It is important to recognize that elderly patients may be unable to tolerate standard front-line regimens due to underlying comorbidities such as cardiomyopathy. Based on the encouraging relapsed/refractory data, the bendamustine-BV regimen was evaluated as a front-line regimen in a 20-patient study for those over the age of 60 years and considered ineligible for anthracycline-based chemotherapy.37 This doublet combination yielded a remarkable ORR of 100% with 88% CR; however, 65% of patients experienced serious side effects, including two deaths within the first 30 days of treatment, leading to discontinuation of bendamustine and study closure. The HALO trial evaluated the same combination in 22 advanced stage patients aged 60–80 at a lower dose (BV 1.2 mg/kg every three weeks for six cycles).38 A lower CR rate of 59% was seen; however, 13 of these 15 patients completed the full 6 cycles of therapy and 10 maintained a CR at 9 month follow-up. The attenuated dose of BV appears to be more manageable for older patients when combined with bendamustine, but more long-term data are necessary to understand whether this is a feasible front-line regimen.
BRENTUXIMAB AND CHECKPOINT INHIBITION
Unique to cHL, malignant RS cells make up only a small fraction of tumor bulk (~1%), and are surrounded by a dense inflammatory infiltrate of T- and B- lymphocytes, histiocytes, neutrophils, eosinophils, and stromal cells.39,40 Domination of the tumor microenvironment by suppressive CD4+ T-lymphocytes41 secondary to RS cell chemokine and cytokine secretion42,43 as well as T-lymphocyte exhaustion by programmed cell death protein 1 (PD-1) activation creates a unique opportunity for intervention with immune checkpoint inhibitors (CPI). CPI, namely PD-1 inhibitors, have demonstrated impressive ORRs of 66–69%44,45 in relapsed/refractory cHL, leading to accelerated FDA approval of anti-PD-1 IgG4 mAbs, nivolumab and pembrolizumab, in relapsed/refractory cHL (after failed ASCT in the case of nivolumab). PD-1 inhibition is effective due to the significant overexpression of programmed death-ligand 1 (PD-L1) by RS cells in cHL, which is secondary to chromosome 9p24.1 amplification.46 PD-1 activation on T-lymphocytes leads to decreased antigen recognition and effector function, thereby promoting cancer cell survival.47 Inhibiting this signal by binding either PD-1 or PD-L1 allows the immune system to execute previously blocked immune surveillance and allow for cancer cell death.
Despite their impressive ORRs, the CR rates with CPI are lower,44,45 thus leaving room for their investigation in combination with other therapies. CPIs are capable of achieving more robust responses when administered with novel agents, even in the post-ASCT salvage setting. The combination of BV 1.8 mg/kg and nivolumab 3 mg/kg for four cycles in 61 cHL patients at first relapse produced an ORR of 82% and CR of 61%,48 with 54 patients successfully proceeding to ASCT. Of note, immune-related reactions (IRR) occurred in 44% of patients, though most were mild, necessitating only 8% of patients to undergo systemic corticosteroid therapy. There was no significant correlation between IRR and ASCT outcomes noted in the study, although follow-up was relatively short.
BV has been studied with dual immunotherapy agents in a multi-arm phase I study with nivolumab and ipilimumab, an anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor.49 As part of this study, 18 patients (7 s/p ASCT) received BV + nivolumab and attained an ORR of 88% and CR of 61%, comparable to prior reports with this doublet. The 1-year PFS was 68% and median OS was not reached after a median follow-up of two years. Twenty-one patients (9 s/p ASCT) were treated with BV + ipilimumab and achieved ORR of 76% and CR of 57%; 1-year PFS was 60% and median OS not reached after a median follow-up of three years. In the triplet arm of BV with nivolumab and ipilimumab, the ORR was 82% among 22 patients (9 s/p ASCT). The CR rate and 1-year PFS was modestly higher at 73% and 72%. Toxicities were mostly of grades I-II severity, although there were two deaths related to pneumonitis in the cohorts treated with nivolumab. This study has been expanded and is currently enrolling patients randomized to BV + nivolumab vs BV + nivolumab + ipilimumab in relapsed and refractory patients [NCT01896999]. While the initial responses have been encouraging, longer follow up is necessary to understand the durability of this approach. Additionally, a randomized design is necessary to better understand the benefit of dual immunotherapy over a single immunotherapeutic when administered with BV.
RETREATMENT WITH BRENTUXIMAB VEDOTIN
As indications for BV expand, an area of clinical concern is efficacy with retreatment and the development of resistance. In vitro and in vivo cHL models demonstrate that BV resistance may be linked to intrinsic MMAE resistance as well as MMAE transport (namely by MDR1) to the extracellular space.50 Retreatment with BV has been explored in a small study of 21 patients who developed progressive disease after previously achieving a response with a brentuximab containing regimen. Retreatment with BV produced an ORR of up to 60% and CR of 30%.51 The estimated median duration of response was 9.2 months, ranging from 0–19.5+ months. As expected, there was an increased incidence of peripheral motor neuropathy that was primarily low grade. Based on preclinical data indicating that BV can initiate a localized antitumor response and the hypothesis that BV may have synergy with nivolumab, the addition of nivolumab to BV is being explored in patients who have had an initial inadequate response to BV [NCT01703949].
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