Dennis A. Eichenauer

The prognostic impact of variant histology in nodular lymphocyte- predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG).

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of all Hodgkin lymphoma cases. The aim of this study was to evaluate the prognostic implication of histopathologic NLPHL variants. Biopsies of 423 NLPHL patients treated within 9 prospective clinical trials performed by the German Hodgkin Study Group were classified as tumor cell-rich cases (n = 10), typical NLPHL (n = 308), or histopathologic variants (n = 105). Histopathologic variants were characterized by the presence of lymphoma cells outside the B-cell nodules or B-cell depletion of the microenvironment. Compared with typical NLPHL, histopathologic variants were associated with advanced disease (29.5% vs 14.6%, P = .0012) and a higher relapse rate (18.1% vs 6.5% at 5 years, P = .0009). Variant histology represented an independent prognostic factor (odds ratio = 2.955) in a multivariate model of progression/relapse. A prognostic score, including the risk factors variant histopathologic growth pattern, low serum albumin, and male gender, was derived from this model and allowed the definition of 3 distinct risk groups. NLPHL patients presenting with histopathologic variants have a poorer outcome compared with those showing typical histology. The newly developed prognostic score combining histologic and clinical features allows allocating NLPHL patients to defined risk groups.

Brentuximab vedotin for relapsed or refractory CD30 hematologic malignancies: the German Hodgkin Study Group experience

The CD30-targeting Ab-drug conjugate brentuximab vedotin (SGN-35) was recently approved for the treatment of relapsed Hodgkin lymphoma and anaplastic large-cell lymphoma by the Food and Drug Administration. In the present study, we report the experience of the German Hodgkin Study Group with brentuximab vedotin as single agent in 45 patients with refractory or relapsed CD30(+) Hodgkin lymphoma who were treated either in a named patient program (n = 34) or in the context of a safety study associated with the registration program of this drug. In these very heavily pretreated patients, an objective response rate of 60%, including 22% complete remissions, could be documented. The median duration of response was 8 months. This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in heavily pretreated CD30(+) malignancies.

Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group

Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/MDS) represent severe late effects in patients treated for Hodgkin lymphoma (HL). Because more recent data are scarce, we retrospectively analyzed incidence, outcome, and risk factors for the development of t-AML/MDS after HL. A total of 11,952 patients treated for newly diagnosed HL within German Hodgkin Study Group trials between 1993 and 2009 were considered. At a median follow-up of 72 months, t-AML/MDS was diagnosed in 106/11,952 patients (0.9%). Median time from HL treatment to t-AML/MDS was 31 months. The median age of patients with t-AML/MDS was higher than in the whole patient group (43 vs 34 years, P < .0001). Patients who received 4 or more cycles of BEACOPP(escalated) had an increased risk to develop t-AML/MDS when compared with patients treated with less than 4 cycles of BEACOPP(escalated) or no BEACOPP chemotherapy (1.7% vs 0.7% vs 0.3%, P < .0001). The median overall survival (OS) for all t-AML/MDS patients was 7.2 months. However, t-AML/MDS patients proceeding to allogeneic stem cell transplantation had a significantly better outcome with a median OS not reached after a median follow-up of 41 months (P < .001).

ABVD in Older Patients With Early-Stage Hodgkin Lymphoma Treated Within the German Hodgkin Study Group HD10 and HD11 Trials

PURPOSE Older patients with Hodgkin lymphoma (HL) account for approximately 20% of all HL patients. ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy is regarded as standard of care in these patients. However, little is known on feasibility and efficacy of ABVD in this age group. PATIENTS AND METHODS We analyzed the feasibility and efficacy of four cycles of ABVD in older patients age 60 to 75 years with early-stage HL who were treated within the German Hodgkin Study Group (GHSG) HD10 and HD11 trials; results were compared with those of younger patients treated within these trials. RESULTS In total, 1,299 patients received four cycles of ABVD, and 117 of those patients were older than age 60 years (median, 65 years). In 14% of older patients, treatment was not administered according to protocol, mainly because of excessive toxicity. The mean delay of treatment was twice as high in the older patients (2.2 v 1.2 weeks). Fifty-nine percent of older patients achieved a relative dose-intensity of at least 80% compared with 85% of younger patients. Major toxicity (WHO grade 3 and 4), including leucopenia, nausea, infection, and others, was documented in 68% of older patients with a treatment-related mortality of 5%. Complete response was achieved in 89% of older patients, 3% had progressive disease, and 11% relapsed. At a median observation time of 92 months, 28% of the patients had died, and the 5-year progression-free survival estimate was 75% (95% CI, 66% to 82%). CONCLUSION In patients age ≥ 60 years with HL, four cycles of ABVD is associated with substantial dose reduction, treatment delay, toxicity, and treatment-related mortality.

ADAM10 Inhibition of Human CD30 Shedding Increases Specificity of Targeted Immunotherapy In vitro

CD30 is a transmembrane protein selectively overexpressed on many human lymphoma cells and therefore an interesting target for antibody-based immunotherapy. However, binding of therapeutic antibodies stimulates a juxtamembrane cleavage of CD30 leading to a loss of target antigen and an enhanced release of the soluble ectodomain of CD30 (sCD30). Here, we show that sCD30 binds to CD30 ligand (CD153)-expressing non-target cells. Because antibodies bind to sCD30, this results in unwanted antibody binding to these cells via sCD30 bridging. To overcome shedding-dependent damage of normal cells in CD30-specific immunotherapy, we analyzed the mechanism involved in the release. Shedding of CD30 can be enhanced by protein kinase C (PKC) activation, implicating the disintegrin metalloproteinase ADAM17 but not free cytoplasmic calcium. However, antibody-induced CD30 shedding is calcium dependent and PKC independent. This shedding involved the related metalloproteinase ADAM10 as shown by the use of the preferential ADAM10 inhibitor GI254023X and by an ADAM10-deficient cell line generated from embryonically lethal ADAM10(-/-) mouse. In coculture experiments, the antibody-induced transfer of sCD30 from the human Hodgkins lymphoma cell line L540 to the CD30-negative but CD153-expressing human mast cell line HMC-1 was inhibited by GI254023X. These findings suggest that selective metalloproteinase inhibitors blocking antibody-induced shedding of target antigens could be of therapeutic value to increase the specificity and reduce side effects of immunotherapy with monoclonal antibodies.

State of the art in the treatment of Hodgkin lymphoma

Hodgkin lymphoma (HL) has become one of the most easily curable malignancies in oncology. More than 80% of patients can be cured with risk-adapted treatment that includes chemotherapy and radiotherapy. This progress is mainly due to the development of multi-agent chemotherapy and improved radiation techniques; however, severe, life-threatening treatment-related side effects occur, which include organ toxicity and secondary malignancies. Thus, the treatment approaches must be carefully balanced between optimal disease control and the risk of long-term sequelae. Although this article is meant to provide an overview of the current treatment approaches for patients with HL, in many instances conflicting results from various clinical trials are available, and a personal judgment is inevitable. Here, we focus on evidence from large clinical trials with solid conclusions.

Hodgkin's Lymphoma in Adolescents Treated With Adult Protocols: A Report From the German Hodgkin Study Group

PURPOSE The standard of care for adolescent patients with Hodgkins lymphoma (HL) is undefined, particularly the choice between pediatric and adult protocols. Thus, we compared risk factors and outcome of adolescents and young adults treated within study protocols of the German Hodgkin Study Group (GHSG). PATIENTS AND METHODS Three thousand seven hundred eighty-five patients treated within the GHSG studies HD4 to HD9 were analyzed; 557 patients were adolescents age 15 to 20 years, and 3,228 patients were young adults age 21 to 45 years. Results Large mediastinal mass and involvement of three or more lymph node areas were more frequent in adolescents (P < .001). The incidence of other risk factors did not differ significantly between age groups. With a median observation time of 81 months for freedom from treatment failure (FFTF) and 85 months for overall survival (OS), log-rank test showed no significant differences between age groups regarding FFTF (P = .305) and a superior OS (P = .008) for adolescents. Six-year estimates for FFTF and OS were 80% and 94%, respectively, for adolescents and 80% and 91%, respectively, for young adults. After adjustment for other predictive factors, Cox regression analysis revealed age as a significant predictor for OS (P = .004), with a higher mortality risk for young adults. Secondary malignancies were more common in young adults (P = .037). CONCLUSION Outcome of adolescent and young adult patients treated within GHSG study protocols is comparable. These data suggest that adult treatment protocols exhibit a safe and effective treatment option for adolescent patients with HL. However, longer follow-up, including assessment of late toxicity, is necessary for final conclusions.

Long-Term Course of Patients With Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the German Hodgkin Study Group

PURPOSE The optimal treatment of stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined. Thus, we performed an analysis using the database of the German Hodgkin Study Group. PATIENTS AND METHODS The long-term outcome of 256 patients with stage IA NLPHL was evaluated. Patients had received combined-modality treatment (CMT; n = 72), extended-field radiotherapy (EF-RT; n = 49), involved-field radiotherapy (IF-RT; n = 108), or four weekly standard doses of rituximab (n = 27) within German Hodgkin Study Group clinical trial protocols between 1988 and 2009. RESULTS The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Most patients were male (76%). The whole patient group had a median follow-up of 91 months (CMT: 95 months; EF-RT: 110 months; IF-RT: 87 months; rituximab: 49 months). At 8 years, progression-free survival and overall survival rates were 88.5% and 98.6% for CMT, 84.3% and 95.7% for EF-RT, and 91.9% and 99.0% for IF-RT, respectively. Patients treated with rituximab had 4-year progression-free and overall survival rates of 81.0% and 100%, respectively. A second malignancy during the course of follow-up was diagnosed in 17 (6.6%) of 256 patients. A total of 12 deaths occurred. However, only one patient died from NLPHL. CONCLUSION Tumor control in this analysis was equivalent with CMT, EF-RT, and IF-RT. Therefore, IF-RT, which is associated with the lowest risk for the development of toxic effects, should be considered as standard of care for patients with stage IA NLPHL. Rituximab alone is associated with an increased risk of relapse in this patient population.

Phase 2 study of BACOPP (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) in older patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG)

For older patients with early unfavorable or advanced stage Hodgkin lymphoma (HL) the prognosis is much worse than for younger HL patients. We thus developed a new regimen, BACOPP (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone), to improve both tolerability and efficacy of treatment for older HL patients. Between 2004 and 2005, 65 patients with early unfavorable or advanced stage HL aged between 60 and 75 years were enrolled in this phase 2 trial. Treatment consisted of 6 to 8 cycles of BACOPP. Residual tumor masses were irradiated. Primary endpoints were feasibility as determined by adherence to protocol and overall response rate. Secondary endpoints included toxicity, freedom from treatment failure, and progression free and overall survival. For the final analysis 60 patients (92%) were eligible; 75% of treatment courses were administered according to protocol. World Health Organization grade 3/4 toxicities occurred in 52 patients. Fifty-one patients (85%) achieved complete remission, 2 (3%) partial remission, and 4 (7%) developed progressive disease. With a median observation time of 33 months, 18 patients died (30%), including 7 treatment-associated deaths. Three patients died before response assessment. Thus, the BACOPP regimen is active in older HL patients but is compromised by a high rate of toxic deaths. This trial was registered at www.clinicaltrials.gov as #NCT00284271.

Brentuximab vedotin (SGN-35) in patients with transplant-naive relapsed/refractory Hodgkin lymphoma

Abstract Only limited data are available on the role of brentuximab vedotin (SGN-35) in transplant-naive relapsed or refractory patients with Hodgkin lymphoma (HL). We thus retrospectively analyzed 14 patients with primary refractory or relapsed HL who were treated with brentuximab vedotin as single agent in a named patient program, who had not received prior high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) due to refractory disease (n = 9), comorbidity (n = 4) and unknown reasons (n = 1). Brentuximab vedotin resulted in an overall response rate of 71% (10/14) with five complete responses (CRs). Five of those patients with refractory disease and four patients with relevant comorbidity responded. Consolidating ASCT (n = 4) or allogeneic SCT (n = 1) was performed in five patients. Median progression-free survival (PFS) was 9 months and the median overall survival (OS) was not reached. These data indicate the therapeutic efficacy of brentuximab vedotin in chemotherapy-refractory transplant-naive patients with HL.