Treatment protocol
| Treatment element/drug . | Single or daily dose . | Days of application per elementa . |
|---|---|---|
| Induction/consolidation, protocol I | ||
| Phase A | ||
| Prednisone (PO) | 60 mg/m2 per day | 1-28fg |
| Vincristine (IV) | 1.5 mg/m2 per dose (max 2 mg) | 8, 15, 22, 29 |
| Daunorubicin (PI over 1 hour) | 30 mg/m2 per dose | 8, 15, 22,h 29 h |
| L-asparaginase (PI over 1 hour) | 5000 IU/m2 per dose | 12, 15, 18, 21, 24, 27, 30,f 33f |
| Methotrexate (IT) | 12 mg/dosei | 1, 12, 33j |
| Phase B (only SR/MR) | ||
| Cyclophosphamide (PI over 1 hour) | 1000 mg/m2 per dose | 36, 64 |
| Cytarabine (IV) | 75 mg/m2 per dose | 38-41, 45-48, 52-55, 59-62 |
| 6-mercaptopurine (PO) | 60 mg/m2 per day | 36-63 |
| Methotrexate (IT) | 12 mg/dosei | 45, 59 |
| Extracompartment therapy (only SR/MR) | ||
| Protocol M | ||
| 6-mercaptopurine (PO) | 25 mg/m2 per day | 1-56 |
| Methotrexate (PI over 24 hours)b | 5000 mg/m2 per dose | 8, 22, 36, 50 |
| Methotrexate (IT) | 12 mg/dosei | 8, 22, 36, 50 |
| Protocol MCA (only MR patients randomized into MR-2) | ||
| 6-mercaptopurine (PO) | 25 mg/m2 per day | 1-56 |
| Methotrexate (PI over 24 hours)b | 5000 mg/m2 per dose | 8, 22, 36, 50 |
| Methotrexate (IT) | 12 mg/dosei | 8, 22, 36, 50 |
| Cytarabine (PI over 24 hours) | 200 mg/m2 per dose | 9, 23, 37, 51 |
| Intensive consolidation (only HR) (HR-1′/HR-2′/HR-3′) × 2 | ||
| Element HR-1′c | ||
| Dexamethasone (PO) | 20 mg/m2 per day | 1-5 |
| Vincristine (IV) | 1.5 mg/m2 (max 2 mg) | 1,k 6k |
| Methotrexate (PI over 24 hours)b | 5000 mg/m2 per dose | 1 |
| Cyclophosphamide (PI over 1 hour) | 200 mg/m2 per dose | 2-4 (5 doses, 12-hour intervals) |
| Cytarabine (PI over 3 hours) | 2 g/m2 per dose | 5 (2 doses, 12 h interval) |
| L-asparaginase (PI over 6 hours) | 25 000 IU/m2 per dose | 6 |
| Methotrexate/cytarabine/prednisolone (IT) | 12/30/10 mg/dosei | 1 |
| Element HR-2′c | ||
| Dexamethasone (PO) | 20 mg/m2 per day | 1-5 |
| Vindesine (IV) | 3 mg/m2 per dose (max 5 mg) | 1, 6 |
| Methotrexate (PI over 24 hours)b | 5000 mg/m2 per dose | 1 |
| Ifosfamide (PI over 1 hour) | 800 mg/m2 per dose | 2-4 (5 doses, 12-hour intervals) |
| Daunorubicin (PI over 24 hours) | 30 mg/m2 per dose | 5 |
| L-asparaginase (PI over 6 hours) | 25 000 IU/m2 per dose | 6 |
| Methotrexate/cytarabine/prednisolone (IT) | 12/30/10 mg/dosei | 1l |
| Element HR-3′c | ||
| Dexamethasone (PO) | 20 mg/m2 per day | 1-5 |
| Cytarabine (PI over 3 hours) | 2 g/m2 per dose | 1-2 (4 doses, 12-hour intervals) |
| Etoposide (PI over 1 hour) | 100 mg/m2 per dose | 3-5 (5 doses, 12-hour intervals) |
| L-asparaginase (PI over 6 hours) | 25 000 IU/m2 per dose | 6 |
| Methotrexate/cytarabine/prednisolone (IT) | 12/30/10 mg/dosei | 5 |
| Reinduction, protocol II | ||
| Phase A | ||
| Dexamethasone (PO) | 60 mg/m2 per day | 1-21g |
| Vincristine (IV) | 1.5 mg/m2 per dose (max 2 mg) | 8, 15, 22, 29 |
| Doxorubicin (PI over 1 hour) | 30 mg/m2 per dose | 8, 15, 22, 29 |
| L-asparaginase (PI over 1 hour) | 10 000 IU/m2 per dose | 8, 11, 15, 18 |
| Phase B | ||
| Cyclophosphamide (PI over 1 hour) | 1000 mg/m2 per dose | 36 |
| Cytarabine (IV) | 75 mg/m2 per dose | 38-41, 45-48 |
| 6-thioguanine (PO) | 60 mg/m2 per day | 36-49 |
| Methotrexate (IT) | 12 mg/dosei | 45, 59m |
| Maintenance therapyd | ||
| Methotrexate (PO) | 20 mg/m2 per dosen | Once a week |
| 6-mercaptopurine (PO) | 50 mg/m2 per dayn | Daily |
| Only MR patients randomized into MR-B | ||
| Methotrexate (PO) | 20 mg/m2 per dosen | Once a week |
| 6-mercaptopurine (PO) | 50 mg/m2 per dayn | Daily |
| Dexamethasone (PO)e | 6 mg/m2 per day | 1-7 per pulse |
| Vincristine (IV)e | 1.5 mg/m2 per dose (max 2 mg) | 1, 7 per pulse |
| Treatment element/drug . | Single or daily dose . | Days of application per elementa . |
|---|---|---|
| Induction/consolidation, protocol I | ||
| Phase A | ||
| Prednisone (PO) | 60 mg/m2 per day | 1-28fg |
| Vincristine (IV) | 1.5 mg/m2 per dose (max 2 mg) | 8, 15, 22, 29 |
| Daunorubicin (PI over 1 hour) | 30 mg/m2 per dose | 8, 15, 22,h 29 h |
| L-asparaginase (PI over 1 hour) | 5000 IU/m2 per dose | 12, 15, 18, 21, 24, 27, 30,f 33f |
| Methotrexate (IT) | 12 mg/dosei | 1, 12, 33j |
| Phase B (only SR/MR) | ||
| Cyclophosphamide (PI over 1 hour) | 1000 mg/m2 per dose | 36, 64 |
| Cytarabine (IV) | 75 mg/m2 per dose | 38-41, 45-48, 52-55, 59-62 |
| 6-mercaptopurine (PO) | 60 mg/m2 per day | 36-63 |
| Methotrexate (IT) | 12 mg/dosei | 45, 59 |
| Extracompartment therapy (only SR/MR) | ||
| Protocol M | ||
| 6-mercaptopurine (PO) | 25 mg/m2 per day | 1-56 |
| Methotrexate (PI over 24 hours)b | 5000 mg/m2 per dose | 8, 22, 36, 50 |
| Methotrexate (IT) | 12 mg/dosei | 8, 22, 36, 50 |
| Protocol MCA (only MR patients randomized into MR-2) | ||
| 6-mercaptopurine (PO) | 25 mg/m2 per day | 1-56 |
| Methotrexate (PI over 24 hours)b | 5000 mg/m2 per dose | 8, 22, 36, 50 |
| Methotrexate (IT) | 12 mg/dosei | 8, 22, 36, 50 |
| Cytarabine (PI over 24 hours) | 200 mg/m2 per dose | 9, 23, 37, 51 |
| Intensive consolidation (only HR) (HR-1′/HR-2′/HR-3′) × 2 | ||
| Element HR-1′c | ||
| Dexamethasone (PO) | 20 mg/m2 per day | 1-5 |
| Vincristine (IV) | 1.5 mg/m2 (max 2 mg) | 1,k 6k |
| Methotrexate (PI over 24 hours)b | 5000 mg/m2 per dose | 1 |
| Cyclophosphamide (PI over 1 hour) | 200 mg/m2 per dose | 2-4 (5 doses, 12-hour intervals) |
| Cytarabine (PI over 3 hours) | 2 g/m2 per dose | 5 (2 doses, 12 h interval) |
| L-asparaginase (PI over 6 hours) | 25 000 IU/m2 per dose | 6 |
| Methotrexate/cytarabine/prednisolone (IT) | 12/30/10 mg/dosei | 1 |
| Element HR-2′c | ||
| Dexamethasone (PO) | 20 mg/m2 per day | 1-5 |
| Vindesine (IV) | 3 mg/m2 per dose (max 5 mg) | 1, 6 |
| Methotrexate (PI over 24 hours)b | 5000 mg/m2 per dose | 1 |
| Ifosfamide (PI over 1 hour) | 800 mg/m2 per dose | 2-4 (5 doses, 12-hour intervals) |
| Daunorubicin (PI over 24 hours) | 30 mg/m2 per dose | 5 |
| L-asparaginase (PI over 6 hours) | 25 000 IU/m2 per dose | 6 |
| Methotrexate/cytarabine/prednisolone (IT) | 12/30/10 mg/dosei | 1l |
| Element HR-3′c | ||
| Dexamethasone (PO) | 20 mg/m2 per day | 1-5 |
| Cytarabine (PI over 3 hours) | 2 g/m2 per dose | 1-2 (4 doses, 12-hour intervals) |
| Etoposide (PI over 1 hour) | 100 mg/m2 per dose | 3-5 (5 doses, 12-hour intervals) |
| L-asparaginase (PI over 6 hours) | 25 000 IU/m2 per dose | 6 |
| Methotrexate/cytarabine/prednisolone (IT) | 12/30/10 mg/dosei | 5 |
| Reinduction, protocol II | ||
| Phase A | ||
| Dexamethasone (PO) | 60 mg/m2 per day | 1-21g |
| Vincristine (IV) | 1.5 mg/m2 per dose (max 2 mg) | 8, 15, 22, 29 |
| Doxorubicin (PI over 1 hour) | 30 mg/m2 per dose | 8, 15, 22, 29 |
| L-asparaginase (PI over 1 hour) | 10 000 IU/m2 per dose | 8, 11, 15, 18 |
| Phase B | ||
| Cyclophosphamide (PI over 1 hour) | 1000 mg/m2 per dose | 36 |
| Cytarabine (IV) | 75 mg/m2 per dose | 38-41, 45-48 |
| 6-thioguanine (PO) | 60 mg/m2 per day | 36-49 |
| Methotrexate (IT) | 12 mg/dosei | 45, 59m |
| Maintenance therapyd | ||
| Methotrexate (PO) | 20 mg/m2 per dosen | Once a week |
| 6-mercaptopurine (PO) | 50 mg/m2 per dayn | Daily |
| Only MR patients randomized into MR-B | ||
| Methotrexate (PO) | 20 mg/m2 per dosen | Once a week |
| 6-mercaptopurine (PO) | 50 mg/m2 per dayn | Daily |
| Dexamethasone (PO)e | 6 mg/m2 per day | 1-7 per pulse |
| Vincristine (IV)e | 1.5 mg/m2 per dose (max 2 mg) | 1, 7 per pulse |
PO indicates orally; IV, intravenous push; PI, intravenous infusion; IT, intrathecally.
Adjustments of time schedule were allowed if clinical condition and bone marrow recovery were inadequate (according to protocol guidelines).
A loading dose of 10% was infused over 30 minutes, the remaining 90% over 23.5 hours. Leucovorin rescue was given at hours 42, 48, and 54 (each 15 mg/m2). Increased leucovorin doses was given, when MTX levels at hour 42 or later were >1.0 μmol/L. If the MTX level at hour 54 was >0.25 μmol/L, rescue was continued at 6-hour intervals until MTX levels were ≤0.25 μmol/L.
Each HR′ block was given twice (Figure 1).
Maintenance was given from end of intensive chemotherapy until 104 weeks after diagnosis, for boys in SR until 156 weeks.
Six pulses were given every 10 weeks.
In HR, protocol I/phase A was given with only 21 days of prednisone and 6 doses of L-asparaginase.
Steroids were tapered over 9 days.
In SR, the daunorubicin doses on days 22 and 29 were omitted.
Doses were adjusted for children younger than 3 years.
The day 33 IT methotrexate dose was scheduled on day 27 in HR patients. Patients with CNS status CNS2, TLP+, or CNS3 received additional IT methotrexate on days 18 and 27 (SR or MR) or on day 18 (HR).
Vincristine was omitted in the first HR-1′ course.
Patients with CNS status CNS 3 received additional IT methotrexate on day 5.
Patients with CNS status CNS 3 received additional IT methotrexate on days 1 and 18.
Doses were adjusted to WBC (target range, 2000-3000/μL).