Addition of lenalidomide to r-chop improves outcomes in newly diagnosed diffuse large B-cell lymphoma

June 2021 Editor's pick Jolien Blokken

Due to its single-agent activity, synergy with rituximab and chemotherapy, and modest toxicity profile, lenalidomide has long been a prime candidate for combination with chemo-immunotherapy in the frontline treatment of diffuse large B-cell lymphoma (DLBCL). The phase II ECOG ACRIN E1412 study now demonstrates that the addition of lenalidomide to R-CHOP (R2CHOP) indeed improves the outcome of newly diagnosed DLBCL patients, including patients with activated B-cell-like subtype.

Expert opinion of dr. Jan Van Droogenbroeck, Haematologist, AZ Sint-Jan

“For patients with diffuse large B-cell lymphoma (DLBCL) it is not yet clear whether ‘less is more’ holds true for their treatment regimen. Therefore, a randomised phase II ECOG study assessed the addition of lenalidomide to R-CHOP (R2CHOP) versus classical R-CHOP in the treatment of newly diagnosed DLBCL. Patients with stage II bulky – IV disease, an international prognostic index of at least 2 and an ECOG performance status of maximum 2 were randomly assigned (1:1) to R2CHOP and R-CHOP for six cycles. In total, 394 patients were included in the trial, of which 280 were evaluated in this article. Ninety-four of them had activating B-cell-like (ABC) DLBCL, 122 germinal centre B-cell-like DLBCL, 18 were unclassifiable and 46 remained unknown. The ORR and CR were respectively 92% and 68% for patients in the R-CHOP arm, as compared to 97% and 73% for patients in the R2CHOP arm. The conclusion therefore is that the addition of lenalidomide to R-CHOP improves the outcome of patients with DLBCL, including those with ABC type.”

As approximately 40% of patients with DLBCL will relapse after initial chemo-immunotherapy, improving frontline therapy in DLBCL has been the focus of intensive research over the last decade.1-4 Lenalidomide previously demonstrated single-agent activity in relapsed and refractory DLBCL.5,6 Moreover, it can be safely combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) without affecting the dose intensity of chemo-immunotherapy. Particularly in non-germinal centre B-cell like (GCB) DLBCL, the R2CHOP regimen demonstrated promising results in single-arm phase II studies.7,8 The Eastern Cooperative Oncology Group (ECOG) E1412 phase II now compares R2CHOP with R-CHOP in patients with newly diagnosed DLBCL.9

ECOG E1412 study design

Eligible patients were adults of at least 18 years with newly diagnosed, untreated, histologically proven DLBCL, measurable, stage II bulky (> 10 cm) to stage IV disease, an ECOG performance status 0-2, and an International Prognostic Index (IPI) of 2-5. Baseline patient characteristics were well-balanced between treatment arms with a median age of 66 years. The majority of patients had relatively high-risk disease: 96% had stage III or IV, 46% had ≥ 2 extra-nodal site involvement, and 24% had a high IPI of 4 or 5. Patients were randomly assigned (1:1) to R-CHOP or R2CHOP. Patients in the R-CHOP arm received one dose each of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 all on day 1, and prednisone 100 mg/m2 once a day on days 1-5 of each cycle every 21 days for 6 cycles. Patients in the R2CHOP arm, in addition to R-CHOP, received 25 mg of lenalidomide daily on days 1-10 of each cycle. All patients received prophylactic G-CSF (pegfilgrastim or filgrastim per local practice), and patients taking lenalidomide received aspirin 325 mg once a day as thromboembolism prophylaxis. In total, 349 patients were enrolled in the study, of which 280 patients (145 in R2CHOP and 135 in R-CHOP) were evaluable for efficacy analysis; 94 were activated B-cell like (ABC) DLBCL, 122 GCB DLBCL, 18 unclassifiable, and 46 unknowns.

Safety and efficacy of R2CHOP versus R-CHOP

The ORR and CR rates were reported at 92% and 68% for R-CHOP and 97% (p= 0.06) and 73% (p= 0.43) for R2CHOP, respectively. In addition, R2CHOP was found to be associated with a 34% reduction in the risk of progression or death (PFS) compared to R-CHOP (HR[95%CI]: 0.66[0.43-1.01], one-side p= 0.03). The 1-, 2-, and 3-year PFS rates were 84% vs. 73%, 76% vs. 69%, and 73% vs. 62% for R2CHOP versus R-CHOP, respectively. Of note, the PFS improvement obtained with R2CHOP was mainly seen in patients with ABC DLBCL (HR: 0.64) and was less pronounced in patients with GCB DLBCL (HR: 0.82). Also with respect to overall survival (OS), R2CHOP outperformed R-CHOP with a 3-year OS rate of 83% vs. 75% (one-sided p= 0.05).

Significantly different rates of grade ≥ 3 AEs with R2CHOP and R-CHOP were found for diarrhoea (6% vs. 1%, p= 0.005), anaemia (29% vs. 20%, p= 0.03), febrile neutropenia (25% vs. 14%, p= 0.003), thrombocytopenia (34% vs. 13%, p< 0.001), and electrolyte abnormalities (5% vs. 2%, p= 0.06). In total, 8% of patients in the R2CHOP and 3% of patients in the R-CHOP arm discontinued treatment due to AEs. There were nine treatment-related deaths: two in the R2CHOP arm and seven in the R-CHOP arm.

Conclusion

The ECOG-ACRIN E1412 study demonstrated a potential clinical benefit of adding lenalidomide to R-CHOP in newly diagnosed patients regardless of cell-of-origin and in patients with ABC DLBCL.

References

  1. Coiffier B, et al. N Engl J Med. 2002;346:235-42.
  2. Hebermann TM, et al. J Clin Oncol. 2006;24:3121-7.
  3. Farooq U, et al. Br J Haematol. 2017;179:50-60.
  4. Nowakowski GS, et al. J Natl Cancer Inst. 2016;108:djw257.
  5. Witzig TE, et al. Ann Oncol. 2011;22:1622-7.
  6. Czuczman MS, et al. Clin Cancer Res. 2017;23:4127-37.
  7. Nowakowski GS, et al. J Clin Oncol. 2017;33:251-7.
  8. Vitolo U, et al. Lancet Oncol. 2014;15:730-7.
  9. Nowakowski GS, et al. J Clin Oncol. 2021:39:1329-38.
X