Clinical relevance of the lung resistance protein in diffuse large B-cell lymphomas.
Drug resistance of non-Hodgkin's lymphomas may involve mechanisms of the multidrug resistance phenotype including the lung resistance protein (LRP) and the multidrug resistance protein (MRP1). To determine the clinical relevance of these multidrug resistance factors in previously untreated diffuse large B-cell lymphomas (n = 48), we studied LRP and MRP1 expression in lymphoma cells and their impact on clinical outcome. LRP and MRP1 expression were immunohistochemically assessed by means of the monoclonal antibodies LRP-56 and MRPr1, respectively. LRP was positive in 23% and MRP1 in 44% of the samples. LRP expression was associated with higher tumor stage (P = 0.03), elevated serum lactate dehydrogenase levels (P = 0.01), and the International Prognostic Index (P = 0.0001). LRP-positive patients had a lower complete response rate to polychemotherapy than LRP-negative patients (18 versus 65%; P = 0.006). Patients with LRP expression had a shorter overall survival than those without LRP expression (median of 0.9 years versus median not reached; P = 0.001). MRP1 expression was independent of clinical and laboratory parameters and had no impact on the outcome of chemotherapy or survival of the patients. These data suggest that LRP expression but not MRP1 expression is an important mechanism of drug resistance associated with worse clinical outcome in previously untreated diffuse large B-cell lymphomas. Thus, the reversal of LRP-mediated drug resistance may improve clinical outcome in diffuse large B-cell lymphoma in the future. (+info)
Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial.
BACKGROUND: The purpose of this study was to compare the efficacy of the hybrid chemotherapeutic regimen COPP/ABV/IMEP (cyclophosphamide-vincristine-procarbazine-prednisone-doxorubicin-bleomycin-vinbl astine-ifosfamide-methotrexate-etoposide) (CAI) with that of the standard regimen COPP/ABVD (COPP/ABV, dacarbacine) (CA) in the treatment of advanced-stage Hodgkin's disease (HD). PATIENTS AND METHODS: Between January 1988 and January 1993, 588 eligible patients with HD in stages IIIB and IV were randomly assigned to a treatment or control group. The treatment group received four cycles of CAI over a complete cycle duration of 43 days. The control group received four cycles of CA over 57 days. Both groups then received consolidating radiotherapy. RESULTS: Five hundred and eighty-four patients were suitable for arm comparison. Patients in each group were similar in age, sex, histological subtype and clinical risk factors. Complete remission rates, overall survival and freedom from treatment failure at 7 years were similar for the two groups: 77% versus 78%, 73% versus 73% and 54% versus 56% for CAI and CA, respectively. Differences in acute chemotherapy-related toxicity were significant, however. Prognostic factor analysis confirmed the relevance of the International Prognostic Index and revealed that stage IVB, low hemoglobin, low lymphocyte count, high age and male gender were associated with a poor prognosis CONCLUSION: The rapidly alternating hybrid CAI did not give superior results when compared with the standard regimen CA in advanced-stage HD. (+info)
A prospective study of a new combination chemotherapy regimen in patients older than 70 years with unfavorable non-Hodgkin's lymphoma.
PURPOSE: A prospective trial with a new combination of etoposide, mitoxantrone, and prednimustine (VMP), specifically devised for elderly patients with non-Hodgkin's lymphoma (NHL), was undertaken. PATIENTS AND METHODS: Between January 1987 and April 1990, 52 consecutive unselected patients older than 70 years (median age, 75.6 years) with stage I to IV intermediate- and high-grade NHL, or with stage III to IV low-grade malignancy with symptomatic disease received etoposide and prednimustine 80 mg/m2 orally for 5 days and mitoxantrone 8 to 10 mg/m2 day 1 intravenously (IV), every 21 days. Fourteen patients were previously treated. RESULTS: Among the 48 assessable patients, the objective response rate was 81%; 46% of the patients achieved a complete response (CR). The overall toxicity seemed to be acceptable, with 15 (7%) episodes of grade 4 leukopenia and 41 (18%) episodes of grade 3, over a total of 226 administered cycles. The median survival was 12 months. The patients who obtained CR have a longer survival than those who did not (34 v 8 months; P less than .001). Fifty-eight percent of patients achieving CR were free from relapse at 24 months; up to 36 months from the start of therapy, 25% were free from relapse. As far as patients affected by diffuse histiocytic lymphoma, 66% of previously untreated patients obtained a CR, and 55% of them were still disease-free at 24 months from the start of therapy. CONCLUSION: We conclude that VMP is effective, well tolerated, and feasible on an outpatient basis in an unselected, elderly population affected by unfavorable NHL. (+info)
Impact of first- and second-line treatment for Hodgkin's lymphoma on the incidence of AML/MDS and NHL--experience of the German Hodgkin's Lymphoma Study Group analyzed by a parametric model of carcinogenesis.
High-dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin's disease patients: an Italian study group report.
Fifty patients with recurrent Hodgkin's disease have been treated with high-dose therapy followed by autologous bone marrow transplantation. Forty-one patients had extranodal sites of relapse and 31 patients had constitutional symptoms. Two patients had been treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), lomustine, vinblastine, procarbazine, and prednisone (CcVPP), and radiation; 16 patients with MOPP, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), radiation, and lomustine, etoposide, and prednisone (CEP); 20 patients with alternating MOPP/ABVD, and 12 patients with alternating MOPP/ABVD followed by CEP and radiation. Eighteen patients had progressive disease during alternating MOPP/ABVD protocol alone or during conventional salvage therapy; 32 patients had had a complete remission with first-line therapy but later relapsed, 25 of them having received conventional salvage therapy; 12 achieved no response or progression ("resistant-relapse" patients); and 13 responded partially or completely ("sensitive-relapse" patients). Complete remission occurred in 24 patients (48%) with a median duration of 24 months and 16 patients (32%) achieved partial response with a median duration of 9 months, for an overall response rate of 80%. Ten patients failed to respond and died in progressive disease 1 to 10 months (median, 6 months) after transplantation. Toxicity was significant including infections (20%), liver enzymes and alkaline phosphatase elevations (100%), and carmustine lung toxicity (7%). There were two treatment-related deaths; one patient died of Pseudomonas aeruginosa septicemia and another patient died of cerebral hemorrhage. These results validate the procedure of high-dose therapy followed by autologous bone marrow transplantation in inducing remission in these advanced, highly-treated patients. Clearly, the question of whether high-dose therapy and transplantation will eventually supersede new conventional salvage therapies will be addressed after controlled clinical studies. (+info)
Studies on the pharmacokinetics of chlorambucil and prednimustine in man.
1 Chlorambucil (10 mg) and prednimustine (20 mg), the prednisolone ester of chlorambucil, were administered orally on separate occasions to six patients. 2 Chlorambucil was rapidly absorbed such that the parent compound was observed in the plasma 30 min after administration. 3 A preliminary comparison of chlorambucil levels following oral and intravenous administration, and after repeat oral dosage indicated that chlorambucil was well (greater than 70%) and consistently absorbed. 4 Following prednimustine no parent drug or alkylating metabolites (chlorambucil or phenyl acetic mustard) could be detected in the plasma. 5 In studies with intravenously administered chlorambucil plasma levels of the parent drug were described by a two-compartment open model with first-order kinetics. Significant levels of the cytotoxic metabolite phenyl acetic mustard were detected. 6 It is concluded that: a. the bioavailability of orally administered prednimustine is much lower than that of chlorambucil. Thus the use of prednimustine in routine combination therapy is not recommended. b. due to the lower therapeutic index of phenyl acetic mustard in experimental systems, the production of this metabolite in man may be disadvantageous. Thus research aimed at producing chlorambucil analogues, which cannot be metabolised, seems justified. (+info)
Ifosfamide, epirubicin and etoposide (IEV) therapy in relapsed and refractory high-grade non-Hodgkin's lymphoma and Hodgkin's disease.
BACKGROUND: A fundamental principle in the therapeutic strategy for recurrent lymphomas is the employment of agents that are not part of the usual front line combination regimens. Ideally, the cytotoxic agents should lack complete cross resistance with those utilized up front. PATIENTS AND METHODS: A three-drug combination of ifosfamide, epirubicin and etoposide (IEV) was used to treat 20 patients with relapsing or refractory high-grade non-Hodgkin's lymphoma (HG-NHL) or Hodgkin's disease (HD). RESULTS: Of 14 patients with HG-NHL, 5 (36%) achieved a complete response (CR) and 4 partial remission (PR), giving an overall response rate of 64%. To date, all the complete responders are still in CR at +5, +5, +6, +7, and +9 months, respectively. Of 6 patients with HD, 4 (66%) obtained CR and 2 PR, giving an overall response rate of 100%. The 4 CRs are still in remission after +4, +5, +9, and +13 months, respectively. Clinical and hematologic toxic effects were moderate: neutropenia was responsible for delaying treatment for a week in 6 patients. CONCLUSIONS: These results confirm the efficacy of the IEV regimen in inducing a good remission rate with moderate side effects in relapsing/refractory HG-NHL and HD patients and they show that further investigations with this combination are warranted. (+info)
Autologous progenitor cell transplantation: prior exposure to stem cell-toxic drugs determines yield and engraftment of peripheral blood progenitor cell but not of bone marrow grafts.
Agents with stem cell-toxic potential are frequently used for salvage therapy of Hodgkin's disease (HD) and high-grade non-Hodgkin's lymphoma (NHL). Because many patients with relapsed or refractory lymphoma are candidates for autologous progenitor cell transplantation, possible toxic effects of salvage chemotherapy on progenitor cells must be taken into account. In a retrospective study, we have analyzed the influence of a salvage regimen containing the stem cell-toxic drugs BCNU and melphalan (Dexa-BEAM) on subsequently harvested bone marrow (BM)- and peripheral blood-derived progenitor cell grafts (PBPC) and compared it with other factors. Progenitor cells were collected from 96 patients with HD or high-grade NHL. Seventy-nine grafts were reinfused (35 PBPC and 44 BM) after high-dose chemotherapy. Compared with patients autografted with BM, hematopoietic recovery was significantly accelerated in recipients of PBPC. For PBPC, the number of Dexa-BEAM cycles ( > or = v > 1) was the predominate prognostic factor affecting colony-forming unit-granulocyte-macrophage (CFU-GM) yield (66 v 6.8 x 10(4)/kg, P = .0001), CD34+ cell yield (6.6 v 1.6 x 10(6)/kg, P = .0001), neutrophil recovery to > 0.5 x 10(9)/L (9 v. 11 days, P = .0086), platelet recovery to > 20 x 10(9)/L (10 v 15.5 days, P = .0002), and platelet count on day +100 after transplantation (190 v 107 x 10(9)/L, P = .031) using univariate analysis. Previous radiotherapy was associated with significantly lower CFU-GM and CD34+ cell yields but had no influence on engraftment. Patient age, patient sex, disease activity, or chemotherapy other than Dexa-BEAM did not have any prognostic impact. Multivariate analysis confirmed that Dexa-BEAM chemotherapy was the overriding factor adversely influencing CFU-GM yield (P < .0001), CD34+ cell yield (P < .0001), and platelet engraftment (P < .0001). BM grafts were not significantly affected by previous Dexa-BEAM chemotherapy or any other variable tested. However, prognostic factors favoring the use of BM instead of PBPC were not identified using joint regression models involving interaction terms between the graft type (PBPC or BM) and the explanatory variables investigated. We conclude that, in contrast to previous radiotherapy or other chemotherapy, exposure to salvage regimens containing stem cell-toxic drugs, such as BCNU and melphalan, is a critical factor adversely affecting yields and performance of PBPC grafts. Marrow progenitor cells appear to be less sensitive to stem cell-toxic chemotherapy. PBPC should be harvested before repeated courses of salvage chemotherapy involving stem cell-toxic drugs to preserve the favorable repopulation kinetics of PBPC in comparison with BM. (+info)