The currently available nucleoside analogs, such as fludarabine, have revolutionized the approach to the treatment of indolent lymphoid malignancies. Fludarabine is the most effective agent for the treatment of chronic lymphocytic leukemia (CLL) and also exhibits major activity in low-grade NHL. Despite the impressive rates of complete remissions, patients with these malignancies remain incurable, and new agents are needed.
Several approaches are under study to achieve higher response rates and more durable remissions. A major focus has been on identifying new agents with unique mechanisms of action. One of the most exciting of the new drugs is compound 506U, the prodrug of arabinosylguanine (ara-G). This agent has demonstrated impressive activity in a variety of T-cell malignancies, such as acute lymphocytic leukemia (ALL) and T-cell lymphoblastic leukemia (T-LBL), with complete remissions occurring even in patients who have not responded to bone marrow transplantation (Kurtzberg et al: J Clin Oncol 14:1750 [abstract 2022], 1996).
Although compound 506U is believed to act specifically against T-cell disorders, responses have been observed in more than 30% of patients with B-cell CLL who did not respond to fludarabine and an alkylating agent. A national trial is underway to confirm these observations. The major toxicities of this agent include immunosuppression and neurologic effects, which appear to be schedule-dependent.
Gandhi et al (abstract #418) have demonstrated that intracellular concentrations of compound 506U correlate well with response to therapy (Gandhi et al: J Clin Oncol 17:3607-3615, 1998) Such studies should help identify patients most likely to benefit from this drug.
A national trial is currently evaluating compound 506U in patients with CLL who have not responded to both fludarabine and an alkylating agent. Additional trials are studying the drug in children and adults with T-cell ALL and lymphoblastic lymphoma.Future trials will study compound 506U in peripheral T-cell NHL and cutaneous T-cell NHL, as well as in indolent lymphomas.
Bruce D. Cheson, MD