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

Omar, Abdallah A.; Basiouny, Lina; Elnoby, Ahmed S.; Zaki, Abeer; Abouzid, Mohamed

doi:10.1186/s43046-022-00126-3

Journal of the Egyptian National Cancer Institute

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 weeks^a ▪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 years^b ▪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 week^c 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 weeks^d 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
VIII^e 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/week^f ▪Site irradiation: 2500 — 3500 R^g		-	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 + CYT^θ
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 months^h 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			▪HDMTX (IV): 2g/M² — 2 doses/week	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 ▪MTX^o
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 except^p 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
XV^k 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/M^2r ▪Imatinib (PO): 40 mg/M^2l		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 chemotherapy^m ▪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 dependent^ρt 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
XVI^k 2007–2017	4–6 weeks ▪PRD (PO): 40 mg/M²/day^q ▪DEX (PO): 10 mg/M²/day^q ▪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/M^2l			Intrathecal chemotherapy, dose age dependent^st 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 dependent^s 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

^astudy III had 42 days, ^b group IVa took the full dose while group IVb took the half dose, ^c1st randomization, only group VIa administered the intensive chemotherapy, ^d2nd randomization, only groups VIa1 and VIb1, ^eif marrow not in remission after 1 month, PRD (PO): 40 mg/M²/day + DAN (IV): 25mg/M²/day-3 doses, ^fif the patient had CNS leukemia, group a, ^gIf the patient had mediastinal mass, group b; θ–50 mg/M²/week, ^hlate intensification after 15–30 months from complete remission. Patients are assigned into 4 groups, ⁱinitiated either after complete remission is achieved or after the intensive phase, ^jfrom 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, ^kintrathecal 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, ^ltwice daily for Ph-positive patients starting from day 22, ^mfor high risk only, before bone marrow transplantation, ⁿas originally reported, ^ogiven interchangeably every 6 weeks for 5 courses of each (first year), ^pthe period of the continuation phase was 120 weeks for girls and 146 weeks for boys, ^qdexamethasone 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

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