Vol. 4, 2717-2721, November 1998 Clinical Cancer Research 2717 Chemotherapy Immediately following Autologous Stem-Cell Transplantation in Patients with Advanced Breast Cancer1 Zia Rahman, John Kavanagh, Richard Champlin, Richard Giles, Elie Hanania, Siqinq Fu, Zifei Zu, Rakesh Mehra, Frankie Holmes, Andrzej Kudelka, David Claxton, Claire Verschraegen, James Gajewski, Michael Andreeff, Shelly Heimfeld, Ronald Berenson, Debra Ellerson, Leslie Calvert, Eugene Mechetner, Tanya Holzmayer, Andrew Dayne, Joy Hamer, Carlos Bachier, Jeffrey Ostrove, Donna Przepiorka, Barbara Burtness, Richard Cote, Robert Bast, Gabriel Hortobagyi, and Albert Deisseroth2 The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [Z. R., J. K., R. Ch., R. G., E. H., Z. Z., R. M., F. H., A. K., D. C., C. V., J. G., M. A., D. E., L. C., J. H., C. B., D. P., R. Ba., G. H., A. De.]; Cell Pro, Inc., Bothell, Washington 98021 [S. H., R. Be.]; Ingenex, Inc., Menlo Park, California 94025 [E. M., T. H., A. Da.]; Magenta Corporation, Rockville, Maryland 20850 IJ. 0.]; University of Southern California, Los Angeles, California 90033 [R. Co.]; and the Medical Oncology Section of the Yale University School of Medicine and the Genetic Therapy Program of the Yale Cancer Center, Yale University. New Haven, Connecticut 06520-8032 [5. Q. F., B. B., A. De.] ABSTRACT Most patients relapse after high-dose chemotherapy (HDCT) with autologous stem-cell transplantation (ASCT) for metastatic breast cancer. Further chemotherapy imme- diately after hematopoietic recovery from ASCT is not given for fear of irreversibly damaging the newly engrafted stem cells. In a pilot chemoprotection trial, autologous CD34+ cells from patients with metastatic breast cancer were ex- Received 5/1/98; revised 7/28/98; accepted 7/31/98. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with I8 U.S.C. Section 1 734 solely to indicate this fact. I Supported by the Susan G. Komen Foundation (to A. De.). the Hull Development Fund (to A. De. from the Genetic Therapy Program of the Yale Cancer Center), the Ensign Professorship of the Yale University School of Medicine (to A. Dc.), the Anderson Chair for Cancer Treat- ment and Research (to A. De.) of The University of Texas M. D. Anderson Cancer Center, the George and Barbara Bush Fund for Leu- kemia Research (to A. De), and NIH Grants (to A. De.) P01 CA 49639 and P01 CA 55164. R. G. is a paid consultant and received research support from Ingenex, Inc. 2 To whom requests for reprints should be addressed, at Medical On- cology Section, Department of Internal Medicine, and the Genetic Therapy Program of the Yale Cancer Center, Yale University School of Medicine, WWW 221, 333 Cedar Street, New Haven, CT 06520-8032. Phone: (203) 737-5608; Fax: (203) 737-5698; E-mail: deisseroab@ maspo2.mas.yale.edu. posed to a replication-incompetent retroviral vector carry- ing MDR-1 eDNA and then reinfused after HDCT. Immedi- ately on recovery, patients received multiple courses of escalating dose paclitaxel. All of the 10 patients tolerated reinfusion of modified cells without any toxicity and had myeloid engraftment within 12 days (range, 11-14). The bone marrow cells of three patients contained vector MDR- 1-positive cells only at the time of the first course of post- transplant paclitaxel, indicating that the MDR-1 vector. modified cells had only short-term engrafting potential. A total of 83 courses of paclitaxel were administered starting at a median of 30 (range, 21-32) days from ASCT. The median dose of paclitaxel was 225 mg/m2 and the median interval between paclitaxel cycles of therapy was 21 (range, 20-41) days. Five of the six CR patients were able to receive all of the 12 courses of paclitaxel. Three patients who had achieved less than a complete response to the HDCT (2 patients) and partial response (1 patient) were converted to complete clinical responses during the 12 cycles of paclitaxel. No delayed toxicity or bone marrow failure was noted in these patients with a median follow-up of 2 years from ASCT. This is the first study of chemotherapy immediately after transplantation with autologous CD34+ cells. These data indicate that paclitaxel can be safely administered im- mediately after ASCT without any delayed toxicities. Pacli- taxel given immediately after ASCT can further improve the response to pretransplant chemotherapy in patients with advanced breast cancer. INTRODUCTION Breast cancer is moderately chemosensitive and several preclinical studies (1 , 2). retrospective reviews (3, 4), and ran- domized studies (5, 6) have shown a relationship between dose and response. HDCT3 with ASCT has consistently resulted in CR rates of 50-60%, and responses have been reported even in patients with tumors that are resistant to standard-dose chemo- therapy. However, most of the patients eventually relapse after HDCT and ASCT, and only 15-20% of patients with overtly metastatic breast cancer are reported to survive 5 years after HDCT. (7, 8) Although the alkylating agent containing HDCT may dam- age the DNA of all of the cancer cells, some of the cells may escape genotoxic stress-induced apoptosis by DNA repair mech- anisms. Patients who have undergone HDCT with ASCT are usually not given additional posttransplant chemotherapy imme- diately posthematopoietic recovery after ASCT because of con- cern that the newly engrafted hematopoietic stem cells would be 3 The abbreviations used are: HDCT, high-dose chemotherapy; ASCT. autologous stem-cell transplantation: CR, complete response; MDR, multiple drug resistant (or multidrug resistance). 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