Background: The RICOVER-60 trial established 6 cycles CHOP-14 plus 8 2-week applications of rituximab (8xR) as the optimal treatment for elderly patients with DLBCL [Pfreundschuh et al., Lancet Oncol 2008; 9: 105-116]. With a 2-year PFS of 90% and OS of 91% for patients with favourable prognosis (defined as IPI=1 [age >60 years], no bulky disease) a controlled reduction of treatment intensity appeared to be justified for this population. We hypothesized that patients with a negative PET (metabolic complete remission = mCR) after 4xR-CHOP-14 might be spared further chemotherapy (ChT), while patients not in mCR might benefit from the addition of RT. To ensure that this strategy does not put patients at risk, an interim analysis was planned after 40% of the expected events for a comparison with RICOVER-60.
Patients and Methods: 61 to 80 year-old IPI=1 pts. without bulky (≥7.5 cm) disease were randomized to 4xCHOP-14 or 4x-CHLIP-14 (liposomal instead of conventional vincristine) in combination with 8 2-week applications of rituximab. Primary endpoint was the comparison of the neurotoxicity of conventional and liposomal vincristine. Patients with a negative PET after 4x-R-CHOP/R-CHLIP-14 completed the remaining 4xR, while PET-positive (Deauville 3-5 as by central review) patients in addition received 2 additional CHOP/CHLIP-14 + plus IS-RT (39.6 Gy) to the originally involved sites.
Results: This planned interim analysis was performed to compare patient outcome with the old (fixed) and the new PET-adapted (flexible) treatment strategy. Compared to 74 RICOVER-60 pts. who had received 6xCHOP-14 plus 8xR, OPTIMAL>60 pts. were older (median: 71 vs. 68 years; p=0.009), with a larger proportion of patients >70 and >75 years. Despite the unfavourable demographics, outcome of the OPTIMAL>60 pts. receiving R-CHOP/CHLIP-14 was non-inferior to RICOVER-60 (2-y-PFS: 94% vs. 90% ; 2-y-OS 98% vs. 91%). In a multivariable analysis adjusting for strata (age >75 years and male sex), the hazard ratio of the OPTIMAL>60 compared to the RICOVER-60 was 0.5 (95% CI: 0.2-1.5; p=0.208) for PFS and 0.2 (95% CI: 0.1-0.9; p=0.036) for OS. 82% pts. were in mCR after 4xR-CHOP/CHLIP-14 and received no further ChT; 18% were PET-positive and thus to receive 2 additional CHOP/CHLIP-14 plus IS-RT, and their outcome was as good as that of mCR patients.
Conclusion: A PET-based treatment strategy allows sparing 2 cycles ChT in 82% of patients without compromising their outcome. 4xCHOP/CHLIP-14 plus 8xR for patients with a negative PET after 4 cycles of immunochemotherapy in OPTIMAL>60 is at least as good as 6xCHOP-14 plus 8xR in RICOVER-60 and appears to provide a normal life expectancy for this elderly population with a median age of 71 years. 2 additional ChT cycles plus IS-RT appear to compensate for the assumed worse prognosis of PET-positive patients, which might be in part due to the early start of RT made possible by the 2-week ChT regimens. The 98% 2y-OS is the best reported to date for this elderly population and should be the reference to which alternative strategies should be compared. Updated 3-year results will be reported. S upported by Amgen, Roche, Spectrum
Christofyllakis: medac: Other: travel expenses, event fees; Gilead: Other: travel expenses, event fees. Haenel: Roche, Novartis: Honoraria. Schmidt: Janssen: Other: Travel grants; Amgen: Membership on an entity's Board of Directors or advisory committees. Huebel: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hellwig: Employment at University Hospital Regensburg, Germany: Employment; Research Funding by Saarland University, Saarbruecken, Germany: Research Funding.
Asterisk with author names denotes non-ASH members.