Methodology of clinical trials evaluating the incorporation of new drugs in the first line treatment of patients with diffuse large B-cell lymphoma (DLBCL): a critical review

Abstract

Purpose

The first line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been performed over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed.

Patients and Methods

Reports of phase 3 trials evaluating the addition of molecularly targeted agents (MTA) or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phase1 and 2 trials which preceded these phase 3 trials were also reviewed.

Results

Among six phase 3 trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary endpoint. The other 5 trials did not show an improved outcome with the addition of the new agent. The preceding phase 1 and 2 trials were very heterogeneous in their endpoints and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase 3 trials.

Conclusion

The standard of care for DLBCL is still R-CHOP. Phase 1/2 trials failed to predict the results of subsequent phase 3 trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase 2 trials evaluating new agents in DLBCL needs to be better defined in the future.