Background
Multicenter, open-label phase III RCT (n=391), relapsed/refractory CLL/SLL after ≥1 prior therapy and considered inappropriate for purine analogues (no response or relapse within 12 mo of last purine analogue dose).
Interventions and follow up
Arm A: Ibrutinib 420 mg PO daily until progression
Arm B: Ofatumumab IV (300 mg wk 1, then 2000 mg weekly x7 then q4wk x17, up to 24 wks); crossover to ibrutinib allowed at progression
Primary endpoint: PFS
Median follow-up: 9.4 mo (primary); 65 mo (long-term update)
Arm B: Ofatumumab IV (300 mg wk 1, then 2000 mg weekly x7 then q4wk x17, up to 24 wks); crossover to ibrutinib allowed at progression
Primary endpoint: PFS
Median follow-up: 9.4 mo (primary); 65 mo (long-term update)
Results
mPFS: NR vs 8.1 mo (A vs B); HR 0.22, 95%CI 0.15-0.32, P<.001
mOS: NR in either arm; HR 0.43, 95%CI 0.24-0.79, P=.005
ORR (PR or better): 43% vs 4%; OR 17.4, 95%CI 8.1-37.3, P<.001
del(17p13.1) PFS: NR vs 5.8 mo, HR 0.25, 95%CI 0.14-0.45
Long-term mPFS: 44.1 vs 8.1 mo, HR 0.148, 95%CI 0.113-0.196, P<.001
Long-term mOS: 67.7 vs 65.1 mo, HR 0.63, 95%CI 0.418-0.975 (crossover-censored)
Long-term ORR/CR: ibrutinib ORR 91%, CR/CRi 11%
mOS: NR in either arm; HR 0.43, 95%CI 0.24-0.79, P=.005
ORR (PR or better): 43% vs 4%; OR 17.4, 95%CI 8.1-37.3, P<.001
del(17p13.1) PFS: NR vs 5.8 mo, HR 0.25, 95%CI 0.14-0.45
Long-term mPFS: 44.1 vs 8.1 mo, HR 0.148, 95%CI 0.113-0.196, P<.001
Long-term mOS: 67.7 vs 65.1 mo, HR 0.63, 95%CI 0.418-0.975 (crossover-censored)
Long-term ORR/CR: ibrutinib ORR 91%, CR/CRi 11%
Adverse events
Hematologic/cytopenias (grade ≥3): Neutropenia 16% vs 14%; thrombocytopenia 11% vs 4%.
Infections (grade ≥3): Pneumonia 7% vs 5%.
Other: Diarrhea 4% vs 2%; atrial fibrillation 3% vs 0%. Discontinuation for AEs 4% in each arm; fatal AEs 4% vs 5%.
Infections (grade ≥3): Pneumonia 7% vs 5%.
Other: Diarrhea 4% vs 2%; atrial fibrillation 3% vs 0%. Discontinuation for AEs 4% in each arm; fatal AEs 4% vs 5%.
Conclusions
Ibrutinib was superior to ofatumumab in PFS, OS, and response in relapsed/refractory CLL/SLL, including high-risk del(17p) disease.
Key Limitations
Short initial follow-up; high crossover from ofatumumab confounds long-term OS. Ofatumumab is a relatively weak comparator. Atrial fibrillation/bleeding risks of first-generation BTK inhibition apparent on extended follow-up.
Clinical Context
Practice-changing trial supporting FDA/EMA approval of ibrutinib in relapsed/refractory CLL. ESMO endorses BTK inhibitors as preferred therapy in this setting; second-generation agents (acalabrutinib, zanubrutinib) now favored for improved cardiac tolerability.