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Table 1 Treatment protocol St. Jude Total Therapy studies from I to XVI for childhood ALL

From: St. Jude Total Therapy studies from I to XVII for childhood acute lymphoblastic leukemia: a brief review

Protocol Remission induction Intensive chemotherapy Prophylactic therapy Continuation therapy
I
1962–1965
4–6 weeksa
▪PRD (PO): 40 mg/M2/day — (divided into 3 to 4 doses)
▪VCR (IV): 1.5 mg/M2/week
1 week
▪6MP (IV): 1 gm/M2 — 3 days, followed by the following:
▪MTX (IV): 10 mg/M2/day — 3 days, followed by the following:
▪CYC (IV) 600 mg/M2 — once
Meanwhile, PRD was discontinued gradually over 14 days
▪500 R 60Co CSI irradiationn 3 years
▪6MP (PO): 50 gm/M2/day
▪MTX (IV): 20 mg/M2/week
▪CYC (IV) 200 mg/M2/week
▪VCR (IV): 1 mg/M2/week (full or half dose)
II
1963–1966
▪500 R 60Co CSI irradiationn  3 years
▪6MP (PO): 50 gm/M2/day or MTX (IV): 20 mg/M2/week
▪CYC (IV): 200 mg/M2/2 weeks
▪VCR (IV): 1 mg/M2/2 weeks
III
1962–1965
11 days
▪1200 R 60Co CSI irradiation
3 yearsb
▪6MP (PO): 50 gm/M2/day
▪MTX (IV): 20 mg/M2/day
▪CYC (IV): 200 mg/M2/week
▪VCR (IV): 1 mg/M2/week
IV
1965–1967
-
V
1967–1968
2.5 weeks
▪2400 60Co cranial irradiation
▪MTX (IT): 12 mg/M2 — twice weekly for five doses
3–5 years
▪6MP (PO): 50 gm/M2/day
▪MTX (IV): 20 mg/M2/day
▪CYC (IV): 200 mg/M2/week
Every 10 weeks
▪PRD (PO): 40 mg/M2/day — 15 days
▪VCR (IV): 1.5 mg/M2/week — 3 doses
VI
1968–1970
4 to 6 weeks
▪PRD (PO): 40 mg/M2/day — (divided into 3 to 4 doses)
▪VCR (IV): 1.5 mg/M2/week
▪DAN (IV): 25 mg/M2/week
1 weekc
Group A
▪6MP (IV): 1 gm/M2 — 3 days, followed by
▪MTX (IV): 10 mg/M2/day — 3 days, followed by
▪CYC (IV): 600 mg/M2 — once
Group B
▪None
4 weeksd
Groups A1/B1
▪2400 R 60Co CSI
Groups A2/B2
▪None
3 years
▪6MP (PO): 50 gm/M2/day
▪MTX (IV): 20 mg/M2/day
▪CYC (IV): 200 mg/M2/week
Every 70 days
▪PRD (PO): 40 mg/M2/day — 15 days
▪VCR (IV): 1.5 mg/M2/week — 3 doses
VII
1970–1971
4 to 6 weeks
▪PRD (PO): 40 mg/M2/day — (divided into 3 to 4 doses)
▪VCR (IV): 1.5 mg/M2/week
- Groups CM/CMVP
▪2400 R 60Co CSI
▪MTX (IT): 12 mg/M2 — twice weekly for five doses
Groups CS/CSVP
▪2400 R 60Co cranial irradiation
2.5 years
▪6MP (PO): 50 gm/M2/day
▪MTX (IV): 20 mg/M2/week
▪CYC (IV): 200 mg/M2/week
Groups CMVP/CSVP added (every 12 weeks)
▪PRD (PO): 40 mg/M2/day — 15 days
▪VCR (IV): 1.5 mg/M2/week — 3 doses
VIIIe
1972–1975
4 to 6 weeks
▪PRD (PO): 40 mg/M2/day — (divided into 3 to 4 doses)
▪VCR (IV): 1.5 mg/M2/week — 4 doses
▪ASP (IV): 10,000 units/M2/week — 2 doses (one on day 2 or 3 and the last one at day 8)
▪MTX (IV): 12 mg/M2/weekf
▪Site irradiation: 2500 — 3500 Rg
- Preventive:
▪2400 R 60Co cranial irradiation — 18 days
▪MTX (IT): 12 mg/M2 — twice weekly for five doses
Therapeutic
Group A above
▪3000 R 60Co CSI — 28 days
▪MTX (IT): 12 mg/M2 — twice weekly for four doses
2.5 to 3 years
Groups A/B/C
▪6MP (PO): 50 gm/M2/day
▪MTX (IV): 20 mg/M2/week
▪CYC (IV): 200 mg/M2/week
The rest of the patients were randomized as follows:
Group1: MTX
Group2: MTX + 6MP
Group3: MTX + 6MP + CYC
Group4: MTX + 6MP + CYC + CYTθ
IX
1975–1979
4 weeks
▪PRD (PO): 40 mg/M2/day
▪VCR (IV): 1.5 mg/M2/week — 4 doses
▪DAN (IV): 25 mg/M2/week
Patients are randomized to receive either the following:
▪ASP (IV): 10,000 lU/M2 — (2 doses, on days 3 and 9)
OR
▪ASP (IV): 10,000 lU/M2 — twice/week for 4 doses
▪CYT (IV): 300 mg/M2 — twice/week for 4 doses
15–30 monthsh
Group PVD
▪PRD (PO): 40 mg/M2/day — 2 weeks
▪VCR (IV): 1.5 mg/M2/week — 3 weeks
▪DAN (IV): 25 mg/M2/week — 2 weeks
Group VC
▪VCR (IV): 1.5 mg/M2/week — 3 weeks
▪CYC (IV): 300 mg/M2/week — 3 weeks
Group VM-26 + ara-C
▪VM26 (IV): 165 mg/M2 twice weekly for 2 doses
▪CYT (IV): 300 mg/M2 twice weekly for 2 doses
Group ASP
▪ASP (IM): 10,000 IU/M2 daily for 5 doses
18 daysi
▪2400 R 60Co cranial irradiation (age adjusted)
▪MTX (IT): 12 mg/M2, 5 times (maximum dose, 15 mg)
2.5 years
▪MTX (IV): 20 mg/M2/week
▪6MP (PO): 50 mg/M2/day
X
1979–1983
4 weeks
▪PRD (PO): 40 mg/M2/day
▪VCR (IV): 1.5 mg/M2/week
▪ASP (IV): 10,000 units/M2 (on days 4, 8, 12, 15)
▪MTX (IT): 12 mg/M2 (max. 12 mg, on days 15 & 29)
Followed by 78 weeks of continuation therapy:
▪6MP — once a day and MTX — once a week with 5 intermittent doses of VM26 and CYT every 10 weeks only until week 52
▪Preventive CNS therapy after 1 year of persistent remission
High-risk relapse — add the following:
▪VM26 (IV): 150 mg/M2
▪CYT (IV): 300 mg/M2 — twice weekly pre- and post-conventional induction therapy
▪1800 R 60Co cranial irradiation
▪MTX (IT): 5 doses 12mg/M2
Treatment A — 3 weeks
▪MTX (IV): 200 mg/M2 followed by 24-h infusion 800 mg/M2
▪MTX (IT): 12 mg/M2
▪Leucovorin rescue (IV)j: 30 mg/M2, 12 and 18 h post-MTX infusion and 3 mg/M2 orally/12 h for 3 doses with IV hydration (5% dextrose and 0.2% NaCl, 100 mL/M2/h) and urinary alkalinization (NaHCO3, 1 g/M2 orally/6 h) given 2 h before each infusion of HDMTX
Then 120 weeks of the following:
▪6MP (PO): 50 mg/M2 — daily
▪MTX (PO): 25 mg/M2 weekly with intermittent shots of high dose
▪MTX every 6 weeks until week 72
OR
Treatment B — 72 to 120 weeks
78 weeks of continuation therapy
▪6MP — once a day and MTX — once a week with 5 intermittent doses of VM26 and CYT every 10 weeks only until week 52 and preventive CNS therapy after 1 year of persistent remission
RTSC group
▪MTX (IT): 12 mg/M2 (every 3 months)
HDMTX group
▪HDMTX + IT-MTX
▪6MP + IT-MTX
▪Doxo + Cyclo
▪VM26 + CYT
▪MTX (IV): 200 mg/M2 — followed by 24-h IV every 1.5 months for 18 months
▪MTX (IT): 12 mg/M2 — 12 weeks for 30 months
▪6MP (PO): 50 mg/M2
▪CYC (PO): 100 mg/M2/day
▪DOX (IV): 30 mg/M2
▪VM26 (IV): 150 mg/M2
▪CYT (IV): 300 mg/M2 — every 2 week
XI
1984–1988
4–6 weeks
▪PRD (PO): 40 mg/M2/day — (divided into 3 to 4 doses)
▪VCR (IV): 1.5 mg/M2/week
▪DAN (IV): 26mg/M2
▪ASP (IV): 1000000 units/M2
▪VM26 (IV): 200 mg/M2
▪CYT (IV): 300 mg/M2
▪HDMTX (IV): 2g/M2 — 2 doses/week High risk
▪13–15 doses of TIT
▪1800 R 60Co cranial irradiation
▪2400 R initially CNS infiltration
Low risk
▪9 doses of TIT only
High riskn
Four pairs of drugs rotated every week or every 6 weeks
▪VP16 and CYC
▪6MP and MTX
▪VM26 and CYT
▪PRD and VCR
Low riskn
▪Randomized to take the four pairs of drugs
OR
▪6MP and MTX — 3 weeks
▪PRD and VCR — 1 week
XII
1988–1991
3 weeks
High risk
▪18–20 doses TIT
▪1800 R 60Co CSI
▪2400 R initially CNS infiltration
Low risk
▪13 doses of TIT
Patient stratified and randomized to talk individualized dose or conventional dose
▪HDMTX
▪6MP (given as permanent drugs 120 weeks)
▪MTX (given as permanent drugs 120 weeks)
ORξ
▪VM26
▪CYT
▪6MP
▪MTXo
XIIIA
1991–1994
Pre-induction chemotherapy (2–4 days)
▪HDMTX (IV): 1 mg/M2
OR
▪LDMTX: 30 mg/M2 every 6 h before the induction
Induction chemotherapy
▪The same of XI except; VP16 was given instead of VM26
2 weeks
▪HDMTX (IV): 2g/M2 — 2 doses/week
▪6MP (PO): 75 mg/M2/day
3 weeks
High risk
▪22 to 26 doses TIT
▪1800 R 60Co cranial irradiation
▪2400 R initially CNS infiltration
Low risk
▪15 doses of TIT only
120 weeks
High riskn
▪CYC + VP16
▪MTX + 6MP
▪MTX + CYT
▪PRD + VCR + ASP
▪VP16 + CYC
▪HDMTX + 6MP
▪CYT + VP16
▪PRD + VCR + ASP
Low riskn
▪6MP + MTX (120 weeks)
▪HDMTX pulses/8 weeks
▪PRD +VCR/4 weeks
Reinduction weeks (32–37)
▪PRD (PO): 40 mg/M2/day — (divided into 3 to 4 doses)
▪VCR (IV): 1.5 mg/M2/week
▪DAN (IV): 26mg/M2
▪ASP (IV): 1000,000 units/M2
▪VM26 (IV): 200 mg/M2
▪CYT (IV): 300 mg/M2
▪HDMTX (IV): 2g/M2 — 2 doses/week
XIIIB
1994–1998
Pre-induction chemotherapy (2–4 days)
▪6MP (1 g/M2)
OR
▪HDMTX (IV): 1 g/M2
▪6MP: 1 g/M2
OR
▪LDMTX (PO): 30 mg/M2
▪6MP 1 g/M2
3 weeks
High risk
▪26 doses TIT
▪1800 R 60Co cranial irradiation
▪2400 R initially CNS infiltration
Low risk
▪13 doses of TIT only
The same of XIIIA except the following:
▪PRD was replaced with DEX
▪ASP was given only during the reinduction phase
XIV
1998–1999
2 weeks
High risk
▪HDMTX (IV): 5 g/M2 — 2 doses /week
▪6MP (PO): 75 mg/M2/day
Low risk
▪HDMTX (IV): 2.5 g/M2 — 2 doses/week
▪6MP (PO): 75 mg/M2/day
During the entire treatment period
High risk
▪23 doses of TIT
Low risk
▪16 doses of TIT
The same of XIIIB exceptp the following:
Low risk
▪HDMTX (PO): 2.5 g/M2
High risk
▪HDMTX (PO): 5 g/M2
Reinduction phase
▪At day 1, 8 PEG-ASP + idarubicin
▪At day 15, PEG-ASP only
▪VCR (IV): 1.5 mg/M2/week
▪DEX (PO): 8 mg/M2/day
XVk
2000–2007
4–6 weeks
▪PRD (PO): 40 mg/M2/day
▪VCR (IV): 1.5 mg/M2/week — divided into 4 doses
▪DAN (IV): 25 mg/M2/week
▪L-ASP (IM): 10,000 units/M2 divided into 5 doses
▪CYC (IV): 1000 mg/M2 — once
▪CYT (IV): 75 mg/M2 — 8 doses
▪6MP (PO): 60 mg/M2r
▪Imatinib (PO): 40 mg/M2l
Consolidation phase (8 weeks)
▪HDMTX targeted dose depending on risk status, days 1, 15, 29, and 43
▪6MP (PO): 50 mg/M2/day, days 1–56
Intensive chemotherapym
▪DEX (PO): 20 mg/M2
▪CYT (IV): 2 g/M2
▪VP16 (IV): 100 mg/M2
▪L-ASP (IM): 25,000 units/M2
▪1 dose of IT chemotherapy
Intrathecal chemotherapy, dose age dependentρt
Low risk with CNS1
▪13 doses of TIT
Low risk with CNS2
▪18 doses of TIT
Standard risk cases with CNS1
▪16 doses of TIT
Standard risk cases with CNS2
▪18 doses of TIT
Standard/high-risk cases or CNS3
▪24 doses of TIT
120 weeks
High risk
▪ASP (IM): 25,000 units/M2/day
▪6MP (PO): 50 mg/M2 divided into 7 doses
▪DEX (PO): 12 mg/M2/day
▪VCR (IV): 2 mg/M2
▪DOX (IV): 30 mg/M2
▪3 cycles reinduction I and 3 cycles reinduction II
Low risk
▪6MP (PO): 75 mg/M2 plus
▪MTX (IV or IM): 40 mg/M2
▪DEX (PO): 8 mg/M2
▪VCR (IV): 2 mg/M2 alternating with the following:
▪3 cycles reinduction I and 3 cycles reinduction II
Reinduction after continuation therapy
Reinductions I and II for low risk
▪DEX (PO): 8 mg/M2/day
▪VCR (IV): 1.5 mg/M2/week (max. 2 mg)
▪L-ASP (IM): 10,000 units/M2 — once a week
▪DOX (IV): 30 mg/M2/week
Reinduction I for standard/high risk
▪DEX (PO): 8 mg/M2/day
▪VCR (IV): 1.5 mg/M2/week
▪DOX (IV): 30 mg/M2
▪L-ASP (IM): 25,000 units/M2 — divided into 3 doses
Reinduction II for standard/high risk
▪As mentioned in reinduction I plus high-dose CYT (IV): 2 gm/M2
XVIk
2007–2017
4–6 weeks
▪PRD (PO): 40 mg/M2/dayq
▪DEX (PO): 10 mg/M2/dayq
▪VCR (IV): 1.5 mg/M2/week — divided into 4 doses
▪DAN (IV): 25 mg/M2/week
▪L-ASP (IM): 10,000 units/M2 divided into 5 doses
▪CYC (IV): 1000 mg/M2 — once
▪CYT (IV): 75 mg/M2 — 8 doses
▪6MP (PO): 60 mg/M2
▪Imatinib (PO): 40 mg/M2l
Intrathecal chemotherapy, dose age dependentst
Low risk with CNS1:
▪13 doses of TIT
low risk with CNS2
▪17 doses of TIT
Standard risk cases with CNS1
▪16 doses of TIT
Standard-risk cases with CNS2
▪20 doses of TIT
Standard-/high-risk cases or CNS3
▪27 doses of TIT
120 weeks
Low-risk patients
▪Two reinduction cycles
▪DEX (PO): 8 mg/M2
▪VCR (IV): 2 mg/M2
Standard or high risk
▪PEG-ASP (IV): 2,500 vs. 3,500 units/M2 — 15 doses
▪Intermittent doses of DOX (IV): 30 mg/M2
▪VCR (IV): 2 mg/M2
▪DEX (PO): 12 mg/M2
▪Two reinduction cycles
▪6MP (PO): 50 mg/M2
▪MTX (IV): 40 mg/M2
Reinduction after continuation therapy
Reinduction I for low risk
▪DEX (PO): 8 mg/M2/day (t.i.d.)
▪VCR (IV): 1.5 mg/M2/week — divided into 3 doses
▪PEG-ASP (IV): 2,500 or 3,500 units/M2 -divided into 2 doses
▪DOX (IV): 30 mg/M2/day
▪IT chemotherapy, dose age dependent, day 1
Reinduction II for low risk
▪DEX (PO): 8 mg/M2/day
▪VCR (IV): 1.5 mg/M2/week — divided into 3 doses
▪PEG-ASP (IV): 2,500 or 3,500 units/M2 — divided into 2 doses
▪IT chemotherapy, dose age dependent, day 1
From week 21 to the end of the therapy
▪6MP (PO): 75 mg/M2
▪MTX (IV or IM): 40 mg/M2
▪6MP (PO): 75mg/M2 — intermittent
▪DEX (PO): 8 mg/M2
▪VCR (IV): 2 mg/M2 (max. 2 mg)
Reinduction I for standard/high risk
▪DEX (PO): 8 mg/M2/day — t.i.d.
▪VCR (IV): 1.5 mg/M2/week — divided into 3 doses
▪DOX (IV): 30 mg/M2
▪PEG-ASP (IV): 2,500 or 3,500 units/M2
Reinduction II for standard/high risk and MLL infants
▪DEX (PO): 8 mg/M2/day — t.i.d.
▪VCR (IV): 1.5 mg/M2/week
▪PEG-ASP (IV): 2,500 or 3,500 units/M2
▪High-dose CYT (IV): 2 gm/M2
▪IT chemotherapy, dose age dependents
From week 21 to the end of the therapy
▪PEG-ASP (IV): 2,500 vs 3,500 units/M2 every other week separated by the following:
▪CYC (IV): 300 mg/M2 plus
▪CYT (IV): 300 mg/M2
▪6MP (PO): 75mg/M2
▪MTX (IV or IM): 40 mg/M2
▪DEX (PO): 12mg/M2
▪VCR (IV): 2 mg/M2 (max. 2 mg)
▪PEG-ASP (IV): 2,500 and 3,500 units/M2
  1. study III had 42 days, b group IVa took the full dose while group IVb took the half dose, 1st randomization, only group VIa administered the intensive chemotherapy, 2nd randomization, only groups VIa1 and VIb1, if marrow not in remission after 1 month, PRD (PO): 40 mg/M2/day + DAN (IV): 25mg/M2/day-3 doses, if the patient had CNS leukemia, group a, If the patient had mediastinal mass, group b; θ–50 mg/M2/week, late intensification after 15–30 months from complete remission. Patients are assigned into 4 groups, initiated either after complete remission is achieved or after the intensive phase, from the protocol development perspective, there is a lack of information if leucovorin rescue was reported in each following protocol, however, from the toxicity perspective, HDMTX must be followed by leucovorin administration, intrathecal therapy will be administered on days 1 and 19, dose age dependent. Patients with a high risk of CNS relapse will receive additional IT treatments on days 8 and 26, twice daily for Ph-positive patients starting from day 22, for high risk only, before bone marrow transplantation, as originally reported, given interchangeably every 6 weeks for 5 courses of each (first year), the period of the continuation phase was 120 weeks for girls and 146 weeks for boys, dexamethasone will replace prednisone in patients with early T-cell precursor immunophenotype, rreplaced by thiopurine in thiopurine S-methyltransferase deficiency or hematotoxicity, s day 1: MTX + hydrocortisone + CYT doses and routes are age-dependent MTX 6, 8, 10, or 12 mg; hydrocortisone 12, 16, 20, or 24 mg; and CYT 18, 24, 30, or 36 mg for age 1, 1–1.99, 2–2.99, and 3 years, respectively, t CNS irradiation is removed except in refractory CNS leukemia or patients with lymphoblasts in the CSF. ALL, acute lymphoblastic leukemia, ASP asparaginase, CNS central nervous system, CSF cerebrospinal fluid, CS craniospinal irradiation, CYC cyclophosphamide, CYT cytarabine, DAN daunorubicin, DEX dexamethasone, DOX doxorubicin, HDMX high-dose methotrexate, IV intravenous, L-ASP-L asparaginase, LLy lineage lymphoblastic lymphoma, MTX methotrexate, PCP, Pneumocystis carinii pneumonia, PEG polyethylene glycol, PO oral, PRD prednisone, RBCs red blood cells, RTSC cranial irradiation/sequential chemotherapy, t.i.d. three times a day, TIT triple intrathecal therapy, VCR vincristine, VM26 teniposide, VP16 etoposide, WBCs white blood cells