Ibrutinib and standard immunochemotherapy in younger, high-risk patients with diffuse large B-cell lymphoma: A phase II study of GLA.

Younger patients with high-risk diffuse large B-cell lymphoma (DLBCL) frequently have unfavourable outcomes. We conducted a prospective phase II study evaluating ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOEP+I) in patients aged 18-60 years with DLBCL and age-adjusted international prognostic index ≥2. Patients received ibrutinib (560 mg daily, d1-112) combined with eight cycles of R-CHOEP q2w. The primary end-point was 2-year progression-free survival (PFS). Outcomes were compared exploratorily with those of patients with identical inclusion criteria treated with R-CHOEP alone in the R-MegaCHOEP phase III trial (n = 130). Forty patients started R-CHOEP+I. Ibrutinib was administered for a median of 96 days, and 42% of patients completed treatment fully according to protocol. The overall response rate was 92%. Sixty-eight per cent received all R-CHOEP cycles compared with 88% in R-MegaCHOEP; 22% vs. 49% of patients with bulky and/or extranodal disease underwent radiotherapy. With a median follow-up of 31 months, 2-year PFS was 83% (95% CI, 71-95) vs. 75% (95% CI, 67-82) after R-CHOEP alone (p = 0.237). Exploratory cell-of-origin analyses suggested favourable outcomes in activated B-cell-type disease, but these findings remain descriptive. Grade ≥3 haematological adverse events were frequent, although no treatment-related deaths occurred. In this prematurely closed phase II study, the addition of ibrutinib to R-CHOEP showed encouraging activity. However, findings remain exploratory and hypothesis generating only.