Use of cytokines in the treatment of acute myelocytic leukemia: a critical review.

PURPOSE: The colony-stimulating factors (CSFs) have been evaluated in patients with acute myelocytic leukemia (AML), both as potential priming agents and during and/or following induction chemotherapy to shorten the period of myelosuppression. The purpose of this review is to evaluate critically the safety and efficacy of the CSFs, primarily granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF), in the treatment of patients with AML. METHODS: All phase III trials that have either been presented or published that used CSFs during and/or following induction chemotherapy in patients with de novo AML are discussed. Relevant background information and future directions are also addressed. RESULTS AND CONCLUSION: There have been six phase III trials that used either GM-CSF or G-CSF in induction therapy in patients with AML. It is difficult to compare these trials due to differences in patient age, induction therapy administered, disease characteristics, whether leukemia response or documentation of marrow hypoplasia was required before cytokine use, and the different cytokines administered during the study. In particular, the timing of CSF administration in relation to the chemotherapy may be important due to the different biologic effects these agents may have on leukemia cells, such as leukemia cell recruitment. Most of these studies administered either GM-CSF or G-CSF before or during induction therapy, as well as following completion of chemotherapy until neutrophil recovery. Only one of six trials required documentation of marrow hypoplasia before CSF use. Despite these differences, administration of either GM-CSF or G-CSF was found to be safe without an increase in acute toxicity or an increase in relapse rates. In addition, most trials demonstrated a significant improvement in neutrophil recovery, with several trials demonstrating an improvement in complete remission and overall survival rates. Therefore, the use of selected CSFs may be of benefit following induction chemotherapy in those patients with AML who are at increased risk for early morbidity and mortality.

Successful marrow transplantation for acute myelocytic leukemia following therapy for Hodgkin's disease.

Five patients with acute myelocytic leukemia (AML) after combined modality therapy for Hodgkin's disease (HD) were treated with cyclophosphamide and busulfan followed by bone marrow transplantation (BMT). Four patients received allogeneic transplants from histocompatibility locus antigen (HLA)-compatible siblings and the fifth patient received an autologous marrow treated with 4-hydroperoxycyclophosphamide. Two patients died of complications of acute graft-v-host disease (GVHD) despite prophylaxis with either low-dose cyclophosphamide or cyclosporine. The remaining three patients were alive and disease-free 382, 617, and 620 days after transplant. These initial results are encouraging and more patients with treatment-related AML need to be evaluated with both allogeneic and autologous BMT to fully elucidate the potentially curative role of this intensive therapy in an otherwise fatal hematologic malignancy.

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.

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.

Granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein versus granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for non-Hodgkin's lymphoma: results of a randomized double-blind trial.

PURPOSE: A phase III trial to compare PIXY321 with granulocyte-macrophage colony-stimulating factor (GM-CSF) following high-dose therapy and autologous bone marrow transplant (ABMT) was conducted to evaluate the time to hematopoietic recovery. PATIENTS AND METHODS: One hundred seventy-seven patients with non-Hodgkin's lymphoma (NHL) receiving ABMT were randomized to receive either PIXY321 750 micrograms/m2/d divided into two subcutaneous (SC) doses or GM-CSF 250 micrograms/m2/d as a 2-hour intravenous (IV) infusion starting on day 0 post-ABMT for a maximum of 28 days. RESULTS: The median time to reach an absolute neutrophil count (ANC) > or = 500/microL in the PIXY321 group was 17 days versus 19 days in the GM-CSF group (P = .07) and the median time to reach platelet transfusion independence in the PIXY321 group was 25 days versus 23 days in the GM-CSF group (P = .30). The toxicity profiles of the two agents appeared to be equivalent with the exception of more patients in the PIXY321 group with a rash (64%) compared with the GM-CSF group (48%) (P = .028). A logistic regression model identified the use of a non-total-body irradiation (TBI) regimen and/or receipt of unpurged marrow and a body-surface area greater than 2.0 m2 as predictive of faster neutrophil engraftment, and those three factors, as well as the receipt of < or = two prior chemotherapy regimens as predictive for rapid platelet engraftment. CONCLUSION: There was a trend toward a slight improvement in neutrophil engraftment post-ABMT with the PIXY321 administered by an SC route compared with GM-CSF administered by an IV route. However, no differences could be identified between the two agents with respect to the time to platelet transfusion independence. Patient, regimen, and graft characteristics were most predictive of the engraftment tempo.

Post-remission therapy of acute myelocytic leukemia in adults: curability breeds controversy.

The curability of acute myelocytic leukemia (AML) in adults relies upon two treatment strategies. The first is induction therapy to effectively reduce the patient's leukemia burden and allow for recovery of normal hematopoiesis. Once this is achieved and the patient enters a complete remission, further potentially curative post-remission therapy can be administered. Induction therapy has not changed significantly over the past two decades, relying primarily on conventional-dose cytarabine and an anthracycline combination. Post-remission therapy, on the other hand, has changed with the introduction of more intensive and aggressive cytoreductive treatment as well as utilization of myeloablative regimens followed by either allogeneic or autologous bone marrow transplantation (BMT). The scope of this review is to evaluate the different curative post-remission treatment approaches for adult patients with AML. Discussions will focus on younger patients (less than 65 years) with responsive disease who enter a complete remission and then have post-remission therapy options available to them. Often, decisions concerning post-remission therapies are based solely on age and the availability of compatible donors; however, since understanding of the biology of leukemia has expanded and treatment strategies have improved, our ability to recommend particular treatment approaches has also evolved. We are now in a position to recommend therapeutic options based on disease and host characteristics.

Cures of leukemia with aggressive postremission treatment: an update of timed sequential therapy (Ac-D-Ac).

A cure rate can be obtained with intensive cytoreductive treatment given to a subset of patients with acute myelocytic leukemia in bone marrow remission. This report updates our experience with postremission timed sequential therapy using cytarabine and daunorubicin (Ac-D-Ac) and compares it with other brief, aggressive strategies including bone marrow transplantation. The median disease-free survival (DFS) of all patients treated in remission is 2.5 years with a greater than 40% probability of DFS at 8 years. These results are similar to those achieved with bone marrow-ablative and other intensive but nonablative treatment plans.

Cure of acute myelocytic leukemia in adults: a reality.

Adult acute myelocytic leukemia (AML) is a curable disease in responsive patients with aggressive treatment in remission. Over the past decade at the Johns Hopkins Oncology Center, AML has been treated with either allogeneic bone marrow transplantation or with intensive timed sequential treatment using high dose cytarabine in remission. With either treatment modality comparable cure rates were obtained. The role, if any, of randomized trials to adequately determine the preferred treatment for appropriate patients has yet to be defined.

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.

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.

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.

Thrombotic thrombocytopenic purpura associated with FK506 following bone marrow transplantation.

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) have been observed after bone marrow transplantation (BMT), typically occurring 1-6 months following BMT. We describe two patients who developed TTP very early after BMT while receiving intravenous FK506. They were treated with platelet support and plasma exchange (PE) using either fresh frozen plasma (FFP) or cryosupernatant fraction of plasma (CFP), resulting in remission of TTP activity.

Tacrolimus (FK506)-induced cerebral blindness following bone marrow transplantation.

Three patients who developed acute onset of cerebral blindness within 5-47 days of BMT using tacrolimus (FK506) as primary GVHD prophylaxis are described. This syndrome has been described with the use of cyclosporin A (CsA) and FK506 in solid organ transplant recipients. CsA-induced cerebral blindness has also been noted in BMT recipients but to date there have been no reports of this complication in BMT patients receiving FK506. We have noted a striking similarity in the clinical and radiographic presentations between these patients and those with CsA-associated cerebral blindness. Reversibility within 1-2 weeks of onset and the potential for substitution of CsA for FK506 in these patients is described.

Bronchiolitis obliterans organizing pneumonia as a complication of allogeneic bone marrow transplantation.

We report a patient who underwent two allogeneic bone marrow transplants for chronic myelogenous leukemia, initially in 1984 and again after relapse in 1990, who developed an identical pulmonary syndrome at a similar interval following each transplant. The patient presented with a non-productive cough, bilateral inspiratory crackles, and multiple patchy infiltrates on chest X-ray. Pulmonary function testing revealed a restrictive abnormality but no obstructive defects. The appearance of this pulmonary disorder after each transplant coincided with the development of chronic graft-versus-host disease. In both instances, this pulmonary syndrome completely reversed with corticosteroid therapy. The patient's chest computed tomographic scan and lung biopsy specimens were consistent with the diagnosis of bronchiolitis obliterans with organizing pneumonia (BOOP). While bronchiolitis obliterans has been reported following allogeneic transplant, BOOP has not previously been reported in this setting.

Phase I study of busulfan, cyclophosphamide, and timed sequential escalating doses of cytarabine followed by bone marrow transplantation.

In both animal models and human studies in leukemia, residual disease on day 8 following myelosuppressive therapy is in a proliferative phase and therefore may be sensitive to the S-phase specific drug cytarabine. Based on this concept, 17 patients with refractory or relapsed leukemia or lymphoma undergoing either autologous or allogeneic bone marrow transplantation (BMT) were treated on a Phase I protocol using high doses of busulfan (16 mg/kg, days -10, -9, -8, -7) and cyclophosphamide (120 mg/kg, days -6, -5) followed by escalating doses of a 48-h continuous infusion of cytarabine (starting dose 1000 mg/m2/48 h, days -3, -2). Ten patients received autologous transplants (two with Hodgkin's disease, seven with non-Hodgkin's lymphoma, one with chronic myelogenous leukemia (CML) in blast phase). Seven received allogeneic BMT (two with refractory acute myelocytic leukemia (AML), one with refractory acute lymphoblastic leukemia (ALL) undergoing a second BMT, one with Burkitt's-type leukemia, one with ALL in fifth relapse and two with CML in accelerated/blast phase). Two of these patients received a T cell-depleted haploidentical transplant. The maximum tolerated dose of cytarabine was 1500 mg/m2/48 h; a pulmonary syndrome including dyspnea, hypoxemia, and interstitial infiltrates which responded to aggressive diuresis was the dose limiting toxicity. Of the 10 patients who received cytarabine doses of 2000 or 2500 mg/m2/48 h, five patients developed adult respiratory distress syndrome (ARDS) with three patients requiring intubation; two recovered. Of the nine patients with lymphoma, seven responded with complete tumor clearance (CTC) with two patients tumor-free 13 and 15 months post-BMT, one remained refractory and one died too early to evaluate (TETE).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Encephalopathy is the dose-limiting toxicity of intravenous hepsulfam: results of a phase I trial in patients with advanced hematological malignancies.

Hepsulfam is a bisulfamic ester which is similar in structure to busulfan and is believed to act as a bifunctional alkylator inducing both DNA-DNA and DNA-protein crosslinks. Prior studies in patients with refractory solid tumors have identified the dose-limiting toxicity of hepsulfam to be cumulative myelosuppression resulting in prolonged leukopenia and thrombocytopenia. This phase I trial was designed to determine the maximally tolerated dose of hepsulfam administered intravenously in patients with refractory leukemias and other advanced hematologic malignancies. Hepsulfam was administered as a 30-min or 2-h intravenous infusion to 21 patients with advanced leukemia or multiple myeloma. All patients had been extensively treated and had progressive disease. Cycles were repeated every 5 weeks. Cohorts of patients were treated at 360, 480, 640, and 800 mg/m2. The dose-limiting toxicity of intravenous hepsulfam was severe encephalopathy. The single patient treated at 800 mg/m2 became comatose within 48 h and required 3 weeks for his mental status to return to baseline. There were, however, no irreversible neurological sequelae. Several patients treated at 640 mg/m2 had clinical evidence of toxic deliriums and slowing of alpha rhythm waves on electroencephalograms indicative of a gray-matter encephalopathy. When hepsulfam was infused over 30 min, patients complained of uncomfortable parasthesias, but when the drug was administered over 2 h, these acute symptoms were less common. Myelosuppression was observed in most patients. Among those patients who had some suppression of their leukemia, peripheral blood counts recovered to pretreatment levels after 3-5 weeks. Apart from CNS toxicity, non-hematologic toxicity was minimal. Pharmacokinetic studies demonstrated rapid clearance of hepsulfam so that the drug was not reliably detected in the plasma after 24 h. The recommended phase II dose of hepsulfam as a single 2-h intravenous infusion is 480 mg/m2, but this dose provided relatively little clinical benefit for patients with refractory leukemia. The dose-limiting toxicity is CNS toxicity with increasingly severe encephalopathy at doses > or = 640 mg/m2. It would be reasonable to investigate further dose escalation of hepsulfam in a divided dose schedule to minimize the peak concentrations which may be related to the encephalopathy. EEG monitoring is recommended for early detection of slowing of alpha rhythm waves. Hematopoietic stem cell support will probably be required at total doses exceeding 800 mg/m2.

Role of autologous bone marrow transplantation for patients with acute and chronic leukemias.

Autologous bone marrow transplantation has been increasingly used as effective curative therapy for patients with acute myelocytic leukemia or acute lymphoblastic leukemia who are not candidates for allografting. Its potential role for patients with chronic myelocytic leukemia is considered investigational; however, recent advancements in stem cell separation may make autologous transplantation an attractive alternative for this disease as well. The timing of the autologous transplant and the role of marrow purging are discussed in depth. In addition, post-transplant immune modulation and the use of growth factors and other cytokines following autologous reinfusion are currently being investigated.

A pilot study of prophylactic aerosolized amphotericin B in patients at risk for prolonged neutropenia.

Invasive aspergillosis continues to be a significant cause of morbidity and mortality in patients with prolonged neutropenia. We performed a phase I trial of escalating doses of aerosolized amphotericin B given by a face mask nebulizer system with a disposable bacterial exhale filter. Five, 10, 15, and 20 mg of drug were dissolved in sterile water and inhaled over 10 to 15 minutes twice daily. Tolerance was studied in 26 patients (18 transplant recipients, and 8 leukemia patients). No side effects were observed at any dose level. Prophylactic treatment ended for 14 patients (54%) when intravenous (IV) amphotericin B was begun empirically for antifungal coverage following fevers. Eleven patients (43%) continued inhaled amphotericin B until blood counts recovered. One patient was taken off study when she developed cardiogenic pulmonary edema. No patient developed clinically suspicious or pathologically documented infection with invasive aspergillosis. Prophylactic aerosolized amphotericin B is well tolerated at 5, 10, 15, and 20 mg twice daily dosing. In addition, prophylactic aerosolized amphotericin B does not appear to sensitize patients to the subsequent use of IV amphotericin B. Although this study suggests that prophylactic inhaled amphotericin B is well tolerated and effective, a large scale controlled trial is needed.