Evaluation of two plasma fucosyltransferases as marker enzymes in non-Hodgkin's lymphoma.

Levels of two fusosyltransferases were measured in plasmas of patients with non-Hodgkin's lymphoma at different phases of the disease. The level of a GDP-fucose: galactoside fucosyltransferase (EC 2.4.1.69) was found elevated in nonresponding patients and was correlated with estimated tumor burden. Enzyme levels in the normal range were found in patients in remission, maintained on chemotherapy, or unmaintained. The plasma level of a GDP-fucose; N-acetylglucosaminide fucosyltransferase (EC 2.4.1.68) was elevated in all individuals receiving drug therapy regardless of diesease status, but returned to normal levels during unmaintained remissions.     

Clinical pharmacokinetics of high-dose mitomycin C

Summary The pharmacokinetic profile of high-dose mitomycin C was determined in blood plasma and urine of twelve patients with advanced malignancies in a program including autologous bone marrow transplantation. A total dose of 60 mg/m² was given, either as a single 60-min infusion or divided into infusions of 30 mg/m² on each of 2 days or 15 mg/m² on each of 4 days. One group was given 15-min infusions. Samples of blood plasma and urine were analyzed by high-performance liquid chromatography. Drug concentrations in plasma followed a biphasic pattern, with a terminal elimination half-life of 45 min. This half-life value and other parameters were unaffected by dose level, infusion time, and repeated doses. The lower peak plasma concentrations following 30 mg/m² given as 60-min infusions compared to the same dose given over 15 min may have accounted for a dramatic drop in the incidence of a severe hemorrhagic colitis. Mitomycin C was excreted in urine at about the same rate as it was eliminated from plasma, but a larger percentage of the dose appeared in urine after 15-min infusions than after 60-min infusions. The pharmacokinetic profile, together with clinical observations, suggests that the dose-limiting toxicity of mitomycin C may be related to peak drug levels, and that both these levels and the toxicity are lessened as the infusion time is increased.     

Chronic graft-versus-host disease: clinical manifestation and therapy

Chronic graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in long-term survivors of allogeneic stem cell transplantation. The immunopathogenesis of chronic GVHD is, in part, TH-2 mediated, resulting in a syndrome of immunodeficiency and an autoimmune disorder. The most important risk factor for chronic GVHD is prior history of acute GVHD and strategies that prevent acute GVHD also decrease the risk of chronic GVHD. Other important risk factors are the use of a non-T cell-depleted graft, and older age of donor and recipient. Whether recipients of peripheral blood stem cells are at increased risk of chronic GVHD remains unsettled. There are no known pharmacologic agents which can specifically prevent development of chronic GVHD. Agents which have efficacy in the treatment of autoimmune disorders have been utilized as therapy for established chronic GVHD and are associated with response rates of 20% to 80%. Most responses are confined to skin, soft tissue, oral mucosa and occasionally liver. Bronchiolitis obliterans responds infrequently to therapy and is associated with a dismal prognosis. Newer, promising therapeutic strategies under investigation include thalidomide, photopheresis therapy, anti-tumor necrosis factor and B cell depletion with anti-CD20 monoclonal antibody.     

Unrelated donor bone marrow transplantation using a chemotherapy-only preparative regimen for adults with high-risk acute myelogenous leukemia

Limited data are available for adults undergoing unrelated donor (URD) BMT for AML using chemotherapy-only preparative regimens. Previous studies incorporated irradiation, included adults and children, and excluded secondary leukemia. Herein we report long-term outcomes for adults with poor-prognostic AML receiving a novel regimen of busulfan (16 mg/kg), cytarabine (8,000 mg/m(2)), and cyclophosphamide (120 mg/kg) (BAC), followed by URD BMT. From June 1995 through October 2001, 45 adults were enrolled. Adverse features included unfavorable cytogenetics (49%), secondary AML (47%), leukemia at transplant (42%), and extramedullary disease (16%). At time of BMT, 23 were in remission (12 CR1) while 22 had leukemia. Four (9%) died early. Acute and chronic GVHD rates were 44 and 67%, respectively. Seventeen (38%) were disease-free 52 months post-BMT; 13 were leukemia-free (eight CR1) at transplant. Eleven relapsed. Three-year DFS and OS were 42 and 46%, respectively. DFS and OS were longer, and relapses less, for those in CR at time of BMT. Secondary leukemia, cytogenetics, cell dose, and GVHD did not influence outcome. In poor-risk AML, BAC provided cytoreduction comparable to reported TBI-containing regimens, when administered for URD BMT. With decreasing treatment-related mortality, it is justified to proceed early to URD BMT for patients with poor prognostic features.     

Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma

This study compares the probability of disease progression, progression-free survival, and overall survival between patients undergoing an allogeneic or autologous transplant for multiple myeloma using an identical preparative regimen. Patients received a preparative regimen of TBI, busulfan, and cyclophosphamide followed by an allogeneic or autologous transplant. In the allogeneic group (n = 21), six patients received bone marrow and 15 received G-CSF mobilized PBSC; all autologous patients (n = 35) received PBSC mobilized with cyclophosphamide and G-CSF. Allogeneic donors were HLA-identical (n = 20) or one-antigen mismatched (n = 1) siblings. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (n = 10), tacrolimus/methotrexate (n = 6), cyclosporine/methotrexate (n = 4), or cyclosporine (n = 1). The groups were evenly matched for gender, pretransplant therapy, disease status at time of transplant, myeloma subtype, and time from diagnosis to transplant. The median age was significantly lower in the allogeneic group (48 vs 55 years, P < 0.01). In the allogeneic group the probabilities of developing acute GVHD grade II-IV and chronic GVHD were 55% and 82%, respectively. The Kaplan-Meier probability of disease progression was significantly lower in the allogeneic group (11% vs 64%, P < 0.001) compared to the autologous group. Although progression-free (60% vs 30%, P = 0.19) and overall survival at 2 years (60% vs 42%, P = 0.39) favored the allogeneic group, this did not reach statistical significance. Within the allogeneic transplant group, patients age 50 years or under had a 3-year overall survival significantly higher when compared to older patients (79% vs 29%, P = 0.03). Using identical preparative regimens, allogeneic transplantation reduced disease progression compared to autologous transplantation for myeloma. This suggests that allogeneic transplantation induces a graft-versus-myeloma (GVM) effect.     

Extrachromosomal gene amplification in acute myeloid leukemia; Characterization by metaphase analysis,comparative genomic hybridization,and semi-quantitative PCR

A case of acute myeloid leukemia (M-3) with complex karyotypic aberrations and double minute (dmin) chromosomes is presented. The patient had no history of prior exposure to mutagenic or carcinogenic agents or of other malignancies. She died from CNS involvement six weeks after the initial diagnosis. We used comparative genomic hybridization to identify the amplified sequences presumed to represent the dmin of the leukemic cells; the tumor/normal ratios indicated increased signal intensity at 8q24. This localization prompted investigation by semi-quantitative PCR that revealed amplification of the MYC oncogene. The extent of chromosome aberrations and the oncogene amplification, both linked with poor prognosis, may relate to the rapid course of this patient's disease. © 1993 Wiley-Liss, Inc.     

A Phase II Study of BTI-322, a Monoclonal Anti-CD2 Antibody, for Treatment of Steroid-Resistant Acute Graft-Versus-Host Disease

BTI-322, a rat monoclonal IgG2b directed against the CD2 antigen onT cells and natural killer (NK) cells, blocks primary and memoryalloantigen proliferative responses in vitro. We have evaluated thepharmacokinetics and safety of BTI-322 during treatment of 20 transplant recipients with steroid-refractory acute graft-versus-host disease (GVHD). Treatment consisted of BTI-322 by intravenous (IV)bolus or 30-minute infusion at approximately 0.1 mg/kg/d for 10 days inaddition to continuing high-dose steroids and tacrolimus orcyclosporine. Pharmacokinetic sampling was performed in 10 patients;the t_1/2 ± SE was 9.1 ± 1.3 hours, the C_maxwas 2,549 ± 291 ng/mL, the Vd was 3.97 ± 0.95 L, andthe Vd/kg was 0.05 ± 0.01 L/kg. Ten patients experienced transientdyspnea sometimes accompanied by nausea, vomiting, diarrhea, andtachycardia shortly after the initial bolus dose of drug, but seriousdrug-related adverse events were not seen during the remainder of theinfusions. At the end of treatment (day 11), there were six patientswith complete responses and five with a reduction in grade of GVHD fora total response rate of 55% (95% confidence interval[CI], 32% to 77%). Antibodies targeting CD2 may beactive in the treatment of acute GVHD, and evaluation of a humanizedform of BTI-322 is warranted.     

Intensity-modulated radiation therapy reduces the dose to normal tissue in T2N0M0 squamous cell carcinoma of the glottic larynx

The purpose of this paper was to compare intensity-modulated radiation therapy (IMRT) and conventional planning for T2N0M0 squamous cell carcinoma (SQCC) of the glottic larynx. Three patients with T2N0M0 SQCC are presented who were treated with IMRT. Conventional plans were also generated for comparison purposes. Isodose distributions and dose-volume histograms (DVHs) were generated for all the plans to evaluate the fitness of the plan as well as the differential benefit of IMRT vs. conventional treatment. The isodose distributions that were obtained by the IMRT plan are much more conformal to the planning target volume (PTV) and clearly show that less healthy tissue is subjected to a high-dose level, thus reducing toxicity. IMRT offers better comformality without compromising the PTV coverage and delivers less dose to normal tissues as compared to conventional radiation therapy in T2N0M0 SQCC of the glottic larynx. With an increase in conformality, it is expected to have an increase in the therapeutic ratio.     

Combination chemotherapy with mitomycin C, adriamycin, and cyclophosphamide (MAC) in stage III and IV ovarian cancer

Twenty-nine patients with stages III and IV epithelial carcinomas of the ovary were treated with a combination of mitomycin-C, adriamycin, and cyclophosphamide (MAC). A 62% response rate (CR + PR) was observed in previously untreated patients with a median survival of responding patients of 100+ weeks, compared to 29 weeks for nonresponding patients (p less than 0.001). Toxicity was acceptable with moderate to severe but manageable myelosuppression. Prospective, randomized trials comparing this drug combination to others with demonstrated efficacy are indicated.     

Evidence for clonal disease by magnetic resonance imaging in patients with hypoplastic marrow disorders

Some patients with hypoplastic marrow disorders, including aplastic anemia (AA), are at risk for clonal evolution to myelodysplastic syndromes (MDS) and leukemia. Magnetic resonance imaging (MRI) of marrow of the spine, pelvis, and femurs was performed in 24 patients with hypoplastic marrow disorders. In 12 patients (three AA, nine MDS) MRI was compatible with the clinical and biopsy diagnoses and served to define the spectrum of marrow patterns in these disorders. In eight patients with hypocellular marrow biopsies and a clinical diagnosis of AA, MRI showed an unexpected inhomogeneous or diffuse cellular pattern. Concurrent or subsequent marrow or cytogenetic studies have led to diagnoses of hypoplastic MDS in seven of these patients. In four patients with prolonged hypoplasia after bone marrow transplantation for lymphoma, a speckled pattern superimposed on a fatty background appeared in serial MRI studies. One case evolved to AML, two developed megaloblastic foci, and one remains hypoplastic at 19 months. This study suggests that MRI is able to detect early clonal disease in patients with AA, and can distinguish AA from hypoplastic MDS.