Treatment With Four Cycles of R-CHOP Is Non-Inferior to Six Cycles in Some Aggressive B-Cell Non-Hodgkin Lymphomas

For patients with aggressive B-cell non-Hodgkin lymphoma (NHL) and a favorable prognosis, treatment with four cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) was non-inferior to a standard 6-cycle regimen with respect to 3-year progression-free survival (PFS) and overall survival (OS), according to results from the phase III FLYER trial published in The Lancet.

This non-inferiority was accompanied by “a relevant reduction of toxic effects,” the authors, led by Viola Poeschel, MD, from Saarland University Medical School in Germany, wrote. “Thus, chemotherapy can be reduced without compromising outcomes in this population.”

Between December 2005 and October 2016, the open-label, non-inferiority FLYER trial enrolled patients between the ages of 18 and 60 years of age who had stage 1 or 2 disease, a maximal tumor diameter of <7.5 cm, and an Eastern Cooperative Oncology Group performance status score of 0 to 1. The trial was performed at 138 different sites across Denmark, Germany, Israel, Italy, and Norway.

Patients were randomized to one of two treatment groups:

  • 6 cycles of R-CHOP (n=295)
  • 4 cycles of R-CHOP plus 2 additional doses of rituximab (n=293)

Rituximab was administered at 375 mg/mg2 per cycle. The remainder of the CHOP regimen, administered intravenously on day one, consisted of the following:

  • cyclophosphamide 750 mg/m2
  • doxorubicin 50 mg/m2
  • vincristine 1.4 mg/m2 (up to 2 mg)

In addition, prednisone or prednisolone 100 mg was administered orally (corticosteroid choice at the discretion of the investigator) on days 1 through 5. Each treatment cycle was repeated every 21 days.

Baseline characteristics were well-balanced between the groups, the investigators noted, except for B symptoms, which were more frequent in the 4-cycle group (9% vs. 3%; p=0.002). Median ages in the 4-cycle and 6-cycle groups were 49 years and 47 years, and most patients in each group had a diagnosis of diffuse large B-cell lymphoma (DLBCL; 86% and 84%).

Over a median follow-up of 66 months (interquartile range = 42-100), the 3-year PFS rates among the intention-to-treat population (the study’s primary endpoint) were 96% in the 4-cycle group and 94% in the 6-cycle group. This translated to an absolute difference in 3-year PFS of 3%, which met the prespecified non-inferiority margin of –5.5%.

In addition, the 3-year event-free survival (EFS) rates were the same in the 4-cycle and 6-cycle groups (89% for each), and 3-year OS rates were 99% and 98%, respectively.

Both groups experienced high rates of remission, the researchers reported. At the end of therapy, 91% of patients in the 4-cycle group had a complete response or unconfirmed complete response, compared with 92% of patients in the 6-cycle group. More information about the response rates are available in the TABLE.

The investigators also estimated 5-year outcomes in post-hoc analyses, although these types of analyses have inherent limitations. Again, the survival rates were similar between the 4-cycle and 6-cycle groups:

  • 5-year PFS: 94% and 94%
  • 5-year EFS: 87% and 88%
  • 5-year OS: 97% and 98%

In the safety population, which included all patients who received ≥1 dose of study drug, a total of 294 hematologic adverse events (AEs) were documented in the 4-cycle group, compared with 426 hematologic AEs in the 6-cycle group, as expected given the fewer numbers of cycles. The authors also observed a lower number of non-hematologic AEs in the 4-cycle group (1,036 vs. 1,280). The most commonly reported AEs were leukocytopenia (n=171 and n=237, respectively) and infections (n=116 and n=156).

The reduced number of chemotherapy cycles was not accompanied by a difference in the incidence of development of secondary neoplasia: 6% in the 4-cycle group versus 5% in the 6-cycle group. “However, to assess long-term toxicity of curative immunochemotherapy, a longer follow-up than that in our study is necessary,” the authors concluded.

Limitations of the study included the lack of systematic assessment of participants’ quality of life, as well as the lack of analysis of patients’ biologic risk factors. In addition, the study did not enroll patients older than 60 years of age or those with bulky disease, which may reduce the generalizability of the findings for those with such less favorable features.

The study authors report no relevant conflicts of interest.


Poeschel V, Held G, Ziepert M, et al. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2020;394:2271-2281.