DLBCL

Addition of bortezomib to R-CHOP does not significantly improve outcomes in patients with non-GCB DLBCL

In a recent issue of Journal of Clinical Oncology, John P. Leonard from Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, USA, and colleagues reported results from a phase II study to evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non– germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).

The primary end point of this open-label, multicenter, randomized phase II trial was progression free survival (PFS) in patients with non-GCB DLBCL with secondary end points including overall survival (OS), overall response rate (ORR), complete response (CR) rate, and fluorodeoxyglucose-positron emission tomography (FDG-PET) negative rate after two cycles and after the end of six cycles, duration of response (DOR), time to progression (TTP), and safety. Overall, 206 patients (pts) were enrolled from 69 US centers between October 2009 and July 2013 and were randomly assigned to R-CHOP (n=103) or bortezomib plus R-CHOP (VR-CHOP) (n=103).

Key Highlights:
  • Pts required to have untreated DLBCL with one or more measurable tumor masses >1x1.5 cm and ECOG performance status of 0 to 2
  • R-CHOP arm:
    • Rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (maximum 2 mg) administered intravenously on Day 1 plus oral prednisone 100mg on Days 1 to 5
  • VR-CHOP arm:
    • Rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (maximum 2 mg) administered intravenously on Day 1 plus oral prednisone 100mg on Days 1 to 5
    • Bortezomib 1.3 mg/m2 intravenously on days 1 and 4 of each cycle
  • Response and disease progression were assessed by using CT scans at baseline, end of Cycle 2, end-of-treatment (EOT) visit, and every 3 months until disease progression, withdrawal, death, or study termination/completion
  • FDG-PET scans were also used at baseline, end of Cycle 2, EOT visit, and thereafter if required to establish CR
Efficacy:
  • 86 pts in the R-CHOP arm completed all six cycles of treatment:
    • Median follow-up: 34.3 months
    • Median PFS not reached
    • 2-year PFS = 77.6%
    • ORR = 98%, CR = 49%
    • FDG-PET negative rate at EOT visit = 53%
    • OS not reached
    • 2-year OS = 88.4%
  • 86 pts in the VR-CHOP arm completed all six cycles of treatment
    • Median follow-up: 34.4 months
    • Median PFS not reached
    • 2-year PFS = 82%
    • ORR = 96%, CR = 56%
    • FDG-PET negative rate at EOT visit = 59%
    • OS not reached
    • 2-year OS = 93%
Safety:
  • Grade 3 adverse events (AEs):
    • R-CHOP = 71% pts
    • VR-CHOP = 79% pts
  • Hematologic AEs:
    • Neutropenia
      • R-CHOP = 53% pts
      • VR-CHOP = 49% pts
    • Anemia
      • R-CHOP = 7% pts
      • VR-CHOP = 13% pts
    • Febrile neutropenia
      • R-CHOP = 8% pts
      • VR-CHOP = 7% pts

In summary, the authors concluded that adding two doses of bortezomib per cycle to R-CHOP did not significantly improve outcomes at around 34 months of follow-up in patients with non-GCB DLBCL. A possible reason for the lack of benefit with VR-CHOP therapy was that only two doses of bortezomib were given per 21-day cycle, whereas the standard schedule for bortezomib in multiple myeloma is four doses per cycle on Days 1, 4, 8, and 11. Despite the inability to demonstrate a benefit of bortezomib with R-CHOP, the authors remain encouraged about the potential of COO-directed therapy in DLBCL.

References
  1. Leonard J.P. et al. Randomized phase II study of R-CHOP with or without bortezomib in previously untreated patients with non–germinal center B-cell–like diffuse large B-cell lymphoma. Journal of Clinical Oncology. 2017 Nov 1. DOI: 10.1200/JCO.2017.73.2784