A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis.

To evaluate the incidence of therapy-related acute leukaemia (t-AL) after single-agent mitoxantrone (MITO) treatment, we reviewed medical records of patients in three studies of single-agent MITO therapy for multiple sclerosis (MS) and existing literature on MITO therapy in MS, leukaemia, and solid tumors. Of 1378 MITO recipients in the three MS studies (mean cumulative dose of 60 mg/m2 and mean follow-up of 36 months), one patient had t-AL, an observed incidence proportion of 0.07% [95% confidence interval (CI) = 0.00-0.40%]. There were no cases of t-AL in published reports of nine additional studies of single-agent MITO therapy for MS. There was one published case report of acute promyelocytic leukoemia detected five years after initiating MITO therapy for MS. The observed incidence proportion of t-AL is very low in patients who received MITO as single-agent therapy for MS. Although these observations provide preliminary reassurance, extended follow-up of these patients and those who receive higher cumulative doses of MITO is required to define the long-term risk of t-AL after MITO therapy for MS.

Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS.

BACKGROUND: Mitoxantrone (MITO) is associated with dose-related cardiotoxicity when administered concomitantly with other cytotoxic agents with or without radiotherapy for leukemia and solid tumors. OBJECTIVE: To review observed cardiotoxicity of single-agent MITO therapy for MS. METHODS: Records of 1,378 patients from three clinical trials of MITO treatment for MS were reviewed for signs and symptoms of cardiac dysfunction and left ventricular ejection fraction (LVEF) results. Duration of follow-up was a median of 29 months (4,084 patient-years). RESULTS: No patients experienced congestive heart failure (CHF) before treatment. Cumulative MITO doses ranged from 2 to 183 mg/m(2) (mean 60.5 mg/m(2), median 62.5 mg/m(2)), and 141 patients received >100 mg/m(2). Two of 1,378 patients experienced CHF after initiating MITO therapy. Of 1,378 patients, 779 completed baseline and scheduled follow-up LVEF testing. Baseline LVEF was >50% in all 779 patients. Seventeen of 779 patients had asymptomatic LVEF of <50% (incidence proportion = 2.18%, 95% CI = 1.28 to 3.47%). Although the incidence of asymptomatic LVEF of <50% was not significantly related to monthly versus 3-monthly therapy, duration of therapy, age, or gender, asymptomatic LVEF of <50% trended higher with a cumulative dose of >/=100 mg/m(2) (5.0%) than with <100 mg/m(2) (1.8%) (p = 0.06). CONCLUSIONS: The observed incidence of CHF in patients with MS who received a mean cumulative dose of 60.5 mg/m(2) MITO was <0.20%. Continued monitoring of patients with MS who are receiving MITO is needed to determine whether the incidence of CHF increases with higher cumulative MITO doses and prolonged follow-up.

Phase I study of recombinant human CD40 ligand in cancer patients.

PURPOSE: To determine the toxicity, maximum-tolerated dose (MTD), and pharmacokinetics of recombinant human CD40 ligand (rhuCD40L) (Avrend; Immunex Corp, Seattle, WA), suggested in preclinical studies to mediate cytotoxicity against CD40-expressing tumors and immune stimulation. PATIENTS AND METHODS: Patients with advanced solid tumors or intermediate- or high-grade non-Hodgkin's lymphoma (NHL) received rhuCD40L subcutaneously daily for 5 days in a phase I dose-escalation study. Subsequent courses were given until disease progression. RESULTS: Thirty-two patients received rhuCD40L at three dose levels. A total of 65 courses were administered. The MTD was 0.1 mg/kg/d based on dose-related but transient elevations of serum liver transaminases. Grade 3 or 4 transaminase elevations occurred in 14%, 28%, and 57% of patients treated at 0.05, 0.10, and 0.15 mg/kg/d, respectively. Other toxicities were mild to moderate. At the MTD, the half-life of rhuCD40L was calculated at 24.8 +/- 22.8 hours. Two patients (6%) had a partial response on study (one patient with laryngeal carcinoma and one with NHL). For the patient with laryngeal cancer, a partial response was sustained for 12 months before the patient was taken off therapy and observed on no additional therapy. Three months later, the patient was found to have a complete response and remains biopsy-proven free of disease at 24 months. Twelve patients (38%) had stable disease after one course, which was sustained in four patients through four courses. CONCLUSION: The MTD of rhuCD40L when administered subcutaneously daily for 5 days was defined by transient serum elevations in hepatic transaminases. Encouraging antitumor activity, including a long-term complete remission, was observed. Phase II studies are warranted.

Mitoxantrone and fludarabine in the treatment of patients with non-Hodgkin's lymphoma failing primary therapy with a doxorubicinor mitoxantrone-containing regimen.

Patients with recurrent lymphoma of any grade were treated with mitoxantrone (12 mg/m2 given intravenously (IV) over 15-30 minutes on day 1) followed by fludarabine at a dose of (25 mg/m 2 given IV over 30 minutes on days 1-3) every 28 days fludarabine at a dose of (25 mg/m2 given IV over 30 minutes on days 1-3) every 28 days. All patients had failed one prior chemotherapy regimen that contained either doxorubicin or mitoxantrone, total dose not exceeding 350 mg/m2 doxorubicin or 80 mg/m2 mitoxantrone. mitoxantrone. Thirty one patients (22 with intermediate- or high-grade and 9 with low-grade NHL) were enrolled. Median age was 63 years (range: 21 to 87). The objective response rate for patients with intermediate/high-grade NHL was 55% (27% with CR) and 89% (56% with CR) for patients with low-grade NHL. Median time to disease progression was 5.1 months for patients with intermediate/high-grade NHL and 10.8 months for patients with low-grade NHL. Median time to death for patients with intermediate/high-grade disease was 11.4 months. Median time to death for patients with low-grade NHL was not calculable as only one death (due to respiratory failure) occurred in this group 6.5 months after study start. The regimen was well tolerated. Grade 3/4 neutropenia was reported in 80% (24 of 30) of patients and Grade 3/4 thrombocytopenia in 19% (6 of 31) of patients. Nine hospitalizations for adverse events (primarily fever and neutropenia) occurred among eight patients, all with intermediate/high-grade NHL, during a total of 118 cycles of therapy. Further studies of this combination regimen in patients with intermediate/high-grade NHL and studies combined with monoclonal antibodies in low-grade NHL are warranted.

Mitoxantrone and paclitaxel combination chemotherapy in metastatic breast cancer.

This study evaluated mitoxantrone and paclitaxel combination chemotherapy in the treatment of patients with metastatic breast cancer. Thirty-seven patients who had developed progressive disease after prior chemotherapy were treated with mitoxantrone (14 mg/m2) and paclitaxel (150 mg/m2) every 21 days for a maximum of six cycles. The most frequent grade 3 or 4 nonhematological toxicities were fever and nausea. Grade 4 neutropenia occurred in 71% of patients. Cardiotoxicity occurred in 2 patients, both of whom had previously received doxorubicin. Objective response was achieved in 35% of patients (5% complete response and 30% partial response) and 41% had stable disease. Median time to disease progression and median survival were 6 and 12 months, respectively. The percent of patients with an objective response was not different for those who had received prior doxorubicin or had chemotherapy in the preceding 6 months. This regimen appears to be effective and well tolerated as salvage therapy and merits further evaluation.

Ex vivo expansion of frozen/thawed CD34+ cells isolated from frozen human apheresis products.

Human CD34+ cells purified from frozen mobilized peripheral blood apheresis products (n = 7) were studied immediately (freshly isolated) or refrozen and studied after > 30 days storage in liquid nitrogen (refrozen/thawed). The proliferation and differentiation of freshly isolated or refrozen/thawed CD34+ cells were examined after 10 days of serum-supplemented suspension culture with recombinant human hematopoietic growth factors. The proliferative capacity (fold increase) of the refrozen/thawed CD34+ cells (mean +/- SD, 54.3 +/- 34.3) was comparable to the freshly isolated CD34+ cell cultures (49.0 +/- 42.4). Two-color flow cytometry of the CD34+ cultured cell populations, fresh and refrozen/thawed, displayed typical patterns of neutrophil differentiation into CD15/CD11b neutrophil precursors. The colony-forming ability of freshly isolated and refrozen/thawed CD34+ cells showed no significant differences (p > 0.05) in the total number or type of colony-forming units (CFU-GM, CFU-M, BFU-E, CFU-GEMM) obtained. In addition, the cloning efficiencies of freshly isolated (19.5 +/- 7.6%) and refrozen/thawed CD34+ cells (21.9 +/- 12.7%) were comparable (p = 0.366). These data suggest that CD34+ cells enriched from frozen apheresis blood products can be either used immediately or stored in liquid nitrogen and thawed with minimal effect on their ability to proliferate and differentiate in liquid culture.

The clinical effectiveness and financial impact of utilizing peripheral blood progenitor cells as rescue therapy following autologous bone marrow transplant.

The use of peripheral blood progenitor cell transplant as rescue therapy after high-dose chemotherapy and autologous bone marrow transplant significantly decreases transfusion, laboratory, room, and total charges. An improvement in clinical indicators also points toward decreased patient morbidity. Additional cost reductions may be realized by greater utilization of outpatient care, thereby further reducing room and total charges.

Tandem peripheral blood progenitor cell transplants as initial therapy for metastatic breast cancer.

PURPOSE: To investigate the use of two sequential courses of high-dose chemotherapy and peripheral blood progenitor cell (PBPC) transplant as initial therapy for patients with untreated metastatic breast cancer. The goal of the study was to maximize treatment intensity through the use of two non-cross-resistant regimens, each equal in intensity to that used in single transplants. METHODS: PBPC were collected after a course of granulocyte colony-stimulating factor (G-CSF) only or of cyclophosphamide, etoposide, and G-CSF. The first transplant regimen consisted of thiotepa (600 mg/m2), cyclophosphamide (6000 mg/m2), and carboplatin (800 mg/m2). After recovery from the first transplant, responding patients received a second course of therapy consisting of busulfan (16 mg/kg) and etoposide (60 mg/kg). RESULTS: Forty-four patients were enrolled. Five patients did not proceed to transplantation due to tumor progression during PBPC mobilization. Five patients achieved complete response after the first transplant, and 14 were in complete remission at the end of the therapy. Six patients remain free of disease after a median followup of 22 months (range 12-27+ months). The 2-year event-free survival for complete responders is 25.4% (standard error 14.4%). Engraftment was prompt, with a median of 8 and 13 days, respectively, to reach a neutrophil count of 500/mm3 and a platelet count of 50,000/mm3. As a result of the gastrointestinal toxicity of the first course, the median interval between transplants was 68 days. The toxicities of the second transplant course were principally hepatic and muco-cutaneous. Hepatic veno-occlusive disease occurred in 12 patients and was a contributor to the death of three. CONCLUSIONS: Rapid hematologic recovery achieved with PBPC made possible the administration of two courses of high-dose chemotherapy without compromising the intensity of either transplant regimen. The adverse effects of the second course, however, were substantially higher than predicted. The outcome of patients achieving a complete response is promising. Overall, the antitumor benefit of this approach in patients with previously untreated metastatic disease was not superior to that achieved with single transplants in patients responding to standard-dose chemotherapy.

Detection of tumor cells in the bone marrow, peripheral blood, and apheresis products of breast cancer patients using flow cytometry.

One of the possible drawbacks to autologous bone marrow (BM) and peripheral blood progenitor cell (PBPC) transplantation in breast cancer patients is the potential for tumor cell contamination in the transplanted product. To assess the presence of breast cancer cells, we have developed a flow-cytometric method using cytokeratin-FITC and CD45-phycoerythrin (PE) to detect very low levels of cytokeratin-positive (CK+) tumor cells in mononuclear cell (MNC) preparations. In a model system using PBMNC and the breast cancer cell line CAMA, the sensitivity of detection of this flow-cytometric method was one tumor cell in 200,000 MNC. This method was used to evaluate BM, PB, and apheresis products (AP) from 44 patients with metastatic breast cancer. When possible, stained cytologic examination was performed on smears of the unprocessed specimens and on flow cytometry-sorted cells. Results indicated that CK+ tumor cells could be detected by flow cytometry in all three specimen types. When present, however, the tumor content (per MNC) tended to be higher in BM than in PB or AP. Samples from a given patient taken serially over the course of chemotherapy revealed variable results, suggesting that the presence of tumor contamination may be sporadic and requires evaluation of each stem cell product. Of 75 samples tested with both flow cytometry and cytology, the results were concordant in 54 cases (72%). In the remaining samples, flow cytometry only was positive in 15 cases (20%), and cytology only was positive in six cases (8%). This flow-cytometric technique is useful in the evaluation of transplant products for CK+ tumor cell contamination.

Patterns of failure following bone marrow transplantation for metastatic breast cancer: the role of consolidative local therapy.

PURPOSE: The purpose of this analysis is to evaluate the patterns of failure and the role of local therapy in conjunction with bone marrow transplantation (BMT) for metastatic or recurrent breast cancer. METHODS AND MATERIALS: Between June 1986 and November 1991, 46 patients with hormone unresponsive metastatic or recurrent breast cancer underwent high dose chemotherapy (HDC) with hematopoietic stem cell support. The most commonly used preparative regimen consisted of thiotepa (750 mg/m2), cisplatin (150 mg/m2), and cyclophosphamide (120 mg/kg) followed by autologous BMT. Consolidative surgery or irradiation was considered in patients whose cancer responded to BMT and had localized sites of disease. RESULTS: Six patients (13%) died of BMT-related complications. Of the remaining 40 patients, 22 were candidates for consolidative therapy, and 18 of those patients received consolidative irradiation (17 patients) or surgery (1 patient) to one or more sites. At median follow-up of 27 months (range, 20-78), 12 of 18 (67%) patients have continuous local control at the 22 consolidated sites (1 of 4 controlled at chest wall sites, 7 of 8 at regional nodal sites, 7 of 7 at localized bone sites, and 1 of 3 at lung/mediastinal sites). Toxicity of consolidative irradiation was mainly limited to myelosuppression in 6 of 17 patients. Two patients did not complete the consolidative local therapy, one because of hematologic toxicity and one because of rapid systemic tumor progression during treatment. CONCLUSION: In patients with localized areas of extravisceral metastases, consolidative irradiation is feasible with acceptable hematologic toxicity. Consolidative irradiation can result in continuous local control, especially in isolated bone metastases and in regional nodal sites; however, the advantage is less clear in patients undergoing consolidative irradiation for chest wall failures. Because distant visceral metastases still remain a major site of failure after this HDC regimen, a more effective systemic therapy is needed. Consolidative local treatment should be considered in future HDC/BMT protocols for metastatic breast cancer, especially in localized nodal and osseous sites.

Angiotensin converting enzyme inhibitors in bone marrow transplant recipients with depressed left ventricular function.

Pre-existing left ventricular dysfunction in patients undergoing induction therapy with cyclophosphamide prior to bone marrow transplantation (BMT) has resulted in overt heart failure in a large number of patients. This fact excludes the majority of such patients from consideration for BMT at many centers. We sought to determine if prophylactic treatment with the angiotensin converting enzyme inhibitor enalapril prevents this deterioration in pre-existing left ventricular dysfunction. We treated six consecutive patients with initial left ventricular ejection fractions (LVEF) by radionuclide gated blood pool imaging (RGBP) of < 50% (42 +/- 7%) with enalapril 5 mg orally twice per day started 48 h prior to induction therapy and continued throughout the follow-up period. Serial RGBP imaging demonstrated an increase in LVEF in all patients to 54 +/- 6% (P < 0.005). No patient experienced clinical deterioration during a follow-up period of 18 +/- 11 months. We conclude that prophylactic treatment with enalapril may prevent deterioration in pre-existing mild left ventricular dysfunction during BMT.

Successful pregnancy in a bone marrow transplant recipient following oocyte donation.

We describe the successful establishment of pregnancy in a woman status post-bone marrow transplantation using assisted reproduction. Oocyte donation offers women with gonadal failure secondary to cytotoxic agents a reasonable chance at child-bearing.

Pulmonary complications of bone marrow transplantation: a comparison of total body irradiation and cyclophosphamide to busulfan and cyclophosphamide.

PURPOSE: To retrospectively compare the acute and long-term pulmonary toxicities of total body irradiation and busulfan in bone marrow transplantation. METHODS AND MATERIALS: From March 1984 through February 1991, 144 patients received high-dose therapy with cyclophosphamide plus either total body irradiation (TBI-CY) or busulfan (BU-CY) followed by bone marrow rescue. Treatment protocols were based on disease type. Cyclophosphamide dose was 120-200 mg/kg, given in 2-4 days. Total body irradiation was given as 12 Gy in four fractions over 4 days, or 14.4 Gy in eight fractions over 4 days. Busulfan dose was 16 mg/kg given over 4 days. RESULTS: Seventy-nine patients were treated with TBI-CY and 65 patients with BU-CY. More patients in the TBI group had allogeneic transplants (40 vs. 18). Pulmonary events occurred in 48 patients, 19 in BU-CY and 29 in TBI-CY. Of the 58 patients with allogeneic transplants, 21 (36%) developed chronic graft-vs.-host disease (GVHD), and 10 of those patients developed pulmonary complications (including 2 with obliterative bronchitis and 1 with asthma). Interstitial pneumonitis (IP) occurred in 14 patients, 12 in the TBI-CY group and 2 in the BU-CY group. Cytomegalovirus and pneumocystis infections were associated with IP in 11 of those patients. Fatal idiopathic IP occurred in one patient in each of the TBI-CY and BU-CY groups. Multivariate analysis showed that only chronic GVHD and prior bleomycin use were significant predictors of interstitial pneumonitis; no difference was seen between TBI-CY and BU-CY. CONCLUSIONS: Pulmonary complications were most commonly associated with GVHD and prior bleomycin use. The incidence of cytomegalovirus or pneumocystis carinii pneumonitis was greater in the patients receiving the TBI regimen; fatal pulmonary complications were not significantly different between TBI and nonTBI regimens.

Busulfan-containing pre-transplant regimens for the treatment of solid tumors.

This study investigated the toxicity and efficacy of busulfan-containing pre-transplant regimens in patients with solid tumors. The majority of these patients were also treated on protocols involving two transplant courses aiming at further reducing tumor burden. Between October 1984 and November 1993, we treated 44 patients with recurrent breast cancer (n = 28), sarcoma (n = 10) or ovarian cancer (n = 6) with one of two busulfan-containing regimens. All patients except two had measurable disease prior to transplantation. Twenty-one patients had not received chemotherapy for metastatic disease. Of the remaining 23 patients treated with standard-dose chemotherapy, 14 had progressive disease. Busulfan 16 mg/kg was paired with cyclophosphamide 200 mg/kg (BuCY) or with etoposide 60 mg/kg (Bu-Vp). The Bu-Vp combination (32 courses) was used as the second preparative regimen in patients who had received thiotepa, carboplatin and cyclophosphamide for their first transplant. The BuCY regimen was used in 16 courses, either for single or for tandem transplant. Bone marrow cells only were used in 17 transplants and peripheral blood progenitor cells, with or without bone marrow, in 31 courses. Treatments were usually well tolerated. Common toxicities included mucositis, skin rash and veno-occlusive disease of the liver (fatal in two). One patient developed generalized seizures during busulfan therapy. Hematologic recovery was significantly accelerated with peripheral progenitor cells and permitted the administration of closely spaced tandem transplants. Two patients receiving sequential transplants with BuCY experienced severe long-term neurologic and pulmonary toxicity. Objective responses were noted in 26 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of colony-forming cells, long-term culture initiating cells and CD34+ cells in apheresis products from patients mobilized for peripheral blood progenitors with different regimens.

Peripheral blood progenitor cell (PBPC) populations used for transplantation were analyzed for the presence of CD34+ cells, colony-forming cells (initial CFC), and long-term culture initiating cells (LTC-IC) cultured on irradiated stroma for 5 weeks. Thirty-eight leukapheresis products were studied from 11 patients with breast cancer, 2 with non-Hodgkin's lymphoma and 1 with ovarian cancer harvested during recovery from either cyclophosphamide (CY) chemotherapy or cyclophosphamide-VP16 with G-CSF (CY-VP-G). CY-VP-G products had a threefold higher median number of mononuclear cells collected, a fivefold higher median concentration of CD34 and LTC-IC and a threefold higher concentration of initial-CFC when compared with CY products. CY-VP-G products had a significantly higher ratio of CFU-GM to BFU-E than the CY-mobilized products. Significant correlations of r = 0.89 and r = 0.68 were observed when comparing CD34 and CFC in products from CY or CY-VP-G patients, respectively. Analysis of the regression lines indicated that slopes of these regression lines were significantly different with a ratio of CD34 to initial CFC of 15:1 in the CY-VP-G products versus 5.2:1 with the CY products. These data indicate a higher cloning efficiency of the CD34+ population in the products from CY-mobilized patients. Significant correlations of r = 0.9 (CY) and r = 0.53 (CY-VP-G) were observed when the initial CD34 concentration and the LTC-IC were compared. Comparison of initial CFC with LTC-IC also showed significant correlations (r = 0.94, CY; r = 0.58, CY-VP-G) in samples from both patient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine monitoring improves graft-versus-host disease prophylaxis after bone marrow transplantation.

OBJECTIVE: The principal objective of this study was to determine whether a relationship exists between trough cyclosporine concentrations measured by HPLC and the development of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. DESIGN: A retrospective analysis of 59 consecutive human leukocyte antigen-matched bone marrow transplants. Patients received uniform GVHD prophylaxis with cyclosporine and methotrexate. Whole blood trough cyclosporine concentrations were measured at least twice weekly during hospitalization and weekly after discharge. SETTING: A dedicated bone marrow transplant unit in an academic center. MAIN OUTCOME MEASURES: The means of cyclosporine concentrations were assessed for each patient on a weekly basis during the first 50 days after transplant. These means were compared between patients developing grade 2-4 acute GVHD and patients without significant GVHD. RESULTS: Eighteen patients developed acute GVHD at a median of 25 days after bone marrow transplant (range 10-50). There was no correlation between the development of GVHD and patient age, diagnosis, donor age, donor gender, donor-recipient gender mismatch, and time to neutrophil engraftment (> 1000 x 10(6) cells/L). Although mean weekly cyclosporine concentrations were consistently lower in patients developing acute GVHD, the difference in values compared with those of patients with GVHD was not statistically significant. Mean weekly cyclosporine concentrations at the time of neutrophil engraftment were statistically associated with the development of GVHD. Patients with GVHD had mean +/- SD concentrations of 174 +/- 69 ng/mL, significantly lower than 254 +/- 114 ng/mL in patients without GVHD. Furthermore, the rate of GVHD was 82 percent in patients with mean concentrations < 200 ng/mL at the time of neutrophil engraftment as compared with a rate of 34 percent in patients with concentrations > or = 200 ng/mL (relative risk = 2.4). Also, mean cyclosporine concentrations measured during the week of onset of GVHD were significantly lower compared with mean cyclosporine concentrations of all other patients at risk of GVHD during that week. CONCLUSIONS: Cyclosporine concentrations are associated with the development of acute GVHD. Patients with HPLC whole blood concentrations < 200 ng/mL are at significantly higher risk of developing GVHD, particularly if these concentrations are observed during the week of neutrophil engraftment. More effective GVHD prophylaxis could be achieved by careful monitoring of cyclosporine concentrations after transplant.

Treatment of metastatic breast cancer with a split-course high-dose chemotherapy regimen and autologous bone marrow transplantation.

PURPOSE: We investigated the role of high-dose chemotherapy and autologous bone marrow transplantation (ABMT) as the initial systemic treatment in patients with hormone-unresponsive metastatic breast cancer. We studied a regimen involving a split-course schedule using sequential administration of two pairs of alkylating agents separated by 5 days of rest. The rest period was intended to provide time for recovery from the treatment-immediate adverse effects, thereby allowing further dose escalation. PATIENTS AND METHODS: The treatment consisted of thiotepa 225 to 300 mg/m2/d (days - 11 to -9), cisplatin 50 to 100 mg/m2/d (days - 11 and -3), and cyclophosphamide 60 mg/kg/d (days - 3 and -2). Dose escalation was performed in the initial 15 patients before reaching dose-limiting toxicities. When feasible, responding patients received posttransplant irradiation to sites of residual or prior bulky disease. Patients with bone marrow or CNS involvement, prior pelvic irradiation, or age greater than 55 years were excluded. RESULTS: Thirty-nine patients with measurable or assessable tumor were enrolled: 23 with visceral metastases, 11 with only soft tissue disease, and five with skeletal involvement. Twenty-five patients had received no chemotherapy for metastatic disease before transplantation. The dose-limiting toxicities of this therapy were renal and gastrointestinal. Six patients died from complications: four of a fungal infection and two of hemorrhage. A complete response was achieved in 14 patients (36%), three of whom are free of disease at 79+, 55+, and 40+ months after transplantation. Ten of 25 patients not treated with standard-dose chemotherapy for metastatic disease achieved a complete response (40%). The three patients in continuous remission were in the untreated relapse group. CONCLUSION: This single high-dose treatment achieved a relatively high complete response rate in patients with metastatic breast cancer and may have cured some of them. On the other hand, the split-course dose schedule as tested here did not permit significant dose-intensification.

Sequential transplants using mobilized peripheral blood progenitor cells.

Modest success has been achieved with the use of high-dose cytotoxic therapy and bone marrow transplantation in solid tumors. Patient outcome can potentially be improved with further intensification of the therapy. The rapid hematologic recovery achieved with mobilized peripheral blood progenitor cells (PBPC) may reduce the toxicity of transplantation enabling the use of sequential courses of myeloablative therapy. We report on 42 patients with solid tumors enrolled in a tandem transplant protocol involving the use of PBPC mobilized with cyclophosphamide (4 g/m2), etoposide (1 g/m2), and granulocyte-colony-stimulating factor (G-CSF: 10 micrograms/kg/day). This regimen significantly increased the number of circulating progenitor cells; only 1-2 aphereses were sufficient to collect 2.5 x 10(8)/kg mononuclear cells, our goal for each transplant course. The median number of circulating colony-forming units (CFU) and CD34+ cells obtained for each transplant course were 70.3 x 10(4)/kg, and 11.7 x 10(6)/kg, respectively. There was a significant correlation between the numbers of CD34+ cells and CFU measured in the apheresis product (r = 0.49, P = .003). The first transplant regimen given to 38 patients consisted of thiotepa, carboplatin, and cyclophosphamide. The second transplant regimen given to 29 patients consisted of busulfan and etoposide. Hematologic recovery was comparable after each of the two transplant courses. The median time to neutrophil recovery over 0.5 x 10(9)/L and to platelet transfusion independence was 9 and 8 days, respectively. There was no difference in engraftment rates after transplant with PBPC only (n = 28 courses) compared to transplant with PBPC plus bone marrow (n = 39 courses).(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of hypermenorrhea with leuprolide in premenopausal women undergoing bone marrow transplantation.

We report on the use of leuprolide to prevent heavy menstrual bleeding that often occurs before platelet engraftment in premenopausal women undergoing bone marrow transplantation (BMT). Leuprolide, a synthetic analog of gonadotropin-releasing hormone (Gn-RH-a), was given to 34 patients by intravenous bolus injection, 1 mg daily, until platelet recovery. The median duration of therapy was 50 days (range 16-170). When necessary, patients self-administered the drug after discharge from the hospital. No adverse effects could be related directly to the use of leuprolide. Leuprolide effectively prevented menstruation in 25 patients (73%), failed in seven (21%), and two patients were not evaluable. The success of leuprolide therapy was related to the time of onset of treatment, as anticipated from the gradual effect of Gn-RH-a on the menstrual cycle. The failure rate was only 6% (one of 16 patients) when leuprolide was started at least 2 weeks prior to the development of thrombocytopenia, compared to a failure rate of 33% (six of 18 patients) when leuprolide was started at a later time. We conclude that leuprolide as a single agent is a safe and effective method to prevent menstrual bleeding during BMT. Additional studies are needed to determine the best timing for the onset of therapy and the relative benefit of leuprolide compared to other prophylactic approaches in patients with lengthy thrombocytopenia.