Phase II trial assesses safety and efficacy of R-CyBorD for NHL

In January 2018, Mohamad Bassam Sonbol from the Hematology and Oncology Division of Mayo Clinic, Phoenix, AZ, and colleagues, investigated the efficacy and safety of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBorD) treatment against low-grade non-Hodgkin lymphoma (NHL), in a phase II study (NCT00711828), published ahead of print in Leukemia & Lymphoma.

Rituximab alone has proved to be a successful first-line treatment against indolent mature B-cell lymphoma (NCT00112931), nevertheless disease progression and relapse, following rituximab, still occur in a patient fraction. The aim of this study was to assess whether a combined drug regiment (R-CyBorD) benefits relapsed or refractory patients, with various types of low-grade NHL. The primary endpoint of the study was objective response rate (ORR on assessment), as defined by either a complete response (CR) or a partial response (PR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), duration of response (DOR) and safety, following administration of R-CyBorD.

Study overview

• 21 patients with relapsed or refractory indolent NHL were enrolled in the study with a median age of 69 years
• 8 had follicular lymphoma (FL) (38.1%; Grade 1 & 2), 8 had mantle cell lymphoma (MCL) (38.1%) and 5 lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) (23.8%)
• Patients were treated with 375 mg/m² rituximab (IV) on Day 1 and 40 mg dexamethasone (oral) together with 1.3 mg/m² bortezomib (IV) on Days 1, 8, 15, 22 on a 28-day cycle. Treatment continued for two more cycles beyond best response, or a maximum of 12 cycles

Key findings

• For all NHL subtypes: ORR = 62% (13/21), CR = 19% (4/21) and PR = 43% (9/21)
• For FL patients: ORR = 88% (7/8: CR = 4, PR = 3)
• For MCL patients: ORR = 25% (2/8: PR = 2)
• For LPL/WM patients: ORR = 80% (4/5: PR = 4)
• Median DOR not reached
• Median PFS = 11.6 months [95% CI (3.8-not reached)]
• Median OS = 54.8 months [95% CI (20.3-54.8%)]
• 24-month post-treatment: PFS = 43% [95% CI (22-62%)] and OS = 71% [95% CI (47-86%)]

Safety

• Grade ≥ 3 adverse events (AEs) = 67% (14/21)
• Most common AEs: neutropenia (38%), leukopenia (33%), thrombocytopenia (29%), anaemia (28%), peripheral neuropathy (24%) and fatigue (14%)
• Infectious AEs: one patient with Grade 3 infectious colitis, one with Grade 2 skin infection and one with Grade 2 upper respiratory infection
• 57% (8/14) patients reported with neuropathy worsening post treatment

The results from this phase II trial suggested that the combined use of rituximab with cyclophosphamide, bortezomib and dexamethasone might be effective in only certain NHL subtypes. In support of this, patients with relapsed or refractory FL had a higher response rate from R-CyBorD treatment (ORR = 88%) than MCL patients (ORR = 25%). Along with the differential effect of R-CyBorD on NHL subtypes, drug toxicity should also be taken into careful consideration. Although manageable, Grade ≥ 3 AEs were observed in a considerable number of patients (67%) and were mainly of a hematologic phenotype. A main limitation of the study, mentioned by the authors, was that the overall sample size was small and because of this, so was the sample size within the NHL subtypes. The authors hope that with further larger randomized trials, R-CyBorD could be a potential treatment option for relapsing patients with FL or LPL/WM.