Brentuximab Vedotin in Combination with Bendamustine for Patients with Hodgkin Lymphoma who are Relapsed or Refractory after Frontline Therapy

Background

Patients (pts) with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline therapy typically undergo salvage chemotherapy followed by high-dose conditioning and autologous stem cell transplant (ASCT). Improved outcomes have been reported for pts who achieve complete remission (CR) with salvage chemotherapy prior to ASCT. Variable CR rates (19%-60%) and significant toxicities are associated with standard salvage therapy in the first relapse setting. Brentuximab vedotin and bendamustine have independent mechanisms of action and are highly active with manageable safety profiles when administered as single agents to pts with HL who relapse after ASCT (brentuximab vedotin: 34% CR [Younes, 2012]; bendamustine: 33% CR [Moskowitz, 2013]). This phase 1/2, single-arm, 2-stage, open-label study was designed to evaluate the safety and efficacy of brentuximab vedotin in combination with bendamustine for the treatment of pts with HL in first relapse (ClinicalTrials.gov #NCT01874054).

Methods

Pts received an outpatient IV infusion of 1.8 mg/kg brentuximab vedotin on Day 1 with 90 mg/m² bendamustine on Days 1 and 2 of 3-week cycles for up to 6 cycles. Pts could undergo ASCT any time after Cycle (C) 2 and post-transplant resume treatment with brentuximab vedotin as monotherapy for up to16 total doses. Phase 1 was designed to determine the recommended dose of bendamustine in combination with brentuximab vedotin. During this phase, the dose of bendamustine was to be de-escalated if ≥4/10 pts experienced dose-limiting toxicity (DLT), defined as any C1 toxicity requiring a dose delay of ≥14 days. During phase 2, bendamustine was administered at the recommended dose in order to assess the CR rate of the combination. Response was assessed by the investigator per Cheson 2007.

Results

Forty-five pts (58% female) with a median age of 35 yrs (range, 19-79) have been enrolled. Fifty-eight percent of pts had relapsed disease and 42% of pts primary refractory disease after frontline therapy. A median of 13.1 mos (range, 3- 98) had elapsed since initial diagnosis.

No DLTs were observed in the safety cohort, thus the recommended dose of bendamustine in combination with brentuximab vedotin was 90 mg/m². Pts received a median of 2 cycles (range, 1-6) of the combination.

The main toxicity observed with the combination was infusion-related reactions. The most common symptoms (≥10%) were dyspnea (13%), flushing (13%), and chills (11%). The majority of reactions occurred within 24 hours of C2 infusion and were considered related to both agents. Premedication with corticosteroids and antihistamines was instituted with a protocol amendment and appeared effective. Prior to the amendment, 36% (9/25 unique pts) of treated pts had reactions that were either serious adverse events (SAEs) (n=6), Grade 3 in severity (n=8), and/or led to treatment discontinuation (n=6). Following premedication implementation, 15% (3/20 unique pts) of treated pts had such events (0 SAEs, 1 treatment discontinuation, and 2 Grade 3 toxicities).

The CR rate of the combination was 82% (28/34 pts evaluable for response) and the overall objective response rate (CR and partial remission) 94% (32/34 pts). The majority of CRs (24/28 pts) were achieved after 2 cycles of combination therapy. Stem cell mobilization and collection was considered adequate in all 24 pts who underwent the procedure. The median number of CD34+ cells collected was 4.3 x10⁶ (range, 1.7- 16.0 x10⁶) in a median of 2 apheresis sessions (range, 1-5). To date, 20 pts have undergone ASCT, the majority after C2 (12 pts) or C3 (6 pts), and 13 pts have resumed brentuximab vedotin as monotherapy. One patient with CR developed progressive disease 3 cycles post-transplant. The median duration of remission for pts who obtained a CR has not been reached (95% CI: 8.7,– [range, 0.03+-10.4+ months]).

Conclusions

The outpatient regimen of brentuximab vedotin 1.8 mg/kg on Day 1 in combination with bendamustine 90 mg/m² on Days 1 and 2 of 3-week cycles has a manageable safety profile with premedication. The very high CR rate observed on combination treatment compares favorably with historical data. The durability of responses observed to date and the success of stem cell mobilization and collection suggest that the regimen may represent a promising approach for maximizing responses prior to ASCT in pts with HL who are either relapsed or are refractory after frontline therapy.