Evaluation of intensification and maintenance programs in the treatment of acute lymphoblastic leukemia.

This cooperative prospective study was designed to answer the following questions in cases with acute lymphoblastic leukemia induced to achieve complete remission with the combination of vincristine and prednisone (if by day 29 the bone marrow was not M1, daunorubicin was added to the former regimen) and who received preventive CNS therapy with 2400 rad of cobalt-60 to craniocervical region and simultaneously intrathecal methotrexate and dexamethasone: 1) Is a short intensification with cytosine-arabinoside and cyclophosphamide immediately after complete remission useful? 2) Does the use of weekly doses of 6-mercaptopurine and methotrexate have the same maintenance effect as daily 6-mercaptopurine and twice weekly methotrexate? and 3) Do further 3 month-doses of intrathecal methotrexate and dexamethasone help to decrease still more the incidence of meningeal leukemia? From October 1972 to December 1975, 473 previously untreated patients entered this study and 465 (390 children and 75 adults) are evaluated in this paper. Of them, 373 (80%) achieved complete remission (children 84% and adults 61%). Out of 109 "high risk" children (one or more of the following characteristics at diagnosis: marked organomegaly, mediastinal widening, leukocytosis above 50000/mm3 and CNS involvement) 83 (76%) and out of 281 "standard risk" children (all the others) 244 (87%) achieved complete remission. The median duration of complete remission according to different prognostic factors was as follows: "high risk" children 10 months, adults 24 months and "standard risk" children 25 months. Duration of complete remission of the "standard risk" children in relation to with or without intensification, daily or weekly maintenance and additional intrathecal therapy or none, showed no significant difference; however, those who received intensification, daily maintenance and further intrathecal therapy behaved slightly better. Median survival for all the cases of this study was as follows: adults 10 months, "high risk" children 12 months and "standard risk" children 26 months. At 36 months, 13% of "high risk" children, 25% of adults and 39% of "standard risk" children are still alive. We conclude that the variables studied in this protocol did not show significant extension of complete remission, however the sum of them seems to offer some advantage. Moreover, what appears clear is the importance of prognostic factors which must be taken into account in future studies.

Immunocompetence and prognosis in children with acute lymphoblastic leukemia: combination of two different maintenance therapies.

Intensive chemotherapy in patients with leukemia produced immunosuppression. The level of immunocompetence correlates with prognosis. The immunological function of 29 children with acute lymphoblastic leukemia (ALL) in complete remission and on 2 different maintenance therapies was evaluated and compared with 16 normal children (Group A). Sixteen children (Group B) with ALL received 6 mercaptopurine (6MP) daily and methotrexate (MTX) twice a week, and 13 children (Group C) received 6MP and MTX weekly for maintenance. There was depression of both cellular immunity, measured by the number of T cells and skin tests, and humoral immunity, measured by number of B cells, primary antibody production to typhoid vaccine, and levels of immunoglobulins. However, continuous maintenance therapy (Group B) produced significantly more severe immunosuppression of cellular immunity than the intermittent therapy (Group C). Humoral immunity was equally depressed in both groups of leukemia patients, but was less altered than cellular immunity. Concomitantly, patients with intermittent maintenance chemotherapy had less hematologic depression, fewer episodes of infection, and fewer died in complete remission. Patients of both groups with higher levels of immunocompetence had better prognosis with longer duration of complete remission than patients with severe immunosuppression. Out of 6 patients with "favorable immunocompetence" only 1 relapsed at 7 months and the other 5 remain in complete remission from 8 to 31 months. Among 23 leukemic patients with "unfavorable immunocompetence," 15 relapsed and 8 remain in complete remission from 9 to 26 months.