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A novel Hodgkin's disease (HD) derived cell line, L1236, was established from the peripheral blood of a patient with advanced Hodgkin's disease. Analysis of immunoglobulin (Ig) gene rearrangements revealed a biallelic Ig heavy chain and a monoallelic Ig kappa light chain gene rearrangement, pointing to a B-lymphoid origin of these cells. No DNA of Epstein-Barr virus was detected in L1236. The cells expressed the HD-associated surface antigens CD30 and CD15 as well as the transferrin receptor (CD71). Cytogenetic analysis of early passages of L1236 cells revealed a grossly disordered karyotype including cytogenetic aberrations described previously in other HD-derived cell lines. The Hodgkin/Reed-Sternberg (H-RS) cell origin of L1236 cells is further confirmed by Kanzler et al (Blood 87:3429, 1996), who found identical Ig gene rearrangement sequences in L1236 cells and H-RS cells of the same patient's bone marrow. L1236 cells expressed antigens necessary for efficient antigen presentation to T cells including HLA class I and II, B7.1 and B7.2, as well as adhesion molecules ICAM 1 and LFA 3. The cells secreted the interleukins (IL)-6, -8, -10, tumor necrosis factor (TNF) alpha, interferon (IFN) gamma, transforming growth factor (TGF) beta, and the granulocyte-macrophage colony stimulating factor (GM-CSF). After subcutaneous inoculation into SCID mice, a necrotic regression of initially growing tumors at the injection site was followed by disseminated intralymphatic growth. Our findings, together with the results of Kanzler et al, demonstrate that H-RS cells of B-lymphoid origin were present in the peripheral blood of a patient with advanced HD. These cells exerted a malignant phenotype with regard to their in vitro and in vivo characteristics.

To evaluate the effects of deglycosylated ricin A-chain (dgA) immunotoxins against disseminated Hodgkin's lymphoma, we used RFT5.dgA (CD25) and IRac.dgA (70 kD) to treat L540Cy Hodgkin cells in severely immunodeficient SCID mice. In this model, more than 90% of the animals developed multiple lymphomas in various organs such as the lymph nodes, liver, bone marrow, and extranodal sites that killed untreated animals after a mean survival time (MST) of 36.3 days. A single intraperitoneal injection of 8 micrograms of either immunotoxin rendered 95% (RFT5.dgA) and 93% (IRac.dgA), respectively, of mice tumor-free when applied 1 day after tumor challenge. The MST of the RFT5.dgA-treated group was extended by more than 80 days (P < .00001). SCID mice treated 12 days after tumor challenge had lower remission rates (46%), suggesting that the antitumor effect of the immunotoxins depends on the number of tumor cells present. We conclude that ricin A-chain immunotoxins have potent antitumor effects against disseminated Hodgkin's tumors in SCID mice and that this model is ideally suited for the evaluation of different immunotoxin treatment modalities.

Background: Combined modality treatment of chemotherapy (usually ABVD) followed by involved field irradiation (IF) is today a standard treatment regimen for early stage Hodgkin′s lymphoma (HL)in stages I-II without risk factors in most study groups. The complete remission rates achieved with this treatment strategy are more than 90%. However, the question arises, whether treatment intensity of chemotherapy, radiotherapy or both may be further reduced in these patients. Aim: In the HD10 trial of the GHSG, reduction of ABVD cycles as well as reduction of IF- RT dose were investigated. Methods: Patients were randomized between 4 cycles of ABVD followed by 30 Gy IF radiotherapy as standard treatment (arm A), 4 cycles ABVD + 20 Gy IF (arm B), 2 cycles ABVD + 30 Gy IF (arm C) and 2 cycles ABVD + 20 Gy IF (arm D). Results: Between May 1998 and May 2002, 1131 HL patients with early stage disease (CS I,II without risk factors) were randomized. 847 patients (75%) were evaluable for this second interim analysis performed in August 2003. Patient characteristics were well balanced between the treatment arms. In total, 98.4% of the patients reached complete remission. Progressive disease or no change were observed in 0.9% of patients, relapse rate was 2.5%. In total, thirteen patients died during the study (1,5%). During chemotherapy there were 19% leukopenia as the most common WHO grade III/IV toxicity (4xABVD: 22 %, 2xABVD: 15%). Radiotherapy was well tolerated with dysphagia in 2.3%. Altogether ten secondary neoplasias were seen: 1AML, 4 NHL and 5 solid tumors. After a median observation time of two years, overall survival (OS) and freedom from treatment failure (FFTF) rates were 98.5% and 96.6%, respectively. No statistical differences in FFTF and OS were detected between 4xABVD and 2xABVD. In addition, there was no statistical difference between the different doses of radiotherapy (30Gy vs. 20Gy). Conclusions: Since only few events were observed, the results of this interim analysis can be interpreted as a trend that therapy intensity in combined modality treatment of early stage might be further reduced in terms of the number of chemotherapy cycles as well as the radiotherapy dose, even in IF-RT setting.

Background: Combined modality treatment consisting of chemotherapy (CT) followed by involved field radiotherapy (IF-RT) is the standard treatment for intermediate stage (early unfavourable) Hodgkin′s lymphoma (HL). Despite high complete remission (CR) rates comparable to early favorable stage HL, failure rates are remarkably higher in this group of patients. Aim: In the HD 11 multicenter trial of the GHSG, introduction of the BEACOPP regimen for intensification of chemotherapy in combination with dose reduction of IF-RT on 20 Gy was tested in an attempt to improve therapy outcome. Methods: Between May 1998 and July 2002, 1363 patients aged 16–75 suffering from intermediate stage HL (CS I, IIA with risk factors or IIB with elevated ESR and/or 3 3 nodal areas) were randomised according to a factorial design between: 4 cycles of ABVD followed by 30 Gy IF-RT (arm A - standard treatment), 4 ABVD + 20 Gy IF-RT (arm B), 4 BEACOPP basis + 30 Gy IF-RT (arm C) and 4 BEACOPP basis + 20 Gy IF-RT (arm D). Results: In the fourth interim analysis in August 2003, 1047 (77%) patients were evaluable for chemotherapy and 982 (72%) for radiotherapy evaluation. Patient characteristics were well balanced between the treatment arms in regard to age, gender, clinical stage, histopathology and performance status. 95.1% patients reached CR, 2.0% suffered progression, the relapse rate was 5.9%, the mortality rate 3.2%. The most frequent haematological toxicity was leucopenia observed in 33% of patients (ABVD: 27%, BEACOPP: 40%). Infection rate was 5% (ABVD: 4%, BEACOPP:7%). The most frequent toxicity during radiotherapy was dysphagia in 5.6%. Nine secondary neoplasias were observed: 2 AML, 3NHL, 4 solid tumors. After a median observation time of two years overall survival (OS) was 97.4% (95%-CI: 96-98) and freedom from treatment failure (FFTF) was 89.9% (95%-CI: 88-92). Both for FFTF and OS, there was no sequential significant difference either between ABVD and BEACOPP arms nor between 30 Gy and 20 Gy IF-RT arms. Conclusions: At two years of median observation time, no differences in treatment outcome were detected either between chemotherapy regimes nor between the different doses of radiotherapy. The low FFTF (89,9 % at two years) led us to further intensification of treatment by the introduction of 2 cycles of escalated BEACOPP + 2 cycles ABVD +30 Gy IF-RT in the next study generation (HD14 study).