Four hundred thirty-four children, with good-risk acute lymphocytic leukemia (ALL), were assigned randomly to receive intensive or less intensive maintenance therapy with 6-mercaptopurine and methotrexate, plus vincristine and prednisone pulses in such a way that patients on treatment 1 had their leukocyte counts maintained between 1500 and 3000/mm3. Patients on treatment 2 had leukocyte counts maintained between 3000 and 4500/mm3. Absolute granulocyte counts were maintained above 500/mm3 on both groups. All children received induction treatment with vincristine, prednisone and L-asparaginase and had central nervous system (CNS) prophylaxis with cranial irradiation and intrathecal methotrexate. The overall remission rate was 94%. Event-free survival at 8 years was 44% (SE, 5.6%). There was no significant difference in outcome between treatments 1 and 2 (P = 0.83). The incidence of infection was similar overall and not significantly different between treatment arms.
The Pediatric Oncology Group (POG) undertook a prospective randomized trial using a single chemotherapy regimen with or without trimethoprim/sulfamethoxazole (TS). In a previous acute lymphocytic leukemia (ALL) study of initial therapy, investigators were free to use TS prophylaxis or not. Analysis of those data seemed to favor TS for duration of continuous complete remission. In the study reported here, of 126 randomized patients with ALL, 63 received TS. There was no effect of TS on disease-free survival after 3 years follow-up. Overall severe toxicity did not differ. However, granulocytopenia was somewhat more severe in the TS group. Hepatic toxicity, measured by enzyme elevation approached significance in the TS group versus controls. Some institutions declined randomization and treated with or without TS as a routine. Outcome and toxicities did not differ from randomized patients. There was no statistically significant effect on severe, life-threatening or fatal infection between the randomized TS versus control groups. Children not receiving TS developed varicella more often, a disease for which one would not expect TS to show a preventative effect. Pneumocystis pneumonias were not reported. The authors conclude that TS prophylaxis did not increase the continuous complete remission rate in children with ALL or decrease the incidence of infection. Toxicity is somewhat higher on TS.
Four hundred thirty patients with high-risk acute lymphoid leukemia were entered on the acute leukemia in childhood protocol (AlinC 12) of the Pediatric Division of the Southwest Oncology Group (now the Pediatric Oncology Group) between 1976 and 1979. This study was a prospective randomized comparison of two regimens that had as their primary differences: (1) an intensification period with Cytoxan (cyclophosphamide) and asparaginase after induction; (2) a period of intravenous methotrexate before initiating maintenance; and (3) in the regimen that had those two additions, triple-drug chemoprophylaxis of the central nervous system (CNS) using methotrexate, hydrocortisone, and cytosine arabinoside as compared to cranial irradiation and intrathecal methotrexate. All patients received vincristine and prednisone induction, 6-mercaptopurine and methotrexate maintenance, and vincristine and prednisone pulse intensification. There was no significant difference in the rate of bone marrow relapse. However, overall disease-free survival favored the arm with intensification and chemoprophylaxis because of a lesser incidence of extramedullary relapse. Thus, for treatment 1 versus treatment 3 the two-sided P values were for overall disease-free survival 0.16; bone marrow relapses 0.13; all CNS relapses 0.04; and all extramedullary disease relapses 0.013. It is concluded that intensification as delivered in this protocol protects against testicular relapse and that chemoprophylaxis is adequate prophylaxis against isolated CNS relapse.
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