Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

These are the following secondary objectives:

- To determine if CNS irradiation can be safely omitted in the context of the systemic
therapy used in the protocol.

- To identify whether prolonged (24 hour) intravenous infusions of HDMTX produce greater
methotrexate polyglutamate (MTXPG) accumulation than short (4 hour) infusions 42 hours
after 1 gm/m2 of HDMTX, stratified for lineage (T- vs B-lineage) and ploidy
(hyperdiploid vs non-hyperdiploid B-lineage).

- To determine whether prolonged (24 hour) intravenous infusions of HDMTX produce greater
antileukemic effects than short (4 hour) infusions, based on the inhibition of de novo
purine synthesis in bone marrow blasts and the decrease in circulating blasts during the
4 day "window" prior to initiation of conventional remission induction therapy.

- MRD

- Other exploratory objectives

Details of Treatment Plan

Treatment will consist of three main phases, Remission Induction, Consolidation, and
Continuation. Treatment with an Upfront HDMTX Window for research purposes will be optional.

All patients will receive IT therapy on day 1, dose is age dependent.

Upfront High-Dose Methotrexate Window

HDMTX (1 g/m2) as a 4 hour infusion versus as a 24 hour infusion. Leucovorin rescue will be
given.

Remission Induction

Prednisone 40 mg/m2/day PO Days 5 - 32 Vincristine 1.5 mg/m2/week IV Days 5, 12, 19, 26
Daunorubicin 25 mg/m2/week IV Days 5, 12 L-asparaginase 10,000 Unit/m2/dose IM Days 6, 8, 10,
12, 14, 16 (19, 21, 23) Cyclophosphamide 1000 mg/m2/dose IV Day 26 Cytarabine 75 mg/m2/dose
IV Days 27-30, 34-37 6-Mercaptopurine 60 mg/m2/dose PO Days 26-39 Imatinib 40 mg/m2 bid for
Ph positive patients starting Day 22 of induction. Intrathecal therapy will be administered
on day 1 and 19, dose age dependent. Patients with high risk of CNS relapse will receive
additional IT treatments on days 8 and 26.

Consolidation Treatment

High dose methotrexate targeted dose depending on risk status, days 1, 15, 29, and 43 and
mercaptopurine 50 mg/m2/day, days 1-56.

Reintensification treatment for patients with high risk disease:

Patients with high risk disease will be offered the option of hematopoietic stem cell
transplant (HSCT) and may receive an additional 1-2 cycles of reintensification treatment
prior to maximize the anti-leukemic kill before transplant.

Dexamethasone 20 mg/m2 PO days 1-3 Cytarabine 2 g/m2 IV x 4 doses, days 3-5 Etoposide 100
mg/m2 IV x 5 doses, days 3-5 L-asparaginase 25,000 Units/m2 IM day 6 Intrathecal treatment
Day 5

Continuation Treatment (lasts 120 weeks for girls and 146 weeks for boys)

Treatment will depend on risk classification: low versus standard versus high risk

Treatment weeks 1 to 20:

Week Standard/High Risk Low Risk

1. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR

2. 6MP + ASP 6MP + MTX

3. 6MP + ASP 6MP + MTX

4. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR

5. 6MP + ASP 6MP + MTX

6. 6MP + ASP 6MP + MTX

7. Reinduction I§ Reinduction I

8. Reinduction I Reinduction I

9. Reinduction I Reinduction I

10. 6MP + ASP 6MP + MTX

11. DOX + VCR + 6MP + ASP 6MP + MTX

12. 6MP + ASP 6MP + MTX

13. 6MP + ASP 6MP + MTX

14. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR

15. 6MP + ASP 6MP + MTX

16. 6MP + ASP 6MP + MTX

17. Reinduction II Reinduction II

18. Reinduction II Reinduction II

19. Reinduction II Reinduction II

20. No chemotherapy 6MP + MTX

Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5 days,
Days 1-5 Doxorubicin 30 mg/m2 IV, Day 1 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1
Mercaptopurine 50 mg/m2 PO daily x 7 days (std/high risk), Days 1-7 75 mg/m2 PO daily x
7 days (low risk), Days 1-7 L-asparaginase 25,000 Unit/m2 IM, Day 1 Methotrexate 40
mg/m2 IV or IM, Day 1

Reinduction I and II

This phase of treatment will be started at weeks 7 and 17 after bone marrow examination
confirms complete remission. Reinduction treatment will be given twice: weeks 7 to 9 and
weeks 17 to 19 for all patients.

Reinduction I for Standard/High Risk ALL:

Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15, 21, Vincristine 1.5 mg/m2/week IV
(max 2 mg) Days 1, 8, 15, Doxorubicin 30 mg/m2 Days 1, 8, L-asparaginase 25,000 Unit/m2
IM Days 1, 8, 15, Intrathecal chemotherapy, dose age dependent Day 1.

Reinduction II for Standard/High Risk ALL:

Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21, Vincristine 1.5 mg/m2/week IV
(max 2 mg) Days 1, 8, 15, L-asparaginase 25,000 Unit/m2, weekly IM Days 1, 8, 17,
Intrathecal chemotherapy, dose age dependent Day 1 High-dose cytarabine 2 gm/m2 IV q 12
Days 15, 16

Reinduction I and II for Low Risk ALL Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8,
15-21 Vincristine 1.5 mg/m2/week IV (max 2 mg), Days 1, 8, 15 L-asparaginase 10,000
Unit/m2/thrice weekly IM Days 2, 4, 6, 8, 10, 12, 15, 17, 19 Doxorubicin 30 mg/m2/week
IV Day 1 Intrathecal chemotherapy, dose age dependent on Day 1

Treatment Weeks 21 to end of therapy Week Standard/High Risk Low Risk

21. 6MP + MTX 6MP + MTX

22. 6MP + MTX 6MP + MTX

23. Cyclo + Ara-C 6MP + MTX

24. DEX + VCR 6MP + DEX + VCR

25. 6MP + MTX 6MP + MTX

26. 6MP + MTX 6MP + MTX

27. Cyclo + Ara-C 6MP + MTX

28. DEX + VCR 6MP + DEX + VCR

Mercaptopurine 75 mg/m2 PO, daily x 7 days, Days 1-7 Methotrexate 40 mg/m2 IV or IM, Day 1
Cyclophosphamide 300 mg/m2 IV, Day 1 Cytarabine 300 mg/m2 IV, Day 1 Dexamethasone 12 mg/m2
(std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5, Day 1-5 Vincristine 2.0 mg/m2 IV
push (max. 2 mg), Day 1

The same treatment (weeks 21-28) will be repeated for a total of 6 times (until week 68).
After week 68, all patients will receive daily 6MP and weekly MTX with pulses of
dexamethasone and vincristine every 4 weeks until week 100, after which only 6MP and
methotrexate will be given. Intrathecal treatment will be given every 8 weeks only to
patients at high risk of CNS relapse after week 48 and will be discontinued after week 96.
Continuation therapy will be discontinued after 120 weeks in girls and after 146 weeks in
boys

Patients who meet the criteria of high-risk ALL are candidates for allogeneic hematopoietic
stem cell transplantation. However, if the option is declined by the patients or guardians,
or the procedure is deemed unsuitable by the attending physician and the principal
investigator, the patient will remain on study and continue to receive chemotherapy

Inclusion Criteria:

- Diagnosis of non-B-cell ALL by immunophenotyping, as determined by the reactivity
pattern to a panel of monoclonal antibodies with flow cytometry as well as morphology
and cytochemical staining.

- Age range: 1 to 18 years (inclusive).

Exclusion Criteria:

• Previously treated with chemotherapy for one week or longer.