Karolin Behringer

Secondary Amenorrhea After Hodgkin’s Lymphoma Is Influenced by Age at Treatment, Stage of Disease, Chemotherapy Regimen, and the Use of Oral Contraceptives During Therapy: A Report From the German Hodgkin’s Lymphoma Study Group

PURPOSE Long-term survivors of successfully treated Hodgkins lymphoma (HL) are at risk for late complications. Among these, infertility for female patients is of major importance. The subject of this analysis is to evaluate the menstrual status after HL therapy. PATIENTS AND METHODS From 1994 to 1998, the German Hodgkins Lymphoma Study Group conducted clinical trials for early-, intermediate-, and advanced-stage HL (trials HD7 to HD9) involving a total of 3,186 patients. A survey was carried out to evaluate the menstrual status after therapy. The following factors were assessed concerning their influence on amenorrhea: age, treatment, stage, and the use of oral contraceptives during chemotherapy. RESULTS A total of 405 women aged younger than 40 years answered the study questions. After a median follow-up of 3.2 years, 51.4% of the women receiving eight cycles of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) had continuous amenorrhea. Amenorrhea was significantly more frequent after dose-escalated BEACOPP compared with doxorubicin, bleomycin, vinblastine, and dacarbazine; cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine; or standard BEACOPP (P = .0066). Amenorrhea after therapy was most pronounced in women with advanced-stage HL (P < .0001), in women older than 30 years at treatment (P = .0065), and in women who did not take oral contraceptives during chemotherapy (P = .0002). CONCLUSION Most women who are treated for advanced-stage HL experience amenorrhea after therapy. Amenorrhea is significantly more frequent in women with advanced-stage HL receiving eight cycles of dose-escalated BEACOPP and in women older than 30 years at first treatment. Furthermore, the data show a statistical association between the use of oral contraceptives and return of menstrual cycle, which is subject to further investigation.

Gonadal Function and Fertility in Survivors After Hodgkin Lymphoma Treatment Within the German Hodgkin Study Group HD13 to HD15 Trials

PURPOSE To optimize fertility advice in patients with Hodgkin lymphoma (HL) before therapy and during survivorship, information on the impact of chemotherapy is needed. Therefore, we analyzed gonadal functions in survivors of HL. PATIENTS AND METHODS Women younger than age 40 and men younger than 50 years at diagnosis in ongoing remission at least 1 year after therapy within the German Hodgkin Study Group HD13 to HD15 trials for early- and advanced-stage HL were included. Hormone parameters, menstrual cycle, symptoms of hypogonadism, and offspring were evaluated. RESULTS A total of 1,323 (55%) of 2,412 contacted female and male survivors were evaluable for the current analysis (mean follow-up, 46 and 48 months, respectively). Follicle-stimulating hormone, anti-Müllerian hormone, and inhibin B levels correlated significantly with therapy intensity (P < .001). Low birth rates were observed in survivors after advanced-stage treatment within the observation time (women, 6.5%; men, 3.3%). Regular menstrual cycle was reported by more than 90% of female survivors of early-stage HL (recovery time mostly ≤ 12 months). After six to eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, menstrual activity was strongly related to age (< v ≥ 30 years: 82% v 45%, respectively; P < .001; prolonged recovery time). Thirty-four percent of women age ≥ 30 years suffered severe menopausal symptoms (three- to four-fold more frequently than expected). In contrast, male survivors had mean levels of testosterone within the normal range and reported no increased symptoms of hypogonadism. CONCLUSION The present analysis in a large group of survivors of HL provides well-grounded information on gonadal toxicity of currently used treatment regimens and allows risk-adapted fertility preservation and comprehensive support during therapy and follow-up.

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).

Role of Hematotoxicity and Sex in Patients With Hodgkin's Lymphoma: An Analysis From the German Hodgkin Study Group

PURPOSE Several scores have described sex as a prognostic factor in patients with Hodgkins lymphoma (HL). However, little is known how sex-specific factors influence treatment outcome. We systematically investigated sex differences with regard to pretreatment characteristics and therapy-related variables, and examined their influence on the outcome of HL patients. PATIENTS AND METHODS This analysis comprises 4,626 HL patients of all prognostic risk groups who were enrolled onto the multicenter studies HD4 to HD9 of the German Hodgkin Study Group. At 5.5 years, 2,050 female and 2,576 male patients were analyzed. RESULTS Male and female patients had similar prognostic factors. There was more acute chemotherapy-related hematotoxicity in women, especially more severe leucopenia (WHO grade 3/4, 69.9% female and 55.2% male; P < .0001). Importantly, this did not translate into more infections. Female patients had similar response rates but fewer relapses and deaths, leading to a significantly better freedom from treatment failure (FFTF; at 66 months, 81% female [95% CI, 79% to 82%] and 74% male [95% CI, 72% to 76%]). Severe leucopenia during chemotherapy was strongly associated with better FFTF, both for males and females. In addition, when only those patients who developed severe leucopenia within the first two cycles of chemotherapy were included, the factor maintained its protective role. CONCLUSION The protective role of severe leucopenia suggests the testing of a more individualized therapy. In future trials, this therapy may be tailored in a response-adapted manner depending on the individual toxicity profile within the first cycles.

Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial

BACKGROUND In the HD14 trial, 2×BEACOPPescalated+2×ABVD (2+2) has improved the primary outcome. Compared with 4×ABVD, this benefit might be compromised by more infertility in women. Therefore, we analyzed gonadal function and fertility. PATIENTS AND METHODS Women≤45 years in ongoing remission at least 1 year after therapy were included. Hormone parameters, menopausal symptoms, measures to preserve fertility, menstrual cycle, pregnancies, and offspring were evaluated. RESULTS Three hundred and thirty one of 579 women addressed participated (57.2%) and 263 per-protocol treated patients qualified (A=ABVD: 137, B=2+2: 126, mean time after therapy 42 and 43 months, respectively). Regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. Follicle-stimulating hormone and anti-Muellerian hormone were significantly better in arm A. However, pregnancies after therapy favored arm B (A: 15%, B: 26%, P=0.043) and motherhood rates were equivalent to the German normal population. Multivariate analysis revealed prophylactic use of gonadotropin-releasing hormone (GnRH) analogues as highly significant prognostic factor for preservation of fertility (odds ratio=12.87, P=0.001). Severe menopausal symptoms were frequent in women≥30 years (A: 21%, B: 25%). CONCLUSIONS Hormonal levels after 2+2 indicate a reduced ovarian reserve. However, 2+2 in combination with GnRH analogues does not compromise fertility within the evaluated observation time.

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.

Relapsed Hodgkin Lymphoma in Older Patients: A Comprehensive Analysis From the German Hodgkin Study Group

PURPOSE Progression or relapse of Hodgkin lymphoma (HL) is common among older patients. However, prognosis and effects of second-line treatment are thus far unknown. PATIENTS AND METHODS We investigated second-line treatment and survival in older patients with progressive or relapsed HL. Patients treated within German Hodgkin Study Group first-line studies between 1993 and 2007 were screened for refractory disease or relapse (RR-HL). Patients with RR-HL age ≥ 60 years at first-line treatment were included in this analysis. RESULTS We identified 105 patients (median age, 66 years); 28%, 31%, and 41% had progressive disease, early relapse, or late relapse, respectively. Second-line treatment strategies included intensified salvage regimens (22%), conventional polychemotherapy and/or salvage-radiotherapy with curative intent (42%), and palliative approaches (31%). Median overall survival (OS) for the entire cohort was 12 months; OS at 3 years was 31% (95% CI, 22% to 40%). A prognostic score with risk factors (RFs) of early relapse, clinical stage III/IV, and anemia identified patients with favorable and unfavorable prognosis (≤ one RF: 3-year OS, 59%; 95% CI, 44% to 74%; ≥ two RFs: 3-year OS, 9%; 95% CI, 1% to 18%). In low-risk patients, the impact of therapy on survival was significant in favor of the conventional polychemotherapy/salvage radiotherapy approach. In high-risk patients, OS was low overall and did not differ significantly among treatment strategies. CONCLUSION OS in older patients with RR-HL can be predicted using a simple prognostic score. Poor outcome in high-risk patients cannot be overcome by any of the applied treatment strategies. Our results might help to guide treatment decisions and evaluate new compounds in these patients.

Female fertility after cytotoxic therapy--protection of ovarian function during chemotherapy of malignant and non-malignant diseases.

Abstract:  Due to the dramatic improvements in cure and survival of young patients of reproductive age suffering from malignant or systemic disease, the preservation of fertility and ovarian function during cytostatic treatment has become of increased importance during the last decade. Pharmacological therapy with GnRH analogues and the cryopreservation of ovarian tissue are discussed in this context. The value of these treatment procedures and their potential clinical applications are critically reviewed in this article.

Lymphocyte‐predominant and classical Hodgkin's lymphoma – comparison of outcomes

Abstract:  Introduction: Lymphocyte predominant Hodgkins lymphoma (LPHL) differs in histological and clinical presentation from classical Hodgkins lymphoma (cHL). Treatment of LPHL patients using standard Hodgkins lymphoma (HL) protocols leads to complete remission (CR) in more than 95% of patients. However, differences in terms of relapse rates, survival and freedom from treatment failure (FFTF) between LPHL and cHL patients were suggested by a recent intergroup analysis. To obtain a more comprehensive picture, we reviewed all LPHL‐cases registered in the GHSG database and compared patient characteristics and treatment outcome with cHL patients. Patients and methods: We retrospectively analyzed 8298 HL patients treated within the GHSG trials (HD4–HD12): 394 LPHL patients and 7904 cHL patients. From 394 LPHL patients 63% were in early stage, 16% in intermediate and 21% in advanced stage of disease. Of the 7904 cHL patients analyzed, 22% were in early, 39% in intermediate and 39% in advanced stages. About 9% of LPHL patients had B symptoms compared to 40% in cHL patients. Results: About 91% LPHL vs. 86% cHL patients in early stages, 86% vs. 83% in intermediate and 79% vs. 75% in advanced stages reached CR/CRu. Additional analysis for LPHL IA patients showed 98% CR/CRu after extended field, 100% after involved field (IF) and 98% CR/CRu after combined modality treatment. About 0.3% LPHL patients developed progressive disease (PD) compared to 3.7% cHL patients. The relapse rate of LPHL patients was very similar to cHL (8.1% vs. 7.9%). There were 2.5% secondary malignancies in LPHL and 3.7% in cHL patients. About 4.3% LPHL patients and 8.8% cHL patients died. The FFTF rates for LPHL and cHL patients at a median observation of 41 or 48 months were 92% and 84%, respectively. The OS for LPHL and cHL patients was 96% and 92%, respectively. Conclusion: The cHL patients present more frequently with advanced stages and B symptoms compared to LPHL patients. There was no difference in treatment outcome in terms of CR/CRu, PD and mortality between LPHL and HL. Surprisingly, there were also no differences in patients with relapse.

Cancer-related fatigue in patients with and survivors of Hodgkin's lymphoma: a longitudinal study of the German Hodgkin Study Group

BACKGROUND Patients with Hodgkins lymphoma might have persistent fatigue even years after treatment. However, knowledge of the development of fatigue persisting long after completion of treatment is limited. Therefore, we did a detailed analysis of fatigue in our first-line clinical trials for early-stage favourable (HD13 trial), early-stage unfavourable (HD14 trial), and advanced-stage (HD15 trial) Hodgkins lymphoma. Beyond the description of fatigue from diagnosis up to 5 years after treatment, we aimed to assess any effect of patient characteristics, disease characteristics, or treatment characteristics on persistent fatigue. METHODS In this longitudinal study, we included patients with early-stage favourable, early-stage unfavourable, and advanced-stage Hodgkins lymphoma from the HD13, HD14, and HD15 trials, respectively, aged between 18 and 60 years. Eligible patients for these trials had newly diagnosed, histologically proven Hodgkins lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or lower, HIV negativity, and absence of comorbidity disallowing protocol treatment. We used the fatigue scale of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire to assess fatigue from diagnosis up to 5 years after the end of treatment. The primary outcomes of interest in this study were fatigue scores in the second and fifth year after end of treatment. We estimated the effect of different disease, patient, and treatment characteristics on fatigue with multiple regression analyses and identified fatigue trajectories with growth mixture models. The regression analyses and growth mixture models used robust and full information maximum likelihood estimates to account for missing data. The HD13, HD14, and HD15 trials are registered as international standard randomised controlled trials, ISRCTN63474366, ISRCTN04761296, and ISRCTN32443041, respectively. FINDINGS The HD13 trial enrolled patients with early-stage favourable disease from Jan 28, 2003, to Sept 30, 2009; the HD14 trial enrolled patients with early-stage unfavourable disease from Jan 28, 2003, to Dec 23, 2009; and the HD15 trial enrolled patients with advanced-stage disease from Jan 28, 2003, to April 18, 2008. 5306 patients were enrolled in these trials. We analysed 4215 patients with any valid fatigue assessment up to 5 years after the end of treatment. Patients with higher tumour burden at diagnosis had more fatigue at baseline (mean fatigue score in HD13: 30·8 [SD 28·0]; in HD14: 39·8 [29·4], and in HD15: 49·0 [30·2]). Fatigue scores (FA) in the second year after the end of treatment were 28·5 (24·7) in HD13, 28·8 (24·4) in HD14, and 30·7 (24·4) in HD15; in the fifth year after the end of treatment FA was 30·8 (26·0) in HD13, 27·1 (24·8) in HD14, and 28·2 (24·9) in HD15. Predictors of fatigue in the second and fifth year after end of treatment were baseline fatigue (p<0·0001) and age as a continuous variable (p<0·0001). In addition to preceding fatigue and age, patient sex and Hodgkins lymphoma specific risk factors at baseline did not consistently and significantly improve the prognosis of fatigue in the first, second, and fifth year after end of treatment. There was no significant effect of treatment on fatigue scores in the second and fifth year after treatment. INTERPRETATION Our findings show a high incidence of severe acute and persistent fatigue in Hodgkins lymphoma survivors, which is largely independent of tumour stage and treatment. Our results contribute to a better understanding of fatigue in patients with Hodgkins lymphoma and Hodgkins lymphoma survivors and could inform development of urgently needed intervention strategies. FUNDING Deutsche Krebshilfe.