A Phase II Trial of Combination Bortezomib (Velcade®) and Rituximab for Untreated “High Tumor Burden” Indolent Non-Hodgkin Lymphoma (NHL).
Authors: David Kevin A. , Smith Mitchell R. , Lossos Izidore S. , Roubal Eren , Winter Jane N. , Rosen Steve T. , Gordon Leo I. , Evens Andrew M. 
Published: April 2020

Abstract
Traditional therapy for patients with symptomatic and/or high-risk indolent NHL most commonly includes rituximab combined with multiagent cytotoxic chemotherapy. However some patients are not able to tolerate chemotherapy due to advanced age and/ or co-morbidities. Further, combination of novel, targeted agents (non-chemotherapeutic) have been infrequently tested in newly diagnosed indolent NHL patient populations. Overall response rate (ORR) with single-agent rituximab in prior data for untreated indolent NHL was 73% with a complete remission (CR) rate of 37% following maintenance therapy (JCO2002; 20: 4261), although a good portion of patients in that series had low tumor burden at study entry. We hypothesized that frontline bortezomib and rituximab therapy would be effective and well tolerated for untreated “high tumor burden” indolent NHL. We have conducted a Simon 2-stage phase II trial for untreated indolent NHL. All patients were required to have “high tumor burden” as defined by Groupe D’Etude des Lymphomes Folliculaires (GELF) criteria. Induction therapy consisted of 3 cycles: bortezomib given at 1.6 mg/m2 days 1, 8, 15, and 22 q35 days for all 3 cycles and rituximab at 375 mg/m2 x 4 weekly doses for cycle 1, then day 1 only for cycles 2 and 3. Abbreviated consolidation therapy was subsequently given with 1 dose of each drug q2 months x 8 months. Responses were assessed by computerized tomography (CT) according to Cheson criteria (JCO 1999). We report here the results of the first stage of this 2-stage trial. Twenty-two patients have enrolled, of whom 17 were in the 1st stage. There were 9 women and 8 men; median age was 63 years (range 46–78 years). 14 patients had follicular lymphoma (FL), 2 marginal zone lymphoma, and 1 small lymphocytic lymphoma. 13 of 17 patients had stage IV disease and 4 had stage III. The median Follicular Lymphoma International Prognostic Index (FLIPI) was 3 (range 1–4) and the median follow-up was 13 months (range 1–24 months). Responses according to cycle number are shown in Table 1. After only 1 cycle, the ORR was 29% (all partial remissions (PRs)) with 71% stable disease (SD). Following cycle 3, ORR was 59% (24% CR). From cycle 1 to 3, 4/5 PRs converted to CR, 6 SDs converted to PR, while 1 PR and 4 SDs progressed or were removed from the study at physician discretion. 8 of 12 eligible patients have completed consolidation therapy. Following consolidation, 1 PR converted to CR and 2 SDs converted to PR for an ORR of 71%. According to histology, the ORR among FL patients after consolidation therapy was 86% (CR 36%, PR 50%). Therapy was very well tolerated. Grade 3 toxicities seen were lymphopenia, partial small bowel obstruction, and fatigue (all in 1 patient); no grade 4 toxicities occurred. Furthermore, no cytopenias or neurotoxicity was seen. Accrual to the 2nd stage is being completed. In summary, we found in the 1st stage of this phase II trial that bortezomib/rituximab combination therapy for untreated high tumor burden indolent NHL is well tolerated and active. Response rates improved throughout therapy (i.e., from cycle 1 through consolidation), although the CR rate achieved was low compared with chemotherapy-based regimens. Chemotherapy-based therapy should be considered standard therapy for frontline “high tumor burden” indolent NHL, although non-chemotherapy options may be considered for patients not anticipated to tolerate intensive therapy. Furthermore, responses seen here with bortezomib/rituximab, in a uniform high tumor burden patient population, were similar to rituximab alone in lower tumor burden populations. Analysis of clinical trials/reports in indolent NHL should include critical assessment of patient selection and future trials in high tumor burden should incorporate novel therapies into rituximab-chemotherapy based regimens.
Table 1. Response according to cycle/treatment.
After Cycle 1 After Cycle 3* Following consolidation therapy** *Three patients had PD, while 2 patients were taken off study (without PD) at physician discretion. **Eight of 12 eligible patients have completed post-induction therapy. ORR 29% (5/17) 59% (10/17) 71% (12/17) CR 0% 24% (4/17) 30% (5/17) PR 29% (5/17) 35% (6/17) 41% (7/17) SD 71% (12/17) 12% (2/17) 0% PD/off trial 0% 29% (5/17) 29% (5/17)