BFM- 95 (German Protocol)

Regimen

For Medium and High Risk Patients
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
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).
Do not administer methotrexate in the absence of normal creatinine and creatinine clearance.
6-Mercaptopurine is to be temporarily ceased if cytarabine if postponed and further doses to be given at the end of the cycle.

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
Vincristine is capped at 2mg

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
Cytarabine blocks should commence when WBC > 0.5 x 109/L and platelets > 30 x 109/L
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
Cranial irradiation usually commences day 38. Doses as follows:

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

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