Trial Information

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

There are multiple secondary objectives in this trial:

- To estimate the overall event-free survival of patients treated with risk-directed
therapy

- To identify the plasma methotrexate (MTX) concentrations that produce maximum
intracellular accumulation of active metabolites (methotrexate polyglutamates, MTXPG)
in vivo, in relation to major cell lineage and genotype

- To determine the relation between MTXPG accumulation in leukemic lymphoblasts and
antileukemic effects, as measured by the inhibition of de novo purine synthesis, and by
the decrease in circulating blasts during the 4 days after initiation of single-agent
high-dose methotrexate treatment

- To determine if plasma MTX concentrations exceeding those required for maximum MTXPG
accumulation cause a paradoxical decrease in the accumulation of long-chain MTXPG in
lymphoblasts, (e.g., due to "feedback inhibition" of folypolyglutamate synthetase)

- To determine if there are significant differences in lymphoblast uptake of MTX and
expression of the reduced folate carrier in T-lineage vs B-lineage lymphoblasts, and in
hyperdiploid vs non-hyperdiploid B-lineage lymphoblasts

- To investigate whether atovaquone (ATQ) is as effective as
trimethoprim-sulfamethoxazole (TMP-SMZ) in preventing Pneumocystis carinii pneumonitis
(PCP)

- To investigate whether or not the administration of G-CSF at the onset of febrile
episodes in neutropenia patients after induction or any of the two reinductions will
affect the extent and duration of fever.

- To determine whether levels of minimal residual disease in peripheral blood (PB)
reflect those measured in the bone marrow (BM) by immunologic or molecular techniques

- To assess the degree of DNA damage in somatic cells (leukocytes) during treatment

- To explore whether genetic polymorphisms of enzymes important in metabolism of
antileukemic agents (e.g. methylene tetrahydrofolate reductase, thiopurine
methyltransferase, glutathione transferases) are correlated with MTX pharmacology in
lymphoblasts, acute toxicities and long-term outcome

- To explore whether the development of anti-asparaginase antibodies or CSF depletion of
asparaginase is correlated with acute toxicities and long-term outcome

- To assess the relation between MRI changes of brain (especially white matter
abnormalities) from HDMTX and intrathecal treatment, neurologic and cognitive deficits,
CSF levels of homocysteines and diminished quality of life

- To investigate whether early MRI changes are related to late MRI abnormalities,
neurologic and cognitive deficits, and diminished quality of life

- To correlate changes in MRI, neurologic or cognitive deficits and diminished quality of
life with selected pharmacokinetic variables

- To determine the prevalence of low bone density and to correlate this complication with
potential risk factors

Details of Treatment Interventions:

Treatment will consist of three main phases, Remission Induction (including an Upfront HDMTX
Window), Consolidation, and Continuation.

Window Therapy Upfront HDMTX is considered the first part of remission induction treatment.
HDMTX will be given by vein over 24 hours (one day). MTX 500 mg/m2 for standard risk and 250
mg/m2 for low-risk cases will be given over 1 hour, followed immediately by maintenance
infusion (4500 mg/m2 for standard/high-risk or 2250 mg/m2 for low-risk cases) over 23 hours.

Remission Induction Therapy (6-7 weeks) The remaining induction treatment will begin with
Prednisone 40 mg/m2/day PO (tid) 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 U/m2/dose IM (thrice
weekly) days 6, 8, 10, 12, 14, 16 (19, 21, 23), and triple intrathecal treatment, followed
by Etoposide 300 mg/m2/dose IV over 2 hr days 26, 29, 33, plus Cytarabine 300 mg/m2/dose IV
over 2 hr Days 26, 29, 33.

Triple intrathecal chemotherapy (MHA) is used for the remaining treatment with dosages based
on age Frequency and total number of triple intrathecal treatment for Remission Induction
are based on the patient's risk of CNS relapse.

Consolidation (2 weeks) Patients receive High dose Methotrexate (HDMTX) 2.5 gm/m2 (low-risk)
or 5 gm/m2 (standard-or-high-risk) IV over 24 hr days 1 and 8 and 6-Mercaptopurine 25
mg/m2/day PO days 1 to 14. All patients will receive triple intrathecal therapy weekly for
two doses on Days 1 and 8.

Continuation treatment (120 weeks for girls and 146 weeks for boys) Post-remission
continuation treatment begins 7 days after the second course of HDMTX of the consolidation
treatment, provided that the ANC ≥300/mm3 and platelet count ≥ 50 x 109/L. Continuation
treatment will be 120 weeks for girls and 146 weeks for boys and differs according to the
risk classification.

Reinduction Treatment This phase of treatment will be started at weeks 12 and 28 after bone
marrow examination confirms complete remission.

Reinduction treatment will be given twice:

Weeks 12 to 16 and week 28 to 32 for standard/high risk cases; weeks 12 to 15 and weeks
28-31 for low-risk cases. Leucovorin rescue (5 mg/m2) will be given at 24 and 30 hours after
the intrathecal treatment during both remission reinduction treatments. No chemotherapy will
be given weeks 16 and 32 for standard/high risk patients.

Standard- or High-Risk Leukemia

- DEX (dexamethasone) 8 mg/m2 PO daily (tid) x 7 days and VCR (vincristine) 1.5 mg/m2 IV
push (max. 2 mg) will be given weeks 1, 5, 9, 17, 21, 25, 33, 37, 41, 45, 49, 53, 57,
61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, and 117.

- VP16 (etoposide) 300 mg/m2 IV over 2 hours and CTX (cyclophosphamide) 300 mg/m2 IV
short infusion will be given weeks 2, 6, 10, 18, 22, 26, 34, 38, 42, 46, 50, 54, 58,
62, 66, 70, 74, 78, 82, 86, 90, and 94.

- 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and MTX (methotrexate) 40 mg/m2 IV or
IM weeks 3, 8, 11, 19, 24, 27, 35, 39, 40, 43, 47, 48, 51, 55, 56, 59, 63, 64, 67, 71,
72, 75, 79, 80, 83, 87, 88, 91, 95, 96, 98, 99, 102, 103, 104, 106, 107, 110, 111, 112,
114, 115, 118, 119, and 120, and weeks 121-146 for boys.

- MTX (methotrexate) 40 mg/m2 IV or IM and Ara-C (cytarabine) 300 mg/m2 IV push will be
given weeks4, 20, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, and 116.

- 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and HDMTX 5 gm/ gm/m2 will be given
week 7 and 23.

- HDMTX 5 gm/ gm/m2 and Ara-C (cytarabine) 300 mg/m2 IV push will be given weeks 15 and
31.

Reinduction Treatment-Standard/High Risk

- DEX (dexamethasone) 8 mg/m2 PO daily (tid) days 1-21,

- VCR (vincristine) 1.5 mg/m2/week IV (max. 2 mg) days 1, 8, and 15

- PEG-asparaginase 2500 U/m2/week IM weeks 28-31, days 8, and 15

- Idarubicin 5 mg/m2/week IV days 1 and 8

- HDMTX 5 gm/m2 IV day 22

- ITMHA (methotrexate+hydrocortisone+ara-C), age dependent, IT day 1

- High-dose cytarabine 2 gm/m2 IV q 12 hr Days 23, and 24 Low Risk

- 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and MTX (methotrexate) 40 mg/m2 IV or
IM weeks 1, 2, 3, 4, 6, 8, 10,, 11, 16, 18- 20, 22, 24, 26, 27, 32, 34- 36, 38-40, 42-
44, 46-48, 50-52, 54-56, 58-60, 62-64, 66-68, 70-72, 74-76, 78-80, 82-84, 86-88, 90-92,
94-96, 98-100, 102-104, 106-108, 110-112, 114-116, 118-120 and weeks 121-146 for boys.

- 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days, MTX (methotrexate) 40 mg/m2 IV or
IM, DEX (dexamethasone) 8 mg/m2 PO daily (tid) x 7 days and VCR (vincristine) 1.5 mg/m2
IV push (max. 2 mg) weeks 5, 9, 17, 21, 25, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73,
77, 81, 85, 89, 93, 97, 101, 105, 109, 113, and 117.

- 6MP (6-mercaptopurine) 75 mg/m2 PO daily x 7 days and HDMTX 2.5 gm/m2 weeks 7, 15, 23
and 31.

Reinduction Treatment-Low Risk

- DEX (dexamethasone) 8 mg/m2 PO daily days 1-21,

- VCR (vincristine) 1.5 mg/m2/week IV push (max. 2 mg) days 1, 8, and 15

- PEG-asparaginase 2500 U/m2/week IM days 8, and 15

- Idarubicin 5 mg/m2/week IV day 1

- HDMTX 2.5 gm/m2 day 22

- ITMHA (methotrexate+hydrocortisone+ara-C), age dependent, IT day 1 and 22

- 6 MP 75 mg/m2/day PO days 22-28 IT Chemotherapy

- Triple intrathecal treatment will be given to low-risk cases with CNS-1 status on weeks
1, 2, 7, 12, 15, 23, 28, 31, 39, 47, and 54.

- Triple intrathecal treatment will be given to low-risk cases with CNS-2 or traumatic
CSF status on weeks 1, 2, 7, 12, 15, 19, 23, 28, 31, 36, 39, 43, 47, and 54.

- Triple intrathecal treatment will be given to standard/high-risk cases on weeks 1, 2,
7, 12, 19, 23, 28, 36, 39, 43, 47, and 54.

- Triple intrathecal treatment will be given to other standard/high-risk cases with WBC
≥100 x 109/L, T-cell ALL with WBC ≥50 x 109/L, presence of Philadelphia chromosome, MLL
rearrangement, near haploidy, or CNS-3 status on weeks 1, 2, 7, 12, 19, 23, 28, 36, 39,
43, 47, 54, 64, 72, 80, and 88.

Hematopoietic Stem Cell Transplantation Patients who meet the criteria of high-risk ALL will
be offered the option of transplantation with a matched, related or unrelated donor.
However, if the option is declined or if a suitable donor is not available, the patient will
remain on study and continue to receive chemotherapy.