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H Tesch

Publications and source records attributed to H Tesch.

At least 55 records · Page 3Linked to original sources
PubMed1999

Successful peripheral blood stem cell mobilization with etoposide (VP-16) in patients with relapsed or resistant lymphoma who failed cyclophosphamide mobilization.

High-dose chemotherapy (HDCT) followed by autologous blood stem cell transplantation is considered the treatment of choice for patients with relapsed or resistant aggressive non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). However, several authors report failure of standard mobilization regimens in 29% to 56% of these patients making the completion of HDCT impossible and as a result, negatively influencing long-term outcome. Thus, effective new regimens for patients failing initial mobilization are needed. Here we report the results of using etoposide as a mobilizing agent in 16 patients with primary resistant or relapsed malignant lymphoma who had failed prior mobilization of peripheral blood stem cells (PBSC) with cyclophosphamide (4 g/m2) followed by G-CSF. The use of etoposide 500 mg/m2 (days 1-4) + G-CSF resulted in the successful collection of adequate numbers of PBSC with a median harvest of 3.6 x 10(6)/kg (range 2.2-12.6) CD34+ cells in all 16 patients. In 7/16 (44%) patients, the target yield of at least 2.0 x 10(6) CD34+ cells was harvested by a single apheresis and the maximum number of separations for all patients was two. No excessive toxicities appeared, allowing all patients to proceed to myeloablative chemotherapy. In addition, median peak values of circulating CD34+ cells were significantly higher after etoposide as compared to cyclophosphamide (49.2/microl vs 4.7/microl; P = 0.0004). These results indicate that etoposide + G-CSF is a highly effective mobilization regimen in patients who have failed cyclophosphamide mobilization.

Adult↗
PubMed1999

The AT-rich region between -54 to -66 is important for the promoter activity of interleukin-10 in Epstein-Barr virus positive Burkitt's lymphoma cells.

IL-10 is an important regulatory cytokine. The recent characterization of the 5'-flanking region of IL-10 led to the identification of the promoter region. The infection of B cells with EBV induces IL-10 production which may contribute to EBV-induced transformation. In the present report, IL-10 promoter elements involved in the constitutive expression of IL-10 in EBV-positive lymphoma cells are described. The AT-rich region between -54/-66 from the transcriptional start site was found to be important for IL-10-promoter activity in BL36. A point mutation at position -60 (T/A) was associated with over 90% reduction of luciferase activity in the cell lines BL36 and BL74. The conversion of A/T at position -57 led to enhanced promoter activity. In addition the AT-rich region could serve as an enhancer for the beta-globin basic promoter. In BJAB cells (EBV-negative), sequences between -205/-139 rather than the AT-rich region were involved in IL-10 promoter regulation. This underlines the importance of the AT-rich region for EBV-associated IL-10 promoter regulation. Our results further the understanding of how the IL-10 gene could be regulated in B cell lymphomas.

AT Rich Sequence↗
PubMed1999

Detection of a Hodgkin/Reed-Sternberg cell specific immunoglobulin gene rearrangement in the serum DNA of a patient with Hodgkin's disease.

We analysed multiple serum samples from a patient with mixed cellularity Hodgkin's disease for the Hodgkin/Reed-Sternberg cell clone-specific rearranged Ig gene sequence. The clone-specific sequence could be detected in DNA extracted from a serum sample obtained during clinical relapse but not in serum samples obtained during or after treatment following relapse.

Adult↗
PubMed1999

Expression of epstein-barr virus nuclear antigen 1 is associated with enhanced expression of CD25 in the Hodgkin cell line L428.

Epstein-Barr virus is associated with several human malignancies including Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkin's disease (HD). To examine the effect of Epstein-Barr virus nuclear antigen 1 (EBNA-1) in the pathogenesis of HD, we transfected the gene into the HD cell line L428. EBNA-1 expression was associated with significantly enhanced CD25 expression (interleukin 2 [IL-2]-receptor alpha chain) in transient and stably transfected L428 cells but did not affect the expression of IL-2 receptor beta and gamma chains. There was no up-regulation of the B-cell activation molecules CD23, CD30, CD39, CD40, CD44, CD71, and CD54 (intercellular adhesion molecule 1) or enhanced production of IL-6, IL-10, lymphotoxin alpha, and the soluble form of CD25. Stable EBNA-1-expressing L428 cells were nontumorigenic in SCID mice but showed enhanced lymphoma development in nonobese diabetic-SCID mice compared to mock-transfected cells.

Animals↗
PubMed1999

Dexa-BEAM is not effective in patients with relapsed or resistant aggressive high-grade non-Hodgkin's lymphoma.

The aim of the present study was to evaluate the feasibility and response of the Dexa-BEAM regimen as a salvage therapy followed by high-dose chemotherapy (HDCT) with peripheral blood stem cell transplantation (PBCST) in responding patients with high-grade relapsed or resistant aggressive non-Hodgkin's lymphoma (NHL). Sixteen pretreated patients (mean age 44, range 26-59) with relapsed (8) or resistant (8) NHL were treated with 1-4 cycles of Dexa-BEAM (dexamethasone, BCNU, etoposide, cytarabine, melphalan) in order to attain maximal response. Patients achieving complete response (CR) or partial response (PR) received HDCT with PBSCT. The conditioning regimen used was BEAM. Three patients achieved CR and one patient PR, resulting in an overall response rate of 25%. Three of four responding patients underwent high-dose chemotherapy and were successfully transplanted with autologous blood stem cells. Progressive disease developed in one patient after transplantation. Myelosuppression (WHO grade III- grade IV), the major side effect, was observed in all courses of Dexa-BEAM. Myelosuppression-related infection WHO grade IV occurred in four patients. The protocol was not well tolerated in this heavily pretreated group of patients with four severe myelosuppression-related infections WHO grade IV and one treatment-related death. The overall response rate in this study is not comparable to other salvage regimens published and led to the discontinuation of the trial. In conclusion Dexa-BEAM was only effective in a minority of patients with refractory or relapsed aggressive NHL and was not useful as a cytoreductive regimen prior to HDCT.

Adult↗
PubMed1998

Moderate dose escalation for advanced stage Hodgkin's disease using the bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone scheme and adjuvant radiotherapy: a study of the German Hodgkin's Lymphoma Study Group.

The BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen, a rearranged and accelerated version of the standard COPP/adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, has been shown to be effective and safe in a previous pilot study for advanced stage Hodgkin's disease (HD). The present study aimed to determine a maximum practicable dose of three drugs, ie, etoposide, adriamycin, and cyclophosphamide, for which acute toxicities were acceptable and to assess the feasibility of the escalated scheme. Sixty untreated patients with advanced stage HD were enrolled in this study. Radiotherapy was given in 44 patients (73%) after chemotherapy to initial bulk lesions and residual disease. Granulocyte-colony stimulating factor (G-CSF) was given from day 8 to prevent prolonged neutrocytopenia and severe infections. The intended doses of adriamycin, etoposide, and cyclophosphamide in the BEACOPP schedule could be substantially escalated: adriamycin from 25 to 35, cyclophosphamide from 650 to 1,200, and etoposide from 100 to 200 mg/m2. The major toxicities were leukocytopenia and thrombocytopenia with considerable heterogeneity between individual patients. Of 60 patients, 56 (93%) achieved a complete remission (CR). At a median observation of 32 months, the rates of survival and freedom from treatment failure (FFTF) were estimated to be 91% (95% confidence interval 83% to 99%) and 90% (82% to 98%). These results show that a moderate dose escalation of adriamycin, cyclophosphamide, and etoposide of the baseline BEACOPP regimen is feasible. The escalated BEACOPP regimen shows very encouraging results in advanced stage HD and is now being compared in a randomized phase III study with BEACOPP at baseline dose level.

Adolescent↗
PubMed1998

Detection of clonal Hodgkin and Reed-Sternberg cells with identical somatically mutated and rearranged VH genes in different biopsies in relapsed Hodgkin's disease.

Hodgkin's disease (HD) represents a malignant lymphoma in which the putative malignant Hodgkin and Reed-Sternberg (H-RS) cells are rare and surrounded by abundant reactive cells. Single-cell analyses showed that H-RS cells regularly bear clonal Ig gene rearrangements. However, there is little information on the clinical evolution of HD in a given patient. In this study, we used the single-cell polymerase chain reaction (PCR) to identify H-RS cells with clonal Ig gene rearrangements in biopsy specimens of patients with relapsed HD. The obtained clonal variable region heavy-chain (VH) gene rearrangements were used to construct tumor-clone-specific oligonucleotides spanning the complementarity determining region (CDR) III and somatically mutated areas in the rearranged VH gene. A number of biopsies were obtained during a period of 3 years from two HD patients. H-RS cells with identical VH rearrangements were detected in two separate infiltrated lymph nodes from one patient with nodular sclerosis HD. In a second patient with mixed cellularity HD subtype, clonal VH rearrangements with identical sequences were detected in infiltrated spleen and two lymph node biopsies. Despite the high sensitivity of the PCR method used (one clonal cell in 10(5) mononuclear cells), residual H-RS cells were not found in peripheral blood, leukapheresis material, purified CD34(+) stem cells or bone marrow. The results show that different specimens from relapsed patients suffering from classical HD carry the same clonotypic IgH rearrangements with identical somatic mutations, demonstrating the persistence and the dissemination of a clonal tumor cell population. Thus, PCR assays with CDRIII-specific probes derived from clonal H-RS cells are of clinical importance in monitoring the dissemination of HD and tumor progression and could be useful for analysis of minimal residual disease after autologous stem cell transplantation.

Adult↗
PubMed1998

Isolation of viable Hodgkin and Reed-Sternberg cells from Hodgkin disease tissues.

Hodgkin disease (HD) is characterized by a small number of malignant Hodgkin and Reed-Sternberg (H/RS) cells among a major population of nonmalignant cells. The analysis of H/RS cells has been hampered by their low frequency and fragility. Here, we describe the isolation of viable H/RS cells from HD affected tissues by high gradient magnetic cell sorting (MACS) according to expression of CD30. The cells were enriched to a purity of up to 50%. H/RS cells were distinguished from other CD30(+) cells by the expression of CD15, their size and granularity. No CD30/CD15 double-positive cells could be enriched from a lymph node affected by the lymphocyte predominant subtype of HD, activated lymph nodes or peripheral blood of healthy donors. For two cases of HD individual MACS-purified H/RS cells and H/RS cells micromanipulated from tissue sections of the same lymphoma specimens were analyzed for Ig gene rearrangements. In both cases, identical V gene rearrangements were amplified from both sources of H/RS cells, showing that H/RS cells were successfully enriched. Moreover, the finding that in both cases no additional Ig gene rearrangements other than the ones identified in the H/RS cells micromanipulated from tissue sections were amplified from the MACS-purified H/RS cells further supports the monoclonality of these cells throughout the affected lymph nodes. The isolation of viable H/RS cells ex vivo is prerequisite for a direct study of gene expression by those cells and of their interaction with cells in their vicinity.

Adolescent↗
PubMed1998

[Pathogenesis and therapy of Hodgkin lymphoma].

Although the pathogenesis of Hodgkin's disease is not clear, molecular analyses reveal characteristic features. EBV infection can be demonstrated in more than 50% of cases at the DNA or protein level. Recently, immunoglobulin gene rearrangements were found in single Hodgkin and Reed-Sternberg cells. Sequence analyses revealed that the rearranged Ig genes have frequently somatic mutations, which indicate that the cells are derived from the germinal center. These rearrangements may be used as defined markers to detect residual disease after chemotherapy. Modern polychemotherapy regimen and radiotherapy are very effective, and 60-90% of patients, depending on stage of the disease and risk factors, can be cured. Salvage therapy for relapsed patients including high-dose chemotherapy with autologous stem cell support frequently results in remission although duration is frequently short. New immunotherapy strategies with immunotoxins or bispecific antibodies are currently analysed in clinical studies.

Combined Modality Therapy↗
PubMed1998

Cytosine arabinoside, etoposide and aclarubicin (AVA) for the treatment of acute myeloid leukemia (AML) in elderly patients.

BACKGROUND: Elderly patients (age > or = 60 years) with acute myeloid leukemia (AML) have unfavourable prognoses when polychemotherapy regimens are used, because therapy response is characterized by low remission rates, short remission duration and high toxicity. PATIENTS AND METHODS: A phase II trial in elderly AML patients was conducted to determine the efficacy of two induction courses of a moderately-dosed combination of aclarubicin (25 mg/m2, 30 min i.v., days 1-4), etoposide (100 mg/m2, 30 min i.v., days 1-3) and conventional-dose cytosine arabinoside (ara-C, 100 mg/m2, c.i.v., days 1-3 and 30 min i.v., q 12 hours, days 4-7) (AVA-7), followed by one consolidation treatment using a reduced-dose schedule over five days (AVA-5) after three months in CR. RESULTS: Thirty-two AML patients with a median age of 66.2 years (range 60-76) were included in the study: three of them had histories of preexisting myelodysplasia and one of polycythemia vera. Following 1-2 courses of AVA-7 17 patients (53%) achieved CR, two PR (6%), and nine had resistant disease (28%); the overall response rate was thus 59%. Toxicity was significant but acceptable, with an overall treatment-related death rate of five of 32 patients (16%) after 63 courses of AVA. The median disease-free survival (DFS) was 12 months, and the median survival of all patients was 16.6 months. CONCLUSIONS: These results indicate that the combination of aclarubicin, etoposide and conventional-dose ara-C is effective in elderly AML patients. The relatively brief remission duration requires new consolidation and maintenance therapy approaches.

Aclarubicin↗
PubMed1998

Favorable outcome of patients with relapsed or refractory Hodgkin's disease treated with high-dose chemotherapy and stem cell rescue at the time of maximal response to conventional salvage therapy (Dex-BEAM).

BACKGROUND: Disease status before high-dose chemotherapy with autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PBSCT) is an important predictor of transplantation-related toxicity and event-free survival (EFS) for patients with relapsed or refractory Hodgkin's disease (HD). We performed a phase II study in patients with relapsed or refractory HD to evaluate the feasibility of four cycles of Dexa-BEAM followed by high-dose chemotherapy with ABMT or PBSCT. PATIENTS AND METHODS: Twenty-six patients (median age 30, range 20-40 years) were treated with 2-4 courses of dexamethasone, carmustine, etoposide, cytarabine and melphalan (Dexa-BEAM) as salvage chemotherapy in order to attain maximal response. Patients achieving complete response (CR) or partial response (PR) received high-dose chemotherapy with ABMT or PBSCT. The conditioning regimen used was CVB (cyclophosphamide, carmustine, etoposide). RESULTS: Eighteen patients responded to Dexa-BEAM, resulting in a response rate of 69%. At the time of transplant 16 patients were in CR two patients in PR. At present 14 patients transplanted are in continuous CR (median follow-up 40 months, range 14-60 months). Two patients with PR after four courses of Dexa-BEAM relapsed and died three months posttransplantation. Two patients with CR at the time of transplant relapsed after nine and 13 months respectively. Eight patients had rapid progressive disease after 2-4 cycles of Dexa-BEAM. One patient with progressive disease died in gram-negative sepsis after four cycles of Dexa-BEAM. There was no transplantation-related death. CONCLUSION: These data suggests the use of high-dose chemotherapy followed by stem cell transplantation at the time of maximal response.

Adult↗
PubMed1998

Lymphocyte predominant Hodgkin's disease: pathology and clinical implication.

The special nature and course of lymphocyte rich variants of Hodgkin's disease (HD) has been the subject of pathological and clinical studies since the 1930s. Patients with lymphocyte predominant (LP) HD, predominantly male and 25-45 years old, usually present with early clinical stage, cervical or inguinal involvement and few if any adverse prognostic factors. The disease progresses slowly, with fairly frequent relapses which are rarely fatal. Nonetheless, cases with advanced stage and deaths from Hodgkin's disease have been observed in LPHD. Recently, immunological studies have lead to a clear distinction between LPHD and classical HD including a lymphocyte rich classical version (LRCHD). Secondary low-grade NHLs occur more frequently after LPHD than after classical HD. They seem to be disease-related rather than treatment-induced. LPHD patients in earlier studies have tended to have a better prognosis than classical HD patients. When cohorts of the same clinical stage are compared, under modern protocol treatment this advantage seems to be minimal or absent. LPHD patients tend to relapse frequently but they survive these relapses better than classical HD patients. The resemblance to non-neoplastic disorders, capability for ongoing mutation, favorable clinical presentation and good survival rates after relapse all suggest that the optimal primary treatment strategy might be less intensive for LPHD than for classical HD. Late toxicities, which contribute considerably to the death rate, could thus be reduced. The long survival of several early stage LPHD patients without any treatment beyond lymph node excision could favour a 'watch-and-wait' strategy, albeit only after rigorous staging. New experimental therapy techniques such as immunotherapy might also be suitable. These possibilities must first be tested in a large-scale prospective study.

Adult↗
PubMed1998

BEACOPP: a new regimen for advanced Hodgkin's disease. German Hodgkin's Lymphoma Study Group.

The BEACOPP chemotherapy regimen for advanced Hodgkin's disease employs a rearranged schedule permitting a shortened three-week cycle. With haematological growth factor support, the dosages of cyclophosphamide, etoposide and adriamycin could be moderately escalated. The 3-armed multicentre HD9 trial (recruitment 1993-1998; 1300 patients randomised) aimed to compare BEACOPP with the standard COPP/ABVD chemotherapy and to detect and measure the gain in efficacy, if any, due to moderate dose escalation of BEACOPP. Eight cycles were given, followed by local irradiation. The most recent interim analysis, with 689 evaluable patients, circa 40% of all expected events and a median observation time of 27 months, showed significant differences in progression rate (P) and in two-year freedom from treatment failure (F) between the treatment arms, with escalated BEACOPP (P = 2%, F = 89%) better than baseline BEACOPP (P = 9%, F = 81%) better than COPP/ABVD (P = 13%, F = 72%). Survival was not significantly different. Acute toxicity was more severe due to dose escalation, but remained manageable. These preliminary results suggest that BEACOPP improves efficacy. Moderate dose escalation is feasible with G-CSF support and appears likely to make a worthwhile improvement in the cure rate. The results must await confirmation (or otherwise) by the final analysis including all randomised patients and sufficiently mature data.

Adolescent↗
PubMed1998

Current clinical trials for the treatment of adult Hodgkin's disease: common strategies and perspectives.

Strategies in the treatment of adult Hodgkin's disease (HD) are changing strikingly in current clinical trials. In early as well as in intermediate stage HD a common aim of most study groups now is the reduction of radiation dose and volume in order to minimize severe late effects like myocardial damage and secondary neoplasias. As a consequence extended field irradiation is abandoned in nearly all trials, and combined modality treatment will be used not only in intermediate, but also in early stage HD. In advanced stage HD new chemotherapy regimens, based on the principle of a moderate dose escalation, for the first time seem to improve the therapeutic outcome. Thus, the priority in current clinical trials for advanced stage HD is the long-term evaluation of these new regimens with regard to treatment efficacy and toxicity.

Adult↗
PubMed1998

BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group.

PURPOSE: The HD9 trial aims to evaluate whether moderate dose escalation and/or acceleration of standard polychemotherapy is beneficial for advanced-stage Hodgkin's disease (HD). Two variants of a novel bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) scheme (standard and escalated dose) are compared with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). PATIENTS AND METHODS: The randomized, three-arm trial recruited patients in stages IIB and IIIA with risk factors and stages IIIB and IV. BEACOPP in baseline dose contains all drug dosages of COPP/ABVD (except vincristine and procarbazine) rearranged in a shorter, 3-week cycle. Escalated BEACOPP uses higher doses of cyclophosphamide, doxorubicin, and etoposide with granulocyte colony-stimulating factor (G-CSF) support. After eight chemotherapy cycles, initial bulky and residual disease is irradiated. The trial is monitored and analyzed by means of a sequential strategy. RESULTS: An interim analysis with 505 assessable patients and a median follow-up of 23 months showed a significant inferiority (according to sequential monitoring strategy) of the COPP/ABVD regimen in progression rate and freedom from treatment failure (FFTF) compared with the pooled results of both BEACOPP variants. The 24-month FFTF rate was 75% for COPP/ABVD and 84% for BEACOPP pooled (P = .034). There was 12% progressive disease with COPP/ABVD and 6% with BEACOPP pooled. Differences in survival were not significant in sequential analysis. The acute toxicity of baseline BEACOPP resembled that of COPP/ABVD; escalated BEACOPP showed increased but manageable hematologic toxicity. CONCLUSION: Combined with local irradiation, BEACOPP in one or both variants shows superior disease control compared with COPP/ABVD, with acceptable acute toxicity. Further follow-up is required to assess the effect of dosage and the effect on survival and late toxicities.

Adolescent↗
PubMed1997

Single-step purification of bispecific monoclonal antibodies for immunotherapeutic use by hydrophobic interaction chromatography.

A method for large scale production and single-step purification of bispecific antibodies is described. Hybrid-hybridomas were grown in hollow-fibre bioreactors with an average yield of 8 to 12 g of immunoglobulin per month. Bispecific antibodies were purified from the bioreactor supernatant by hydrophobic interaction chromatography which resolves bispecific antibodies, monospecific immunoglobulins, and culture medium supplements in one single chromatographic step. Proteins were analyzed by ELISA, SDS-PAGE, isoelectric focussing, indirect fluorescence staining, CTL-stimulation and T-cell proliferation assays. Finally, antibody preparations were checked for the presence of endotoxin and mouse DNA. Our results suggest that functional bispecific antibodies for use in therapeutic applications can be batch purified from bioreactor harvest by hydrophobic interaction chromatography in a single step. Compared to other methods such as affinity chromatography (protein A/G), ion-exchange or hydroxyapatite chromatography, our protocol offers a substantial reduction in labor time, cost, protein loss, and risk of contamination.

Animals↗
PubMed1997

Prevention of Epstein-Barr virus-induced human B-cell lymphoma in severe combined immunodeficient mice treated with CD3xCD19 bispecific antibodies, CD28 monospecific antibodies, and autologous T cells.

Bispecific CD3 x antitumor antibodies in combination with coactivating CD28 antibodies can induce resting T cells to proliferate and to lyse syngeneic tumor cells (M. Azuma et al., J. Immunol., 150: 2091-2101, 1993; M. Azuma et al., J. Exp. Med., 177: 845-850, 1993). This combination of antibodies may therefore be useful for active immunotherapy of malignant tumors. In this study, we present a preclinical model to evaluate CD3xCD19 bispecific antibodies. We investigated whether bispecific antibodies prevent the development of malignant EBV-induced lymphomas in severe combined immunodeficient (SCID) mice which lack functional B and T lymphocytes (G. C. Bosma et al., Immunogenetics, 29: 54-57, 1989). SCID mice were engrafted (i.p.) with peripheral blood lymphocytes and EBV and treated after 3 days with CD3xCD19 bispecific antibodies and CD28 antibodies. Our data demonstrate that the growth of B cell lymphomas can be prevented in SCID mice by treatment with CD3xCD19 bispecific antibodies and that B-lymphoma-specific T cells can be recruited. In contrast to in vitro experiments, there was no clear effect of CD28 administration which is due to high expression of B7-1 on the transplanted B cells. Lymphoma-bearing mice had elevated titers of interleukin10 in the serum, in contrast to tumor-free animals. As shown by PCR analysis, there was no evidence of dormant B-lymphoma cells in specimens from surviving mice. In the spleen of surviving mice, rearranged human T-cell receptor gamma gene segments were detectable. Furthermore, mice that were initially treated with CD3xCD19 and CD28 antibodies did not develop lymphomas upon rechallenge with EBV-infected mononuclear cells of the same donor, whereas control animals did. Our results obtained from this autologous human B-lymphoma model have implications for the design and evaluation of new immunotherapeutic modalities for the treatment of human B-cell lymphoma with bispecific antibodies.

Animals↗