravenous (CI) octreotide acetate in bone marrow transplant (BMT) and leukemia patients. Following chemotherapy, BMT and leukemia patients who developed > or = 600 ml of stool volume in a 24-hr period were randomized to receive loperamide 4 mg po q6h or octreotide 150 micrograms mixed in hyperalimentation solution or normal saline and administered CI. Patients were assessed at 48 hr intervals for decrease in stool volume from baseline. Complete response (CR) was defined as > or = 50% from baseline stool volume (BSV). Patients receiving octreotide who did not achieve a CR at 48 hr were dose escalated by doubling the dose to a maximum of 2,400 micrograms with evaluations at 48 hr intervals. Patients receiving loperamide who did not achieve a CR at 48 hr had treatment discontinued. A total of 36 patients were enrolled in the study. Of these, all were evaluable for intention to treat, and 31 were evaluable for initial response. Based on intent to treat at the initial 48 hr, patients receiving loperamide had a higher complete response rate (86% vs. 45%, P = 0.033) than did those who received octreotide. By treatment analysis (patients who actually received the drug), patients receiving loperamide had a higher complete response rate (92% vs. 56%, P = 0.0448) than did those who received octreotide at the 150 micrograms dosage level. Additional octreotide patients eventually achieved a CR at a higher dosage level (78%). Loperamide at maximal doses of 4 mg po q6h is more effective than octreotide 150 micrograms CI in treating diarrhea following chemotherapy in BMT and leukemia patients. Higher doses of octreotide may be required in a significant number of patients not responding to lower doses.