The treatment of older Hodgkin lymphoma patients.

The outcome of patients with Hodgkin lymphoma (HL) has dramatically improved over the past decades and continues to improve with the development of novel targeted therapies, such as the immunoconjugate brentuximab vedotin and the checkpoint inhibitors nivolumab and pembrolizumab. Moreover, with the use of response-adapted strategies using positron-emission-tomography (PET), the overall intensity of treatment for most patients can be reduced, resulting in less acute and late toxicity. However, these advances are mainly restricted to younger patients, as advances in patients above the age of 60 years ('older' patients) have been much less pronounced. Furthermore, about one third of all HL patients are among the older population, but only 5-10% of the patients treated in current HL clinical trials are ≥60 years old. HL in older patients is characterized by aggressive disease and unfavourable prognostic features as B symptoms and predominance of advanced stages. In addition, tolerance to curative chemotherapy is drastically reduced in older patients resulting in excessive toxicity and insufficient treatment due to therapy delays and dose reductions. Therefore, there is a significant unmet medical need in older HL patients for less toxic and effective therapies, and an important gap of knowledge concerning this growing population of patients. Recent advances on epidemiology, characteristics and treatment of older HL patients will be summarized in this article.

Phase 2 study of PVAG (prednisone, vinblastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma.

Approximately 20% of all Hodgkin lymphoma (HL) patients are older than 60 years and have a poor prognosis, mainly because of increased treatment-related toxicity resulting in reduced overall dose intensity and more treatment-related mortality. To possibly improve the treatment of elderly HL patients, the German Hodgkin Study Group developed a new regimen, PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine). In this multicenter phase 2 study, elderly HL patients in early unfavorable and advanced stages received 6 to 8 cycles of PVAG and additional radiotherapy if they were not in complete remission (CR) after chemotherapy. Endpoints included feasibility, acute toxicity, and response rate. Fifty-nine patients 60 to 75 years of age (median, 68 years) were eligible for analysis; 93% had advanced stage disease. WHO grade 3/4 toxicities were documented in 43 patients; 46 patients responded with CR/CR uncertain (78%). Within 37 months median observation time, 15 progressions or relapses and 17 deaths were observed, of which 8 were related to HL and 1 was the result of treatment-related toxicity. The 3-year estimates for overall survival and progression-free survival were 66% (95% CI, 50%-78%) and 58% (95% CI, 43%-71%), respectively. We conclude that PVAG is safe and feasible in elderly HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00147875.

Volumetric assessment of mediastinal lymphoma masses in Hodgkin lymphoma.

The large mediastinal mass (LMM) at initial staging represents a risk factor in Hodgkin lymphoma (HL) and is measured by X-ray. Depending on location of the LMM, different results can occur regardless of the initial lymphoma volume. To assess this risk factor more accurately, we evaluated the method of volumetry in 77 patients of HD13/14 study of the German Hodgkin Study Group. Furthermore, volume calculations based on three or only one diameter, were performed to simplify volume assessment. Inter-rater reliability was good for all methods. The 3-diameter measurement produced larger volumes than volumetric assessment with an intraclass correlation coefficient (ICC) of 0.93, which could be improved to 0.95 by multiplying volumes with a correction factor of 0.86. The 1-dimensional measurement strongly overestimated the volume with an ICC of 0.7. In conclusion, the simplified volume estimation based on 3 largest diameters provides a reliable concept for the staging of HL patients.

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.

Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial.

PURPOSE: Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied. PATIENTS AND METHODS: Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT. RESULTS: With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy. CONCLUSION: Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.