Treating Early-Stage DLBCL on the FLYER: What Lesson for Radiation Therapy?

Abstract

The combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and the anti-CD20 monoclonal antibody rituximab has been standard of care for diffuse large B-cell lymphoma (DLBCL) since 2006, based on results from three randomized Phase III clinical trials: GELA/LNH 98-5, Intergroup/E4494, and MInT (1–3). These trials showed that the addition of rituximab to 6-8 cycles of anthracycline-based chemotherapy increased overall survival (OS) and progression free (PFS) or event free survival (EFS) in both older patients (>60) with advanced-stage DLBCL (GELA/LNH-98-5 and E4494), and younger patients (≤60) with favorable-risk disease, defined as stage II-IV with 0-1 International Prognostic Index (IPI) risk factors or bulky stage I disease (MInT). The MInT trial showed that 6 cycles of R-CHOP every 21 days (R-CHOP-21) are sufficient in younger DLBCL patients with favorable features and that patients with early-stage DLBCL (Ann Arbor I and II) and no tumor bulk (variably defined) had excellent outcomes without radiation therapy (RT), making R-CHOP x 6 an alternative to R-CHOP x 3 + RT (3). A subset of patients (N=101) with age-adjusted IPI 0 and disease bulk <7.5 cm had very favorable outcomes (PFS and OS at 6 years 89.6% and 94.9%, respectively). Did this population actually need 6 cycles of R-CHOP? Or could fewer cycles be sufficient (without RT)? While the FLYER trial was not designed to directly answer the RT question, it is relevant for RT decisions in clinical practice. The FLYER trial was an international, randomized Phase III study conducted between December 2005 and October 2016 in the very favorable subset identified in the MInT trial, i.e. “young” patients (age 18-60) with stage I/II (based on CT or PET/CT) untreated CD20-positive aggressive B-cell lymphoma, without bulky disease, and with no age-adjusted IPI risk factors (4). The study enrolled 592 patients, of which 85% had DLBCL. Patients were randomized to receive R-CHOP every 21 days for 4 cycles, followed by an additional two doses of rituximab (n=297), or six cycles of R-CHOP every 21 days (n=295). Radiation was planned only in patients with testicular involvement, as prophylaxis to the contralateral testis. The study asked whether a reduction in chemotherapy to 4 cycles would be non-inferior to standard treatment with 6 cycles, with a non-inferiority margin of -5.5%. After median follow-up of 66 months, the study met its primary endpoint, with an absolute difference in 3-yr PFS of 3% (96% with 4 cycles R-CHOP plus two doses of rituximab vs 94% with 6 cycles R-CHOP) and no difference in 3-yr EFS or OS (89% vs 89% and 99% vs 98%, respectively). Forty patients progressed or relapsed. Rates of relapse for patients with complete response (CR) or unconfirmed complete response (CRu),