Title: Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study

Chiappella, A et al.


What You Need to Know:

According to results of a phase 3 study, intensification of R-CHOP therapy (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) should not be considered as an upfront treatment strategy for young patients with diffuse large B-cell lymphoma with a poor prognosis.

Trial Design:

  • Open-label, multicenter phase 3 study utilized a 2×2 factorial design “to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18–65 years) with untreated high-risk diffuse large B-cell lymphoma”
  • 399 patients were randomized (1:1:1:1)
  • No transplantation group: received R-CHOP-14 (375 mg/m2 rituximab, 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, and 1.4 mg/m2 vincristine on day 1 + 100 mg prednisone on days 1–5 administered in a 14-day cycle for 8 cycles) or R-MegaCHOP-14 (R-CHOP-14 except for 1200 mg/m2 cyclophosphamide and 70 mg/m2 doxorubicin for six cycles)
  • Transplantation group: received R-CHOP-14 for four cycles then R-MAD (375 mg/m2 rituximab on day 1 or 4, 2000mg/m2 cytarabine, and 4 mg/m2 dexamethasone every 12 h on days 1–3 + 8 mg/m2 mitoxantrone on days 1–3) + BEAM (300 mg/m2 carmustine on day −7, 200 mg/m2 cytarabine twice daily on days −6 to −3, 100 mg/m2 etoposide twice daily on days −6 to −3, and 140 mg/m2 melphalan on day −2) + autologous stem-cell transplantation (day 0) or R-MegaCHOP-14 for four cycles, then R-MAD + BEAM + autologous stem-cell transplantation
  • Primary endpoint: failure-free survival after 2 years; analyzed in intention-to-treat population

Key Outcomes:

  • 199 patients received transplantation, 200 patients did not receive transplantation, 203 patients received R-CHOP-14, and 196 patients received R-MegaCHOP-14
  • 2-year failure-free survival (at a median follow-up of 72 months): 71% for patients who received transplantation (95% CI: 64, 77) vs 62% for patients who did not receive transplantation (95% CI: 55, 68) (HR: 0.65; 95% CI: 0.47, 0.91; P=0.012)
  • 5-year overall survival: 78% for transplantation patients (95% CI: 71, 83) vs 77% for patients who did not receive transplantation (95% CI: 71, 83) (HR: 0.98; 95% CI: 0.65, 1.48; P=0.91)
  • Hematological adverse events grade 3 or higher: experienced by 92% of patients in the transplantation group (183/199) vs 68% of patients in the no transplantation group (135/200)
  • Non-hematological adverse events grade 3 or higher: experienced by 45% of patients in the transplantation group (90/199) vs 16% of patients in the no transplantation group (31/200)
  • Gastrointestinal grade 3 or higher adverse events were most common (experienced by 25% of transplantation patients vs 10% of no transplantation patients)
  • 3% of patients died due to treatment-related causes: 8 patients received transplantation, 5 did not receive transplantation