Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma.
BACKGROUND
The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma.


METHODS
In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival.


RESULTS
After a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group.


CONCLUSIONS
VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).
The authors' affiliations are listed in the Appendix.
Tadeusz
T
Robak
Huiqiang
H
Huang
Jie
J
Jin
Jun
J
Zhu
Ting
T
Liu
Olga
O
Samoilova
Halyna
H
Pylypenko
Gregor
G
Verhoef
Noppadol
N
Siritanaratkul
Evgenii
E
Osmanov
Julia
J
Alexeeva
Juliana
J
Pereira
Johannes
J
Drach
Jiri
J
Mayer
Xiaonan
X
Hong
Rumiko
R
Okamoto
Lixia
L
Pei
Brendan
B
Rooney
Helgi
H
van de Velde
Franco
F
Cavalli
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D003520:Cyclophosphamide / Q000627:therapeutic use; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D000069283:Rituximab; D014750:Vincristine / Q000627:therapeutic use
D058846:Antibodies, Monoclonal, Murine-Derived; D001897:Boronic Acids; D011719:Pyrazines; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D000069286:Bortezomib; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone