Andrew M. Evens, DO, MSc, FACP

Older patients with Hodgkin lymphoma typically do not fare as well as younger patients on standard regimens. A phase II study reported the best outcomes to date in older patients with Hodgkin lymphoma who were treated with sequential brentuximab vedotin (Adcetris) before and after a regimen of doxorubicin, vinblastine, and dacarbazine (AVD).¹

“Brentuximab vedotin before or after AVD is feasible for older patients with Hodgkin lymphoma. This regimen achieves high complete response rates and is generally well tolerated. Survival rates are excellent, and longer follow-up is warranted. This is treatment with a curative intent,” said presenting author Andrew M. Evens, DO, MSc, FACP, Professor at the Rutgers Cancer Institute of New Jersey, New Brunswick, at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition.

The design of the phase II investigator-initiated study utilized sequential therapy as follows: Brentuximab vedotin was given for two initial “lead in” doses/cycles; then AVD was given for six cycles, which was followed by four cycles of brentuximab vedotin for consolidation. Dr. Evens noted that bleomycin was removed from the regimen typically used for younger patients (ABVD).

After the first two cycles of brentuximab vedotin lead-in therapy, the objective response rate was 97% and the complete response rate was 30%; following AVD, the objective response rate was 95% and the complete response rate was 90%; after brentuximab vedotin consolidation therapy, the objective response rate was 95% and the complete response rate was 93%.

Study Population

The study population included people over age 60 years who were newly diagnosed with Hodgkin lymphoma.

“Collectively, older patients are underrepresented in clinical trials. They represent 20% to 30% in population-based studies with Hodgkin lymphoma, but only 5% to 10% have historically been enrolled in clinical trials,” Dr. Evens told listeners.

“Age appears to be an accentuated adverse prognostic factor in Hodgkin lymphoma, with reported 5-year event-free survival rates of less than 35% to 50%. There is no standard treatment approach for older patients. Additionally, data suggest Hodgkin lymphoma may be a different disease in older vs younger patients, with an increased incidence of mixed-cellularity histology and tumor-related Epstein-Barr virus. Previous studies have shown a significant drop-off of outcomes in this age group,” Dr. Evens told the audience. Retrospective data have shown that 5-year progression-free survival in older patients is about 30% to 40% worse and overall survival is about 20% to 30% worse than in younger patients, he continued.

Early data suggested that brentuximab vedotin could be combined with chemotherapy for untreated patients, which led to the current multicenter phase II study.

Study Details

The study enrolled 48 patients with a median age of 69 (up to 88 years old) and a slight male predominance. Epstein-Barr virus was present in 30%, the median performance status (PS) was 1 (25% were PS 2 at study entry), 25% had positive bone marrow, and 82% had stage III/IV disease.

Of these 48 patients, 41 were evaluable. Of the 7 unevaluable patients, 1 died of pancreatitis and 6 withdrew due to toxicities, including 2 due to diarrhea. The 7 unevaluable patients had a Cumulative Illness Rating Scale comorbidity score of 17 vs 5 for the other 41 patients.

Safety Data

Serious adverse events were reported in 42% of patients. Grade 3 and 4 adverse events included neutropenia (60%), infection (15%), febrile neutropenia (8%), transaminitis (6%), renal insufficiency (6%), urinary infection 6%), pneumonia (6%), hyponatremia (6%), fatigue (6%), diarrhea (4%), pancreatitis (4%), and peripheral neuropathy (4%). One-third of patients had grade 2 peripheral neuropathy, with most cases reversible.

“We also advocated liberal use of growth factor and antibiotics for prophylaxis,” Dr. Evens said.

Fifty-two percent of patients completed all intended therapy; 9% withdrew consent; 6% had no response to therapy; and 33% withdrew from the study due to toxicity (12% for peripheral neuropathy).

An intent-to-treat survival analysis of all enrolled patients showed a 2-year progression-free survival rate of 85% and a 2-year overall survival rate of 94%, with a median follow-up of 2.5 years.

In a univariate analysis, age, female gender, and increased Cumulative Illness Rating Scale score were significantly associated with poor prognosis. A multivariate analysis showed that only increasing age was a significant prognostic factor.

“In the future, we want to continue to move the bar. We want to maintain these robust remission and survival rates, but with less toxicity and shorter length of therapy. We need to identify factors for selection of therapy so that we don’t treat patients ‘one size fits all,’” Dr. Evens said. “Our goal here was curative, not palliative,” he stated.

Also presented at the 2017 ASH meeting, the ECHELON-1 study reported excellent outcomes with a regimen of brentuximab vedotin plus AVD (not sequential) in younger patients with Hodgkin lymphoma (median age ~36 years), and results suggested that this regimen might become a new standard of care for younger patients.² (See commentary here.) ■

DISCLOSURE: Dr. Evens has received honoraria for advisory board meetings and reseach funding from Seattle Genetics.

REFERENCES

1. Evens AM, Advani RH, Fanale MA, et al: Sequential brentuximab vedotin before and after Adriamycin, vinblastine, and dacarbazine for older patients with untreated classical Hodgkin lymphoma: Final results from a multicenter phase II trial. 2017 ASH Annual Meeting. Abstract 733. Presented December 11, 2017.

2. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma: The Phase 3 ECHELON-1 Study. 2017 ASH Annual Meeting. Abstract 6. Presented December 10, 2017.