Michael Crump1, Sirpa Leppä2, Luis Fayad2, Je Jung Lee2, Alice Di Rocco2, Michinori Ogura2, Hans Hagberg2, Frederick Schnell2, Robert Rifkin2, Andreas Mackensen2, Fritz Offner2, Lauren Pinter-Brown2, Sonali Smith2, Kensei Tobinai2, Su-Peng Yeh2, Eric D Hsi2, Tuan Nguyen2, Peipei Shi2, Marjo Hahka-Kemppinen2, Don Thornton2, Boris Lin2, Brad Kahl2, Norbert Schmitz2, Kerry J Savage2, Thomas Habermann2. 1. Michael Crump, Princess Margaret Cancer Centre, Toronto, Ontario; Kerry J. Savage, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Sirpa Leppä, Helsinki University Hospital Cancer Center, Helsinki, Finland; Luis Fayad, The University of Texas MD Anderson Cancer Center, Houston, TX; Frederick Schnell, Central Georgia Cancer Care, Macon, GA; Robert Rifkin, US Oncology Research Network and Rocky Mountain Cancer Centers, Denver, CO; Lauren Pinter-Brown, University of California at Los Angeles, Santa Monica, CA; Sonali Smith, University of Chicago, Chicago, IL; Eric D. Hsi, Cleveland Clinic, Cleveland, OH; Tuan Nguyen, Peipei Shi, Marjo Hahka-Kemppinen, Don Thornton, and Boris Lin, Eli Lilly and Company, Indianapolis, IN; Brad Kahl, University of Wisconsin, Madison, WI; Thomas Habermann, Mayo Clinic Cancer Research Consortium, Rochester, NY; Je Jung Lee, Chonnam National University Hwasun Hospital, Gwangju, South Korea; Alice Di Rocco, Sapienza University, Rome, Italy; Michinori Ogura, Tokai Central Hospital, Kakamigahara; Kensei Tobinai, National Cancer Center Hospital, Tokyo, Japan; Hans Hagberg, Akademiska Sjukhuset, Onkologkliniken, Uppsala, Sweden; Andreas Mackensen, University of Erlangen, Erlangen; Norbert Schmitz, Asklepios Klinik St Georg, Hamburg, Germany; Fritz Offner, University of Gent, Gent, Belgium; and Su-Peng Yeh, China Medical University Hospital, Taichung, Republic of China. michael.crump@uhn.ca. 2. Michael Crump, Princess Margaret Cancer Centre, Toronto, Ontario; Kerry J. Savage, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Sirpa Leppä, Helsinki University Hospital Cancer Center, Helsinki, Finland; Luis Fayad, The University of Texas MD Anderson Cancer Center, Houston, TX; Frederick Schnell, Central Georgia Cancer Care, Macon, GA; Robert Rifkin, US Oncology Research Network and Rocky Mountain Cancer Centers, Denver, CO; Lauren Pinter-Brown, University of California at Los Angeles, Santa Monica, CA; Sonali Smith, University of Chicago, Chicago, IL; Eric D. Hsi, Cleveland Clinic, Cleveland, OH; Tuan Nguyen, Peipei Shi, Marjo Hahka-Kemppinen, Don Thornton, and Boris Lin, Eli Lilly and Company, Indianapolis, IN; Brad Kahl, University of Wisconsin, Madison, WI; Thomas Habermann, Mayo Clinic Cancer Research Consortium, Rochester, NY; Je Jung Lee, Chonnam National University Hwasun Hospital, Gwangju, South Korea; Alice Di Rocco, Sapienza University, Rome, Italy; Michinori Ogura, Tokai Central Hospital, Kakamigahara; Kensei Tobinai, National Cancer Center Hospital, Tokyo, Japan; Hans Hagberg, Akademiska Sjukhuset, Onkologkliniken, Uppsala, Sweden; Andreas Mackensen, University of Erlangen, Erlangen; Norbert Schmitz, Asklepios Klinik St Georg, Hamburg, Germany; Fritz Offner, University of Gent, Gent, Belgium; and Su-Peng Yeh, China Medical University Hospital, Taichung, Republic of China.
Abstract
PURPOSE: To compare disease-free survival (DFS) after maintenance therapy with the selective protein kinase C β (PKCβ) inhibitor, enzastaurin, versus placebo in patients with diffuse large B-cell lymphoma (DLBCL) in complete remission and with a high risk of relapse after first-line therapy. PATIENTS AND METHODS: This multicenter, phase III, randomized, double-blind, placebo-controlled trial enrolled patients who were at high risk of recurrence afterrituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients (N = 758) with stage II bulky or stage III to IV DLBCL, three or more International Prognostic Index risk factors at diagnosis, and a complete response or unconfirmed complete response after 6 to 8 cycles of R-CHOP were assigned 2:1 to receive oral enzastaurin 500 mg daily or placebo for 3 years or until disease progression or unacceptable toxicity. Primary end point was DFS 3 years after the last patient entered treatment. Correlative analyses of biomarkers, including cell of origin by immunohistochemistry and PKCβ expression, with efficacy outcomes were exploratory objectives. RESULTS: After a median follow-up of 48 months, DFS hazard ratio for enzastaurin versus placebo was 0.92 (95% CI, 0.689 to 1.216; two-sided log-rank P = .541; 4-year DFS, 70% v 71%, respectively). Independent of treatment, no significant associations were observed between PKCβ protein expression or cell of origin and DFS or overall survival. CONCLUSION: Enzastaurin did not significantly improve DFS in patients with high-risk DLBCL after achieving complete response to R-CHOP. Achievement of a complete response may have abrogated the prognostic significance of cell of origin by immunohistochemistry.
RCT Entities:
PURPOSE: To compare disease-free survival (DFS) after maintenance therapy with the selective protein kinase C β (PKCβ) inhibitor, enzastaurin, versus placebo in patients with diffuse large B-cell lymphoma (DLBCL) in complete remission and with a high risk of relapse after first-line therapy. PATIENTS AND METHODS: This multicenter, phase III, randomized, double-blind, placebo-controlled trial enrolled patients who were at high risk of recurrence after rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients (N = 758) with stage II bulky or stage III to IV DLBCL, three or more International Prognostic Index risk factors at diagnosis, and a complete response or unconfirmed complete response after 6 to 8 cycles of R-CHOP were assigned 2:1 to receive oral enzastaurin 500 mg daily or placebo for 3 years or until disease progression or unacceptable toxicity. Primary end point was DFS 3 years after the last patient entered treatment. Correlative analyses of biomarkers, including cell of origin by immunohistochemistry and PKCβ expression, with efficacy outcomes were exploratory objectives. RESULTS: After a median follow-up of 48 months, DFS hazard ratio for enzastaurin versus placebo was 0.92 (95% CI, 0.689 to 1.216; two-sided log-rank P = .541; 4-year DFS, 70% v 71%, respectively). Independent of treatment, no significant associations were observed between PKCβ protein expression or cell of origin and DFS or overall survival. CONCLUSION:Enzastaurin did not significantly improve DFS in patients with high-risk DLBCL after achieving complete response to R-CHOP. Achievement of a complete response may have abrogated the prognostic significance of cell of origin by immunohistochemistry.
Authors: Alix Y L Zackon; Amy A Ayers; Katherine A Yeager; Mary L Somma; Jonathan W Friedberg; Christopher R Flowers; Loretta J Nastoupil Journal: Leuk Lymphoma Date: 2019-06-04
Authors: A Giro-Perafita; L Luo; A Khodadadi-Jamayran; M Thompson; B Akgol Oksuz; A Tsirigos; B D Dynlacht; I Sánchez; F J Esteva Journal: NPJ Breast Cancer Date: 2020-01-06