== Regimen ==

'''For Medium and High Risk Patients'''<br>

Standard risk patients are, by definition, paediatric patients and are not included in the protocol as it
appears here (See Risk Groups Below)

=== Induction therapy Phase 1 - part 1 ===

Methotrexate 12 mg (12 mg) IT INTRATHECAL Day 1 , 12, (18, 27 CNS DISEASE AT DIAGNOSIS ONLY),
33

Prednisolone 60 mg/m² orally daily days 1 to day 29

Vincristine 1.5 mg/m² IVI Days 8,15,22,29

Daunorubicin 30 mg/m² IVI Days 8,15,22,29

L-asparaginase 5000 units/m² IVI over 60 minutes (ensure test dose has been given) given) Days
12,15,18,21,24,27,30,33

=== Induction therapy, Phase 1 - part 2 ===

6-Mercaptopurine 60 mg/m² orally daily from day 36 to day 63 (28 days total)

Cyclophosphamide 1000 mg/m² by IV infusion Day 36, 64

Mesna 400 mg/m² by IV infusion hours 0, 4 and 8 post cyclophosphamide

Cytarabine 75 mg/m² by IV infusion daily days 38 to 41, 45 to 48, 52 to 55, 59 to 62

Methotrexate 12 mg IT INTRATHECAL Days 45, 59

=== MCA Consolidation ===

Commence this cycle 2 weeks post the completion of Part 1, phase 2<br>

Requirements for commencing consolidation include good general condition, no severe infections,
normal creatinine clearance, ALT and AST <5x upper limit of normal, bilirubin <3x upper limit of normal
and adequate neutrophil/platelet recovery (WBC >1.5, neutrophils > 0.5 and platelets > 50).<br>

Do not administer methotrexate in the absence of normal creatinine and creatinine clearance. <br>

6-Mercaptopurine is to be temporarily ceased if cytarabine if postponed and further doses to be given at

the end of the cycle.<br>
6-Mercaptopurine 25 mg/m² orally days 1 to 56

Methotrexate 500 mg/m² IVI over 30 minutes days 8, 22, 36, 50

Methotrexate 4500 mg/m² by IV infusion over 23.5 hours days 8, 22, 36, 50

Methotrexate 12 mg IT INTRATHECAL days 8, 22, 36, 50

Leucovorin (Calcium folinate) 15 mg/m² IVI at hour 42 post commencement of MTX infusion;
continue Q6H until MTX level <0.25micromol/L days 9, 23, 37, 51

Cytarabine 200 mg/m² as a continuous IV infusion over 24 hours (commence as soon as MTX has
completed) Days 9, 23, 37, 51

=== Protocol 2, part 1 ===

Begin this cycle 2 weeks after completing BFM MCA consolidation and WBC >2.5 x 109/L, ANC >1.0 x
109/L and platelets >100 x 109/L <br>

Vincristine is capped at 2mg<br>

Dexamethasone 10 mg/m² orally days 1 to 21

Methotrexate 12 mg (12 mg) IT ONLY FOR PATIENTS WITH CNS DOSEASE AT DIAGNOSIS days 1,
18

Vincristine 1.5 mg/m² IVI Days 8,15,22,29

Doxorubicin 30 mg/m² IVI Days 8,15,22,29

L-asparaginase 10000 units/m² IVI over 1 to 2 hours Days 8,11,15,18

=== Protocol 2, part 2 ===

Commence when WBC >2.0 x 109/L neutrophils >0.5 x 109/L and platelets >50 x 109/L and creatinine is
normal<br>

Cytarabine blocks should commence when WBC > 0.5 x 109/L and platelets > 30 x 109/L<br>

6-Thioguanine (6-TG) is to be temporarily ceased if cytarabine if postponed and further doses to be

given at the end of the cycle to total dose of 840mg/m2<br>

Cranial irradiation usually commences day 38. Doses as follows:<br>

o 18Gy if CNS involvement or

o 12Gy as prophylactic therapy for T cell ALL, high risk patients and planned allogeneic stem cell
transplant
Thioguanine 60 mg/m² orally daily from day 36 to 49 (14 days total)

Cyclophosphamide 1000 mg/m² by IV infusion over 1 hour Days 36

Mesna 400 mg/m² by IV infusion hour 0, 4 and 8 of cyclophosphamide infusion

Methotrexate 12 mg (12 mg) IT INTRATHECAL Day 38, 45

Cytarabine 75 mg/m² by IV infusion days 38 to 41, 45 to 48 (over 30 to 60 minutes each day)

=== Standard maintenance therapy ===

PCP prophylaxis must be given throughout this consolidation treatment<br>

Usually commences 2 weeks after conclusion of Protocol II depending on WBC and patient’s condition
<br>

6-Mercaptopurine 50 mg/m² orally day 1 to day 70

Methotrexate 20 mg/m² orally weekly for a total of ten doses

No of cycles: 6 cycles with a 1 week break between cycles - i.e. 104 weeks in total

== Risk Groups ==

Standard risk group

* Leukaemic cells < 1000micromol/L in the peripheral blood on day 8 after 7 day prednisone pre-phase

* WBC <20 000 micromol/L and age >1 <6 years

* A complete remission on day 33 (M1-marrow)

* No translocation t(9;22) or BCR/ABL recombination

* No translocation t(4;11) or MLL/AF4 recombination

* No T-immunology

* All six criteria must be met

Medium risk group

* Leukaemic cells < 1000micromol/L in the peripheral blood on day 8 after 7 day prednisone pre-phase

* Complete remission on day 33 (M1-marrow)

* No translocation t(9;22) or BCR/ABL recombination

* No translocation t(4;11) or MLL/AF4 recombination

* All 4 criteria must be met as well as at least one of the following

* Leukocytes > 20000 micromol/L

* Age < 1 year

* Age > 6 years

High risk group

* 1000micromol/L leukaemic cells in the peripheral blood on day 8

* No complete remission on day 33

* Translocation t(9;22) or BCR/ABL recombination

* Translocation t(4;11) or MLL/AF4 recombination

* Each criterion alone qualifies as high risk regardless of age and WBC

== Dose Modifications ==

=== Hepatic dysfunction ===

Daunorubicin & Doxorubicin

Bilirubin 20-50 micromols/L dose at 50%

Bilirubin > 50 micromol/L dose at 25% of total dose.

L-asparaginase - use caution

Vincristine Bilirubin > 50micromol/L dose at 50%

=== Renal impairment ===

Cyclophosphamide

GFR (mL/min) Dose (% of total dose to be given)

> 50 100

<50 omit

Do not administer methotrexate if CrCl <50ml/min

=== Peripheral neuropathy ===

Omit vincristine if grade 2 or above neuropathy