The combinations of brentuximab vedotin (BV) and dacarbazine or BV and bendamustine both led to high objective response rates (ORR) in older patients with previously untreated Hodgkin lymphoma (HL); however, based on the frequency of serious adverse events (AEs), the bendamustine-containing regimen may be “too toxic” for this patient population, according to results of a phase II trial published in Blood.
In this non-randomized, open-label, multicenter, phase II study, Jonathan W. Friedberg, MD, MMSc, from the James P. Wilmot Cancer Center in Rochester, New York, and co-authors evaluated whether combining BV with alkylating agents – either dacarbazine or bendamustine – could enhance the activity of BV without increasing toxicity.
In a previously published phase II study of BV monotherapy as frontline treatment in 27 older patients (≥60 years) with HL, Dr. Friedberg and investigators reported an ORR of 92 percent, a complete remission (CR) rate of 73 percent, and a median duration of response of 9.1 months (range not provided).
In this study, patients were enrolled from 23 U.S. sites between February 2014 and September 2015. They were eligible for inclusion if they had treatment-naïve classical HL (excluding nodular lymphocyte predominant HL), an Eastern Cooperative Oncology Group performance status score of ≤3, and declined or were ineligible for standard frontline chemotherapy. Those with symptomatic neurologic disease that impaired daily activities or that required medications were excluded, as were those with kidney disease requiring ongoing dialysis.
Patients were assigned to receive either:
- BV 1.8 mg/kg plus dacarbazine 376 mg/m2 for up to 12 cycles (n=22; median age = 69 years; range = 62-88 years)
- BV 1.8 mg/kg plus bendamustine 90 mg/m2 for up to 6 cycles (n=20; median age = 75 years; range = 63-86 years)
Subsequent BV therapy was allowed in each arm.
Nearly half of patients in each cohort (11 [50%] in the BV plus dacarbazine cohort and 9 [45%] in the BV plus bendamustine cohort) reported having three or more comorbidities or one or more comorbidity that significantly interfered with their quality of life. Most patients (16 [72%] in the BV plus dacarbazine cohort and 15 [75%] in the BV plus bendamustine cohort) had stage III/IV disease.
For the 21 evaluable patients treated with BV plus dacarbazine and the 17 evaluable patients treated with BV plus bendamustine, the ORR (primary endpoint) was 100 percent in both cohorts. “Despite the advanced age … and significant comorbidity burden of these patients, the majority achieved a CR,” the authors wrote:
- BV plus dacarbazine: 13 CRs (62%) and 8 partial responses (PR; 38%)
- BV plus bendamustine: 15 CRs (88%) and 2 PRs (12%)
After a median follow-up of 21.6 months (range = 14.8-29.0 months) in the BV plus dacarbazine cohort, the median progression-free survival (PFS) was 17.9 months (range = 4.2-29 months). Overall survival (OS) was not reached (range = 14.8-29.0+ months).
After a median follow-up of 10.8 months (range = 2.9-18.2 months) in the BV plus bendamustine cohort, neither the median PFS (range = 2.9-18+ months) or OS (range = 2.9-18.2+ months) were reached.
By February 2016, all patients were off treatment. Nineteen patients (86%) treated with BV plus dacarbazine and 13 patients (65%) treated with BV plus bendamustine are still being followed. More than half of patients (55% in BV plus dacarbazine group and 60% in BV plus bendamustine group) had discontinued treatment because of AEs. One patient (5%) in the BV plus dacarbazine group and six patients (30%) in the BV plus bendamustine group died during follow-up.
After observing early toxicity in the first five patients who completed one treatment cycle of BV plus bendamustine, the study’s Safety Monitoring Committee recommended reducing the bendamustine dose to 70 mg/m2. “Thirty patients were to receive BV plus bendamustine,” the authors reported, “however, serious AE incidence (65%) and two deaths on study led to discontinuation of bendamustine treatment and cessation of enrollment in this arm.”
All patients receiving BV plus dacarbazine experienced at least one treatment-related AE, with nearly half (45%) experiencing a grade ≥3 AE, and 18 percent experiencing a serious AE. The most common AE in this cohort was peripheral sensory neuropathy (77%). However, while “BV plus dacarbazine was well-tolerated overall, with a similar toxicity profile to BV monotherapy,” the authors wrote, “BV plus bendamustine treatment [was associated with] an unacceptably high rate of serious AEs and deaths.”
In the BV plus bendamustine cohort, 95 percent of patients (n=19) experienced at least one treatment-related AE, with 90 percent of patients (n=18) experiencing a grade ≥3 AE. The most common AE in this patient cohort was diarrhea (85%).
“Although the study was not designed to compare treatment arms,” the authors cautioned, they reported that a higher incidence of specific treatment-related AEs, including diarrhea, asthenia/fatigue, hypokalemia, dehydration, weight decrease, hypotension, neutropenia, candidiasis, and pneumonia, and grade ≥3 AEs were observed in the BV plus bendamustine cohort than in the BV plus dacarbazine or the previously published BV monotherapy cohorts.
“The combination of BV [plus] bendamustine is too toxic for elderly patients at the ages, dose levels, and frequencies studied,” the authors concluded. But, “these results suggest BV [plus dacarbazine] may be a treatment option for elderly patients with newly diagnosed HL.” These findings need to be confirmed in larger trials, they added.
The study is limited by its non-randomized design, small patient cohort, and limited follow-up.
Seattle Genetics, Inc., contributed to the production of the study.
The authors report receiving funding from Seattle Genetics, Inc.
Friedberg JW, Forero-Torres A, Bordoni RE, et al. Frontline brentuximab vedotin in combination with dacarbazine or bendamustine in patients aged ≥60 years with HL. Blood. 2017 October 16. [Epub ahead of print]