Ofatumumab generates high response rates in refractory CLL

December 10, 2010

Ofatumumab (Arzerra) demonstrated clinical benefit was superior to historic outcomes with salvage therapies in this setting, according to lead investigator William G. Wierda, MD, PhD. After about 26 months of median follow-up, progression-free survival and overall survival improved in fludarabine-refractory chronic lymphocytic leukemia and in fludarabine-refractory CLL with bulky lymph nodes.

Ofatumumab (Arzerra) monotherapy produced high response rates in patients with refractory, high-risk chronic lymphocytic leukemia (CLL), independent of prior rituximab (Rituxan) therapy, age, stage, and number of prior regimens.

Ofatumumab, which is approved for use in CLL that is refractory to fludarabine (Fludara) and alemtuzumab (Campath), is a fully human CD20 monoclonal antibody. Interim analysis of this pivotal trial among 138 patients demonstrated objective response rates (ORRs) of 58% in fludarabine-refractory (FA-ref) CLL and 47% in fludarabine-refractory CLL with bulky lymph nodes (BF-ref).

This population is at very high risk, with historical ORRs of 20% to 26% and median time to treatment failure of two to three months, explained lead investigator William G. Wierda, MD, PhD, from Houston’s M.D. Anderson Cancer Center. In addition, these patients do not respond to rituximab-based therapy. At the time of presentation, median overall survival (OS) came in at eight months in FA-ref patients and 14 months in BF-ref CLL patients. Major infection rates came in at 60% in FA-ref patients and 45% in BF-ref patients.

Participants were premedicated with paracetamol (1g PO), cetirizine (10 mg PO), and prednisolone (100 mg IV). They were given an initial ofatumumab infusion of 300 mg, then seven weekly 200-mg infusions followed by four additional 200 mg doses at weeks 12, 16, 20, and 24.

Among the 95 patients in the FA-ref group and 111 in the BF-ref group, about three-fourths were male (median age 64 years). Approximately two-thirds were in Rai stage III-IV CLL. The median number of prior therapies was five in the FA-ref group and four in the BF-ref group. About 42% were refractory to prior rituximab.

In the final analysis, ORRs were significantly higher for both FA-ref (51%) and BF-ref (44%) (P = .0001) than for the null hypothesis ORR level of 15% (ORRs above that were deemed to signify therapeutic activity). There were two complete responders in the BF-ref group. After about 26 months median follow-up, progression-free survival (PFS) and OS were similar: PFS at 5.5 months for both; OS at 14.2 months for FA-ref and 17.4 months for BF-ref.

Dr. Wierda reported that baseline characteristics did not significantly affect response rates, but that the presence of a 17p deletion did result in a significantly lower ORR (22% vs 49% for no 17p deletion) in the BF-ref group. There were no significant differences in median PFS according to baseline characteristics. Responses were also similar regardless of prior rituximab treatment or number of prior therapies (ASH 2010 abstract 921).

A landmark analysis at week 12 showed median OS of 10.2 months and 23 months among nonresponders and responders, respectively, in the FA-ref group, and 15.5 months and 27.6 months in nonresponders and responders in the BF-ref group.

Grades 1-3 infusion related-reactions were more common in the first two treatment cycles and abated thereafter. The most commonly reported adverse events were cough (23%), pyrexia (21%), anemia (18%), diarrhea (17%) and neutropenia (17% with 13% ≥grade 3).

There were 20 (21%) deaths in the FA-ref group and 11 (10%) in the BF-ref group. Sepsis was (8%) the most common cause in the FA-ref group, and pneumonia-related deaths occurred in 4% of both groups.

Dr. Wierda concluded that ofatumumab monotherapy has high response rates in high-risk, refractory CLL. “The demonstrated clinical benefit was superior to historic outcomes with salvage therapies in this setting,” he said. Investigations in earlier stage disease with novel combinations including ofatumumab and with ofatumumab maintenance therapy are ongoing.