Long-Term Follow-Up in Five Consecutive ALL-BFM Trials: Supplementary Tables
Long-term follow-up in five consecutive ALL-BFM trials: Supplementary Tables
Supplementary Tables
S. Table 1Details of the treatment protocol ALL-BFM 81
Drug / Dose / Days of application per elementaAll therapy groups / Standard Risk,
Random Arm A / Standard Risk,
Random Arm B / Medium Risk / High Risk
Induction/Consolidation
Protocol I
Phase A
Prednisone (PO) / 60 mg/m2/day / 1-28d
Vincristine (IV) / 1.5 mg/m2/dose (max 2.5 mg) / 1, 8, 15, 22
Daunorubicine (PI over 1 h) / 30 mg/m2/dose / 1, 8, 15, 22
L-Asparaginase (PI over 2-3 h) / 5000 IU/m2/day / 1-22
Phase B
Cyclophosphamide (IV) / 1000 mg/m2/dose / 29, 57
Cytarabine (IV) / 75 mg/m2/dose / 31-34, 38-41, 45-18, 52-55
6-Mercaptopurine (PO) / 60 mg/m2/day / 29-56
Methotrexate (IT) / 12 mg/dosee / 31, 38, 45, 52
Radiotherapyb
Preventive cranial irradiation / dosage depending on age and risk groupf / in parallel to Protocol I B
<1/1-<2/≥2 yrs: 12/15/18 Gy / in parallel to Protocol IB
<1/1-<2/≥2 yrs: 12/15/18 Gy / in parallel to Protocol IB
<1/1-<2/≥2 yrs: 16/20/24 Gy
Interim Maintenance
Standard Interim Maintenance
6-Mercaptopurine (PO) / 50 mg/m2/dayg / 1-56 / 1-56 / 1-56
Methotrexate (PO) / 20 mg/m2/dose, once per weekg / 1, 8, 15, 22, 29, 36, 43, 50 / 1, 8, 15, 22, 29, 36, 43, 50 / 1, 8, 15, 22, 29, 36, 43, 50
Interim Maintenance with Intermediate-dose MTX
6-Mercaptopurine (PO) / 25 mg/m2/day / 1-56
Methotrexate (PI over 24 hc) / 500 mg/m2/dose / 8, 22, 36, 50
Methotrexate (IT) / 12 mg/dosee / 8, 22, 36, 50
Reintensification
Protocol II
Phase ADexamethasone (PO) / 10 mg/m2/day / 1-28d
Vincristine (IV) / 1.5 mg/m2/dose (max 2.5 mg) / 1, 8, 15, 22
Doxobicine (PI over 1 h) / 30 mg/m2/dose / 1, 8, 15, 22
L-Asparaginase (PI over 2-3 h) / 10 000 IU/m2/dose / 1, 4, 8, 11
Phase B
Cyclophosphamide (IV) / 1000 mg/m2/day / 29
Cytarabine (IV) / 75 mg/m2/day / 31-34, 38-41
6-Thioguanine (PO) / 60 mg/m2/day / 29-42
Methotrexate (IT) / 12 mg/dosee / 31, 38
Protocol III
Phase ADexamethasone (PO) / 10 mg/m2/day / 1-14d / 1-14d
Vincristine (IV) / 1.5 mg/m2/dose (max 2.5 mg) / 1, 8 / 1, 8
Doxorubicine (PI over 1 h) / 30 mg/m2/dose / 1, 8 / 1, 8
L-Asparaginase (PI over 2-3 h) / 10 000 IU/m2/dose / 1, 4, 8, 11 / 1, 4, 8, 11
Phase B
Cytarabine (IV) / 75 mg/m2/day / 17-20, 24-27 / 17-20, 24-27
6-Thioguanine (PO) / 60 mg/m2/day / 15-28 / 15-28
Methotrexate (IT) / 12 mg/dosee / 17, 24 / 17, 24
Protocol IV
Phase AVM 26 (PI over 1 h) / 165 mg/m2/dose / 1, 4, 8, 11
ARA-C (PI over 1 h) / 300 mg/m2/dose / 1, 4, 8, 11
Dexamethasone (PO) / 10 mg/m2/day / 15-42d
Vincristine (IV) / 1.5 mg/m2/dose (max 2.5 mg) / 15, 22, 29, 36
Doxorubicine (PI over 1 h) / 30 mg/m2/dose / 15, 22, 29, 36
L-Asparaginase (PI over 2-3 h) / 10 000 IU/m2/dose / 15, 18, 22, 25
Phase B
Cyclophosphamide (IV) / 1000 mg/m2/day / 43
Cytarabine (IV) / 75 mg/m2/day / 45-48, 52-55
6-Thioguanine (PO) / 60 mg/m2/day / 43-56
Methotrexate (IT) / 12 mg/dosee / 45, 52
Maintenance
6-Mercaptopurine (PO) / 50 mg/m2/dayg
Methotrexate (PO) / 20 mg/m2/doseg, once per week / from end of intensive chemotherapy until 78 / 104 weeksh from diagnosis
Abbreviations: PO, orally; IV, intravenous push; PI, intravenous infusion; IT, intrathecally
aAdjustments of time schedule were allowed if clinical condition and bone marrow recovery were inadequate (according to protocol guidelines)
bFor patients with evidence of initial testicular involvement, irradiation of the testes with 24-30 Gy was recommended.
cA loading dose of 10% was given as IV push, the remaining 90% over 23.5 h. Leucovorin rescue was given at hour 48 and 54 (each 12 mg/m2)
dSteroids were subsequently tapered over 9 days.
eDoses were adjusted for children <3 years of age.
fPatients with initial CNS involvement receive craniospinal radiotherapy (cranial/spinal dose age-dependent:<1 yr, 20/15 Gy; 1-<2 yrs, 24/20 Gy; ≥2 yrs 30/24 Gy)
gDoses were adjusted to WBC (target range 2000-3000/µl).
hMaintenance was randomized to be given from end of intensive chemotherapy until 78 or 104 weeks after diagnosis.
S. Table 2Details of the treatment protocol ALL-BFM 83
Drug / Dose / Days of application per elementaAll therapy groups / Standard Risk-low / Standard Risk-high / Medium Risk / High Risk
Block Therapy Pre-Phase
Prednisone Pre-Phase
Prednisone (PO) / 60 mg/m2/day / 1-7f
Methotrexate (IT) / 12 mg/doseg / 1
Block 1 (x2)
Cyclophosphamide / 200 mg/m2/dose / 8, 9, 10, 11, 12, 29, 30, 31, 32, 33
Dexamethasone (PO) / 10 mg/m2/day / 8-12, 29-33
Methotrexate (PI over 24 hb) / 500 mg/m2/dose / 8, 29
Methotrexate (IT) / 12 mg/doseg / 8, 29
VM 26 (PI over 1 h) / 165 mg/m2/dose / 12, 33
ARA-C (PI over 1 h) / 300 mg/m2/dose / 12, 33
Induction/Consolidation
Protocol I
Prednisone Pre-Phase
Prednisone (PO) / 60 mg/m2/day / 1-7f / 1-7f / 1-7f
Methotrexate (IT)c / 12 mg/doseg / 1 / 1 / 1
Phase A
Prednisone (PO) / 60 mg/m2/day / 8-28h
Vincristine (IV) / 1.5 mg/m2/dose (max 2.5 mg) / 8, 15, 22, 29
Daunorubicine (PI over 1 h) / 30 mg/m2/dose / 8, 15, 22, 29
L-Asparaginase (PI over 2-3 h) / 10 000 IU/m2/dose / 26, 29, 32, 35, 38, 41, 44, 47
Phase B
Cyclophosphamide (IV) / 1000 mg/m2/dose / 50, 78
Cytarabine (IV) / 75 mg/m2/dose / 52-55, 59-62, 66-69, 73-76
6-Mercaptopurine (PO) / 60 mg/m2/day / 50-77
Methotrexate (IT)c / 12 mg/doseg / 52 / 66 / 66
Interim Maintenance
Methotrexate (PI over 24 hb) / 500 mg/m2/dose / 8, 22, 36, 50
Methotrexate (IT) / 12 mg/doseg / 8, 22, 36, 50
6-Mercaptopurine (PO) / 25 mg/m2/day / 1-56
Reintensification
Protocol II
Phase ADexamethasone (PO) / 10 mg/m2/day / 1-28h / 1-28h
Vincristine (IV) / 1.5 mg/m2/dose (max 2.5 mg) / 1, 8, 15, 22 / 1, 8, 15, 22
Doxobicine (PI over 1 h) / 30 mg/m2/dose / 1, 8, 15, 22 / 1, 8, 15, 22
L-Asparaginase (PI over 2-3 h) / 10 000 IU/m2/dose / 1, 4, 8, 11 / 1, 4, 8, 11
Phase B
Cyclophosphamide (IV) / 1000 mg/m2/day / 29 / 29
Cytarabine (IV) / 75 mg/m2/day / 31-34, 38-41 / 31-34, 38-41
6-Thioguanine (PO) / 60 mg/m2/day / 29-42 / 29-42
Methotrexate (IT) / 12 mg/doseg / 31, 38 / 31, 38
Protocol IIId
Phase ADexamethasone (PO) / 10 mg/m2/day / 1-14h / 1-14h
Vincristine (IV) / 1.5 mg/m2/dose (max 2.5 mg) / 1, 8 / 1, 8
Doxorubicine (PI over 1 h) / 30 mg/m2/dose / 1, 8 / 1, 8
L-Asparaginase (PI over 2-3 h) / 10 000 IU/m2/dose / 1, 4, 8, 11 / 1, 4, 8, 11
Phase B
Cytarabine (IV) / 75 mg/m2/day / 17-20, 24-27 / 17-20, 24-27
6-Thioguanine (PO) / 60 mg/m2/day / 15-28 / 15-28
Methotrexate (IT) / 12 mg/doseg / 17, 24 / 17, 24
Radiotherapye
Preventive cranial irradiation / dosage depending on age and risk groupi / subsequently to Protocol III<1/1-<2/≥2 yrs: 12/15/18 Gy (randomized vs 8/10/12 Gy) / subsequently to Protocol II
<1/1-<2/≥2 yrs: 12/15/18 Gy / subsequently to Protocol II
<1/1-<2/≥2 yrs: 16/20/24 Gy
Maintenance
6-Mercaptopurine (PO) / 50 mg/m2/dayj
Methotrexate (PO) / 20 mg/m2/dosej, once per week / from end of intensive chemotherapy until 78 / 104 weeksk from diagnosis
Abbreviations: PO, orally; IV, intravenous push; PI, intravenous infusion; IT, intrathecally
aAdjustments of time schedule were allowed if clinical condition and bone marrow recovery were inadequate (according to protocol guidelines)
bA loading dose of 10% was given as IV push, the remaining 90% over 23.5 h. Leucovorin rescue was given at hour 48 and 54 (each 12 mg/m2)
cPatients with initial CNS involvement received additional IT MTX doses on days 15, 29, and 66 of Protocol I
dIn Low-Standard Risk patients, reintensification element Protocol III was given in a randomized manner (Protocol III vs. no reintensification).
eFor patients with evidence of initial testicular involvement, irradiation of the testes with 24-30 Gy was recommended.
fIn patients with high tumor load, prednisone was started with reduced dose.
gDoses were adjusted for children <3 years of age.
hSteroids were subsequently tapered over 9 days.
iPatients with initial CNS involvement received craniospinal radiotherapy (cranial dose age-dependent:<1 yr, 20 Gy; 1-<2 yrs, 24 Gy; ≥2 yrs 30 Gy)
jDoses were adjusted to WBC (target range 2000-3000/µl).
kMaintenance was randomized to be given from end of intensive chemotherapy until 78 or 104 weeks after diagnosis.
S. Table 3Details of the treatment protocol ALL-BFM 86
Drug / Dose / Days of application per elementaInduction/Consolidation / All therapy groups / Standard Risk Group / Risk Group / Experimental Group
Protocol I
Prednisone Pre-Phase
Prednisone (PO) / 60 mg/m2/day / 1-7g
Methotrexate (IT)b / 12 mg/doseh / 1
Phase A
Prednisone (PO) / 60 mg/m2/day / 8-28i
Vincristine (IV) / 1.5 mg/m2/dose (max 2.0 mg) / 8, 15, 22, 29
Daunorubicine (PI over 1 h) / 40 mg/m2/dose / 8, 15, 22, 29
L-Asparaginase (PI over 1 h) / 10 000 IU/m2/dose / 19, 22, 25, 28, 31, 34, 37, 40
Phase B
Cyclophosphamide (PI over 1 h) / 1000 mg/m2/dose / 43, 71
Cytarabine (IV) / 75 mg/m2/dose / 45-48, 52-55, 59-62, 66-69
6-Mercaptopurine (PO) / 60 mg/m2/day / 43-70
Methotrexate (IT)b / 12 mg/doseh / 45, 59
Extra-Compartment Therapy/Consolidation
Protocol M
Methotrexate (PI over 24 hc) / 5000 mg/m2/dose / 8, 22, 36, 50 / 8, 22, 36, 50
Methotrexate (IT) / 12 mg/doseh / 8, 22, 36, 50 / 8, 22, 36, 50
6-Mercaptopurine (PO) / 25 mg/m2/day / 1-56 / 1-56
Intensive Consolidation
Protocol E
Prednisone (PO) / 100 mg/m2/day / 1-7, 15-21, 29-35, 43-59
Methotrexate (PI over 24 hc) / 5000 mg/m2/dose / 8, 22, 36, 50
Methotrexate (IT) / 12 mg/doseh / 8, 22, 36, 50
Cytarabine (PI over 3 h) / 2000 mg/m2/dose / 1-2, 39-30 (2x 4 doses, 12 h intervals)
Ifosfamide (PI over 1 h) / 1000 mg/m2/dose / 15-16, 43-44 (2x 4 doses, 12 h intervals)
Mitoxantrone (IV) / 10 mg/m2/dose / 1, 15, 29, 43
Reintensification
Protocol IId
Phase ADexamethasone (PO) / 10 mg/m2/day / 1-22i
Vincristine (IV) / 1.5 mg/m2/dose (max 2.0 mg) / 8, 15, 22, 29
Doxobicine (PI over 1 h) / 30 mg/m2/dose / 8, 15, 22, 29
L-Asparaginase (PI over 1 h) / 10 000 IU/m2/dose / 8, 11, 22, 25
Phase B
Cyclophosphamide (PI over 1 h) / 1000 mg/m2/day / 36
Cytarabine (IV) / 75 mg/m2/day / 38-41, 45-48
6-Thioguanine (PO) / 60 mg/m2/day / 36-49
Methotrexate (IT) / 12 mg/doseh / 38, 45
Late Reintensification
Protocol Se
Prednisone (PO) / 100 mg/m2/day / 1-7, 14-21
Vindesine (IV) / 3 mg/m2/dose (max 5.0 mg) / 8, 15, 22, 29
VM-26 / 150 mg/m2/dose / 8, 15, 22, 29
Ifosfamide (PI over 1 h) / 1000 mg/m2/dose / 1-2 (4 doses, 12 h intervals)
Cytarabine (PI over 3 h) / 2000 mg/m2/dose / 15-16 (4 doses, 12 h intervals)
Radiotherapyf
Preventive cranial irradiation / dosage depending on age and risk groupj / starting in parallel to Protocol II, Phase B<1/≥1 yrs: 0/12 Gy (0/18 Gy if BFM-RF ≥1.2) / starting in parallel to Protocol II, Phase B
<1/1-<2/≥2 yrs: 0/12/18 Gy
Maintenance
6-Mercaptopurine (PO) / 50 mg/m2/day
Methotrexate (PO) / 20 mg/m2/dose, once per week / from end of intensive chemotherapy until 104 (78) weeksd from diagnosis
Abbreviations: PO, orally; IV, intravenous push; PI, intravenous infusion; IT, intrathecally
aAdjustments of time schedule were allowed if clinical condition and bone marrow recovery were inadequate (according to protocol guidelines)
bPatients with initial CNS involvement received additional IT MTX doses on days 15, 29, and 66 of Protocol I.
cA loading dose of 10% was given as IV push, the remaining 90% over 23.5 h. Leucovorin rescue was started at hour 36 (75 mg/m2) and was given at three-hour intervals until hour 54 followed by six-hour intervals until hour 72 (each 15 mg/m2). Leucovorin doses were increased in case of elevated MTX levels.
dTreatment plan was amended during study; reinduction protocol II was reintroduced in branch SRG and total therapy duration was extended from 78 to 104 weeks.
ePatients of the RG branch in first CR 12 months after diagnosis were randomized to receive or not receive late intensification Protocol S.
fFor patients with evidence of initial testicular involvement, irradiation of the testes with 24 Gy was recommended.
gIn patients with high tumor load, prednisone was started with reduced dose.
hDoses were adjusted for children <3 years of age.
iSteroids were subsequently tapered over 9 days.
jPatients with initial CNS involvement received craniospinal radiotherapy (cranial dose age-dependent:<1 yr, 0 Gy; 1-<2 yrs, 18 Gy; ≥2 yrs 24 Gy)
S. Table 4Details of the treatment protocol ALL-BFM 90
Drug / Dose / Days of application per elementaInduction/Consolidation / All therapy groups / Standard Risk Group / Medium Risk Group / High Risk Group
Protocol I
Prednisone Pre-Phase
Prednisone (PO) / 60 mg/m2/day / 1-7f
Methotrexate (IT) / 12 mg/doseg / 1
Phase A
Prednisone (PO) / 60 mg/m2/day / 8-28h / 8-28h / 8-22h
Vincristine (IV) / 1.5 mg/m2/dose (max 2.0 mg) / 8, 15, 22, 29
Daunorubicine (PI over 1 h) / 30 mg/m2/dose / 8, 15, 22, 29
L-Asparaginase (PI over 1 h) / 10 000 IU/m2/dose / 12, 15, 18, 21, 24, 27, 30, 33 / 12, 15, 18, 21, 24, 27, 30, 33 / 12, 15, 18, 21, 24, 27
Methotrexate (IT) / 12 mg/doseg / 15, 29i
Phase B
Cyclophosphamide (PI over 1 h) / 1000 mg/m2/day / 36, 64 / 36, 64
Cytarabine (IV) / 75 mg/m2/day / 36-39, 45-48, 52-55, 59-62 / 36-39, 45-48, 52-55, 59-62
6-Mercaptopurine (PO) / 60 mg/m2/day / 36-63 / 36-63
Methotrexate (IT) / 12 mg/doseg / 45, 59 / 45, 59
Extra-Compartment Therapy/Consolidation
Protocol M / Protocol M-Ac
Methotrexate (PI over 24 hb) / 5000 mg/m2/dose / 8, 22, 36, 50 / 8, 22, 36, 50
Methotrexate (IT) / 12 mg/doseg / 8, 22, 36, 50 / 8, 22, 36, 50
6-Mercaptopurine (PO) / 25 mg/m2/day / 1-56 / 1-56
L-Asparaginase (IM)c / 25 000 IU/m2/dose / 10, 24, 38, 52c
Reintensification
Protocol II
Phase ADexamethasone (PO) / 10 mg/m2/day / 1-22h / 1-22h
Vincristine (IV) / 1.5 mg/m2/dose (max 2.0 mg) / 8, 15, 22, 29 / 8, 15, 22, 29
Doxobicine (PI over 1 h) / 30 mg/m2/dose / 8, 15, 22, 29 / 8, 15, 22, 29
L-Asparaginase (PI over 1 h) / 10 000 IU/m2/dose / 8, 11, 22, 25 / 8, 11, 22, 25
Phase B
Cyclophosphamide (PI over 1 h) / 1000 mg/m2/day / 36 / 36
Cytarabine (IV) / 75 mg/m2/day / 38-41, 45-48 / 38-41, 45-48
6-Thioguanine (PO) / 60 mg/m2/day / 36-49 / 36-49
Methotrexate (IT) / 12 mg/doseg / 38, 45j / 38, 45j
Intensive Consolidation
(HR-1, HR-2, HR-3) x3de
Block HR-1
Dexamethasone (PO) / 20 mg/m2/day / 1-5
6-Mercaptopurine (PO) / 100 mg/m2/day / 1-5
Vincristine (IV) / 1.5 mg/m2/dose (max 2.0 mg) / 1, 6
Methotrexate (PI over 24 hb) / 5000 mg/m2/dose / 1
Cytarabine (PI over 3 h) / 2000 mg/m2/dose / 5 (2 doses, 12 h interval)
L-Asparaginase (IM) / 25 000 IU/m2/dose / 6
Methotrexate/Cytarabine/Prednisolone (IT) / 12/30/10 mg/doseg / 1
Block HR-2
Dexamethasone (PO) / 20 mg/m2/day / 1-5
6-Thioguanine (PO) / 100 mg/m2/day / 1-5
Vindesine (IV) / 3 mg/m2/dose (max 5 mg) / 1
Methotrexate (PI over 24 hb) / 5000 mg/m2/dose / 1
Daunorubicine (PI over 24 h) / 50 mg/m2/dose / 5
Ifosfamide (PI over 1 h) / 400 mg/m2/dose / 1, 2, 3, 4, 5
L-Asparaginase (IM) / 25 000 IU/m2/dose / 6
Methotrexate/Cytarabine/Prednisolone (IT) / 12/30/10 mg/doseg / 1k
Block HR-3
Dexamethasone (PO) / 20 mg/m2/day / 1-5
Cytarabine (PI over 3 h) / 2000 mg/m2/dose / 1-2 (4 doses, 12 h intervals)
VP-16 / 150 mg/m2/dose / 3, 4, 5
L-Asparaginase (IM) / 25 000 IU/m2/dose / 6
Methotrexate/Cytarabine/Prednisolone (IT) / 12/30/10 mg/doseg / 5
Radiotherapy
Preventive cranial irradiation / dosage depending on age and risk groupl / starting on day 38 of Protocol IIB:<1/≥1 yr: 0/12 Gy / starting at week 5 after the third HR-3 block:
<1/≥1 yr: 0/12 Gy
Maintenance
6-Mercaptopurine (PO) / 50 mg/m2/daym
Methotrexate (PO) / 20 mg/m2/dosem, once per week / from end of intensive chemotherapy until 104 weeks from diagnosis
Abbreviations: PO, orally; IV, intravenous push; PI, intravenous infusion; IT, intrathecally
aAdjustments of time schedule were allowed if clinical condition and bone marrow recovery were inadequate (according to protocol guidelines)
bA loading dose of 10% was given over 0.5 h, the remaining 90% over 23.5 h. Leucovorin rescue was given at hour 42, 48, and 54 (each 15 mg/m2), doses were increased in case of elevated MTX levels
cPatients of the Medium Risk Group were randomized to receive Protocol M or Protocol M-A with additional L-Asparaginase.
dThe three different high-dose chemotherapy blocks HR-1, HR-2 and HR-3 were given three times.
ePatients of branch HR were randomized to receive or not receive G-CSF between the high-dose blocks.
fIn patients with high tumor load, prednisone was started with reduced dose.
gDoses were adjusted for children <3 years of age.
hSteroids were subsequently tapered over 9 days.
iPatients with initial CNS involvement received additional IT MTX doses on days 8 and 22 of Protocol I.
jPatients with initial CNS involvement received additional IT MTX doses on days 8 and 22 of Protocol II.
kPatients with initial CNS involvement received additional IT triple therapy on day 5 of block HR-2.
lCranial irradiation dose for patients with initial CNS involvement was age dependent:<1 yr, 0 Gy; 1-<2 yrs, 18 Gy; ≥2 yrs 24 Gy
m Doses were adjusted to WBC (target range 2000-3000/µl).
S. Table 5Details of the treatment protocol ALL-BFM 95
All therapy groups / Standard Risk / Medium Risk / High Risk
Induction/Consolidation
Protocol I
Prednisone Pre-Phase
Prednisone (PO) / 60 mg/m2/day / 1-7d
Methotrexate (IT) / 12 mg/dosee / 1
Phase A
Prednisone (PO) / 60 mg/m2/day / 8-28f / 8-28f / 8-22f
Vincristine (IV) / 1.5 mg/m2/dose (max 2.0 mg) / 8, 15, 22, 29
Daunorubicine (PI over 1 h) / 30 mg/m2/dose / 8, 15 / 8, 15, 22, 29 / 8, 15, 22, 29
E. coli L-Asparaginase (PI over 1 h) / 5000 IU/m2/dose / 12, 15, 18, 21, 24, 27, 30, 33 / 12, 15, 18, 21, 24, 27, 30, 33 / 12, 15, 18, 21, 24, 27
Methotrexate (IT) / 12 mg/dosef / 12, 33g / 12, 33g / 12, 27h
Phase B
Cyclophosphamide (PI over 1 h) / 1000 mg/m2/day / 36, 64 / 36, 64
Cytarabine (IV) / 75 mg/m2/day / 36-39, 45-48, 52-55, 59-62 / 36-39, 45-48, 52-55, 59-62
6-Mercaptopurine (PO) / 60 mg/m2/day / 36-63 / 36-63
Methotrexate (IT) / 12 mg/dosee / 45, 59 / 45, 59
Extra-Compartment Consolidation Phase
Protocol M
Methotrexate (PI over 24 hb) / 5000 mg/m2/dose / 8, 22, 36, 50 / 8, 22, 36, 50
Methotrexate (IT) / 12 mg/dosee / 8, 22, 36, 50 / 8, 22, 36, 50
6-Mercaptopurine (PO) / 25 mg/m2/day / 1-56 / 1-56
or (randomized):
Protocol MCA
Methotrexate (PI over 24 hb) / 5000 mg/m2/dose / 8, 22, 36, 50
Methotrexate (IT) / 12 mg/dosee / 8, 22, 36, 50
6-Mercaptopurine (PO) / 25 mg/m2/day / 1-56
Cytarabine (PI over 24 h) / 200 mg/m2/dose / 9, 23, 37, 51
Intensive Consolidation
(HR-1’, HR-2’, HR-3’) x3
Block HR-1’
Dexamethasone (PO) / 20 mg/m2/day / 1-5
Vincristine (IV) / 1.5 mg/m2/dose (max 2.0 mg) / 1i, 6i
Methotrexate (PI over 24 hb) / 5000 mg/m2/dose / 1
Cyclophosphamide (PI over 1 h) / 200 mg/m2/dose / 2-4 (5 doses, 12 h intervals)
Cytarabine (PI over 3 h) / 2000 mg/m2/dose / 5 (2 doses, 12 h interval)
E. coli L-Asparaginase (PI over 6 h) / 25 000 IU/m2/dose / 6
Methotrexate/Cytarabine/Prednisolone (IT) / 12/30/10 mg/dosee / 1
Block HR-2’
Dexamethasone (PO) / 20 mg/m2/day / 1-5
Vindesine (IV) / 3 mg/m2/dose (max 5 mg) / 1, 6
Methotrexate (PI over 24 hb) / 5000 mg/m2/dose / 1
Ifosfamide (PI over 1 h) / 800 mg/m2/dose / 2-4 (5 doses, 12 h intervals)
Daunorubicin (PI over 24 h) / 30 mg/m2/dose / 5
L-Asparaginase (PI over 6 h) / 25 000 IU/m2/dose / 6
Methotrexate/Cytarabine/Prednisolone (IT) / 12/30/10 mg/dosee / 1j
Block HR-3
Dexamethasone (PO) / 20 mg/m2/day / 1-5
Cytarabine (PI over 3 h) / 2000 mg/m2/dose / 1-2 (4 doses, 12 h intervals)
Etoposide / 100 mg/m2/dose / 3-5 (5 doses, 12 h intervals)
L-Asparaginase (PI over 6 h) / 25 000 IU/m2/dose / 6
Methotrexate/Cytarabine/Prednisolone (IT) / 12/30/10 mg/dosee / 5
Reintensification
Protocol II
Phase ADexamethasone (PO) / 10 mg/m2/day / 1-22f
Vincristine (IV) / 1.5 mg/m2/dose (max 2.0 mg) / 8, 15, 22, 29
Doxobicine (PI over 1 h) / 30 mg/m2/dose / 8, 15, 22, 29
E. coli L-Asparaginase (PI over 1 h) / 10 000 IU/m2/dose / 8, 11, 22, 25
Phase B
Cyclophosphamide (PI over 1 h) / 1000 mg/m2/day / 36
Cytarabine (IV) / 75 mg/m2/day / 38-41, 45-48
6-Thioguanine (PO) / 60 mg/m2/day / 36-49
Methotrexate (IT) / 12 mg/dosee / 38, 45k
CRT
Preventive cranial irradiation / dosage depending on age and risk groupl / Only T-ALL, starting on day 38 of Protocol IIB:<1/≥1 yr: 0/12 Gy / starting at week 5 after the third HR-3 block:
<1/≥1 yr: 0/12 Gy
Maintenance
6-Mercaptopurine (PO) / 50 mg/m2/daym
Methotrexate (PO) / 20 mg/m2/dose, once per weekm / from end of intensive chemotherapy until 104/156n weeks from diagnosis / from end of intensive chemotherapy until 104 weeks from diagnosis / from end of intensive chemotherapy until 104 weeks from diagnosis
Abbreviations: PO, orally; IV, intravenous push; PI, intravenous infusion; IT, intrathecally
aAdjustments of time schedule were allowed if clinical condition and bone marrow recovery were inadequate (according to protocol guidelines)
bA loading dose of 10% was given over 0.5 h, the remaining 90% over 23.5 h. Leucovorin rescue was given at hour 42, 48, and 54 (each 15 mg/m2), doses were increased in case of elevated MTX levels
cPatients of the Medium Risk Group were randomized to receive Protocol M or Protocol M-A with additional L-Asparaginase.
dIn patients with high tumor load, prednisone was started with reduced dose.
eDoses were adjusted for children <3 years of age.
fSteroids were subsequently tapered over 9 days.
gPatients with initial CNS involvement received additional IT MTX doses on days 18 and 27 of Protocol I.
hPatients with initial CNS involvement received additional IT MTX doses on day 18 of Protocol I.
iVincristine was omitted in the 1st HR-1’ course.
jPatients with initial CNS involvement received additional IT triple therapy on day 5 of block HR-2.
kPatients with initial CNS involvement received additional IT MTX doses on days 1 and 18 of Protocol II.
lCranial irradiation dose for patients with initial CNS involvement was age dependent:<1 yr, 0 Gy; 1-<2 yrs, 12 Gy; ≥2 yrs 18 Gy
m Doses were adjusted to WBC (target range 2000-3000/µl).
nIn SR, maintenance was given for girls until 104 weeks and for boys until 156 weeks from diagnosis