Treatment of elderly Hodgkin lymphoma patients

Hodgkin lymphoma (HL) is a rather rare malignancy that often affects young adults. The disease is peculiar since the number of malignant cells is rare so that for decades, it was unclear if this was an unusual infection, autoimmune disease, or indeed a malignancy. There are two subtypes of HL: classical HL (cHL) and nodular lymphocyte predominant HL (NLPHL). The history of HL dates back to the first half of the 19th century when this lymphoid disease was described by Dr Thomas Hodgkin (1798-1869).1 Children and young adults are often affected by HL representing the largest group of malignant lymphoma up to the age of 39 years.2 Most new cases of HL are in the group of 20- to 34-year-old patients representing nearly 32% of all new lymphoma cases.3 The most comprehensive data set on incidence and cumulative relative survival of HL is derived from the Swedish registry. Their data show that over decades, the prognosis of patients with HL has greatly improved over time, particularly for those patients under the age of 50 years.4 There is also a variety of late side effects after successful treatment for HL including secondary neoplasia such as acute myeloid leukemia (AML) and other leukemias, non-HL, and a variety of solid tumors. The largest overall standardized incidence ratio (SIR) as compared with the general population is observed for AML (22-fold).5 The risk for non-HL is increased by sixfold to 14-fold followed by different solid tumors.6 Unfortunately, the prognosis of patients aged 60 or beyond is still rather poor with no major breakthroughs in recent years. Accordingly, elderly patients were often not included in randomized controlled clinical trials (RCTs), and there are only few trials for elderly patients. As a consequence, the percentage of older patients was often underestimated using data from RCTs.7 Population studies suggest that patients over the age of 60 years account for a substantial proportion of patients in clinical practice representing about 20% of the total HL population.8 Since older patients are clearly underrepresented in clinical trials, an accepted standard for this age group has not been well defined.9 Knowledge based on population studies indicate that most of these patients are treated outside clinical trials.10, 11 Causes of poor outcomes in elderly HL patients are still not fully understood but have been attributed to a combination of factors including comorbidities, poor performance status, disease and biological differences, inability to tolerate chemotherapy at full dose, and increased treatment-related toxicities.7-10 In addition, there are relevant different disease characteristics concerning elderly HL patients including the role of Epstein-Barr virus (EBV), histology, comorbidity, more treatment-related toxicity, and an ill-defined standard treatment. HL patients at first diagnosis are allocated to early favorable, early unfavorable, or advanced stages. For patients in the early favorable group, the German Hodgkin Study Group (GHSG) standard of care is based on our HD10 study demonstrating that two cycles of ABVD followed by 20-Gy involved field radiation therapy (IFRT) are as effective as four cycles of ABVD followed by 30-Gy IFRT.12 In the HD11 trial, early unfavorable patients also received combined modality treatment consisting of either four cycles of ABVD or four cycles of BEACOPP baseline followed by either 20 or 30 Gy.13 ABVD was as good as BEACOPP baseline, but the dose reduction from 30 to 20 Gy after four cycles of ABVD led to less efficacy. When comparing patients treated in the GHSG trails HD10 for early favorable and HD11 for early unfavorable stages, there were only 68 patients over the age of 60 years as compared with 528 patients younger than 60 years. Similarly, patients in early unfavorable stages also had only a total of 49 patients aged over 60 years as compared with 654 aged younger than 60 years. The number of patients with early termination included a total of 18 of 68 patients in the early favorable group and 8 of 49 in the early unfavorable group. Dose delivery showed a relative dose intensity (RDI) of greater than or equal to 0.8 in 56% (n = 68) as compared with 82% in the cohort of patients younger than 60 (n = 521). Very similar, also in the early unfavorable stage patients, the RDI was 63% in the group over 60 years as compared with 88% in those younger than 60. As far as acute toxicity was concerned, there were 40% of patients suffering from grade 3/4 toxicity in those aged 60 years or older as compared with 21% in patients younger than 60 years. The figures are very similar in the early unfavorable stages with a leukopenia of 45% and 23%, respectively. Other major events included infection grade 3/4 in 12% of patients aged over 60 and 4% in those younger than 60; this compares with 6% and 4% in the early unfavorable groups, respectively. In older patients, there is clearly a higher number of grade 3/4, with 67% vs 50% and 69% vs 50% in the early unfavorable group with 18% in the elderly group and 7% in those under 60 years experiencing a grade 3/4 toxicity. The number of patients relapsing or progressing was higher in those patients aged 60 years or older as compared with patients younger than 60. As far as mortality is concerned, there were 22% and 37% in those aged over 60 as compared with a total 3% and 6% in younger patients. These data clearly show that there are significant differences in HL patients older or younger than 60 years. The role of radiotherapy after initial chemotherapy is also an issue and was evaluated in the GHSG HD8 trial.14 Here, a total of 975 patients younger than 60 years were compared with 89 patients older than 60. The median age in this trial was 30 vs 65 years when younger or elderly patients were compared. Comparing patients older than 60 years with those younger than 60, there was clearly a higher radiotherapy-associated toxicity, particularly, in those patients receiving extended field radiotherapy. Here, the difference between those over or under 60 years was 26.5% vs. 14.4%. Another prospectively randomized trial by the GHSG compared elderly patients in advanced stages treated with either COPP-ABVD or BEACOPP baseline. In this trial, HD9elderly, 71 patients were assessable: 29 patients were treated with COPP-ABVD and 42 with BEACOPP baseline.15 There were no differences in terms of tolerability between the different regimens used. At a median follow-up of 18 months, there were no differences in outcome between the two regimens. However, a total of 37 of 68 patients had died (55%). This small randomized trial underscores the poor prognosis of HL patients aged 66 to 75 years. There are very few clinical trials for elderly patients with HL. One study conducted by the GHSG developed a new combination including prednisone, vinblastine, doxorubicin, and gemcitabine (PVAG). This combination was evaluated in a multicenter phase II study and included early unfavorable and advanced stage patients treated with six to eight cycles of PVAG and additional radiotherapy. A total of 59 patients aged 60 to 75 years of age were eligible for analysis; in total, 93% of enrolled patients had advanced stage disease. World Health Organization (WHO) grade 3/4 toxicities were documented in 43 patients. A total of 46 patients responded with complete response (CR) or unconfirmed complete response (CRU) (78%). With 37 months' median observation time, 15 cases of progressive disease or relapse as well as 17 deaths were observed, of which eight were related to HL and one patient died due to treatment-related toxicity. The 3-year overall survival (OS) and progression-free survival (PFS) were 66% (95% confidence interval [CI], 50%-78%) and 58% (95% CI, 43%-71%), respectively.16 The use of the antibody-drug conjugate brentuximab vedotin (BV) was an interesting approach in elderly HL patients. In a phase II clinical trial by Evens and coworkers, elderly patients received two cycles of BV initially followed by six cycles of AVD in responders. Patients achieving a CR or partial response (PR) then had BV consolidation at four standard doses. In total, 17 of 19 evaluable patients (89%) achieved an Overall Response (OR) (12 CR, five PR); two patients had stable disease. A total of 48 patients were enrolled; the median age was 69 years (range 60-88 y), and 63% were male patients. In total, 77% of the 48 enrolled patients completed six cycles of AVD, and 35 patients (73%) received at least one dose of BV consolidation. Overall response and complete remission rates after BV lead-in were 82% and 36%, respectively. After six cycles of additional AVD among 42 evaluable patients, a total of 95% achieved OR and 90% CR. Overall, 20 of 48 patients experienced grade 3 or 4 adverse events. Most common were neutropenia (44%), febrile neutropenia (8%), pneumonia (8%), and diarrhea (6%). The 2-year event-free survival, PFS, and OS rates were 80%, 84%, and 93%, respectively.17 A more recent clinical trial conducted by the GHSG (B-CAP) in elderly HL patients combined BV at standard dose with cyclophosphamide, doxorubicin, and prednisone. A total of 49 patients were treated, and growth factor support was mandatory. The most relevant acute toxicity included 43% grade 4 leukopenia, 41% neutropenia, 6% thrombocytopenia, and 2% infections. Neuropathy grade 3 was observed in 20% of patients. The 1-year estimate of the B-CAP trial was 73.9% (61.1%-86.6%).18 Clearly, more follow-up for this trial is needed. The treatment of relapsed or refractory elderly patients is a clear challenge. There are no prospective clinical trials in this setting so far. A retrospective study performed by the GHSG included 105 patients with a median age of 66 years. Low-risk patients had an OS of 59% in contrast to those with two or three risk factors having an OS of only 9% at 3 years. Importantly, these results were obtained prior to the availability of BV. Potential new options for relapsed or refractory elderly patients include the use of checkpoint inhibitors such as nivolumab and pembrolizumab. So far, no clinical trials addressing only elderly patients treated with checkpoint inhibitors were described.