Table 1.
Treatment regimens. High dose methotrexate versus standard dose methotrexate (Cycle duration in parentheses).
| C-MTX regimen | HDMTX regimen | ||
|---|---|---|---|
| Phase and treatment | Dose and schedule | Phase and treatment | Dose and schedule |
| Induction (4 weeks) | Induction (4 weeks)6 | ||
| IT cytarabine | Age adjusteda Day 1 | IT cytarabine | Age adjusteda Day 1 |
| Vincristine | 1.5 mg/m2 (2 mg max) IV Days 1, 8, 15, 22 | Vincristine | 1.5 mg/m2 (2 mg max) IV Days 1, 8, 15, 22 |
| Pegasparginaseb | 2500 U/m2 IM between Days 4 and 6 (one dose) | Pegasparginase2 | 2500 U/m2 IM between Days 4 and 6 (one dose) |
| Dexamethasone | 6 mg/m2/day in divided doses BID PO/IV Days 1–28 (No tapering) | Dexamethasone | 6 mg/m2/day in divided doses BID PO/IV Days 1–28 (no tapering) |
| IT MTXc | Age adjusteda Days 15, 29 | IT MTXc | Age adjusteda Days 15, 29 |
| Daunorubicin | 25 mg/m2 IV Days 1, 8, 15, 22 | Daunorubicin | 25 mg/m2 IV Days 1, 8, 15, 22 |
| Consolidation (7 weeks) | Consolidation (7 weeks) | ||
| Cyclophosphamide | 1000 mg/m2/day IV Days 1 and 29 | Cyclophosphamide | 1000 mg/m2/day IV Days 1 and 29 |
| Cytarabine | 75 mg/m2/day SQ/IV Days 1–4, 8–11, 29–32, 36–39 | Cytarabine | 75 mg/m2/day SQ/IV Days 1–4, 8–11, 29–32, 36–39 |
| Mercaptopurine | 60 mg/m2/day PO Days 1–14, 29–42 | Mercaptopurine | 60 mg/m2/day PO Days 1–14, 29–42 |
| IT MTXd | Age-adjusteda Days 1,8,15,22 | IT MTXd | Age-adjusteda Days 1,8,15,22 |
| Pegasparaginaseb | 2500 U/m2/day IM Days 18, 46 | Pegasparaginaseb | 2500 U/m2/day IM Days 18, 46 |
| Vincristine | 1.5 mg/m2/day IV Days 15,22,43,50 | Vincristine | 1.5 mg/m2/day IV Days 15,22,43,50 |
| IM-1 (7 weeks) | IM-1 (8 weeks) | ||
| Vincristine | 1.5 mg/m2/day IV Days 1, 11, 21, 31, 41 | Vincristine | 1.5 mg/m2/day IV Days 1, 15, 29, 43 |
| IV MTX | 100 mg/m2/day IV Days 1, 11, 21, 31, 41 (escalate by 50 mg/m2 per dose) | IV MTX (high dose) | 5 gm/m2/day IV Days 1, 15, 29, 43 |
| Pegasparaginase | 2500 U/m2/day IM Days 2, 22 | Mercaptopurine | 25 mg/m2/day PO Days 1–56 |
| IT MTX | Age-adjusteda Days 1, 31 | IT MTX | Age-adjusted1 Days 1, 29 |
| DI-1 (8 weeks) | DI-1 (8 weeks) | ||
| Re-induction (4 weeks) | Re-induction (4 weeks) | ||
| Dexamethasone | 10 mg/m2/day in divided doses BID PO/IV Days 1–7, 15–21 | Dexamethasone | 10 mg/m2/day in divided doses BID PO/IV Days 1–7, 15–21 |
| Vincristine | 1.5 mg/m2/day IV Days 1, 8, 15 | Vincristine | 1.5 mg/m2/day IV Days 1, 8, 15 |
| Doxorubicin | 25 mg/m2/day IV Days 1, 8, 15 | Doxorubicin | 25 mg/m2/d IV Days 1, 8, 15 |
| Pegasparaginase | 2500 IU/m2/day IM Day 4 | Pegasparaginase | 2500 IU/m2/day IM Day 4 |
| IT MTX | Age-adjusteda Day 1 | IT MTX | Age-adjusteda Day 1 |
| Reconsolidation (4 weeks) | Reconsolidation (4 weeks) | ||
| Cyclophosphamide | 1000 mg/m2/day IV Day 29 | Cyclophosphamide | 1000 mg/m2/day IV Day 29 |
| Thioguanine | 60 mg/m2/day PO Days 29–42 | Thioguanine | 60 mg/m2/day PO Days 29–42 |
| Cytarabine | 75 mg/m2/day SQ/IV Days 29–32, 36–39 | Cytarabine | 75 mg/m2/day SQ/IV Days 29–32, 36–39 |
| IT MTX | Age-adjusteda Days 29, 36 | IT MTX | Age-adjusteda Days 29, 36 |
| Vincristine | 1.5 mg/m2/day IV Days 43, 50 | Vincristine | 1.5 mg/m2/day IV Days 43, 50 |
| Pegasparaginase | 2500 U/m2/day IM Day 46 | Pegasparaginase | 2500 U/m2/day IM Day 46 |
| IM-2 (7 weeks) | Same as IM-1 (starting at 50 mg/m2 less than the maximum tolerated dose in IM-1) with IT MTX on Days 1, 31 | IM-2 (7 weeks) | Same as IM-1 of the C-MTX |
| DI-2 (8 weeks) | Same as DI-1 | DI-2 (8 weeks)d | Same as DI-1 |
| Maintenance (12 weeks)e | Maintenance (12 weeks)e | ||
| Vincristine | 1.5 mg/m2 (2 mg max) IV Days 1, 29, 57 | Vincristine | 1.5 mg/m2 (2 mg max) IV Days 1, 29, 57 |
| Dexamethasone | 6 mg/m2/day in divided doses BID PO Days 1–5, 29–33, 57–61 | Dexamethasone | 6 mg/m2/day in divided doses BID PO Days 1–5, 29–33, 57–61 |
| Mercaptopurine | 75 mg/m2/day PO daily | Mercaptopurine | 75 mg/m2/day PO daily |
| MTX | 20 mg/m2/dose PO weekly Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle | MTX | 20 mg/m2/dose PO weekly Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle |
| IT MTX | Age-adjusteda Days 1, 29 of the first 4 cycles, then Day 1 of each cycle thereafter. | IT MTX | Age-adjusteda Days 1, 29 of the first 4 cycles, then Day 1 of each cycle thereafter. |
C-MTX = standard escalating Cappizi methotrexate, HDMTX = high dose methotrexate, IT = intrathecal, IM = intramuscular, IV = intravenous, PO = oral, SQ = subcutaneous, MTX = methotrexate, IM = interim maintenance, DI = delayed intensification.
IT cytarabine was adjusted for age as follows: 1–1.99 years, 30 mg; 2–2.99 years, 50 mg; > 3 years, 70 mg. IT MTX was adjusted for age as follows; 1–1.99 years, 8 mg; 2–2.99 years, 10 mg; > 3 years, 12 mg.
Asparaginase preparation: pegylated asparaginase or L-asparaginase with dose and timing adjustment was used; Erwinia asparaginase replaced pegaspargase/l-asparaginase after severe allergic reactions.
For CNS2 and CNS3: 2 extra doses on days 8 and 22 were added.
Starting day 1 of consolidation for patients treated with C-MTX and day 29 of DI-2 for patients treated with HDMTX, patients with CNS3 at diagnosis received 1,800 cGy to the cranium. 6-Thioguanine oral doses are omitted in DI-2 for patients treated with HDMTX. Patients with testicular disease at diagnosis received 2,400 cGy bilateral testicular radiation in 8 fractions during consolidation therapy if testicular disease was persistent at end of induction. Patients with CNS3 disease at diagnosis did not receive IT methotrexate on days 15 and 22 consolidation therapy.
Total duration of treatment was 38 months for males and 24 months for females.