Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia

Abstract

Purpose: New treatments are needed for patients with fludarabine- and alemtuzumab-refractory (FA-ref) chronic lymphocytic leukemia (CLL) or patients with fludarabine-refractory CLL with bulky (> 5 cm) lymphadenopathy (BF-ref) who are less suitable for alemtuzumab treatment; these groups have poor outcomes with available salvage regimens. Ofatumumab (HuMax-CD20) is a human monoclonal antibody targeting a distinct small-loop epitope on the CD20 molecule. We conducted an international clinical study to evaluate the efficacy and safety of ofatumumab in patients with FA-ref and BF-ref CLL.

Patients and methods: Patients received eight weekly infusions of ofatumumab followed by four monthly infusions during a 24-week period (dose 1 = 300 mg; doses 2 to 12 = 2,000 mg); response by an independent review committee (1996 National Cancer Institute Working Group criteria) was assessed every 4 weeks until week 24 and then every 3 months until month 24.

Results: This planned interim analysis included 138 treated patients with FA-ref (n = 59) and BF-ref (n = 79) CLL. The overall response rates (primary end point) were 58% [corrected] and 47% in the FA-ref and BF-ref groups, respectively. Complete resolution of constitutional symptoms and improved performance status occurred in 57% and 48% of patients, respectively. Median progression-free survival and overall survival times were 5.7 and 13.7 months in the FA-ref group, respectively, and 5.9 and 15.4 months in the BF-ref group, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. Hematologic events during treatment included anemia and neutropenia.

Conclusion: Ofatumumab is an active, well-tolerated treatment providing clear clinical improvements for fludarabine-refractory patients with very poor-prognosis CLL.

Trial registration: ClinicalTrials.gov NCT00349349.

Fig 1.

(A) Progression-free survival (PFS) by patient group. PFS was defined as time from baseline (week 0) to progression (assessed by independent end point review committee) or death. (B) Overall survival (OS) by patient group. OS was defined as time from baseline (week 0) to death. (C) OS according to response status in the fludarabine- and alemtuzumab-refractory (FA-ref) group. (D) OS according to response status in the bulky fludarabine-refractory (BF-ref) group. OS in panels C and D based on landmark analysis at week 12, which includes patients who were alive at the week 12 time point; P value derived from two-sided log-rank test.

Fig 2.

Infusion-related reactions by infusion number.

Fig A1.

(A) Median hemoglobin levels over time in patients with baseline anemia. (B) Median platelet count over time in patients with baseline thrombocytopenia. FA-ref, fludarabine and alemtuzumab refractory; BF-ref, bulky fludarabine refractory.

Fig A2.

Median CD45⁺CD5⁺CD19⁺ cells in peripheral blood over time. FA-ref, fludarabine and alemtuzumab refractory; BF-ref, bulky fludarabine refractory.

Fig A3.

(A) Median neutrophil count over time in all patients. (B) Median hemoglobin levels over time in all patients. (C) Median platelet count over time in all patients. FA-ref, fludarabine and alemtuzumab refractory; BF-ref, bulky fludarabine refractory.