A Phase II Study of Brentuximab Vedotin and Bendamustine for Relapsed/Refractory Follicular Lymphoma

Background:

Follicular lymphoma frequently follows an indolent course requiring only intermittent treatment with survival rates similar to the general population. 20% of patients can experience a more aggressive disease course with shorter remission durations, frequent relapses and shortened survival. Brentuximab vedotin, a CD30 directed antibody drug conjugate, has demonstrated efficacy in treatment of Hodgkin lymphoma and CD30+ non-Hodgkin Lymphoma (NHL). The combination of Brentuximab Vedotin and Bendamustine has been found to be safe and effective as a first salvage regimen in relapsed/refractory Hodgkin's lymphoma. CD30 expression has been described in follicular lymphoma. In a study of 22 follicular lymphoma cases, 32% demonstrated definitive CD30 positivity in malignant cells by immunohistochemistry (Gardner et al. 2001) In this study, we evaluated the efficacy and toxicity of Brentuximab Vedotin in combination with Bendamustine in the treatment of relapsed/refractory follicular lymphoma. Here we report the first interim analysis.

Methods

In this single arm, phase II study, adults with histologically or cytologically confirmed relapsed or refractory follicular lymphoma (grade I, II, IIIa) were eligible for enrollment. CD30 positivity was not required for eligibility. A minimum of 4 cycles of Brentuximab Vedotin (1.8mg/kg IV one day 1 of each 21 day cycle) and Bendamustine (70mg/m² on day 1 and 2 of each 21 day cycle) were administered until progressive disease, autologous stem cell transplant, or unacceptable toxicity. Patients who were not transplant candidates and demonstrated stable disease, partial response or complete response, without excessive toxicity at the completion of 6 cycles of combination therapy, received an additional 10 cycles of single-agent brentuximab vedotin. The primary endpoints were complete and best overall response rate as defined per Lugano criteria.

Results

Between May 2021-May 2024, 10 patients were enrolled in the study with 1 patient subsequently characterized as unevaluable due to ineligibility for treatment on C1D1. Six (60%) patients demonstrated stage III disease, and 4 (40%) had stage IV disease. Two (20%) patients were refractory to their most recent treatment while 7 (70%) were enrolled with relapsed disease. Four (40%) patients received 1 prior line of treatment, 2 (20%) received 6 prior lines and 1 (10%) patient each received 2, 3, 4, and 5 prior lines of therapy. Three (30%) patients received prior radiation treatments.

Five (50%) patients completed 4 cycles of treatment with 1 (10%) patient each completing 2, 6 and 12 cycles. One (10%) patient continues on treatment and has completed 3 cycles with partial response on most recent testing. Four patients were previously treated with Bendamustine-based regimens with 100% ORR with 2 (50%) patients demonstrating complete response and 2 (50%) achieving partial response. Amongst these four patients, 1(10%) patient had previously been refractory to bendamustine based treatment.

As defined by 2014 Lugano criteria, when considering all patients, the best overall response rate was 90% with 9 patients demonstrating either complete or partial response during the trial. The complete response rate was 50% (n=5).

Grade 3 treatment related adverse events were reported in 5 (50%) of patients including sepsis, dehydration, anorexia, fatigue and supraventricular tachycardia. No grade 4 or 5 adverse events were reported. Three patients (30%) reported peripheral motor or sensory neuropathy with 1 patient (10%) endorsing grade 1 neuropathy and 2 (20%) noting grade 2. Two (20%) patients experienced neutropenia and were treated with G-CSF. An additional 2 (20%) patients received prophylactic G-CSF with concern for development of neutropenia. No neutropenic fevers or infections were reported.

Enrollment is ongoing and a subsequent correlative analysis will assess the relationship between CD30 expression and response.

Conclusion

Combination treatment with Brentuximab Vedotin and Bendamustine was safe and active in relapsed/refractory follicular lymphoma with 9 (90%) of patients currently demonstrating response. With the absence of serious grade 4 and 5 adverse effects, the efficacy of Brentuximab Vedotin and Bendamustine provides rationale to consider this combination in the treatment of follicular lymphoma.

Esteghamat:Seagen: Ended employment in the past 24 months, Speakers Bureau. Abedi:Autolus, BMS and Gilead Sciences: Research Funding; CytoDyn: Current holder of stock options in a privately-held company; BMS, Autolus: Consultancy; AbbVie, BMS and Gilead Sciences: Speakers Bureau; Orca Bio: Research Funding. Hoeg:Orca Bio: Research Funding.