Comparison of intermittent or continuous methotrexate plus 6-mercaptopurine in regimens for standard-risk acute lymphoblastic leukemia in childhood (JCCLSG-S811)

Abstract

From 1981 to 1983, 131 previously untreated patients with acute lymphoblastic leukemia (ALL) standard-risk group were entered to the protocol JCCLSG-S811. Of 119 eligible patients, 115 (96.6%) attained complete remission by treatment with prednisone (PRD) plus vincristine (VCR) or vindesine (VDS). After preventive central nervous system (CNS) therapy including 18 Gy cranial irradiation and three doses of intrathecal methotrexate (MTX), the patients were assigned randomly to the two maintenance chemotherapies, Regimen A and Regimen B. Regimen A (intermittent regimen) consisted of PRD (120 mg/m2/day by mouth for 5 days) plus 6-mercaptopurine (6MP) (175 mg/m2/day by mouth for 5 days) plus VCR (2.0 mg/m2 intravenously) alternating biweekly with MTX (225 mg/m2 intravenously). Regimen B (continuous regimen) consisted of 6 M P (50 mg/m2/day by mouth) plus MTX (20 mg/m2/ week by mouth) combined with pulses of PRD and VCR (the same dosages as Regimen A) every 4 weeks. As the late intensification therapy (LIT), five courses of high-dose MTX (2000 mg/m2 per dose per week intravenously for three doses every 12 weeks) with leucovorin rescue were administered to all patients who were in continuous complete remission (CCR) for more than 2 years. Sixty and 55 patients, respectively, were registered in Regimen A and B. The CCR rates in Regimen A and B were 75.1% t 5.8% (mean f 1 SE) and 49.7% ? 7.3% (P < 0.01) at 4 years, and 72.1% k 6.3% and 49.7% ? 7.3% (P < 0.05) at 5 years, respectively. In Regimen B, CNS and testicular relapses increased after 3 years of CCR. In addition, the patients in Regimen B had a much higher incidence of infections than Regimen A. The LIT did not seem to have important effects on the duration of CCR. From these data we conclude that the intermittent cyclic regimen of 6MP and MTX may be more effective as compared to the continuous administration of these drugs in the maintenance chemotherapy.

Long-term results of the Japanese Childhood Cancer and Leukemia Study Group studies 811, 841, 874 and 911 on childhood acute lymphoblastic leukemia

“…In the ALL811 study, we showed that intermittent cyclic administration of intermediate-dose MTX (225 mg/m 2 , intravenous) alternating biweekly 6MP (170 mg/day, orally for 5 days) was more effective than conventional administration of low-dose MTX (20 mg/m 2 /week, orally) and 6MP (50 mg/m 2 , orally, every day). 7 As a result of these data, intermittent cyclic administration of MTX and 6MP has become a standard regimen of maintenance chemotherapy in JCCLSG ALL protocols.…”

“…In ALL811, patients in the LR or IR group were defined as the standard-risk (SR) group. 7 Of HR patients in ALL911, cases with initial leukocyte count greater than 100 Â 10 9 /l were further stratified into a 'high-high-risk' (HHR) group (Table 1).…”

“…[7][8][9][10] An outline of treatment regimens in the protocols and detailed therapy schedules, including drug dosage, are provided in Tables 2 and 3, respectively. ALL811. The main aim of the S811 protocol was a randomized control study of two different maintenance chemotherapies.…”

“…The main aim of the S811 protocol was a randomized control study of two different maintenance chemotherapies. 7 SR patients received a two-drug (VP) induction therapy consisting of vincristine (VCR) and prednisolone (PSL). After achieving complete remission, they were randomized to either arm-A, consisting of intermittent cyclic administration of four drugs (VPM-M regimen), VCR, PSL, 6-mercaptopurine (6MP) and intermediate-dose methotrexate (MTX), or arm-B, consisting of continuous low-dose MTX and 6MP combined with VP pulse.…”

“…[5][6][7][8][9][10][11][12] Here, we show longterm outcomes of patients treated from the early 1980s through the mid 1990s (ALL811, ALL841, ALL874 and ALL911), and also discuss late adverse effects.…”