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.