Trial Information

Total Therapy Study XVI for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

Details of the Treatment Plan:

Treatment will consist of three main phases: Remission Induction, Consolidation, and
Continuation.

1. Remission Induction

- Intrathecal Treatment during Induction

Frequency and total number of triple intrathecal treatments for Remission Induction is
based on the patient's risk of CNS relapse.All patients will receive triple intrathecal
treatment on days 1 and 15. Patients with high risk features may receive additional
triple intrathecal treatment on days 4, 8, 11, and 22.[t(1;19)/E2A-PBX1.

Induction treatment will begin with prednisone, vincristine, daunorubicin,
PEG-asparaginase and triple intrathecal treatment, followed by cyclophosphamide plus
cytarabine plus thioguanine.

Remission Induction Chemotherapy (6-7 weeks) Prednisone 40 mg/m2/day PO (divided
t.i.d.) Days 1 - 28 Dexamethasone will be substituted for prednisone in patients with
early T-cell precursor (ETP) immunophenotype.

Mercaptopurine will be substituted for thiopurine in TPMT HET/deficient patients
Dexamethasone (for ETP immunophenotype only) 10 mg/m2/day PO (divided t.i.d.)Days 1-21;
4 mg/m2/day PO (divided t.i.d) Days 22-24; 2 mg/m2/day PO(divided t.i.d) Days 25-28
Vincristine 1.5 mg/m2 IV (max 2 mg) Days 1, 8, 15, 22 Daunorubicin 25 mg/m2 IV Days 1
and 8 PEG-asparaginase 3,000 Units/m2 IV Day 3

- Participants with Day 15 MRD greater than or equal to 1%: PEG-asparaginase 3,000
Units/m2 IV Day 15

- Participants with Day 15 MRD less than 5% (excluding MLL positive infants):
Cyclophosphamide 1000 mg/m2 IV Day 22 Cytarabine 75 mg/m2/dose IV Days 23-26, 30-33
Thioguanine [Mercaptopurine (TPMT HET/deficient patients only)]60 mg/m2/dose PO Days
22-35 Dasatinib (Ph+ participants only) 40 mg/m2 b.i.d starting Day 22 of induction to
continue until end of treatment

Day 15 MRD > or equal to 5% (excluding MLL+ infants) Cyclophosphamide† 300 mg/m2 IV/
q12 hrs on Days 22-23 Cytarabine 75 mg/m2/dose IV Days 23-26, 30-33 Thioguanine
[Mercaptopurine (TPMT HET/deficient patients only) 60 mg/m2/dose PO Days 22-35
Dasatinib‡ (Ph+ participants only) 40 mg/m2 b.i.d Daily Starting Day 22 of induction to
continue until end of treatment

- Infants with MLL positive rearrangement: Clofarabine 40 mg/m2/dose IV Days 22-26
Etoposide 100 mg/m2/dose IV Days 22-26 Cyclophosphamide 300 mg/m2/dose IV Days 22-26

2. Consolidation Treatment (8 weeks) High Dose Methotrexate (HDMTX) 2.5 gm/ (low risk), or
targeted 65 μM (std/high-risk) days 1, 15, 29 and 43. Mercaptopurine 50 mg/m2/day Days
1 to 56. All patients will receive triple intrathecal therapy every other week for
four doses on Days 1, 15, 29, and 43. Dose is age dependent.

- Reintensification

Patients with high-risk leukemia may receive reintensification therapy and then will be
offered the option of transplant. This treatment will attempt to maximize leukemic cell
kill before allogeneic hematopoietic stem cell transplantation.

Dexamethasone 20 mg/m2/day PO or IV Days 1-6.Cytarabine 2 grams/m2, 3-hour IV infusion
every 12 hours Days 1-2. Etoposide 100 mg/m2, 1-hour IV infusion every 12 hours Days
3-5. Intrathecal methotrexate+hydrocortisone+cytarabine (ITMHA) Day 5; PEG-asparaginase
3,000 units/m2 IV Day 6

Patients with suboptimal response to reintensification may receive one to two cycles of
clofarabine/cyclophosphamide/etoposide/dexamethasone:

Clofarabine 40 mg/m2/day, 2-hour IV infusion Days 1-5 Etoposide 100 mg/m2/day, 2-hour
IV infusion Days 1-5 Cyclophosphamide 300 mg/m2/day, 30-60 minute IV infusion Days 1-5
Dexamethasone 8 mg/m2/day (divided t.i.d) Days 1-5

3. Continuation Treatment (120 weeks)

Abbreviations used below: DEX=dexamethasone; DOX=doxorubicin; VCR=vincristine;
MP=mercaptopurine; PEG-ASP=polyethylene glycol-conjugated asparaginase; MTX=methotrexate;
6MP=mercaptopurine

Weeks 1 through 20 - treatment depends on risk assignment standard-high versus low-risk

Week Standard-/High-Risk Low-Risk

1. DEX+DOX+VCR+MP + PEG-ASP/MP + DEX + VCR

2. MP MP + MTX

3. MP + PEG-ASP/MP + MTX

4. DEX + DOX + VCR + MP/MP + DEX + VCR

5. MP + PEG-ASP MP + MTX

6. MP MP + MTX

7. Reinduction I

8. Reinduction I

9. Reinduction I

10. MP/MP + MTX

11. DOX + VCR +MP + PEG-ASP/MP + MTX

12. MP/MP + MTX

13. MP + PEG-ASP/MP + MTX

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

15. MP + PEG-ASP/MP + MTX

16. MP/MP + MTX

17. Reinduction II

18. Reinduction II

19. Reinduction II

20. No chemotherapy/MP + MTX

Drug Dosages, Schedules and Routes for Continuation Therapy Weeks 1 to 6 and 10 to 16:

Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (divided t.i.d.)
for 5 days, Days 1-5. Doxorubicin 30 mg/m2 IV, Day 1. Vincristine 2 mg/m2 IV push
(max. 2 mg), Day 1 (0.05 mg/kg for patients < 1 year of age or < 10kg in weight). MP
(mercaptopurine) 50 mg/m2 PO daily at bedtime for 7 days (std/high risk), Days 1-7, 75
mg/m2 PO daily at bedtime for 7 days (low risk), Days 1-7. PEG-ASP (PEG-asparaginase)
2,500 vs. 3,500 units/m2 IV randomization, Day 1. Methotrexate 40 mg/m2 IV Day 1.

Dexamethasone, vincristine, and asparaginase will be given regardless of blood counts,
provided that the patient is clinically well. Doxorubicin, mercaptopurine and
methotrexate will be held if white blood count (WBC) <1000/mm3 or absolute neutrophil
count (ANC) <300/mm3. Doxorubicin, mercaptopurine and methotrexate will be reduced
for WBC < 1500/mm3, or if WBC and ANC not increase by at least 2 folds a week after the
start date of dexamethasone pulse.

Reinduction Treatment - This phase of treatment is part of continuation and will be
started at weeks 7 and 17 after bone marrow examination confirms complete remission.
Doxorubicin and HD-cytarabine will be held if ANC < or equal to 300/mm3 or WBC <
1000/mm3.It is preferable to start HD-cytarabine when WBC > or equal to 1800/mm3 and
ANC > 300/mm3 Reinduction treatment will be given twice: weeks 7 to 9 and weeks 17 to
19 for all patients. Intrathecal treatment will be followed by leucovorin rescue (5
mg/m2/dose PO, max 5 mg) at 24 and 30 hours only in patients with prior CNS toxicities
or in patients with WBC < 1500/mm3, or ANC < 500/mm3.

- Reinduction I for Standard/High Risk ALL excluding MLL infants: Dexamethasone 8
mg/m2/day PO (divided t.i.d.) Days 1-8, 15-21. Vincristine 1.5 mg/m2/week IV.
Doxorubicin 30 mg/m2 IV Days 1, 8. PEG-asparaginase 3,500 or 3,500 units/m2 IV Days 1,
15. Intrathecal chemotherapy, Methotrexate + hydrocortisone + Ara-C dose age dependent,
Day 1.

- Reinduction II for Standard/High Risk ALL including MLL infants: Dexamethasone 8
mg/m2/day PO (t.i.d.) Days 1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15.
PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15. High-dose cytarabine 2 gm/m2 IV
q 12 hr Days 15, 16. Intrathecal chemotherapy, dose age dependent, Day 1.

- Reinduction I for Low-Risk ALL: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days
1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15. PEG-asparaginase 2,500 or
3,500 units/m2 IV Days 1, 15. D Doxorubicin 30 mg/m2/IV Day 1. Intrathecal
chemotherapy, dose age dependent, Day 1.

- Reinduction II for Low-Risk ALL: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days
1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15. PEG-asparaginase 2,500 or
3,500 units/m2 IV Days 1, 15. Intrathecal chemotherapy, dose age dependent, Day 1.

- Reinduction I for MLL Infants: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days 1-8
and 15-21. Clofarabine 40 mg/m2/day, -hour IV Days 1-5. Etoposide 100 mg/m2/day, 2-hour
IV Days 1-5. cyclophosphamide 300 mg/m2/day, 1-hour IV Days 1-5. PEG-asparaginase 2,500
or 3,500 units/m2 IV Days 1, 15. Intrathecal chemotherapy, dose age dependent, on Day
1.

- Intrathecal Chemotherapy:

- Triple intrathecal treatment will be given to low-risk cases with CNS-1 status (no
identifiable blasts in CSF) on weeks 7, 12, 17, 25, 33, 41, and 49.

- Triple intrathecal treatment will be given to low-risk cases with CNS-2, traumatic
CSF with blasts status, or WBC > 100 x 109/L on weeks 3, 7, 12, 17, 25, 29, 33,
37, 41, 45 and 49.

- Triple intrathecal treatment will be given to standard/high-risk cases on weeks 7,
12, 17, 25, 29, 33, 37, 41, 45 and 49.

- Triple intrathecal treatment will be given to other standard/high-risk cases with
WBC > or equal to 100 x 109/L, T-cell ALL, t (1;19)/E2A-PBX1, presence of
Philadelphia chromosome, MLL rearrangement, hypodiploidy <44, CNS-2 or CNS-3
status, or traumatic lumbar puncture with blasts on weeks 3, 7, 12, 17, 25, 29,
33, 37, 41, 45, 49, 57, 65, 73, 81, 89 and 97

Treatment (weeks 21 to 29)

Week Standard/High Risk Low Risk

21. MP + PEG-ASP+Dasatinib MP + MTX

22. MP +Dasatinib MP + MTX

23. MP + PEG-ASP + Dasatinib MP + MTX

24. Cyclo + Ara-C + Dasatinib MP + MTX

25. DEX + VCR + PEG-ASP + Dasatinib MP + DEX + VCR

26. MP + Dasatinib MP + MTX

27. MP + PEG-ASP+Dasatinib MP + MTX

28. Cyclo + Ara-C + Dasatinib MP + MTX

29. DEX + VCR +PEG-ASP + Dasatinib MP + DEX + VCR Dasatinib in Ph+ only

Treatment (weeks 30 to end of therapy)

Week Standard/High Risk Low Risk

30. MP + MTX + Dasatinib MP + MTX

31. MP + MTX + Dasatinib MP + MTX

32. Cyclo + Ara-C+Dasatinib MP + MTX

33. DEX + VCR + Dasatinib MP + DEX + VCR

34. MP + MTX + Dasatinib MP + MTX

35. MP + MTX + Dasatinib MP + MTX

36. Cyclo + Ara-C + Dasatinib/MP + MTX

37. DEX + VCR + Dasatinib /MP + DEX + VCR Dasatinib in Ph positive patients only

Drug Dosages, Schedules and Routes for Continuation Therapy from Week 21 to End of Therapy:

Mercaptopurine 75 mg/m2 PO h.s. daily for 7 days, Days 1-7. Methotrexate 40 mg/m2 IV or
intramuscularly (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 (divided
t.i.d.) for 5 days, Day 1-5 (between week 21 and week 68).Decrease dexamethasone to 6 mg/m2
PO daily (divided t.i.d.) x 5 days,Day 1-5 between week 69 and week 101 for all risk groups.

Vincristine2 mg/m2 IV push (max 2 mg), Day 1 (0.05mg/kg for patients < 1 year or < 10 kg).

PEG-ASP 2,500 vs 3,500 units/m2 IV randomization (until week 30)

Dexamethasone, vincristine, and asparaginase will be given regardless of blood counts,
provided that the patient is clinically well. Cyclophosphamide, cytarabine, mercaptopurine
and methotrexate will be held if WBC <1000/mm3 or ANC <300/mm3. Mercaptopurine and
methotrexate will be reduced for WBC < 1500/mm3, or if WBC and ANC do not increase by at
least 2 folds a week after the start date of dexamethasone pulse. Doses of
cyclophosphamide and cytarabine may need to be reduced if patient misses 25% of chemotherapy
and if the low counts deem to be related to this combination.

The same treatment (weeks 30-37) will be repeated for a total of 5 times, until week 69 (see
Section 5.5.3 for intrathecal therapy). After week 69, all patients will receive daily
mercaptopurine and weekly methotrexate interrupted with pulses of dexamethasone,
vincristine, and mercaptopurine every 4 weeks. The dose of dexamethasone will be decreased
to 6 mg/m2 between week 69 and week 101, after which only mercaptopurine and methotrexate
will be given. Intrathecal treatment will be given every 8 weeks only to patients at risk of
CNS relapse after week 49 and will be discontinued after week 97. Continuation therapy will
be discontinued after 120 weeks.

Hematopoietic Stem Cell Transplantation (for 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.