Background: The anti-CD20 monoclonal antibody rituximab, alone or in combination with various chemotherapeutic agents, is the standard of care for patients with indolent non-Hodgkin's lymphoma (iNHL) (Merli et al, 2013). However, due to high relapse rates, there is an unmet need for novel therapeutic agents in these patients. In patients with relapsed follicular lymphoma (FL), an anti-CD 20 monoclonal antibody ofatumumab (OFA; Arzerra®) alone or the chemotherapeutic agent bendamustine (BEN) in combination with rituximab, have been shown to be safe and effective (Hagenbeek et al, 2008; Robinson et al, 2008). The current phase 2 study evaluated the safety and efficacy of OFA in combination with BEN, followed by maintenance with OFA, in patients with relapsed iNHL, who were previously sensitive to rituximab treatment.
Methods: This open-label, single-arm, multicenter, phase 2 study enrolled adult patients with grades 1, 2, and 3a of relapsed CD20+ iNHL with measurable tumor. Patients should have achieved and maintained partial response (PR) or complete response (CR) for ≥ 6 months with previous rituximab therapy alone or in combination with another regimen. This study included an induction phase of OFA and BEN (6 cycles of 28 days each), a maintenance phase of OFA alone for up to 24 months, and follow-up of 36 months. Efficacy end points were CR rate at the end of induction phase (primary end point), overall response rate (ORR; PR or CR) in the induction phase, rate of conversion from PR to CR in maintenance phase, and progression-free survival (PFS). During induction, patients received 1000 mg OFA on day 1 and 90 mg/m2 BEN on days 1 and 2 of each cycle (28 days) for 6 cycles. Patients with CR or PR after induction therapy could receive maintenance OFA (1000 mg IV) every 2 months for up to 24 months.
Results: Of the target sample size of 53 patients, 49 were enrolled. Treatment was discontinued in 35 patients (71.4%) due to disease progression (n = 12), adverse events (AEs; n = 11), patient's decision (n = 5), study closure (n = 3), investigator's discretion (n = 3), or loss to follow-up (n = 1).
Median age (range) was 67 years (35-89); 75.5% were ≥ 60 years of age and 28.6% were females. Most patients (63.3%) had FL. Median time (range) since diagnosis was 71.2 months (14-299) and last relapse was 1.6 months (0-81). Mean cycle numbers (SD) for OFA and BEN were 5.2 (1.7) and 5.4 (1.5), respectively, during induction and 7.2 cycles (4.4) of OFA during maintenance.
The study met its primary end point. After 6 cycles of induction therapy, 12 of 49 patients achieved CR (24.5%; 95% confidence interval [CI]: 13.3%, 38.9%) and 21 had a PR. The ORR at the end of induction therapy was 67.3% (95% CI: 52.5%, 80.1%). Six of 16 patients (37.5%; 95% CI: 15.2, 64.6) with a PR, who continued maintenance OFA, achieved a CR. There were 21 patients (42.9%) who progressed, and the estimated median time (95% CI) to progression was 29.7 months (17.3, not evaluable) (Figure).
Overall, 48 patients (98%) experienced an AE (grade ≥ 3, 69.4%; n = 34), and AEs in 47 patients (95.9%) were suspected to be treatment related. Serious AEs were observed in 18 patients (36.7%). The most common AEs were fatigue (61.2%), nausea (49.0%), constipation (28.6%), and diarrhea (26.5%). Hematologic abnormalities included decrease in lymphocytes (85.7%; grade 3 or 4, 59.2%), WBCs (73.5%; grade 3 or 4, 22.4%), total neutrophils (61.2%; grade 3 or 4, 24.5%), and hemoglobin (49.0%; grade 3 or 4, 2.0%). The most common biochemical abnormalities of any grade included increase in glucose (91.8%), aspartate aminotransferase (AST; 34.7%), and alanine aminotransferase (ALT; 32.7%), and of grade 3 or 4 were increase in uric acid (22.4%) and glucose (14.3%). There were no grade 3 or 4 events of increase in AST or ALT.
Overall, 7 patients (14.3%) died during the study. Of these, 1 patient died due to disease progression within 60 days of stopping treatment. Six patients died during follow-up due to disease progression (n = 2), pneumonia (n = 1), myelodysplastic syndrome (n = 1), squamous cell carcinoma of the lung (n = 1), and chronic obstructive pulmonary disease (n = 1).
Conclusions: The primary end point of the study was met. With a combination of OFA and BEN, 12 of 49 patients (24.5%) achieved CR after 6 months of induction therapy, ORR was 67.3%. Of the patients with PR, 37.5% achieved CR with maintenance therapy with OFA. Though the incidence of AEs was high, it was consistent with that observed for the disease and the therapy.
Kolibaba: Janssen: Research Funding; Gilead Sciences, Inc: Consultancy, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding; Acerta: Research Funding; Genentech: Research Funding; Cell Therapeutics: Research Funding; Celgene: Research Funding. Moezi: Novartis: Speakers Bureau; Takeda: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau. Sharman: Novartis: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding. Xiaoshu: Novartis: Employment. Cannan: Novartis: Employment. Fellague-Chebra: Novartis: Employment.
Asterisk with author names denotes non-ASH members.