Advanced Stage and Relapsed/Refractory Hodgkin Lymphoma
Alternative Regimens in Older Patients
Patients older than 60 years of age often have poor tolerance for ABVD and especially escalated BEACOPP. This results in increased treatment-related mortality and reduced overall dose intensity, with higher relapse rates and poor OS. In an attempt to improve on the results of treatment of elderly patients with Hodgkin lymphoma, alternative regimens have been explored. One example is PVAG (prednisone, vinblastine, doxorubicin, gemcitabine). With this regimen, the 3-year OS was 66% and PFS was 58%. One patient out of 59 died from treatment-related toxicity, which is much improved over the historical figures for elderly patients with Hodgkin lymphoma.27 Another commonly used approach in practice is to simply omit bleomycin from ABVD. In the early-stage setting (GHSG HD-13 trial), this regimen (referred to as AVD) led to 89.6% PFS at 5 years, compared to 93.5% with ABVD.28 It therefore stands to reason that this should be a reasonable option in older or more frail advanced stage cHL patients as well.
Brentuximab has been evaluated as a single-agent therapy for first-line therapy of elderly patients with Hodgkin lymphoma. In a phase 2 study, 27 patients (63% with advanced stage disease) were treated, with a 92% overall response rate and 73% CR rate. However the median duration of remission was disappointing at only 9.1 months.29 Based on this data, single-agent brentuximab appears to be a reasonable and well tolerated option for frail or elderly patients, although with the caveat that long-term disease control is relatively uncommon.
,RESPONSE-ADAPTED FRONTLINE THERAPY USING INTERIM PET SCAN
In recent years, response-adapted treatment approaches have been extensively researched in cHL using iPET. The goal is to reduce toxicity by minimizing therapy in those who achieve negative iPET and/or to intensify treatment for patients with suboptimal response on iPET. Gallamini et al evaluated the prognostic role of an early iPET scan in advanced Hodgkin lymphoma patients (n = 190) treated with ABVD. This study found that patients with positive iPET had a 2-year PFS of 12.8% versus 95.0% in patients with negative iPET. This result was highly statistically significant (P < 0.0001). This study also showed that PET-2 (iPET after 2 cycles of ABVD) superseded the prognostic value of the IPS at diagnosis.30 As a result, numerous subsequent studies have been pursued using iPET for risk-adapted treatment in cHL.
A critical element to the conduct of iPET risk-adapted treatment for cHL is the interpretation of the iPET. In hopes of standardizing iPET interpretation in clinical trials, a scoring system called the Deauville score was developed. The Deauville score ranges from 1 to 5 (Table 3). 
The SWOG (Southwest Oncology Group) S0816 trial (n = 358) evaluated iPET-adapted treatment after 2 cycles of ABVD in stage III or IV Hodgkin lymphoma patients. Patients with positive iPET (Deauville score 4 to 5; n = 60) received escalated BEACOPP for 6 cycles, whereas iPET-negative (Deauville score 1 to 3; n = 271) patients continued to receive 4 more cycles of ABVD. The 2-year PFS was 64% for iPET-positive patients.33 This PFS was much higher than the expected 15% to 30% from prior studies such as Gallamini et al,30 suggesting that the treatment intensification may have been of benefit.
In the HD0801 study (n = 519), newly diagnosed advanced Hodgkin lymphoma patients with positive iPET after 2 cycles of ABVD (n = 103) received early ifosfamide-containing salvage therapy followed by high-dose therapy with autologous stem cell rescue. The 2-year PFS was 76% for PET-2–positive patients, comparable with PET-2–negative patients who had PFS of 81%.34 Again, this result for iPET-positive patients was much better than expected based on the historical control from Gallamini et al, suggesting that the treatment intensification may have been beneficial. It should be emphasized, however, that neither HD0801 nor S0816 were randomized prospective trials; rather, all iPET-positive patients were assigned to an intensified treatment approach.
In the HD18 trial (n = 1100), patients with advanced stage cHL started therapy with escalated BEACOPP and underwent an iPET after 2 cycles. For those with a positive iPET, rituximab was added to escalated BEACOPP in the experimental arm (n = 220) for cycles 3 through 8. The control group (n = 220) continued to receive 6 more cycles of escalated BEACOPP. In the 2 groups, the 3-year PFS was similar (91.4% in escalated BEACOPP, 93% in rituximab + escalated BEACOPP), suggesting no significant benefit with addition of rituximab.35 This study also calls into question whether iPET provides useful information for patients receiving intensive therapy such as escalated BEACOPP, and indicates that the historical control data for iPET-positive patients from Gallamini et al may not be consistently reproduced in other prospective trials. As a result, nonrandomized trials that implement an iPET risk-adapted approach should be interpreted with caution. See Table 4 for a summary of recent trials in advanced stage Hodgkin lymphoma using iPET scan to guide therapy. 
