Phase II Trial of Ofatumumab (OFA) for Older Patients and Patients Who Refuse Fludarabine-Based Regimens with Previously Untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Fludarabine (FLU), cyclophosphamide and rituximab or other FLU based regimens have shown improvement in response rates, progression-free survival, and in some studies overall survival in patients (pts) with previously untreated CLL or SLL. However, the value of FLU based therapies in older pts is less clear with both clinical trial and retrospective analyses showing no improvement in progression-free and overall survival with FLU based therapy. In contrast, regimens that contain rituximab appear to provide benefit across all age groups. OFA is a fully human Immunoglobulin G1 kappa, monoclonal antibody that targets a unique epitope on the CD20 molecule. Pre-clinical data indicate that OFA has greater NK cell and monocyte mediated killing, complement dependent cytotoxicity, and direct killing against CLL cells. Based on pre-clinical and clinical studies indicating possible increased efficacy of OFA in pts with CLL, our aim was to develop an antibody-only regimen for older pts and pts who refuse FLU-based regimens.

Eligible pts had previously untreated CD20+ B-cell CLL(B-CLL) or SLL according to NCI criteria, ECOG PS of ≤2, and were either ≥ 65 years of age, or pts 18–64 years of age who had declined FLU-based regimens. All pts in this study received OFA as an IV infusion once weekly for a total of 8 weeks. To reduce the possibility of infusion reactions, the first dose of OFA was administered at a dose of 300mg. If the initial 300mg dose of OFA was well tolerated, without occurrence of any infusion associated AEs of ≥ grade 3, subsequent doses of OFA (i.e., Week 2 through Week 8) were given at a dose of 2000mg for cohort 1 and 1000mg for cohort 2. Eight weeks after the 8-week induction treatment (tx) ended; pts were assessed for response to the tx. Pts who progressed received no further tx. Pts who responded to the tx or who did not have disease progression received maintenance therapy - OFA at a dose of 2000mg IV for cohort 1 and 1000mg for cohort 2 every 2 months for 2 years (for a total of 12 doses, in the absence of PD or intolerable toxicity) beginning 3 months after the last dose of OFA.

Between 8/2010 and 12/2011, 77 pts were accrued (44 pts on cohort 1, 33 pts on cohort 2), median FU for Cohort 1 was 16.1 months (11.6–20.9) and Cohort 2 7.2 months (3.6–10.7). Median age of cohort 1 was 69 (range 47–88) and cohort 2 was 75 (range 50–93). Rai stage at study entry was I/II/III/IV (cohort 1 15/5/11/14 and cohort 2 9/10/7/7). All pts have completed induction therapy. The most common reason for early discontinuation was due to progressive disease (7 pts). Neutropenia was the most common grade 3/4 hematologic adverse event (10 pts). There were no G3 related non-hematologic AEs in either cohort. Two pts have died (1 due to MI, 1 due to CVA). Response by NCI 1996 criteria and IWCLL 2008 criteria and FISH category are shown below; at the time of this analysis 44 pts on C1 and 22pts on C2 were evaluable for response. Kaplan-Meier estimate of PFS is 74% at 15 months for cohort 1. Time to event data for cohort 2 are immature at this analysis but PFS but will be presented at the meeting.

OFA, when given as a single agent, is well tolerated as front-line therapy in pts with CLL/SLL. Response rates and PFS compare favorably to our previous studies with rituximab using the same response criteria, particularly when differences in the age of pts entered onto the study are considered. The optimal single-agent dose of OFA in the front-line setting remains to be determined. Further follow-up of these data my provide insight in the dose/response relationship.

Off Label Use: Ofatumumab as front-line treatment for CLL/SLL.