An international collaborative (AIEOP-BFM [Associazione Italiana Ematologia Oncologia Pediatrica - Berlin-Franklin-Munster]) treatment protocol for children and adolescents with Acute Lymphoblastic Leukaemia

These 'Protocols' are chemotherapy treatment phases which all combined constitute 2 years of chemotherapy. The drugs are administered either orally, intravenously, or via intramuscular injsection. Patients enrolled on the study will be stratified into 3 treatment groups (standard, medium, and high risk). The stratifications will be determined by certain biologic features of the leukaemia and also by the patients response to treatment. Not all patients will receive every treatment phase - they will receive only those phases tailored to there treatment group. The study also involves 3 randomisations - R1, R2, R-HR. The R1 randomisation is a treatment deintesification for the standard risk group. The R2 and R-HR randomisations will evaluate treatment intensifications for the medium and high risk patient groups. Protocol IA, IA', and IA-CPM all include the following drugs - Prednisone (alternatively prednisolone) p.o or i.v - Vincristine i.v - Daunorubicin i.v - Cyclophosphamide i.v with Mesna - PEG-L-Asparaginase i.v - Methotrexate intrathecally Protocol IA-Dexa - Dexamethasone p.o. or i.v. - Daunorubicin i.v. Protocol IB - Cyclophosphamide i.v give with Mesna - Cytarabine i.v. or s.c. - 6-Mercaptoprine p.o. - Methotrexate intrathecally Protocol IB-ASP+ This protocol is the same as protocol 1B with the addtion of PEG-L-Asparaginase i.v Protocol HR-1 (for all patients in the high risk group) - Dexamethasone p.o. or i.v. - Vincristine i.v. - High-dose Methotrexate i.v - Cyclophosphamide i.v given with Mesna - High-dose Cytarabine i.v - PEG-L-Asparaginase i.v - Methotrexate intrathecally during HD-Methotrexate infusion on day 1 - Granuloctye colony stimulating factor (GCSF) s.c. Protocol HR-2 (for all patients in the high risk group) - Dexamethasone p.o. or i.v. - Vindesine i.v. - High-dose Methotrexate i.v - Ifosfamide i.v given with Mesna - Daunorubicin i.v - PEG-L-Asparaginase i.v - Methotrexate intrathecally given during HD-Methotrexate infusion - Granulocyte colony stimulating factor (GCSF) s.c. Protocol HR-3 (given after HR-2) - Dexamethasone p.o. or i.v. - High-dose Cytarabine i.v - Etoposide i.v - PEG-L-Asparaginase i.v - Methotrexate intrathecally - Granulocyte colony stimulating factor (GCSF) s.c. Protocol M - 6-Mercaptopurine p.o. - High-Dose Methotrexate i.v - Methotrexate intrathecally Protocol IIA - Dexamethasone p.o. or i.v. - Vincristine i.v. - Doxorubicin i.v. - PEG-L-Asparaginase i.v - Methotrexate intrathecally Protocol IIA-ASP+ This protocol is the same as IIA but has the addition of PEG-L-Asparaginase i.v. Protocol IIB - Cyclophosphamide i.v. - Cytarabine i.v. or s.c. - Thioguanine p.o. - Methotrexate intrathecally Protocol IIIA - Dexamethasone p.o. or i.v. - Vincristine i.v. - Doxorubicin i.v. - PEG-L-Asparaginase i.v. - Methotrexate intrathecally Protocol IIIB - Cyclophosphamide i.v. given with Mesna - Cytarabine i.v. or s.c. - Thioguaninie p.o. - Methotrexate intrathecally Protocol DNX-FLA (for patients in the high risk group with MRD non-response) - Fludarabine i.v. - High-dose Cytarabine i.v. - Daunoxome i.v. - Methotrexate intrathecally Protocol Interim Maintenance (HR) - 6-Mercaptopurine p.o. - Methotrexate p.o. - Cranial Radiotherapy during the 1st interim maintenance phase only for selected subgroups of patients Protocol - Maintenance - 6-Mercaptopurine p.o. - Methotrexate p.o. - Methotrexate intrathecally - Cranial radiotherapy Protocol - Maintenance with PEG-L-ASP Treatment is the same as the maintenance protocol but has the addition of PEG-L-Asparaginase i.v. for patients randomised into the experimental arm Prednisone 60 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 1 to 28, Protocol IA, Protocol IA’, Protocol IA-CPM Cytarabine Protocol IB;75 mg/m2/dose i.v. or s.c. days 38-41, 45-48, 52-55 and 59-62. Protocol IIB; 75 mg/m2/dose i.v. or s.c. days 38-41, 45-48. HR-3 2mg/m2/dose p.i. (3 h) every 12 hours on days 1 and 2 (4 doses). Protocol IIIB; 75 mg/m2/dose i.v. or s.c. 2 blocks of 4 days each; days17-20, 24-27. DNX-FLA Block; 2 mg/m2/dose p.i. (3 h) every 24 hours on days 1 to 5 (5 doses). Dexamethasone Protocol IA; 10 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 8 to 28. Protocol IIA; 10 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 1 to 21. HR-2’; 20 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 1 to 5. HR-3’; 20 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 1 to 5. Protocol IIIA; 10 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 1 to 14 (14 days). Doxorubicin Protocol IIA; 30 mg/m2/dose p.i. (1 h) on days 8, 15, 22 and 29. Protocol IIIA; 30 mg/m2/dose p.i. (1 h) on days 1 and 8. Methotrexate Protocol IA, Protocol IA’, Protocol IA-CPM; Methotrexate intrathecally on day 1, 12, 33. In case of initial CNS status CNS 3 or CNS 2 additional intrathecal methotrexate is given on days 19 and 26. Protocol IB; Methotrexate intrathecally on days 45 and 59. Protocol M; Methotrexate intrathecally on days 8, 22, 36 and 50. Protocol IIA; Methotrexate intrathecally on days 1 and 18 only in patients with initial CNS disease (CNS 3). Protocol IIB; Methotrexate intrathecally on days 38 and 45. Protocol IIIA; Methotrexate intrathecally on day 1 of each Protocol IIIA only in patients with initial CNS disease (CNS 3). Protocol IIIB; Methotrexate intrathecally on days 17 and 24. DNX-FLA; Methotrexate intrathecally on day 1. Age-adjusted dose of intrathecal methotrexate: 1 to < 2 years: 8 mg, 2 to < 3 years: 10 mg, 3 years: 12 mg HR-1’; Methotrexate intrathecally during HD-MTX infusion on day 1. High-Dose Methotrexate 5g/m2/dose p.i. (24 h) on day 1. HR-2’; High-Dose Methotrexate 5g/m2/dose p.i. (24 h) on day 1. Methotrexate intrathecally during HD-MTX infusion on day 1. Only in case of initial CNS involvement another dose is given on day 5. HR-3’; Methotrexate intrathecally on day 1. Maintenance; Methotrexate 20 mg/m2/dose p.o. once a week. Methotrexate intrathecally, beginning at week 6 every 6 weeks up to a total of 6 doses is given to the following subgroups (all CNS status CNS 1 or CNS 2): - T-ALL with < 2 years of age at start of maintenance, - T-ALL, non-HR and initial WBC < 100 000/µl - pB-ALL with PPR and/or FCM-MRD day 15 10 % and/or PCR-MRD-MR SER as only HR criteria PEG-asparaginase - Protocol IA, Protocol IA’, Protocol IA-CPM; 2 500 IU/m2/dose p.i. (2 h) on days 12 and 26 (maximal single dose 3 750 IU). Protocol IB-ASP+; 2 500 IU/m2/dose p.i. (2 h) on days 40 , 47, 54, and 61 (maximal single dose 3 750 IU). Protocol IIA; 2 500 IU/m2/dose p.i. (2 h) on day 8 (maximal single dose 3 750 IU). Protocol IIA-ASP+; 2 500 IU/m2/dose p.i. (2 h) (maximal single dose 3 750 IU/) at days 8 and 22. Protocol IIB-ASP+; 2 500 IU/m2/dose p.i. (2 h) on day 36 and 50 (maximal single dose 3 750 IU). HR-1’; 2 500 IU/m2/dose p.i. (2 h) on day 6 (1 dose) (maximal single dose 3 750 IU). HR-2’; 2 500 IU/m2/dose p.i. (2 h) on day 6 (1 dose) (maximal single dose 3 750 IU). HR-3’; 2 500 IU/dose p.i. (2 h) on day 6 (1 dose).(maximal single dose 3 750 IU) IIIA; 2 500 IU/m2/dose p.i. (2 h) on day 1 (1 dose) (maximal single dose 3 750 IU). Maintenance; Only for patients randomized into the experimental arm in randomization R2: 2 500 U/m2/dose p.i. (2 h) every second week, 10 doses in total, starting in Protocol II-ASP+. Vincristine Protocol IA, Protocol IA’, Protocol IA-CPM; Vincristine 1.5 mg/m2/dose i.v. (maximal single dose 2 mg) on days 8, 15, 22, 29. Protocol IIA; Vincristine 1.5 mg/m2/dose i.v. (maximal single dose 2 mg) on days 8, 15, 22, 29. HR-1’; Vincristine 1.5 mg/m2/dose i.v. (maximal single dose 2 mg) on days 1 and 6. Protocol IIIA; Vincristine 1.5 mg/m2/dose i.v. (maximal single dose 2 mg) on days 1 and 8. Daunorubicin Protocol IA, Protocol IA’, Protocol IA-CPM; Daunorubicin 30 mg/m2/dose p.i. (1 h) on days 8, 15, 22 and 29. Only two doses on days 8 and 15 are given to patients randomized into the experimental arm in randomization R1. Protocol IA-Dexa (IAD); Daunorubicin 30 mg/m2/dose p.i. (1 h) on days 8, 15, 22 and 29. Cyclophosphamide Protocol IA-CPM; Cyclophosphamide 1000 mg/m2/dose p.i. (1 h) on day 10. Protocol IB; Cyclophosphamide 1 000 mg/m2/dose p.i. (1 h) on days 36 and 64. Protocol IIB; Cyclophosphamide 1 000 mg/m2/dose p.i. (1 h) on day 36. HR-1’; Cyclophosphamide 200 mg/m2/dose p.i. (1 h) every 12 hours on days 2 to 4. Protocol IIIB; Cyclophosphamide 500 mg/m2/dose p.i. (1 h) on day 15. Mercaptopurine Protocol IB; 6-Mercaptopurine 60 mg/m2/day p.o., days 36 to 63. Protocol M; 6-Mercaptopurine 25 mg/m2/day p.o., days 1 to 56. Thioguanine Protocol IIIB; Thioguanine 60 mg/m2/day p.o., days 15 to 28. Ifosfamide HR2; Ifosfamide 800 mg/m2/dose p.i. (1 h) every 12 hours on days 2 to 4 (5 doses). Etoposide HR3; Etoposide 100 mg/m2/dose p.i. (1 h) every 12 hours on days 3 to 5 (5 doses). Fludarabine DNX-FLA (Applicable to HR patients with “MRD non-response”);Fludarabine 30 mg/m2/dose p.i. (30 min) every 24 hours on days 1 to 5 (5 doses). Daunoxome Daunoxome 60 mg/m2/dose p.i. (1 h) on days 1, 3 and 5. Vindesine HR-2’; Vindesine 3 mg/m2/dose i.v. (maximal single dose 5 mg) on days 1 and 6. p.o. = medication administered orally; i.v. medication administered intravenously; s.c = medication administered by subcutaneous injection