Single Agent Ofatumumab In Patients With Relapsed and/Or Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results From a Phase II Open Label Study

Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains a clinical challenge, with no standard options for elderly or transplant-ineligible patients. Ofatumumab is a fully humanized monoclonal antibody with specificity for CD20 that is currently approved for R/R chronic lymphocytic leukemia. Ofatumumab given for 4 weekly doses elicited an overall response rate (ORR) of 11% in a prior French study of R/R DLBCL. However, a maintenance strategy for stable or responding DLBCL has not been tested and could improve the overall clinical benefit. This phase II open label study of single agent ofatumumab tested the efficacy of a combined induction and maintenance schedule.

Patients with R/R DLBCL who were transplant-ineligible or who had relapsed after transplantation were included. The treatment schedule was ofatumumab 1000 mg weekly for 8 weeks (induction phase). Patients achieving stable disease (SD) or better continued on a maintenance phase receiving ofatumumab at 1000 mg every other week until objective evidence of disease progression or patient/physician decision to withdraw. The primary end-points were overall response (OR) defined as the sum of partial response (PR) and complete response (CR) (Cheson Criteria), and toxicity using NCI criteria (CTCAE v.4). Secondary end-points included time to disease progression (TTP), overall survival (OS), and the overall clinical benefit defined as the sum of SD, CR, and PR.

Eleven patients were enrolled in this trial before it was stopped due to slow accrual. Median age was 67 years (range: 41-89) and 4/11 patients were male. All patients had advanced stage III/IV disease and 10/11 had an Eastern Cooperative Oncology Group performance status of 0 or 1. Median LDH was 246 U/l (range: 160-966), one patient had bulky disease, and one patient had B symptoms. Patients were heavily pre-treated with a median of 4 prior therapies (range: 1-7). One patient had relapsed disease, while the other 10 had disease that was rituximab-refractory. Four patients (36%) had prior transplants (2 autologous, 1 allogeneic, and 1 both). All patients were evaluable for response and toxicity. One patient was taken off study without progression due to hemolytic anemia (possibly related) after 6 months of therapy. Best responses achieved were 2 PR and 2 SD, while 7 patients progressed for an OR of 18% and a clinical benefit rate of 36%. Five patients (1 PD patient received maintenance ofatumumab inadvertently) went on to receive ofatumumab maintenance for a median duration of 4 cycles (range: 1-18). Response lasted for 6 and 9 months respectively in the 2 patients with PR. Subsequent therapies for progressing patients were offered (2 received bendamustine and rituximab, 1 received single agent bendamustine, and 3 had investigational therapies). At a median follow-up of 23 months (range: 5-38), 3 patients remain (27%) alive, median event free survival (EFS) was 2 months (range: 1-11), and median overall survival was 7 months (range: 1-31). Ofatumumab was generally well tolerated with 3 patients developing grade 1/2 infusion reactions. Other toxicities included grade 1/2 diarrhea (63%), anorexia (45%), hyponatremia (36%), and fatigue (36%). No grade 3/4 non-hematologic toxicities were observed. Grade 3/4 neutropenia occurred in 3/11 (27%) patients, one of whom was hospitalized for neutropenic fever. In addition, grade 4 thrombocytopenia occurred in 1 pt.

In this phase II study, we demonstrate modest single agent activity for ofatumumab in heavily pretreated rituximab-refractory DLBCL patients who have failed multiple standard therapies. Ofatumumab was well-tolerated with an acceptable safety profile. Maintenance therapy did not appear to add additional benefit in this small cohort. However, the favorable toxicity profile and modest clinical benefit justify further studies of this antibody in combination with chemotherapy or with other targeted agents.

Nabhan:Genentech: Research Funding, Speakers Bureau; GSK: Research Funding.