Combination Of Ofatumumab and Bortezomib In Patients With Indolent B-Cell Lymphomas Who Relapsed >6 Months After Rituximab-Containing Regimen: A Brown University Oncology Research Group Phase II Study

Based on the activity of ofatumumab in patients with indolent B-cell non-Hodgkin lymphoma (NHL) and the potential synergistic effect of bortezomib in combination with anti-CD20 antibody therapy, a phase II study to investigate the effect of the combination of ofatumumab and bortezomib in patients with relapsed indolent B-cell NHL who relapsed >6 months after receiving a rituximab-containing regimen was initiated.

Patients 18 years or older with a pathologically confirmed low-grade B-cell NHL who relapsed >6 months after a rituximab-containing regimen were included in our study. Other inclusion criteria were ECOG performance status <2, and adequate organ function (creatinine <2 mg/dl, total bilirubin <1.5x ULN, and liver transaminases <2.5x ULN) and bone marrow reserve (neutrophils >0.75, and platelets >50,000/uL). Exclusion criteria included HBV+, HIV+, transformed lymphoma, primary cutaneous lymphoma, central nervous system involvement, <6 months expected survival, and active infection. Treatment consisted of ofatumumab 1,000 mg IV and bortezomib 1.6 mg/m² IV given weekly for 4 weeks (induction), then every 2 months (maintenance) to complete 12 months of therapy. Valacyclovir or acyclovir was given for herpes zoster prophylaxis while on bortezomib. Acetaminophen, diphenhydramine and glucocorticoids were administered prior to ofatumumab infusions. Response was assessed based on the Cheson criteria (2007). A sample size of 44 patients was planned, and an interim analysis after enrollment of 10 patients was undertaken to evaluate safety and early efficacy.

We present data on 10 patients enrolled between October 2010 and April 2013. Median age was 66 years (range 55-93 years); eight patients (80%) were 60 years or older. There were 7 (70%) men and 3 (30%) women. LDH was elevated in 8 patients (80%). ECOG performance status was 0 in 9 (90%) and 1 in 1 patient (10%). Six patients (60%) had a histological diagnosis of follicular lymphoma, 1 (10%) mantle cell lymphoma, 1 (10%) small lymphocytic lymphoma, 1 (10%) marginal zone lymphoma, and 1 (10%) low-grade B-cell lymphoma, not otherwise specified. Stage III/IV was seen in 5 patients (50%). Eight patients (80%) had a high-risk FLIPI score. Median time from initial diagnosis to current therapy was 65 months (range 20-204 months). Median time from last rituximab-containing regimen was 24 months (range 11-48 months). Median number of previous therapies was 2 (range 1-4). Three patients (30%) had previously received radiotherapy. One patient (10%) had previously undergone autologous stem cell transplantation. Response rates after induction therapy were: 1 (10%) complete response (CR), 3 (30%) partial response (PR), 3 (30%) stable disease, 1 (10%) progressive disease, and 2 (20%) not evaluable for response. With exception of 1 patient who continues on therapy, the patients who achieved a response or had stable disease after induction therapy showed progression of disease during maintenance. Median duration of response in patients who responded was 4 months (range 1-9 months). At the time of this report, 7 patients (70%) are alive with disease, 2 (20%) are alive without evidence of disease, and 1 (10%) has expired. Five grade 3 or 4 adverse events (AEs) occurred; grade 4: diarrhea (n=1) and hyperglycemia (n=1); grade 3: infusion reaction (n=1), nausea (n=1) and rash (n=1). No grade 3 or 4 peripheral neuropathy or hematological AEs were observed. The most common grade 1 or 2 AEs were: infusion reactions (n=6), anemia (n=5), thrombocytopenia (n=5), fatigue (n=4), diarrhea (n=4), hyperglycemia (n=4) and lymphopenia (n=4). No deaths have occurred while on therapy.

The combination of ofatumumab and bortezomib given weekly for 4 weeks induced a response in 40% and stable disease in 30% of the patients. However, most of the patients experienced progression of disease during the maintenance phase of the study. Furthermore, there were five grade 3 or 4 AEs associated with therapy. Based on this interim analysis, it was decided to stop enrollment. The combination of ofatumumab and bortezomib, however, appears potentially active and deserves further study. Different schemas of therapy with longer induction or different maintenance schedule could prove to be safer and more effective.

No relevant conflicts of interest to declare.