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...
Cranial radiation has also been associated with an increased risk of second neoplasms, many of which are benign or of low malignant potential, such as meningiomas.[24,45,46] Leukoencephalopathy has been observed after cranial radiation in children with ALL, but appears to be more common with higher doses than are currently administered. In general, systemic methotrexate doses greater than 1 g/m2 should not be given following cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy.
Presymptomatic CNS Therapy Options Under Clinical Evaluation
Treatment options under clinical evaluation include the following:
- COG-AALL0434 (NCT00408005) (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): In the Children's Oncology Group (COG) COG-AALL0434 protocol for patients with T-cell ALL, low-risk T-cell patients (those with NCI standard-risk features and a rapid response to induction therapy) are treated without cranial radiation, and intermediate-risk T-cell patients receive 12 Gy (instead of 18 Gy) cranial radiation. High-risk T-cell patients 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.
- 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 intrathecal triple chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate, with the objective of determining whether intrathecal triple chemotherapy reduces CNS-relapse rates and improves overall EFS. Only patients with CNS3 status at diagnosis will receive cranial radiation (18 Gy). Patients with induction failure or low hypodiploidy are eligible for allogeneic SCT in first remission.
- 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.
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).[15,17] Spinal radiation is no longer used.
Evidence (cranial radiation):
- On the SJCRH Total XV (TOTXV) study, patients with CNS3 status (N = 9) were treated without cranial radiation (observed 5-year EFS, 43% ± 23%). 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%.
- SJCRH and the EORTC have published results of trials that omitted cranial radiation for all patients, including high-risk subsets.[10,21] 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 frequent vincristine/dexamethasone pulses during the first 1 to 2 years of therapy,, 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.
- The long-term EFS for CNS3 patients on these trials ranged from 43% (SJCRH) to 68% (EORTC).