In March 2017, Jeffrey A. Jones, from The Ohio State University, Columbus, OH, USA, and colleagues publishedin The Lancet Haematologyupdated results of their open-label, multicenter, phase III trial investigating the efficacy and safety of idelalisib combined with ofatumumab to treat R/R CLL patients ( NCT01659021).

Between 17 December 2012 and 31 March 2014, 261 patients (median age, 68 years; IQR, 61–74) were enrolled from North America, Europe, and Australia, and were randomly assigned: 174 to idelalisib plus ofatumumab and 87 to ofatumumab alone.

Key Highlights:

Treatment: Control group = IV ofatumumab for up to 24 weeks, initial dose of 300mg on day 1 week 1, followed by 2000mg weekly for 7 weeks, and then every 4 weeks for 16 weeks Investigational group = oral idelalisib 150mg twice daily plus ofatumumab at same schedule as control pts but lower dose of 1000mg from week 2 onward

Median follow-up: investigational group = 16.1 months (IQR, 9.2–21.8); control group = 5.8 months (IQR, 2.7–9.7)

Median PFS: Investigational group = 16.4 months (95% CI, 13.6–19.5) Control group = 8.0 months (95% CI, 5.7–8.2) Investigational del(17p) or TP53 mutated subgroup = 15.5 months (95% CI, 11.1–19.1) Control del(17p) or TP53 mutated subgroup = 5.8 months (95% CI, 4.5–8.4)

Median OS: Investigational group = NR (95% CI, 25.8 months–NR) Control group = NR (95% CI, 21.7 months–NR; adjusted HR, 0.75; P= 0·27) Investigational del(17p) or TP53 mutated subgroup = 25.8 months (95% CI, 22.7–NR) Control del(17p) or TP53 mutated subgroup = 19.3 months (95% CI, 10.7–NR)

Overall median time of exposure: Investigational group = 13.9 months (IQR, 6.8–21.7) of idelalisib and 5.3 months (IQR, 5.3–5.4) of ofatumumab Control group = 4.2 months (IQR, 1.6–5.3) of ofatumumab

Toxicity: The 4 most common AEs were diarrhea, pyrexia, neutropenia, and fatigue in the investigational group; and fatigue, Infusion Related Reactions, nausea, and diarrhea in the control group 157/173 (91%) pts in the investigational group and 48/86 (56%) pts in the control group reported ≥1 grade 3 or worse AE The most common SAEs: investigational group = pneumonia and pyrexia (13% each), febrile neutropenia (12%), and diarrhea (11%); control group = pneumonia (10%) and febrile neutropenia (3%) Serious infections were more common in the investigational group compared to the control group: sepsis (6% vs. 1%), Pneumocystis jirovecii pneumonia (5% vs. 1%), and urinary tract infections (4% vs. 0%) 68 (39%) pts in the investigational group discontinued idelalisib due to an AE; the most common AEs leading to idelalisib discontinuation included diarrhea (9%), pneumonia (3%), pneumonitis (2%), increased alanine transaminase (2%), and colitis (2%) TEAEs leading to death reported in 22 pts (13%) in the investigational group (exposure-adjusted incidence 0.10 per year) vs. 6 (7%) pts in the control group (exposure-adjusted incidence 0.18 per year)



In conclusion, the group stated that adding idelalisib to ofatumumab significantly improved PFS and response, and this benefit was noted regardless of baseline demographic, clinical characteristics, or molecular genetic features of the disease. The group also stated that their results, acquired with longer follow-up endpoints compared to other phase III trials, indicate that idelalisib administered with ofatumumab is safe and effective in relapsed CLL patients, providing an alternative treatment option for patients refractory or intolerant to rituximab-based regimens.