Phase II, Single Arm, Open Label, Single Center Study of Obinutuzumab and Ibrutinib in the Front Line Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

Abstract

Background: Anti-CD-20 immunochemotherapy with cytotoxic agents has been the traditional front-line therapy for patients with the advanced stage indolent non-Hodgkin lymphomas (iNHL) such as follicular (FL) and marginal zone lymphoma (MZL) requiring treatment. For patients with medical comorbidities and advanced age at iNHL diagnosis, treatment regimens without cytotoxic chemotherapy may offer an effective but less toxic option. Combination therapies with non-cytotoxic treatments and anti-CD20 antibodies have been developed in FL and MZL, such as lenalidomide and the anti-CD20 antibody obinutuzumab. The combination of Obinutuzumab and ibrutinib was previously reported in first line treatment of follicular lymphoma (Schmidt et al ASH 2018), but not MZL. In a phase II study, we investigated the front line combination of Ibrutinib plus Obinutuzumab in FL and MZL. Methods: Adult patients with untreated, histologically confirmed Ann Arbor Stage II-IV FL (WHO classification grade 1, 2 or 3a) or MZL (nodal, splenic and extranodal) who had an indication for systemic therapy on the basis of symptoms, high tumor burden, cytopenias and/or other evidence of end-organ damage as per standard modified GELF criteria were eligible. In this single-arm study, patients received ibrutinib 560 mg daily and obinutuzumab in 28-day cycles. Obinutuzumab induction was given on days 1, 8 and 15 of cycle 1, and on day 1 of cycles 2-6. Maintenance therapy was administered if there was at least a partial response based on PET-CT after cycle 7 with obinutuzumab every 8 weeks for a total of 12 doses and ibrutinib 560 mg daily until progression. Treatment response was assessed with PET/CT scans after cycle 4 and 7, followed by every 6 months for 2 years and then annually. Overall response rate (ORR) included complete response (CR) and partial response (PR). The primary study endpoint was ORR after 7 cycles of therapy. Results: Twenty-eight patients were enrolled (15 FL, 13 MZL) and 26 patients were evaluable for ORR after 7 cycles of therapy. The median age was 65 years (range 36-84 years), 11 (39%) presented with B symptoms, 23 (82%) had Ann Arbor Stage III-IV disease, and 18 (64%) had bone marrow involvement. For patients with FL, 11 (73%) had a morphologic grade of 1-2, and 4 (27%) had a morphologic grade of 3a. For patients with MZL, 3 (23%) had nodal, 2 (15%) had splenic, and 8 (62%) had extranodal involvement. The median follow-up time was 2.2 years (3.7 years for FL, 2.1 years for MZL). The overall response rate (ORR) following 7 cycles of therapy was 22/26 (85%) with 11/15 (73%) for FL with 10 having a CR and 1 having a PR for patients with FL and 11/11 (100%) for MZL with 8 having a CR and 3 having a PR for patients with MZL. Progression-free survival (PFS) at 24 months was 81% [67% - 97%, 95%CI] with 66% [45% - 95%, 95%CI] for FL and 100% for MZL patients. Six (5 FL, 1 MZL) patients withdrew due to progression. The most common adverse event was grade 1-2 arthralgia (N=21). The most common grade 3-4 adverse event was infection (N=10), including COVID-19 (N=5), pneumonia (N=2), neutropenic fever not otherwise specified (N=1), influenza (N=1), and diverticulitis (N=1). Conclusions: The chemotherapy free combination of Ibrutinib and Obinutuzumab is effective and well tolerated. The regimen was particularly effective in patients in MZL patients with an ORR and PFS of 100 % after median follow up of 2.1 years, and represents an attractive approach for these patients.