Prospective phase II study of rituximab with alternating cycles of hyper‐ CVAD and high‐dose methotrexate with cytarabine for young patients with high‐risk diffuse large B ‐cell lymphoma

Summary We conducted a prospective randomized phase II study to evaluate two chemotherapy regimens: (i) rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone ( R ‐ HCVAD ) alternating with rituximab, high‐dose methotrexate, and cytarabine ( R ‐ MA ) and (ii) rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone ( R ‐ CHOP ) in diffuse large B ‐cell lymphoma ( DLBCL ). This study randomized patients aged ≤60 years with DLBCL and an age‐adjusted international prognostic index ≥2 to R ‐ HCVAD / R ‐ MA or R ‐ CHOP based on a B ayesian adaptive algorithm. Interim analysis of the first 26 eligible patients showed that the complete response rate ( CRR ) was higher with R ‐ HCVAD / R ‐ MA than R ‐ CHOP ( P  = 0·03); thus, R ‐ CHOP arm was closed. In the final analysis, 49 and 10 eligible patients were treated in R ‐ HCVAD / R ‐ MA and R‐ CHOP arms respectively; CRR were 82% and 60% respectively ( P  = 0·13); 3‐year progression‐free survival ( PFS ) rates were 75·7% and 77·8% respectively ( P  = 0·53). In the R ‐ HCVAD / R ‐ MA arm, 3‐year PFS rates in patients aged 46–60 years and ≤45 years were 70·3% and 87·1% respectively ( P  = 0·13), and the treatment‐associated early mortality rate in patients >45 years was 12%. In conclusion, R ‐ HCVAD / R ‐ MA is associated with excellent outcome in patients ≤45 years old. However, in patients >45 years old, R‐ HCVAD / R ‐ MA is associated with unacceptable mortality rates.