ALL06 A Phase II trial of an intensive pediatric protocol incorporating post-induction stratification based on minimal residual disease levels for the treatment of adolescents aged 15 years and above, and young adults aged up to 40 years, with newly diagnosed acute lymphoblastic leukaemia (ALL)

Intervention

Intervention code Treatment: Drugs

All patients will commence treatment with Protocol I which is an intensive chemotherapy induction protocol. Various prognostic factors such as cytogenetic abnormalities, initial response to prednisolone, achievement of remission, and MRD levels after induction and consolidation, will determine whether patients continue treatment outlined in Protocol M, or are to be treated on the High Risk protocol, or undergo allogeneic Haemopoietic Cell Transplantation (HCT). Patients removed for allogeneic HC .... All patients will commence treatment with Protocol I which is an intensive chemotherapy induction protocol. Various prognostic factors such as cytogenetic abnormalities, initial response to prednisolone, achievement of remission, and MRD levels after induction and consolidation, will determine whether patients continue treatment outlined in Protocol M, or are to be treated on the High Risk protocol, or undergo allogeneic Haemopoietic Cell Transplantation (HCT). Patients removed for allogeneic HCT will be withdrawn from the study, but will continue to be followed, with relapse, disease-free and overall survival data being recorded. PROTOCOL I, Phase 1, Days 1-35: i) Intrathecal Methotrexate (IT MTX) on days 1, 15, 33. ii) Prednisolone (PRED) 60mg/m^2/day orally in 2 divided doses per day on Days 1-7. On Days 8-28 PRED 60mg/m^2/day in 3 divided doses. On Days 29-38: PRED taper in 3 stages every 3 days. Reduce dosage by half at each stage. iii) Vincristine (VCR) 1.5mh/m^2/day IV bolus (maximum single dose 2mg) Days 8, 16, 22 and 29. iv) Daunorubicin (DNR) 30mg/m^2 IV over 1 hr Days 8, 16, 22, 29. v) Pegylated Asparaginase (LINK) 1000U/m^2 IM or IV on Days 8 and 22. PROTOCOL I, Phase 2, Days 36-64: i) Cytarabine (ARA-C) 75mg/m^2/day IV or SC in 4 x 4 day blocks on Days 36, 37, 38, 39; Days 43, 44, 45, 46; Days 50, 51, 52, 53; Days 57, 58, 59, 60. ii) Cyclophosphamide (CPA) 1000mg/m^2/day/IV over 1 hour, Days 36 and 64. iii) 6-Mercaptopurine (MP) 60mg/m^2/day orally on Days 36-63, 28 days total. iv) Intrathecal Methotrexate (IT MTX) on Days 43 and 57 with the second and fourth cytarabine blocks. PROTOCOL M for Standard and Medium Risk only. Scheduled to commence on Day 79 after the start of Protocol 1, provided there is adequate count recovery. i) 6-Mercaptopurine (MP) 25 mg/m^2/day orally over 8 weeks, Days 1-56. ii) High Dose Methotrexate (HD-MTX) 5g/m^2 as a continuous infusion over 24 hours, on Days 8, 22, 36, 50. iii) Intrathecal Methotrexate (IT MTX) administered at 2 hours after the start of the MTX-infusion on Days 8, 22, 36, 50. HIGH RISK PROTOCOL, Block HR-1, normally begins directly after completion of Protocol I. i) Dexamethasone (DEXA) 20mg/m^2/d orally or by IV in 2 divided doses on Days 1-5. ii) Vincristine (VCR) 1.5mg/m^2/daily (maximum single dose 2mg) IV on Days 1 and 6. iii) High Dose Methotrexate (HD-MTX) 5g/m^2, infused IV over 24 hours on Day 1. iv) Cyclophosphamide (CPA) 200mg/m^2/twice daily IV over 1 hour, Days 2-4. v) Cytarabine (HD-ARA-C) 2g/m^2/twice daily, IV over 3 hours on Day 5. vi) Pegylated Asparaginase (ASP) 1000U/m^2 IM or IV on Day 6. vii) Intrathecal Methotrexate (MTX) 12 mg/Cytarabine (ARA-C) 30mg/Hydrocortisone 50mg on Day 1. HIGH RISK PROTOCOL, Block HR-2: The doses and scheduling of i) DEXA ii) HD-MTX/LCV-Rescue iii) ASP iv) MTX/ARA-C/HYDROCORTISONE IT are the same as in block HR-1. Additional therapy in HR2: v) Vindesine (VDS) 3mg/m^2/daily (maximum single dose 5mg) IV on Days 1 and 6. vi) Ifosfamide (IFO) 800mg/m^2/twice daily IV over 1 hour on Days 2-4. vii) Daunorubicin (DNR) 30mg/m^2/daily IV over 1 hour on Day 5. HIGH RISK PROTOCOL, Block HR-3: i) DEXA ii) ASP as in block HR-1. Additional therapy in HR-3: iii) Cytarabine (HD-ARA-C) 2g/m^2/twice daily IV over 3 hours, Days 1-2. iv) Etoposide (VP-16) 100mg/m^2/twice daily IV over 1 hour every 12 hours, Days 3-5. v) Intrathecal Methotrexate, Cytarabine, Hydrocortisone (MTX/ARA-C/HYDROCORTISONE IT) on Day 5. PROTOCOL II, Phase 1, Days 1-35: i) Dexamethasone (DEXA) 10mg/m^2/day orally in 2-3 divided doses, Days 1-21. From Day 22 on, reduce the dose every 3 days by half and stop on Day 29. ii) Vincristine (VCR) 1.5mg/m^2/day IV bolus (maximum single dose 2mg) on Days 8, 15, 22, 29. iii) Doxorubicin (DOX): 30mg/m^2/day IV over 1 hour on Days 8, 15, 22, 29. iv) Pegylated L’Asparaginase 1000U/m^2 IM or IV on Day1. v) Intrathecal Methotrexate (IT MTX) on Days 1, 18 ONLY IF CNS disease at diagnosis. PROTOCOL II, Phase 2, Days 36-50: i) Cytarabine (ARA-C) 75mg/m^2/day IV or SC in 2 x 4 day blocks. Days 36, 37, 38, 39 and Days 43, 44, 45, 46. ii) Cyclophosphamide (CPA) 1000mg/m^2 IV over 1 hour, Day 36. iii) 6-Thioguanine (6-TG) 60mg/m^2/day orally, Day 36-49, a total of 14 days. iv) Intrathecal Methotrexate (IT MTX) at the same time as the first dose of Cytarabine in Block 1 (Day 36) and Block 2 (Day 43). MAINTENANCE THERAPY begins 2 weeks after the end of Protocol II. Total therapy, calculated from the start of Protocol I, is 24 months for all patients. i) 6-Mercapoturine (MP) 50mg/m^2/day orally. ii) Methotrexate (MTX) 20mg/m^2/week, orally once a week at night.
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Comparison

Control group Historical

Paediatric patients diagnosed with the same condition who were treated as part of a different ALLG study (ANZCHOG study 8, ANZCTR registration number ACTRN12607000302459)

Outcomes

Outcome: The primary objective of this study is to determine whether a modified form of the BFM-2000 protocol can be administered to patients with newly diagnosed and untreated ALL aged between 15 and 40 years in a comparable timeframe to patients under 15 years of age. All patients will commence treatment with Protocol 1, which is an intensive chemotherapy induction protocol. Various prognostic factors such as cytogenetic abnormalities, initial response to prednisolone, achiev .... Outcome: The primary objective of this study is to determine whether a modified form of the BFM-2000 protocol can be administered to patients with newly diagnosed and untreated ALL aged between 15 and 40 years in a comparable timeframe to patients under 15 years of age. All patients will commence treatment with Protocol 1, which is an intensive chemotherapy induction protocol. Various prognostic factors such as cytogenetic abnormalities, initial response to prednisolone, achievement of remission, and MRD levels after induction and consolidation, will determine whether patients continue treatment outlined in Protocol M, or are to be treated on the High Risk protocol, or undergo allogeneic HCT. Patients removed for allogeneic HCT will be withdrawn from the study, but will continue to be followed, with relapse, disease-free and overall survival data being recorded.
Timepoint: The primary end-point will be the proportion of patients starting protocol M by day 94 after commencing therapy, or in the case of patients stratified to receive high risk treatment, the start of HR block 1.
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