The Leukemias: A Half-Century of Discovery

The leukemias have long served as model diseases for cancer biology and treatment. The ability to repeatedly and safely sample malignant cells in peripheral blood and bone marrow contributed to fortuitous and seminal discoveries such as the 1960 observation of the Philadelphia chromosome in chronic granulocytic (myeloid) leukemia. Creation of useful experimental systems such as leukemia cell lines 2 and murine models 3 enhanced biologic understanding, and early treatment successes with antifolates 4 and antimetabolites 5 placed the leukemias at the forefront of most of the major developments in modern clinical oncology. By 1964, the founding year of the American Society of Clinical Oncology, the leukemias were unique among cancer subtypes in the number of active drugs available to physicians and their patients, many of which had already been approved by the US Food and Drug Administration (FDA): the antifolate methotrexate; synthetic corticosteroids; the antimetabolites 6-mercaptopurine (6-MP) and 6-thioguanine; the vinca alkaloid vincristine; and several DNA alkylating agents (busulfan, cyclophosphamide, and chlorambucil). Other agents that would later play important roles in leukemia treatment, such as the antimetabolite hydroxyurea (first chemically synthesized in 1869, but not FDA approved for leukemia therapy until 1967) and the first anthracycline, daunorubicin (initially developed as an antibiotic), began clinical development in 1964. But despite this array of exciting and clinically useful new therapies, cures were still rare.