Recurrent childhood lymphocytic leukemia. Clinical and cytokinetic studies of cytosine arabinoside and methotrexate for maintenance of second hematologic remission

Abstract

Fifty-six children with acute lymphocytic leukemic (ALL) who had initial marrow relapses during continuation chemotherapy were retreated with vincristine and prednisone. By one month, 36 of 56 (64%) were again in hematologic remission. Twelve of the remaining 20 achieved marrow remissions with additional therapy. Thus, 48 of 56 patients (85%) achieved second marrow remissions. Continuation therapy consisted of weekly cytosine arabinoside (Ara-C), 150 mg/m2, and methotrexate (MTX), 40 mg/m2. Patients were randomly selected to receive the drugs simultaneously or sequentially (48 hours apart) to evaluate the theoretical advantage of scheduling Ara-C before MTX. In 13 children, drug-induced changes in DNA-synthetic activity were documented before reinduction of remission by determining tritiated thymidine and deoxyuridine labeling indices, autoradiographically, in marrow samples obtained at 0, 4, 24, 48 and 72 hours after a dose of Ara-C and MTX. Neither clinical nor cytokinetic results supported the sequential schedule. The duration of second remissions among 25 patients treated with simultaneous Ara-C and MTX (median = 56 days) did not differ significantly from that of 22 sequentially treated patients (median = 65 days). Moreover, there was no convincing cytokinetic evidence for partial synchronization of the mitotic cycle of leukemia blasts following Ara-C administration. Instead, the labeling indices showed extensive variability from patient to patient, and, in the simultaneously treated group, the drug-induced suppression of lymphoblast labeling was unexpectedly brief, possibly due to relative drug resistance. We conclude that, while reinduction of a second remission in ALL is comparatively easy, effective maintenance treatment for these remissions remains a difficult therapeutic problem. Combinations of Ara-C and MTX, under the conditions of this study, failed to interfere effectively with leukemic cell replication as evidenced by both cytokinetic studies and end results. Cancer 42:2521–2528, 1978.