Early positron emission tomography response-adapted treatment in low-risk diffuse large B-cell lymphoma: an open-label, multicenter, randomized, noninferiority phase III trial.

BACKGROUND: Preliminary reports suggest interim positron emission tomography (PET) could drive treatment duration in limited-stage diffuse large B-cell lymphoma (DLBCL). This phase III randomized study in first-line therapy for DLBCL patients with adjusted-age international prognostic index (aaIPI) risk = 0, evaluates an experimental PET-response adapted approach using PET response after two cycles of R-CHOP to de-escalate treatment duration. PATIENTS AND METHODS: LNH2009-1B study is a two-arm, open-label, multicenter, prospective, randomized phase III noninferiority trial, evaluating treatment de-escalation based on PET after two cycles of R-CHOP in previously untreated DLBCL patients aged 18-80 years, with aaIPI = 0. In the experimental PET-adapted arm, patients with a negative PET after two cycles received four cycles in total of R-CHOP, whereas those with a positive PET after two cycles received a total of six cycles. In the standard arm, treatment was six cycles regardless of PET results after two cycles. No radiotherapy was planned. The primary endpoint was 3 years progression-free survival (PFS). The primary analysis was carried out in the intention-to-treat population. The trial is registered with ClinicalTrial.gov, NCT01285765, recruitment is completed. RESULTS: A total of 650 patients were enrolled, of whom 319 were randomly assigned to the PET-adapted arm and 331 to the standard arm. In the PET-adapted arm, 77.7% of patients had a negative PET scan after two cycles and received a total of four cycles of R-CHOP. The 3-year PFS in PET-adapted and standard arms were 92.0% [95% confidence interval (CI) 88.3% to 94.5%] and 89.2% (95% CI 85.3% to 92.2%), respectively (P value = 0.070). The noninferiority of the experimental PET-adapted arm was demonstrated (hazard ratio 0.72, 95% CI 0.47-1.12, P value < 0.0001). Patients in the PET-adapted arm had fewer adverse events of grades ≥3 (54.7% versus 62.7%, P = 0.046) and serious adverse events (9.5% versus 14.2%, P = 0.039). CONCLUSION: A risk-adapted approach using early PET after two cycles of R-CHOP was beneficial, minimizing toxicity without compromising efficacy in patients treated in first-line therapy for low-risk DLBCL.