Pergamon Leukemia Research Vol. 20, No. 7, 535-549, 1996. pp. Copyright 0 1996 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0145-2126/96 $15.00 + 0.00 PII: SO145-2126(96)00016-11 REVIEW HIGH-DOSE CHEMOTHERAPY IN ADULT ACUTE MYELOID LEUKEMIA: RATIONALE AND RESULTS Roberto Stasi, Adrian0 Venditti, Giovanni Del Poeta, German0 Aronica, Elisabetta Abruzzese, Francesco Pisani, Manrico Cecconi, Mario Masi and Sergio Amadori Chair of Hematology, University of Rome “Tor Vergata”, S. Eugenio Hospital, Rome, Italy (Received 15 December 199.5.Accepted 17 January 1996) Abstrati-Preclinical studies and retrospective evaluations of clinical trials of a number of cytotoxic drugs have provided a rationale for the use of high doses of chemotherapy in adults with acute myeloid leukemia (AML). To maximize cure and remission rates at an acceptable cost in toxicity, many schedules and combinations of dose-intensive chemotherapy have been tested in recent years in patients with de nova disease, cytosine arabinoside (Ara-C) being the most extensively evaluated drug. In this article we review the principal results of both randomized and non-controlled studies. Our analysis indicates that high-dose Ara-C (HIDAC) used during induction results is no substantial benefit relative to conventional doses of drug. On the other hand, consolidation with HIDAC is a major advance in the treatment of this disease. In fact, in individuals less than 60years of age and a favorable or intermediate-risk karyotype, HIDAC-based regimens have resulted in survival estimates comparable to those of autologous or allogeneic bone marrow transplantation. Yet, the role of HIDAC is irrelevant in younger individuals with an unfavorable cytogenetic pattern and detrimental in patients greater than 60years of age. Since recently new cytotoxic agents have expanded the armamentarium of antileukemic drugs, well conducted randomized trials of dose intensive chemotherapy still need to be performed to optimize schedules and combinations of drugs in patients with AML. Copyright 0 1996 Elsevier Science Ltcl. Key words: High-dose chemotherapy, acute myeloid leukemia, adult, cytosine arabinoside, daunorubicin, mitoxantrone, Abbreviations: AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; Ara-C, cytosine arabinoside; HIDAC, high-dose cytosine arabinoside; ZDAC, intermediate-dose cytosine arabinoside; CDAC, conventional-dose cytosine arabinoside; DNR, daunorubicin; IDA, idarubicin; VP-16, etoposide; ASN, asparaginase; 6-TG, 6-thioguanine; MTN, mitoxantrone; VCR, vincristine; PDN, prednisone; ZR, zor- ubicin; MTX, methotrexate; AMSA, amsacrine; CTX cyclo- phosphamide; BCNU, carmustine; ADM, adriamycin; 6-MP, 6-mercaptopurine; ALSG, Australian Leukemia Study Group; SWOG, Southwest Oncology Group; CALGB, Cancer and Leukemia Group B; UCLA, University of California at Los Angeles; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research on the Treat- ment of Cancer; GZMEMA, Gruppo Italian0 per lo studio delle Malattie Ematologiche dell’Adulto; GM-CSF, granulocyte- macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor. Correspondence to: Roberto Stasi, MD, Via de1 Passer0 Solitario 19, 00169 Rome, Italy (Tel: +39 360 248529; Fax: +39 6 260370 E-mail: mc25.58@mclink.it). Introduction The clinical evaluation, prognosis, and therapy for patients with acute myeloid leukemia (AML) has changed drastically over the past two decades. While prior to 1970 patients were rarely cured with chemother- apy alone, current strategies of treatment produce a 5- year disease-free survival (DFS) of nearly 50% in children ;and 2545% in adults less than 60 years of age [l, 21. These advances have occurred as a result of the concomitant improvements of supportive care and chemotherapy protocols, and of the introduction of bone marrow transplantation. Chemotherapy in AML is based on the principle of combining drugs that are each active as single agents. Experimental and clinical data obtained with different types of chemotherapy seem to indicate that also in AML, like in other malignant disorders, a dose-response 535