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

Sponsor

St. Jude Children's Research Hospital (Other)

Overall Status

Terminated

CT.gov ID

NCT00187005

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main purpose of this study is to find out if radiation to the central nervous system (CNS) can be safely omitted with early intensification of chemotherapy and chemotherapy given directly to the CNS. Another purpose is to find out if survival of children with ALL can be improved with risk-directed therapy given on this protocol.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia	Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase Drug: L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine	Phase 3

Detailed Description

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

53 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jul 1, 1998

Actual Primary Completion Date :

Jul 1, 2002

Actual Study Completion Date :

Jul 1, 2002

Arms and Interventions

Arm	Intervention/Treatment
Other: 1	Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase See Detailed Description section for details of treatment interventions. Drug: L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine See Detailed Description section for details of treatment interventions.

Arm

Intervention/Treatment

Other: 1

Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin, PEG-L-asparaginase

See Detailed Description section for details of treatment interventions.

Drug: L-asparaginase, Methotrexate, Idarubicin, Etoposide, Cyclophosphamide, Cytarabine, Mercaptopurine

See Detailed Description section for details of treatment interventions.

Outcome Measures

Primary Outcome Measures

To determine if CNS irradiation can be safely omitted with early intensification of systemic and intrathecal chemotherapy. [Unable to determine]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of non-B-cell leukemia by immunophenotyping (e.g. T-cell, B-cell precursor, or acute undifferentiated leukemia)
Ages less than or equal to 18 years of age
One week or less of prior therapy, limited to glucocorticoids, vinca alkaloids, emergency radiation therapy to the mediastinum and one dose of intrathecal chemotherapy Exclusion Criteria
Participants greater than 18 years of age