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    Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI] - CNS-directed Therapy for Childhood ALL

    Table 2. CNS-Directed Treatment Regimens for Newly Diagnosed Childhood ALL

    Disease Status Standard Treatment Options
    ALL = acute lymphoblastic leukemia; CNS = central nervous system; CNS3 = cerebrospinal fluid with five or more white blood cells/µL, cytospin positive for blasts, or cranial nerve palsies.
    a The drug itself is not CNS-penetrant, but leads to cerebrospinal fluid asparagine depletion.
    Standard-risk ALL Intrathecal chemotherapy
    Methotrexate alone
    Methotrexate with cytarabine and hydrocortisone
    CNS-directed systemic chemotherapy
    Dexamethasone
    L-asparaginasea
    High-dose methotrexate with leucovorin rescue
    Escalating-dose intravenous methotrexate (no leucovorin rescue)
    High-risk ALL Intrathecal chemotherapy
    Methotrexate alone
    Methotrexate with cytarabine and hydrocortisone
    CNS-directed systemic chemotherapy
    Dexamethasone
    L-asparaginasea
    High-dose methotrexate with leucovorin rescue
    Cranial radiation

    A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurologic toxic effects and other late effects.

    Intrathecal Chemotherapy

    All therapeutic regimens for childhood ALL include intrathecal chemotherapy. Intrathecal chemotherapy is usually started at the beginning of induction, intensified during consolidation and, in many protocols, continued throughout the maintenance phase.

    Intrathecal chemotherapy typically consists of one of the following:[5]

    1. Methotrexate alone.
    2. Methotrexate with cytarabine and hydrocortisone (triple intrathecal chemotherapy).

    Unlike intrathecal cytarabine, intrathecal methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.[6]

    CNS-directed Systemic Chemotherapy

    In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis. The following systemically administered drugs provide some degree of CNS prophylaxis:

    • Dexamethasone.
    • L-asparaginase (does not penetrate into CSF itself, but leads to CSF asparagine depletion).
    • High-dose methotrexate with leucovorin rescue.
    • Escalating dose intravenous (IV) methotrexate without leucovorin rescue.

    Evidence (CNS-directed systemic chemotherapy):

    1. In a randomized Children's Cancer Group (CCG) study of standard-risk patients who all received the same dose and schedule of intrathecal methotrexate without cranial irradiation, oral dexamethasone was associated with a 50% decrease in the rate of CNS relapse compared with oral prednisone.[7]
    2. In another standard-risk ALL trial (COG-1991), escalating dose IV methotrexate without rescue significantly reduced the CNS relapse rate compared with standard, low-dose, oral methotrexate given during each of two interim maintenance phases.[8]
    3. In a randomized clinical trial conducted by the former Pediatric Oncology Group, T-cell ALL patients who received high-dose methotrexate experienced a significantly lower CNS relapse rate than patients who did not receive high-dose methotrexate.[9]
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