Hyper-CVAD and High-Dose Methotrexate/Cytarabine Followed by Stem-Cell Transplantation: An Active Regimen for Aggressive Mantle-Cell Lymphoma By Issa F. Khouri, Jorge Romaguera, Hagop Kantarjian, J. Lynn Palmer, William C. Pugh, Martin Korbling, Fredrick Hagemeister, Barry Samuels, Alma Rodriguez, Sergio Giralt, Anas Younes, Donna Przepiorka, David Claxton, Fernando Cabanillas, and Richard Champlin Purpose: Diffuse and nodular forms of mantle-cell lymphoma (MCL) are consistently associated with poor prognosis. In an effort to improve the outcome, we adopted a treatment plan that consisted of four courses of fractionated cyclophosphamide (CY) 1,800 mg/m 2 administered with doxorubicin (DOX), vincristine (VCR), and dexamethasone (Hyper-CVAD) that alternated with high-dose methotrexate (MTX) and cytarabine (Ara-C). After four courses, patients were consolidated with high-dose CY, total-body irradiation, and autologous or allogeneic blood or marrow stem-cell transplantation. Patients and Methods: Forty-five patients were en- rolled; 25 patients were previously untreated, 43 pa- tients had Ann Arbor stage IV disease, and 42 patients had marrow involvement. Forty-one patients had dif- fuse histology, two patients had nodular, and two pa- tients had blastic variants. Results: Hyper-CVAD/MTX-Ara-C induced a response rate of 93.5% (complete response [CR], 38%; partial response [PR], 55.5%) after four cycles of pretransplan- tation induction chemotherapy. All patients who went ^M/ANTLE-CELL LYMPHOMA (MCL) 1 , 2 is a malig- nancy previously known as lymphocytic lymphoma of intermediate differentiation, intermediate lymphocytic lymphoma, or centrocytic lymphoma. 3 -6 The disease is characterized by generalized lymphadenopathy, with fre- quent involvement of the spleen, bone marrow, and gastroin- testinal tract. The median survival is 2 to 5 years, and long-term disease-free survival is uncommon. 7 - 9 Majlis et al l° ' recently showed that the mantle zone variant is rela- tively favorable with a natural history similar to indolent lymphoma, but the diffuse and nodular forms are associated with a poor response to treatment. In their study, only 20% of the patients with diffuse histology achieved a complete remission with a cyclophosphamide (CY), doxorubicin (DOX), vincristine (VCR), and prednisone (CHOP)-like regimen, with a 3-year freedom from disease progression rate of only 26%. High-dose chemoradiotherapy is an effective form of treatment for relapsed non-Hodgkin's lymphoma. 1 ' Recent reports suggest that high-dose therapy and stem-cell trans- plantation may improve the outcome of poor-prognosis intermediate-grade lymphoma patients aged younger than 60 years when used as first remission consolidation. 12 on to undergo transplantation achieved CRs. For the 25 previously untreated patients, the overall survival (OS) and event-free survival (EFS) rates at 3 years were 92% (95% confidence interval [CI], 80 to 100) and 72% (95% CI, 45 to 98) compared with 25% (95% Cl, 12 to 62; P = .005) and 17% (95% Cl, 10 to 43; P = .007), respectively, for the previously treated patients. When compared with a historic control group who received a CY, DOX, VCR, and prednisone (CHOP)-like regimen, untreated patients in the study had a 3-year EFS rate of 72% versus 28% (P = .0001) and a better OS rate (92% v 56%; P = .05). Treatment-related death occurred in five patients: all were previously treated and two received allogeneic transplants. Conclusion: The Hyper-CVAD/MTX-Ara-C program followed by stem-cell transplantation is a promising new therapy for previously untreated patients with MCL. J Clin Oncol 16:3803-3809. o 1998 by American Society of ClinicalOncology. Effective induction chemotherapy is needed to reduce the tumor burden and clear the marrow involvement to allow stem-cell collection for autologous transplantation for pa- tients with nodular or diffuse forms of MCL. We evaluated the effectiveness of a regimen that consisted of four courses of fractionated CY administered with DOX, VCR, and dexamethasone (Hyper-CVAD) that alternated with sequen- tial high-dose methotrexate (MTX) and cytarabine (Ara-C). This regimen was selected based on its demonstrated activity in pediatric' 3 and adultl4 patients with acute lympho- blastic leukemia (ALL). After four courses, patients received high-dose chemoradiotherapy with autologous or allogeneic stem-cell transplantation. From the Departments of Hematology, Pathology, and Clinical Radiology, The University of Texas, M.D. Anderson Cancer Center Houston, TX. Submitted February 24, 1998; accepted August 20, 1998. Address reprint requests to Issa E Khouri, MD, The M.D. Anderson Cancer Center; Section of Blood and Marrow Transplantation, 1515 Holcombe Blvd, Box 65, Houston, TX 77030; Email issafkhouri @mdanderson.org. © 1998 by American Society of Clinical Oncology. 0732-183X/98/1612-0012$3.00/0 Journal of Clinical Oncology, Vol 16, No 12 (December), 1998: pp 3803-3809 3803 Copyright © 1998 by the American Society of Clinical Oncology. All rights reserved. Downloaded from jco.ascopubs.org by Christian Hatton on September 9, 2008 from .