Classical Hodgkin lymphoma (HL) is one of the great success stories of modern oncology. The discovery of the radiosensitive nature of this tumor in the mid-1900s, coupled with the efficacy of the first combination chemotherapy regimen (MOPP), beginning in 1964, turned a uniformly fatal diagnosis of largely 20- to 30-year-old individuals into a curable disease. Since then, the focus has been on improving efficacy and safety of therapies for these predominantly young adults, and today more than 80 percent of HL patients will be cured with first-line therapy.
In North America, the standard therapy for advanced-stage disease is six cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy, which is associated with five-year failure from progression (FFP) and overall survival (OS) rates of 78 percent and 90 percent, respectively.1 Patients with stage 3 or 4 disease with an International Prognostic Score (IPS) of 4 or higher, however, still relapse nearly 40 percent of the time, with a five-year OS of 67 percent, leaving room for improvement. An early-phase study of AVD (doxorubicin, vinblastine, dacarbazine) with the anti-CD30 antibody drug conjugate brentuximab vedotin spurred cautious optimism when 96 percent of patients achieved a complete response, and the five-year FFP was 92 percent.2,3 Based on these results, there was a randomized phase III study of AVD+brentuximab compared with ABVD for the first-line treatment of advanced-stage HL.4 The ESCHELON-1 study results, presented during the Plenary Scientific Session at the 2017 ASH Annual Meeting and later published in the New England Journal of Medicine, met its primary endpoint — a modified progression-free survival (PFS) benefit of AVD+brentuximab over ABVD. The U.S. Food and Drug Administration has now approved this regimen for the upfront treatment of advanced-stage HL. The clinical importance of this benefit, however, has been a matter for debate within the oncology community.
More than 1,300 patients with advanced-stage, previously untreated HL were randomized in a 1:1 fashion to either ABVD (n=670) or AVD+brentuximab (n=664), each for six cycles. About one-quarter of patients had high-risk disease with an IPS score of 4 or higher. The primary endpoint of the study was modified PFS, where a progression event was defined as progression of disease, death from any cause, or evidence of a noncomplete response, including Deauville scores of 3 to 5, and the subsequent initiation of a new anticancer therapy. OS was a key secondary endpoint. At a median follow-up of 24.6 months, the two-year modified PFS was 82.1 percent in the AVD+brentuximab group versus 77.2 percent in the ABVD group (HR, 0.77; p=0.04). Most progression events in each arm were due to progression; evidence of a noncomplete response and subsequent initiation of a new anticancer therapy was rare but occurred more commonly in the ABVD arm versus the AVD+brentuximab arm (22 vs. 9 patients, respectively). Seven of these combined 31 events occurred in patients with a Deauville score of 3 on their end-of-treatment positron emission tomography (PET) scans, which is arguably a complete metabolic response by some standards. Prespecified subgroup analysis identified the following as predictors of benefit from AVD+brentuximab — patients who were: male, had stage IV disease, had more than one extranodal site of disease, had a score of IPS 4 or higher, were younger than 60 years, and were located in North America. There was no survival benefit yet at two-year follow-up. AVD+brentuximab was associated with a higher frequency of neutropenia and febrile neutropenia than with ABVD (58% vs. 45% and 19% vs. 8%, respectively). However, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was recommended by the data and safety monitoring committee for patients treated in the AVD+brentuximab arm, and 83 patients in this arm did receive G-CSF, with improvements in the rates of neutropenic complications. Peripheral neuropathy was also more common in the experimental arm, with up to 67 percent of patients experiencing neuropathy of any grade, and 11 percent with grade 3 neuropathy, versus 43 percent and 2 percent, respectively, following ABVD. The rate of pulmonary toxicity was 2 percent following AVD+brentuximab compared with 7 percent following ABVD. Rates of non-lymphoma-related deaths on study were comparable but were more likely due to infection in the experimental group, and were more likely due to pulmonary toxicity in the ABVD group. Following AVD+brentuximab, up to 37 percent of patients required hospitalization, compared with 28 percent of patients who received ABVD. Fertility was not assessed on this study; it is generally considered to be preserved for a majority of patients following ABVD but is unknown following treatment with brentuximab.
In Brief
Although this study did meet its primary endpoint, it has been met with a mix of enthusiasm and skepticism. Proponents of the study argue that in meeting its primary endpoint it should be a new frontline standard of care for advanced-stage HL patients. Others recognize the small relative benefit for advanced-stage patients on the whole but see a more convincing benefit for the prespecified subgroups who benefited most including stage IV disease and an IPS of four or higher. Critics of this study look at the data differently. First, it includes Deauville 3 end-of-treatment PET scans as progression events if they prompted initiation of a new lymphoma therapy, when many of these patients may not have residual lymphoma necessary of further therapy. Although the number of these events was small, they were slightly more common in the ABVD arm. Second, and perhaps most importantly, we have previously seen a 5 percent PFS benefit without an OS benefit at the expense of greater toxicity, and it has not been practice changing. This is because salvage therapies for relapsed HL are quite effective, and long-term toxicities in this young patient population are significant endpoints that potentially dwarf the benefits of small increases in the rate of relapse. The risks and costs of increased rates of febrile neutropenia and infectious deaths and the need for growth factor support, as well as the higher incidence of ongoing peripheral neuropathy with AVD+brentuximab, are not insignificant and need to be weighed against the modest PFS benefit. The lack of long-term follow-up with regard to fertility of this regimen is another important concern for these 20- and 30-year-old patients. If, on longer follow-up, there continues to be no OS benefit of this regimen over ABVD, it may be hard to convince its current critics that it marks a new standard of care for these patients.
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Competing Interests
Dr. Jacobson indicated no relevant conflicts of interest.
