John Leonard, MD
The current standard for patients with advanced diffuse large B-cell lymphoma (DLBCL) is R-CHOP-21 (21-day rituximab-cyclophosphamidedoxorubicin- vincristine-prednisone). However, while this regimen cures approximately two-thirds of patients, a significant fraction of patients will still relapse, and the prognosis for these patients is poor.
At the 16th Annual International Congress on Hematologic Malignancies, John Leonard, MD, professor of Medicine and Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College in New York City, discussed several novel therapies currently under investigation for DLBCL.
One approach being evaluated is the substitution of an alternate chemotherapy regimen for CHOP in combination with rituximab. One such regimen, R-ACVBP (dose-intensive rituximab-doxorubicincyclophosphamide- vindesine-bleomycinprednisone), features increased dose intensity compared with R-CHOP, sequential consolidation using second-line agents, and central nervous system prophylaxis. This regimen has been compared with R-CHOP in patients with DLBCL who are younger than age 60 years with an ageadjusted International Prognostic Index equal to 1. Phase III results showed significant improvements in both progression-free survival (PFS) and overall survival (OS), but with markedly higher hematologic toxicities in the experimental arm, as well as more toxic deaths. Concerns about these high toxicity rates have prevented wide adoption of the R-ACVBP regimen, even in selected patient populations.
A second regimen under evaluation is R-EPOCH (rituximabetoposide- prednisone-vincristine-doxorubicin-cyclophosphamide), which demonstrated a 5-year PFS of 79% in a phase II trial. A phase III trial, CALGB 50303, is now comparing R-EPOCH with R-CHOP in patients with newly diagnosed DLBCL.
Another approach being tested by many groups involves adding a new agent to R-CHOP-21. According to Leonard, “It’s hard to break away from R-CHOP-21, given that for two-thirds of the patients, it does the job.” Epratuzumab, bortezomib, lenalidomide, enzastaurin, and radioimmunotherapies are just a few of the novel agents being evaluated in combination with R-CHOP. The challenge is to select combinations that show promise in phase II studies to move forward into phase III trials.
“Every [phase II] study looks at different patient populations, at diferent time points, using different statistical measures like progression-free or failure-free survival, so at the end of the day it is really hard to know, is this phase II data worthy of pursuing in a phase III trial? That’s why in large-cell lymphoma, many groups are pursuing a randomized phase II strategy or other novel statistical approaches to try to take forward a new regimen,” explained Leonard.
One such promising regimen is R-CHOP in combination with the proteasome inhibitor bortezomib. This regimen is being evaluated in nongerminal center B-cell (non-GCB)-like tumors, based on the observation that nuclear factor-kappa B (NF-κB) transcriptional activity is upregulated in this subtype. While non-GCB lymphomas generally do poorly with R-CHOP in comparison with GCB-like tumors, when bortezomib was added in a phase II trial, PFS and OS outcomes were similar between the two subtypes. This combination is now being evaluated in non-GCB DLBCL in two phase III trials: PYRAMID (NCT00931918) and LYM2034 (NCT01040871).
“I think these are important studies. I think ultimately what we will be seeing is novel agents that target molecular subtypes of large cell lymphoma that are defined in more modern ways,” said Leonard. “The message here is that for this [high-risk] group of patients, we really need to continue to look and place a high priority on assessing some of these novel approaches.”