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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 continued...

    CNS Therapy for Patients With CNS Involvement (CNS3 Disease) at Diagnosis

    Therapy for ALL patients with clinically evident CNS disease (≥5 WBC/hpf with blasts on cytospin; CNS3) at diagnosis typically includes intrathecal chemotherapy and cranial radiation (usual dose is 18 Gy).[16,18] Spinal radiation is no longer used.

    Evidence (cranial radiation):

    1. SJCRH, DCOG, and the EORTC have published results of trials that omitted cranial radiation for all patients, including high-risk subsets.[11,24] These trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH study also included higher cumulative doses of anthracycline than on Children's Oncology Group (COG) trials, and frequent vincristine/dexamethasone pulses and intensified dosing of L-asparaginase,[11] while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine, during postinduction treatment phases for CNS3 (CSF with ≥5 WBC/µL and cytospin positive for blasts) patients.[24]
      • On the SJCRH Total XV (TOTXV) study, patients with CNS3 status (N = 9) were treated without cranial radiation (observed 5-year EFS, 43% ± 23%).[11] On this study, CNS leukemia at diagnosis (defined as CNS3 status or traumatic lumbar puncture with blasts) was an independent predictor of inferior EFS.
      • On the DCOG-9 trial, the 5-year EFS of CNS3 patients (n = 21) treated without cranial radiation was 67% ± 10%.[12]
      • On the EORTC trial, the 8-year EFS of CNS3 patients (n = 49) treated without cranial radiation was 68%. The cumulative incidence of isolated CNS relapse for those patients was 9.4%.[24][Level of evidence: 2A]

    Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.

    Presymptomatic CNS Therapy Options Under Clinical Evaluation

    Treatment options under clinical evaluation include the following:

    1. COG-AALL0434 (NCT00408005) (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): In the COG protocol (COG-AALL0434) for patients with T-cell ALL, low-risk T-cell patients (those with NCI standard-risk features, no evidence of CNS disease, and a rapid response to induction therapy) are treated without cranial radiation, and intermediate-risk and high-risk T-cell patients receive 12 Gy (instead of 18 Gy) cranial radiation. Patients with CNS3 disease at diagnosis continue to receive 18 Gy cranial radiation. All patients are randomly assigned to receive either high-dose methotrexate (5 g/m2 over 24 hours) with leucovorin rescue or escalating-dose methotrexate without leucovorin rescue during the initial interim maintenance phase of therapy. Intermediate-risk and high-risk patients are also randomly assigned to receive or not receive nelarabine, an antipurine with selective activity in T-lymphoblasts.
    2. COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL): The COG-AALL1131 protocol for patients with high-risk B-precursor ALL includes a randomized comparison of triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate, with the objective of determining whether triple intrathecal chemotherapy reduces CNS-relapse rates and improves overall EFS. Only patients with CNS3 status at diagnosis will receive cranial radiation (18 Gy).
    3. SJCRH Total XVI (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): Patients receive both intrathecal chemotherapy and high-dose methotrexate without radiation therapy. Certain patients with high-risk features, including those with a t(1;19) translocation, receive intensified intrathecal therapy.
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