Bortezomib Plus CHOP-Rituximab for Previously Untreated Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma

Abstract

PurposeThe proteasome inhibitor bortezomib may enhance activity of chemoimmunotherapy in lymphoma. We evaluated dose-escalated bortezomib plus standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R) in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).Patients and MethodsSeventy-six subjects with untreated DLBCL (n = 40) and MCL (n = 36) received standard CHOP every 21 days (CHOP-21) with R plus bortezomib at 0.7 mg/m2(n = 4), 1.0 mg/m2(n = 9), or 1.3 mg/m2(n = 63) on days 1 and 4 for six cycles.ResultsMedian age was 63 years (range, 20 to 87), and International Prognostic Index (IPI) scores were generally unfavorable (39% with IPI of 2, and 49% with IPI of 3 to 5), as were Mantle Cell Lymphoma International Prognostic Index scores in patients with MCL (28% intermediate risk and 39% high risk). Toxicity was manageable, including neuropathy in 49 subjects (8% grade 2 and 4% grade 3) and grade 3/4 anemia (13%), neutropenia (41%), and thrombocytopenia (25%). For DLBCL, the evaluable overall response rate (ORR) was 100% with 86% complete response (CR)/CR unconfirmed (CRu; n = 35). Intent-to-treat (ITT, n = 40) ORR was 88% with 75% CR/CRu, 2-year progression-free survival (PFS) of 64% (95% CI, 47% to 77%) and 2-year overall survival (OS) of 70% (95% CI, 53% to 82%). For MCL, the evaluable ORR was 91% with 72% CR/CRu (n = 32). The ITT (n = 36) ORR was 81% with 64% CR/CRu, 2-year PFS 44% (95% CI, 27% to 60%) and 2-year OS 86% (95% CI, 70% to 94%). IPI and MIPI correlated with survival in DLBCL and MCL, respectively. Unlike in DLBCL treated with R-CHOP alone, nongerminal center B cell (non-GCB) and GCB subtypes had similar outcomes.ConclusionBortezomib with R-CHOP-21 can be safely administered and may enhance outcomes, particularly in non-GCB DLBCL, justifying randomized studies.

The Expression of the Endoplasmic Reticulum Stress Sensor BiP/GRP78 Predicts Response to Chemotherapy and Determines the Efficacy of Proteasome Inhibitors in Diffuse Large B-Cell Lymphoma

“…46 Since the addition of rituximab to polychemotherapy, no other treatments have shown greater benefit in these patients, although some clinical and preclinical trials have shown the efficacy of new combinations of drugs, including proteasome inhibitors. 6,7,30,43 Bortezomib-mediated proteasome inhibition profoundly affects the ER homeostasis and induces an ER stress response that leads to cell death, potentially overcoming the intrinsic resistance to chemotherapy. 44 The use of bortezomib, both as a single agent or in combination with a wide range of agents, is currently under investigation to improve survival in aggressive lymphomas.…”

“…44 The use of bortezomib, both as a single agent or in combination with a wide range of agents, is currently under investigation to improve survival in aggressive lymphomas. 6,9,14,47 Although bortezomib monotherapy is mainly ineffective in DLBCL cell lines, 29 the combination with immunochemotherapy has been shown to benefit a selected group of patients with relapsed or refractory ABC DLBCL 7 and in previously untreated patients with advance disease. 6 We have demonstrated that almost all of the DLBCL cell lines studied were primary resistant to bortezomib monotherapy.…”

“…6,9,14,47 Although bortezomib monotherapy is mainly ineffective in DLBCL cell lines, 29 the combination with immunochemotherapy has been shown to benefit a selected group of patients with relapsed or refractory ABC DLBCL 7 and in previously untreated patients with advance disease. 6 We have demonstrated that almost all of the DLBCL cell lines studied were primary resistant to bortezomib monotherapy. Moreover, we have demonstrated that after bortezomib treatment BiP/GRP78 is induced in the bortezomib-resistant cell lines OCI-LY8 and SUDHL-4, as well as in multiple myeloma and mantle cell lymphoma.…”

“…Recently, R-CHOP-BZ resulted in 86% of complete responses with no differences in terms of overall survival or progressionfree survivals between GCB and ABC subtypes. 6 Preliminary clinical results suggest that bortezomib may have antitumor effects also in the GCB subtype. 6,9,10 The inhibition of proteasome may have sensitized the DLBCL cells to the cytotoxic action of the chemotherapy.…”

“…6 Preliminary clinical results suggest that bortezomib may have antitumor effects also in the GCB subtype. 6,9,10 The inhibition of proteasome may have sensitized the DLBCL cells to the cytotoxic action of the chemotherapy. Other- wise, bortezomib exhibits NF-B-independent cytotoxicity in a wide range of different tumor types 48,[51][52][53] and affects many additional pathways that may be differently used by ABC and GCB subtypes.…”