Five-Year Follow-up of Safety and Efficacy of a Phase III Randomized Trial of Ofatumumab Therapy Versus Physicians' Choice in Patients with Bulky Fludarabine Refractory Chronic Lymphocytic Leukemia

Background: In 2014, a planned interim analysis of an open-label, two-arm, randomized, phase III study of ofatumumab (OFA) vs physicians' choice (PC) treatment (most patients received rituximab-, alemtuzumab-, alkylator-, or fludarabine-based therapies) in patients with bulky fludarabine-refractory chronic lymphocytic leukemia (BFR CLL) was performed to assess the effectiveness of OFA in the time-period prior to administering small molecule kinase inhibitors. The study did not meet its primary endpoint of progression-free survival (PFS) as assessed by the independent review committee (median PFS 5.4 months vs 3.6 months; hazard ratio [HR]=0.79, 95% confidence interval [CI]: 0.50, 1.24; p=0.268). Here, we report the 5-year follow-up of the study.

Methodology: Patients with BFR CLL who required therapy and had received at least 2 prior therapies were randomized (2:1) to receive either OFA or PC therapy. Eligible participants were stratified based on del (17p) status, the Eastern Cooperative Oncology Group (ECOG) Performance Status (0, 1, or 2), and fludarabine-refractory status (no response vs <6 months response).Patients in the OFA arm received an initial dose of 300 mg, followed 1 week (w) later with 2000 mg once weekly for 7 w, followed 4 w later by one infusion of 2000 mg every 4 w for 4 infusions, with total 12 infusions over 24 w. Patients in PC therapy received non-OFA regimen permitted therapies for CLL and standard of care regimens for up to 6 months. After 24 w in the OFA arm, if patients achieved at least stable disease or better, they were further randomized to either OFA extended arm (additional dose regimen of 2000 mg once every 4 w up to 24 w) or OFA observation arm (no further therapy). Patients in PC arm who received OFA after experiencing progressive disease (PD) had an option to receive single-agent OFA therapy in the salvage arm. The primary objective of the study was to evaluate improvement in PFS. The key secondary objectives were overall response rate (ORR), overall survival (OS), and evaluation of safety and tolerability of OFA.

Results: After 24 w of OFA treatment, 122 patients who were randomized to PC (n=43) or OFA (n=79) underwent a second randomization (24 continued OFA in the extended arm and 13 stopped OFA in the observation arm). Of the 43 patients who were randomized to PC arm, 22 received OFA salvage therapy at PD. Patient disposition is described in Figure 1. Patients received a median of 6 and 3 treatment cycles in the OFA and PC arms, respectively. The interim analysis of PFS was presented earlier (Osterborg et al., 2016). The investigator-assessed ORR for the OFA and PC arms remained unchanged from the interim analysis (49% vs 37%, respectively). However, in the OFA salvage arm (55%), there was a 5% increase in the investigator-assessed ORR compared to that of the previous analysis. The median OS for the OFA arm vs PC arm was 19.2 months vs 14.5 months (HR=0.75, 95% CI: 0.48, 1.17; p=0.173, log-rank test). The most common adverse events (AEs) in the OFA and PC arms (>15% in either) were neutropenia (21% vs 19%), pneumonia (18% vs 19%), and anemia (9% vs 19%), respectively. Grade 3, 4, and 5 AEs (>10%) in the OFA and PC arms were neutropenia (17% vs 16%), pneumonia (14% vs 9%), febrile neutropenia (9% vs 12%), and anemia (6% vs 14%), respectively. Serious AEs (≥5%) in the OFA and PC arms were pneumonia (13% vs 16%), febrile neutropenia (9% each), pyrexia (5% vs 7%), anemia (3% vs 9%), sepsis (0% vs 9%), autoimmune hemolytic anemia (0% vs 5%), and neutropenic sepsis (1% vs 5%), respectively. There were 8 (10%) on-treatment deaths in the OFA arm and 5 (12%) on-treatment deaths in the PC arm. Post-treatment anti-cancer therapies are described in Table 1.

Conclusions: At the 5-year follow-up of this phase III trial, there was a numerical but statistically not significant longer median OS (+4.7 months) in the OFA arm. As only few patients had the chance to receive a kinase inhibitor later, the study displays the survival of BFR CLL patients in the period prior to receiving small molecule inhibitors. This and other studies have demonstrated a longer PFS with the use of low-dose maintenance CD20 monoclonal antibody therapy vs not, a finding that may be re-explored in the new targeted therapeutic landscape in CLL. OFA is a safe option in multi-resistant advanced CLL cases.

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