Reduction of Chemotherapy in Aggressive Non-Hodgkin's Lymphoma with Favorable Prognosis

Abstract

Background: Six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) or R-CHOP-like chemotherapy are the standard treatment for aggressive B-cell non-Hodgkin's lymphoma. We hypothesized that four cycles of CHOP plus six applications of rituximab (4x R-CHOP+2xR) are non-inferior to six cycles of R-CHOP in a population with favorable prognosis. Methods: We randomized patients 18 to 60 years of age, stage I-II disease, normal serum lactate dehydrogenase concentration, good ECOG performance status 0-1, without bulky disease (maximal tumor diameter <7.5 cm) to receive 6x R-CHOP or 4x R-CHOP+2xR. The primary endpoint was progression-free survival after three years. Findings: After a median follow-up of 66 months, 3-years progression-free survival of patients with 4x R-CHOP+2xR was 96% (95% confidence interval [CI]: 94%; 99%), which was 3% (95% CI (one-sided): 0%; 6%) better than 6x R-CHOP, demonstrating the non-inferiority of 4x R-CHOP+2xR. Survival after 3 years was 99% (95% CI: 98% - 100%) with 4x R-CHOP+2xR versus 98% (95% CI: 96% - 99%) with 6x R-CHOP. Relapse rates were 4% (95% CI: 2% -7%) in the 4x R-CHOP+2xR group versus 5% (95% CI: 3% - 8%) in the 6x R-CHOP group, respectively. Interpretation: In young patients with aggressive B-cell non-Hodgkin's lymphoma and favorable prognosis outcome after 4 cycles of R-CHOP is non-inferior compared to 6 cycles of R-CHOP, with relevant reduction of toxicity. Thus, chemotherapy can be reduced without compromising outcome in this population. Trial Registration: ClinicalTrials.gov number, NCT00278421. Funding Statement: It was coordinated by the German Study Group for high-grade Non-Hodgkin Lymphoma (DSHNHL) and funded by a German non-profit foundation, the “Deutsche Krebshilfe” (German Cancer Aid), reference number 106369. Declaration of Interests: Referring the Work under Consideration for Publication/During the Conduct of the study: Grants: V. Poeschel: Deutsche Krebshilfe (Non-Profit/Charity Organization); H. Holte: Deutsche Krebshilfe, Roche; Personal Fees: U. Keller: Roche; Relevant financial activities outside the submitted work: Personal Fees: V. Poeschel: Hexal; G. Held: BMS, Roche, Amgen, Spectrum, MSD; A. Viardot: Roche, Kite/Gilead, Pfizer, BMS, Amgen; C. Schmidt: Novartis AG, Gilead, Takeda; L. Truemper: Takeda; U. Keller: Janssen Cilag, BMS, Gilead, Takeda, Amgen, Hexal, Celgene, Astra Zeneca, MSD; R. Marks: Roche, Servier, Merck; M. Kneba: Astra Zeneca; F. Merli: Roche, Takeda, Celgene, Janssen, Gilead, Mundipharma; P. de Nully Brown: Roche; F. Hartmann: BMS, Roche, Boehringer Ingelheim, Sanofi, Celgene, Novartis, Ipsen, Janssen, Gilead; S. Stilgenbauer: Abbvie, Amgen, Astra Zeneca, Celgene, Gilead, GSK, Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Grants: V. Poeschel: Abbvie, Amgen, Roche; G. Held: BMS, Roche; C. Schmidt: Janssen Cilag, Gilead, Takeda; S. Stilgenbauer: Abbvie, Amgen, Astra Zeneca, Celgene, Gilead, GSK, Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Non-financial support: C. Schmidt: Janssen Cilag, Gilead, Takeda; F. Merli: Takeda, Celgene; S. Stilgenbauer: Abbvie, Amgen, Astra Zeneca, Celgene, Gilead, GSK, Roche, Janssen, Novartis, Pharmacyclics, Sunesis All other authors declared no conflicts of interest. Ethics Approval Statement: The study was conducted in accordance with the Helsinki declaration. The protocol and its amendments were approved by the ethics committee of each participating center.