Timed sequential therapy of human leukemia based upon the response of leukemic cells to humoral growth factors

Consecutive studies of timed sequential therapy were conducted in 44 adults with acute myelocytic leukemia. The rationale was based on evidence that bone marrow proliferation in vivo relates temporally to induced humoral stimulatory activities, and on models that demonstrate increased cytotoxicity of cytosine arabinoside to myeloblasts cultured in stimulatory serum. In the initial study (26 patients), humoral stimulation induced by cyclophosphamide reached peak concentrations on Days 8 through 10. When the cycle active drug cytosine arabinoside was infused at that predicted time, complete remissions were induced in 46% of patients, tumor cells cleared in 81%, and unmaintained remissions of 8.5 months were achieved. In an ongoing study (18 patients) with daunorubicin and cytosine arabinoside as the initial drugs in the sequence, the time of measured serum stimulation and the second infusion of cytosine arabinoside beginning on Day 8 correlated directly with an increased in vivo tumor-labeling index. In this study, in vivo tumor-labeling indices correlated with serum proliferative activities in 13 of 15 patients studied. Complete remissions were obtained in 50%, tumors cleared in 78%, and remissions with projected durations of > 18 months were achieved without therapy following the initial single induction course. These results suggest that the predictable kinetics of induced humoral stimulation that correlates in time with increased leukemic cell growth permits coupling the administration of an S-phase drug with increased growth of residual tumor. The proper role of further drug therapy in patients with acute myelocytic leukemia in remission requires further examination.