This article is more than 5 years old. Information may no longer be current.
Brentuximab vedotin before, after chemotherapy improves survival for older patients with Hodgkin lymphoma
Click Here to Manage Email Alerts
ATLANTA — Brentuximab vedotin incorporated sequentially prior to and after chemotherapy conferred some of the best outcomes reported to date for older patients with untreated classical Hodgkin lymphoma, according to phase 2 study results presented at ASH Annual Meeting and Exposition.
“Survival rates are excellent and compare favorably with previously published data,” Andrew M. Evens, DO, MSc, chief of the division of hematology/oncology at Tufts University School of Medicine, said during his presentation. “However, I certainly acknowledge that longer follow-up is warranted.”
Older patients treated with standard regimens for Hodgkin lymphoma often achieve poorer survival and experience greater toxicity than younger patients.
Prior research showed complete remission rates for older patients range from 45% to 76%, and 2-year PFS rates range from 50% to 71%.
Evens and colleagues conducted a multicenter phase 2 study to evaluate whether brentuximab vedotin (Adcetris, Seattle Genetics) given sequentially before and after standard AVD chemotherapy — which consists of doxorubicin, vinblastine and dacarbazine — improved outcomes for older patients with classical Hodgkin lymphoma.
The analysis included 48 patients aged 60 years or older (median age, 69 years; range, 60-80; 62.5% men) with stage IIb to stage IV treatment-naive classical Hodgkin lymphoma. Median ECOG performance status was 1, 82% had stage III or stage IV disease, and 23% had bone marrow involvement. The majority (60%) had International Prognostic Scores of 3 to 7, but no patients had loss of activities of daily living at baseline. Median Cumulative Illness Rating Scale (CIRS) co-morbidity score at baseline was 6 (range, 0-20).
After PET and CT1 staging, patients received two doses of single-agent brentuximab vedotin 1.8 mg/kg, administered 3 weeks apart, followed by six cycles of AVD chemotherapy. Supportive antibiotics were encouraged, and patients could receive granulocyte growth factor.
Responding patients proceeded to consolidation with brentuximab vedotin, administered at 1.8 mg/kg every 3 weeks for four cycles.
Patients had to receive two cycles of AVD to be evaluable for response.
Six patients received fewer than two AVD cycles and were nonevaluable. Reasons included toxicity in the first cycle, wound infection and syncope (n = 2); consent withdrawal (n = 2); hepatic toxicity to brentuximab vedotin lead-in (n = 1); and grade 5 pancreatitis with brentuximab vedotin lead-in (n = 1).
Median CIRS score was significantly higher among patients who received fewer than two AVD cycles (13; range, 10-19) than those who received two or more cycles (5; range, 0-20; P = .001). Median CIRS score was significantly higher for patients who did not receive all cycles of brentuximab vedotin and AVD than those who did complete all cycles (4 vs. 8; P= .03).
Complete remission after AVD served as the primary endpoint, and researchers established a complete remission rate higher than 70% as the threshold for a promising result.
Forty-one patients were evaluable for response.
Researchers reported an ORR of 87% and complete remission rate of 30% after the initial two doses of brentuximab vedotin. After completion of AVD, ORR was 95% and complete remission rate reached 90%.
One patient improved response after consolidation, which increased the post-consolidation therapy complete remission rate to 93%.
In the intent-to-treat population, ORR was 88% and complete remission rate was 81%.
After median follow-up of 24 months (range, 6-46), 2-year PFS among evaluable patients was 90%. Intent-to-treat analysis showed 2-year PFS of 85% and 2-year OS of 94%.
Forty-two percent of patients experienced a serious adverse event.
The most common grade 3 or grade 4 adverse events included neutropenia (60%) and infection (15%). Six percent of patients experienced grade 3 or grade 4 renal insufficiency, pneumonia, urinary infection, transaminitis, fatigue, hyponatremia or febrile neutropenia.
One-third (33%) of all patients experienced grade 2 peripheral neuropathy, but the majority of cases were reversible.
One patient (2%) died from treatment-related pancreatitis. Reasons for study discontinuation included treatment completion (52%), adverse events or toxicity (33%), consent withdrawal or refusal of additional treatment (9%), and progressive disease or death (6%).
Univariate analysis revealed associations between shorter PFS and increasing age (P = .005), female sex (P = .05) and increased CIRS score (P = .006). However, on multivariate analysis, increasing age was the only factor significantly associated with shorter PFS (HR per year above age 60 = 1.19; 95% CI, 1.02-1.37).
The “robust” remission and survival rates have raised the bar for treatment in this setting, Evens said. Future efforts must focus on how to maintain efficacy while reducing toxicity.
Options could include response-adapted design, as well as integration of checkpoint inhibitors or other novel agents.
These efforts are particularly important for older patients and those with multiple comorbidities.
“We need to think about ways to ensure our treatment is not one-size-fits-all,” he said. – by Mark Leiser
Reference:
Evens AM, et al. Abstract 733. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosure: Evens reports consultant roles with AbbVie, Affirmed, Amgen, Celgene, Kite Pharma, Merck, Millennium, Novartis, Pharmacyclics, Seattle Genetics and Spectrum Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to Top
Jakub Svoboda, MD
Treatment of classical Hodgkin lymphoma in the elderly is challenging and a very important area of investigation. These patients do worse than young and adolescent patients. Also, elderly patients often present with more advanced disease and experience more toxicities from conventional chemotherapy agents such as bleomycin. Although brentuximab has excellent results in the relapsed/refractory setting, brentuximab monotherapy as frontline treatment in Hodgkin lymphoma has a relatively short duration of the response. Combining brentuximab concurrently with cytotoxic chemotherapy such as AVD results in excellent outcomes and improved modified PFS over standard ABVD in advanced Hodgkin lymphoma, but some of the toxicities such as neutropenia or neuropathy can be of concern.
In this multicenter phase 1/phase 2 study, the authors designed a regimen using sequential — not concurrent — brentuximab initially for two cycles, followed by AVD for six cycles, followed by brentuximab consolidation for four cycles. Researchers enrolled 48 patients with advanced classical Hodgkin lymphoma aged 60 years or older (median age, 69 years).
The results of this sequential frontline regimen are quite impressive in terms of the efficacy. Although the intent-to-treat analysis showed an ORR of 88% and complete response rate of 81%, the patients who completed all therapy had a complete response rate of 93%, which is very high compared with historical controls in this setting. The fact that about one-third of patients discontinued the protocol treatment due to adverse events indicates that the toxicities with this regimen were common among these older patients.
I view this phase 1/phase 2 study as an important effort to move targeted agents upfront, with the hope to develop well-tolerated and effective treatments. Ultimately, information from trials like this, along with better understanding of the tumor biology and predictors of toxicity, will allow us to design optimal treatment strategies for elderly patients with classical Hodgkin lymphoma, which remains a challenging population.
Click Here to Manage Email Alerts