Subsequent studies have been conducted evaluating BV monotherapy in the post-transplant setting. The AETHERA trial compared BV to placebo for high-risk patients after ASCT.16 In this phase III study, patients were considered at an increased risk for relapse if any of the following were present: primary refractory disease, relapse within 12 months of treatment, or extranodal involvement. Patients were randomized to receive BV (1.8 mg/kg) or placebo within 30–45 days of ASCT every three weeks for up to 16 cycles (n=329), although only half of the cohort was able to receive the full course of therapy. The BV arm was associated with a clinically significant improvement in PFS vs placebo (median PFS 42.9 months vs 24.1 months, p = 0.0013). These data led to the approval of BV as a maintenance regimen for high-risk patients in the post-transplant setting (Table 1). Long-term follow-up data indicated that BV provided a five-year PFS of 59% compared to 41% with placebo (HR 0.52; 95% CI, 0.379–0.717).17
BRENTUXIMAB IN COMBINATION WITH CHEMOTHERAPY
In hopes of recreating the success of rituximab in B-cell malignancies expressing CD20, BV has been extensively studied in combination with chemotherapy. The first explorations were in the relapsed setting. The current approach for patients in first relapse is a platinum-based salvage regimen, such as ICE (ifosfamide, carboplatin, etoposide), in preparation for ASCT. BV in combination with standard cytotoxic salvage regimens, including ICE,18,19 ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin),20 and DHAP (dexamethasone, high-dose cytarabine, cisplatin)21 have been evaluated in small early phase studies. BV with concurrent ICE produced a CR of 70% amongst 24 patients, with 86% proceeding to ASCT.19 The CR rates were modestly higher than previous reports with ICE alone (~60%).22,23 Likewise, BV in combination with ESHAP and DHAP produced CR rates of 75% and 80% respectively.20,21 These are promising interim analyses and longer follow data after final accrual are pending.
Bendamustine, a hybrid alkylating agent currently approved in NHL and CLL, has demonstrated activity in relapsed/refractory cHL patients (ORR 53%, CR 33%).24 As this drug has been administered successfully and safely with monoclonal antibodies and immunotherapy in NHL,25–27 combination with BV was felt to be a reasonable consideration in cHL. LaCasce and colleagues first studied the combination of bendamustine (90 mg/kg) and BV (1.8 mg/kg) in a phase I/II study of 53 patients with previously treated disease.28 Patients achieved an ORR of 93% after a median of two cycles with 74% achieving a CR. Forty patients were able to proceed ASCT, 30 patients after just two cycles. Four of six patients who underwent ASCT in partial remission attained a CR. Estimated two-year PFS and Kaplan-Meier estimated OS were 63% and 95%, respectively; the PFS for those who underwent ASCT was 70%. Notably, there was no significant difference in OS between the group that underwent ASCT and the group that did not. A comparable response rate of 78% was reported amongst 37 patients in the phase II portion of a similar study.29 The combination of BV and bendamustine has become a popular outpatient option, providing a bridge to ASCT as well as a durable option for those not thought to be a candidate for ASCT.
Given the notable improvements in response in the relapsed setting, BV has also been investigated with front-line regimens. The addition of BV to the well-established standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen was explored in a front-line phase I study of 25 patients with advanced stage cHL, producing a CR rate of 95%.30 Due to considerable grade 3+ pulmonary toxicity, however, the protocol was amended to omit bleomycin (AAVD). The utility of bleomycin has been questioned in previously untreated patients, and it was felt that BV potentiated its pulmonary effects. In 26 patients, the AAVD regimen was well-tolerated and induced CR of 96% with a 5-year PFS of 92%.31
The phase III ECHELON-1 trial enrolled 1334 advanced stage patients to receive AAVD vs ABVD.32 The primary endpoint was two-year modified PFS, which used the standard criteria of disease progression and death, but also included patients who achieved a Deauville score of 3–5 after cycle 6 and received subsequent anticancer therapy. The 2-year modified PFS favored AAVD at 82.1% vs 77.2% (p=0.04), with a risk reduction of 23%. With a statistically significant, albeit small clinical benefit of approximately 5%, BV gained FDA approval in combination with AVD for previously untreated advanced stage cHL. Of note, increased adverse events occurred in the AAVD arm with two-thirds of patients developing grade 3–4 peripheral neuropathy. In addition, granulocyte colony-stimulating factor (G-CSF) prophylaxis was mandated due to unacceptable complications from neutropenia. With further analysis, it appears that this regimen would most benefit patients with stage IV disease, IPS of 4–7, young age, or more than one extra-nodal site.
Other studies have evaluated different schedules of BV when administered with chemotherapy (Table 2). Kumar et al reported a CR rate of 93% amongst 30 patients with unfavorable early stage disease who received four cycles of AAVD.33 Of note, 23 patients had bulky disease, including 14 with masses greater than 10 cm. Twenty-five patients in the study subsequently received consolidative involved site radiation therapy (ISRT), all of whom had a CR. At a median follow up of 18 months, the 1-year PFS was 93%.
(To view a larger version of Table 2, click here.)
Evens et al explored a sequential approach to an elderly population with primary advanced stage disease, in which 48 patients received 2 doses of BV followed by 6 cycles of AVD followed by another 4 doses of BV.34 The response rates after the two lead-in doses of BV were comparable to the relapsed setting (ORR 82%, CR 36%), and improved considerably after patients completed the AVD portion (ORR 95%, CR 90%). The 2-year PFS was 84% but favored patients with a lower cumulative index score. This sequential approach allowed for a more tolerable degree of peripheral neuropathy: 4% grade 3 events and 33% grade 2 events. These adverse events were mostly reversible, preserving efficacy. Abramson and colleagues explored the concept of two lead-in doses of BV monotherapy followed by BV with AVD (AAVD) in non-bulky limited stage patients.35 Patients received 4–6 cycles of AAVD based on their interim PET scan results. All 34 patients achieved a CR and the 3-year PFS was 94%. Despite the impressive activity, 62% of patients developed severe neutropenia, including an elderly patient who died of complications of sepsis during the first cycle of AAVD. Like ECHELON-1, the protocol was amended to include G-CSF prophylaxis. This group of investigators is also exploring the omission of vinblastine to minimize toxicity [NCT02505269].
Although ABVD is generally accepted as the front-line standard in cHL, the German Hodgkin Study Group HD21 trial evaluated BV with modified versions of the more intensive eBEACOPP (escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) regimen in a randomized phase II study in advanced stage patients.36 By omitting the vincristine, the investigators were able to maintain efficacy (CR 88%) without significant peripheral neuropathy. The current BRAPP2 trial is investigating the role for BV consolidation after two cycles of eBEACOPP and ISRT in patients with interim PET-2 positivity after two lead-in cycles of ABVD in early stage disease [NCT02298283] (Table 3). Additionally, studies are underway evaluating efficacy of combination BV in pediatric populations, including BV + AVD [NCT02979522] and BV + AV (adriamycin, vinblastine) [NCT02398240].
(To view a larger version of Table 3, click here.)
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