R2CHOP Benefits Patients With Untreated Diffuse Large B-Cell Lymphoma, Regardless of Subtype

For patients with previously untreated diffuse large B-cell lymphoma (DLBCL), adding lenalidomide to the combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) reduced the risk of progression or death by 34%, according to findings published in the Journal of Clinical Oncology. This “signal-seeking” phase II study, conducted by Grzegorz Nowakowski, MD, from Mayo Clinic in Rochester, Minnesota, and colleagues, also demonstrated that early accrual of patients with rapidly progressive disease is possible.

The ECOG-ACRIN E1412 study is a prospective, multicenter, phase II trial that included adults with newly diagnosed, untreated, histologically proven DLBCL. Patients had measurable stage II to IV disease with an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. A total of 349 participants were enrolled and randomized 1:1 to receive either:

  • R-CHOP: rituximab 325 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 on day 1, and prednisone 100 mg/m2 on days 1-5, for 6 cycles
  • R2CHOP: R-CHOP plus lenalidomide 25 mg/day on days 1-10 for each of 6 cycles

Efficacy data were evaluable for 280 patients (145 who received R2CHOP and 135 who received R-CHOP). The most common subtype was germinal center B-cell–like (GCB) DLBCL (n=122), followed by activated B-cell (ABC) DLBCL (n=94). The remaining patients had unclassifiable or unknown subtype.

The authors noted that baseline characteristics were similar between both arms. Participants’ median age was 66 years and 70% of patients had stage IV disease. The median time from treatment to diagnosis was 21 days (21 in the R2CHOP arm and 19 in the R-CHOP arm), they added.

With a median follow-up of three years, 86% and 85% of patients completed all six cycles of R2CHOP and R-CHOP treatment. There were nine treatment-related deaths (2 in the R2CHOP group and 7 in the R-CHOP group).

In the safety population, which included 343 treated patients, adverse events (AEs) were “largely as expected with R-CHOP,” the researchers reported, but there were significantly different rates of grade ≥3 AEs between R2CHOP and R-CHOP for:

  • diarrhea (6% vs. 1%; p=0.005)
  • anemia (29% vs. 20%; p=0.03)
  • febrile neutropenia (25% vs. 14%; p=0.003)
  • thrombocytopenia (34% vs. 13%; p<0.001)
  • electrolyte abnormalities (5% vs. 2%; p=0.06)

The study met its primary endpoint, demonstrating that R2CHOP was associated with lower risk of disease progression or death than R-CHOP (hazard ratio = 0.66; p=0.03). The one-, two-, and three-year rates of progression-free survival (PFS) were 84%, 76%, and 73% in patients who received R2CHOP, compared with 73%, 69%, and 62% in the R-CHOP–treated group.

In addition, R2CHOP was associated with superior overall survival (OS), with a three-year OS rate of 83%, compared with 75% in the R-CHOP group.

The study also met its co-primary endpoint of PFS improvement among patients with ABC DLBCL. R2CHOP reduced the risk of disease progression and death by 36% among the 94 patients with ABC DLBCL, as well as by 18% in the 122 patients with GCB DLBCL.

“The improvement of outcomes in patients with the ABC subtype had the largest impact on the overall positive study results,” the authors noted. “[This trial] supports the notion that cell-of-origin appears to be inadequate to support a precision medicine approach in DLBCL.”
R2CHOP also was associated with a benefit across most subgroups in subset analysis, including analysis according to International Prognostic Index score, bulky disease, and longer time to treatment initiation.

“The E1412 results provide impetus to study lenalidomide and novel lenalidomide analogues and highlight the importance of trial design when incorporating biomarkers in frontline studies,” the authors concluded. Although the authors noted that the addition of lenalidomide appeared to benefit patients across all clinical subsets, they noted that the small number of patients in each subgroup limits the implications of these findings.

The authors report no relevant conflicts of interest.


Nowakowski G, Hong F, Scott DW, et al. Addition of lenalidomide to R-CHOP improves outcomes in newly diagnosed diffuse large B-cell lymphoma in a randomized phase II US Intergroup Study ECOG-ACRIN E1412. J Clin Oncol. 2021 Apr 20;39(12):1329-1338.