Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is characterized by a marked degree of morphologic and clinical heterogeneity. Establishment of parameters that can predict outcome could help to identify patients who may benefit from risk-adjusted therapies. BCL-6 is a proto-oncogene commonly implicated in DLBCL pathogenesis. A real-time reverse transcription-polymerase chain reaction assay was established for accurate and reproducible determination of BCL-6 mRNA expression. The method was applied to evaluate the prognostic significance of BCL-6 expression in DLBCL. BCL-6 mRNA expression was assessed in tumor specimens obtained at the time of diagnosis from 22 patients with primary DLBCL. All patients were subsequently treated with anthracycline-based chemotherapy regimens. These patients could be divided into 2 DLBCL subgroups, one with high BCL-6 gene expression whose median overall survival (OS) time was 171 months and the other with low BCL-6 gene expression whose median OS was 24 months (P =.007). BCL-6 gene expression also predicted OS in an independent validation set of 39 patients with primary DLBCL (P =.01). BCL-6 protein expression, assessed by immunohistochemistry, also predicted longer OS in patients with DLBCL. BCL-6 gene expression was an independent survival predicting factor in multivariate analysis together with the elements of the International Prognostic Index (IPI) (P =.038). By contrast, the aggregate IPI score did not add further prognostic information to the patients' stratification by BCL-6 gene expression. High BCL-6 mRNA expression should be considered a new favorable prognostic factor in DLBCL and should be used in the stratification and the design of risk-adjusted therapies for patients with DLBCL. (Blood. 2001;98:945-951)

A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation.

Intravenous immunoglobulin is approved for use in allogeneic bone marrow transplant recipients for prevention of graft-versus-host disease (GVHD) and infections, but the minimally effective dose has not been established. In this multicenter, randomized, double-blind trial, patients undergoing allogeneic marrow transplantation were randomized to receive 100 mg/kg, 250 mg/kg, or 500 mg/kg doses of intravenous immunoglobulin. Each dose was given weekly for 90 days and then monthly until 1 year after transplant. Six hundred and eighteen patients were evaluated. Acute GVHD (grades 2-4) occurred in 39% of the patients (80 of 206) in the 100 mg/kg group, 42% of the patients (88 of 208) in the 250 mg/kg group, and in 35% of the patients (72 of 204) in the 500 mg/kg group (P = 0.344). Among patients with unrelated marrow donors, a higher dose of intravenous immunoglobulin (500 mg/kg) was associated with less acute GVHD (P = 0.07). The incidences of chronic GVHD, infection and interstitial pneumonia were similar for all three doses of intravenous immunoglobulin. The dose of intravenous immunoglobulin also had no effect on the types of infection, relapse of hematological malignancy or survival. Except for more frequent chills (P = 0.007) and headaches (P = 0.015) in patients given the 500 mg/kg or 250 mg/kg dose of immunoglobulin, adverse events were similar for all three doses. These results suggest that 100 mg/kg, 250 mg/kg, and 500 mg/kg doses of intravenous immunoglobulin are associated with similar incidences of GVHD and infections in most allogeneic marrow transplants. These results should be considered when designing cost-effective strategies for the use of intravenous immunoglobulin in allogeneic marrow transplants receiving other current regimens for prophylaxis of GVHD and infection.

Semi-automated entry of clinical temporal-abstraction knowledge.

OBJECTIVES: The authors discuss the usability of an automated tool that supports entry, by clinical experts, of the knowledge necessary for forming high-level concepts and patterns from raw time-oriented clinical data. DESIGN: Based on their previous work on the RESUME system for forming high-level concepts from raw time-oriented clinical data, the authors designed a graphical knowledge acquisition (KA) tool that acquires the knowledge required by RESUME. This tool was designed using Protégé, a general framework and set of tools for the construction of knowledge-based systems. The usability of the KA tool was evaluated by three expert physicians and three knowledge engineers in three domains-the monitoring of children's growth, the care of patients with diabetes, and protocol-based care in oncology and in experimental therapy for AIDS. The study evaluated the usability of the KA tool for the entry of previously elicited knowledge. MEASUREMENTS: The authors recorded the time required to understand the methodology and the KA tool and to enter the knowledge; they examined the subjects' qualitative comments; and they compared the output abstractions with benchmark abstractions computed from the same data and a version of the same knowledge entered manually by RESUME experts. RESULTS: Understanding RESUME required 6 to 20 hours (median, 15 to 20 hours); learning to use the KA tool required 2 to 6 hours (median, 3 to 4 hours). Entry times for physicians varied by domain-2 to 20 hours for growth monitoring (median, 3 hours), 6 and 12 hours for diabetes care, and 5 to 60 hours for protocol-based care (median, 10 hours). An increase in speed of up to 25 times (median, 3 times) was demonstrated for all participants when the KA process was repeated. On their first attempt at using the tool to enter the knowledge, the knowledge engineers recorded entry times similar to those of the expert physicians' second attempt at entering the same knowledge. In all cases RESUME, using knowledge entered by means of the KA tool, generated abstractions that were almost identical to those generated using the same knowledge entered manually. CONCLUSION: The authors demonstrate that the KA tool is usable and effective for expert physicians and knowledge engineers to enter clinical temporal-abstraction knowledge and that the resulting knowledge bases are as valid as those produced by manual entry.

Tool support for authoring eligibility criteria for cancer trials.

A critical component of authoring new clinical trial protocols is assembling a set of eligibility criteria for patient enrollment. We found that clinical protocols in three different cancer domains can be categorized according to a set of clinical states that describe various clinical scenarios for that domain. Classifying protocols in this manner revealed similarities among the eligibility criteria and permitted some standardization of criteria based on clinical state. We have developed an eligibility criteria authoring tool which uses a standard set of eligibility criteria and a diagram of the clinical states to present the relevant eligibility criteria to the protocol author. We demonstrate our ideas with phase-3 protocols from breast cancer, prostate cancer, and non-small cell lung cancer. Based on measurements of redundancy and percentage coverage of criteria included in our tool, we conclude that our model reduces redundancy in the number of criteria needed to author multiple protocols, and it allows some eligibility criteria to be authored automatically based on the clinical state of interest for a protocol.

Automation and integration of components for generalized semantic markup of electronic medical texts.

Our group has built an information retrieval system based on a complex semantic markup of medical textbooks. We describe the construction of a set of web-based knowledge-acquisition tools that expedites the collection and maintenance of the concepts required for text markup and the search interface required for information retrieval from the marked text. In the text markup system, domain experts (DEs) identify sections of text that contain one or more elements from a finite set of concepts. End users can then query the text using a predefined set of questions, each of which identifies a subset of complementary concepts. The search process matches that subset of concepts to relevant points in the text. The current process requires that the DE invest significant time to generate the required concepts and questions. We propose a new system--called ACQUIRE (Acquisition of Concepts and Queries in an Integrated Retrieval Environment)--that assists a DE in two essential tasks in the text-markup process. First, it helps her to develop, edit, and maintain the concept model: the set of concepts with which she marks the text. Second, ACQUIRE helps her to develop a query model: the set of specific questions that end users can later use to search the marked text. The DE incorporates concepts from the concept model when she creates the questions in the query model. The major benefit of the ACQUIRE system is a reduction in the time and effort required for the text-markup process. We compared the process of concept- and query-model creation using ACQUIRE to the process used in previous work by rebuilding two existing models that we previously constructed manually. We observed a significant decrease in the time required to build and maintain the concept and query models.

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.

A paradigm shift in myelodysplastic syndromes.

A poorly defined transforming event(s) affects the pluripotential bone marrow (BM) stem cell in myelodysplastic syndromes (MDS), conferring a growth advantage upon it which leads eventually to monoclonal hematopoiesis. The progeny of this transformed ancestor undergo recognizable albeit dysplastic maturation. We propose that this picture is further complicated by a variety of cytokines, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta) and interleukin 1beta (IL-1beta) which exert a dual effect on the diseased cells. The immature CD34+ cells are stimulated to proliferate, while their later differentiated daughters are induced to undergo apoptosis accounting for the clinical syndrome of pancytopenia despite hypercellular BMs. Studies directed at measuring the rates of proliferation and apoptosis as well as the levels of TNF-alpha, TGF-beta and IL-1beta confirm this hypothesis and are presented in greater detail. A novel approach towards MDS therapy emerges as a result of this paradigm shift based upon the premise that anti-cytokine therapy would prevent excessive intramedullary apoptosis and result in improved cytopenias as well as cause a slowing down of the diseased precursor cell proliferation resulting in resumption of polyclonal hematopoiesis. Because a number of cytokines function through common lipid second messengers, interruption of this pathway should theoretically cause disruption in the signalling of a cascade of cytokines.

Novel insights into the biology of myelodysplastic syndromes: excessive apoptosis and the role of cytokines.

The paradox of myelodysplastic syndromes (MDS) which present with pancytopenias despite cellular bone marrows (BM) was investigated by conducting detailed studies of proliferation and apoptosis in 89 MDS patients. Our results demonstrated a rapid rate of both proliferation as well as apoptosis. Levels of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and interleukin-1 beta (IL-1 beta) were measured in the same patients. High levels of TNF-alpha were found to correlate with high levels of apoptosis in 83 MDS patients (P = 0.0045). We propose a dual role for TNF-alpha (or other cytokines) in the pathogenesis of MDS. On the one hand, TNF-alpha induces apoptosis in the maturing cells causing pancytopenia while on the other, it stimulates the proliferation of the primitive progenitors accounting for the hypercellular BM frequently seen in MDS. A new model for MDS is presented. The initial abnormality probably affects a primitive hemopoietic progenitor which acquires a growth advantage leading to monoclonal hemopoiesis, which in turn makes these cells susceptible towards acquiring additional mutations and appearance of cytogenetically marked (or unmarked) clones. Cytokines such as TNF-alpha whose source is presently unknown, then contribute towards the clinical syndrome of pancytopenia and hypercellularity.

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.

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.

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.

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.

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.

Autologous bone marrow transplant in acute myeloid leukemia in first remission.

PURPOSE: The Eastern Cooperative Oncology Group conducted a prospective study of postremission high-dose chemotherapy and autologous bone marrow transplantation (autoBMT) in a group of uniformly treated adults with de novo acute myeloid leukemia (AML) to evaluate whether intensive, myeloablative therapy in first complete remission (CR) could improve the disease-free survival. PATIENTS AND METHODS: After initial CR was induced by the combination of daunorubicin, cytarabine, and thioguanine, patients not eligible for allogeneic bone marrow transplantation (alloBMT) were offered autoBMT. Within a median of 2 months after CR, and without intervening postremission therapy, bone marrow was obtained, purged by exposure to 4-hydroperoxycyclophosphamide (4-HC), and cryopreserved. High-dose therapy consisted of oral busulfan over 4 days (16 mg/kg total) followed by intravenous (IV) cyclophosphamide 50 mg/kg daily for 4 days. The cryopreserved marrow was then reinfused. RESULTS: Of the 39 patients scheduled for autoBMT, four relapsed before transplantation. Two of the 35 (6%) transplant patients died of transplant-related complications, and 11 (33%) relapsed a median of 8 months after marrow reinfusion. No relapse has occurred after 24 months posttransplant. With a median follow-up of 31 months, the median disease-free survival period for all 39 patients has not been reached; however, 54% +/- 16% of patients are projected to be alive and disease-free at 3 years. CONCLUSION: Long-term, disease-free survival after autoBMT in AML seems to be better than the outcome after conventional-dose postremission therapy and rivals the results of alloBMT.

Evaluation of pulmonary complications after bone marrow transplantation: the role of pretransplant pulmonary function tests.

To determine whether an association exists between abnormal pulmonary function tests (PFT) before bone marrow transplantation (BMT) and the rate of pulmonary complications after BMT, we retrospectively reviewed all transplants performed in our center between March 1984 and December 1990. A total of 163 patients, 15 years of age and older, with a hematologic malignancy or a solid tumor were treated with intensive therapy and autologous (118) or allogeneic (55) BMT. Sixty patients (37%) developed a pulmonary complication which contributed to patient death in 29 transplants (18%). Patients with pulmonary metastases, prior thoracotomy, or prior radiation to the chest had a higher frequency of abnormal PFT. By univariate analysis, patients with abnormal FVC, FEV1, or TLC before BMT had a significantly increased rate of pulmonary complications (p < 0.005). By multivariate analysis, the rate of pulmonary complications was significantly associated (p = 0.004) with abnormal FEV1 only: in the first 2 months after transplantation the rate was 65% in patients with FEV1 < 70% in contrast to 34% in patients with FEV1 > or = 70% (risk ratio = 1.9). There was no association, however, between abnormal pretransplant PFT and fatal pulmonary complications. We conclude that patients with pretransplant ventilatory defects have a higher risk of pulmonary complications after BMT, but the incidence of fatal complications was not significantly increased, although we cannot exclude a diminished study power due to the sample size. We believe that patients with abnormal PFT should not be excluded from transplantation if the anticipated anti-tumor effect is estimated to be substantial, but additional preventive measures may be necessary.