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Overview of CNS-Directed Treatment Regimens
Source: Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version, National Cancer Institute.
Source updated: April 21, 2025 · Captured 2026-09-09.
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Context: Central Nervous System (CNS)-Directed Therapy for Childhood ALL
At diagnosis, approximately 3% of patients have CNS3 disease (defined as cerebrospinal fluid [CSF] specimen with ≥5 white blood cells [WBC]/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, most children will eventually develop overt CNS leukemia whether or not lymphoblasts were detected in the spinal fluid at initial diagnosis. Therefore, all children with acute lymphoblastic leukemia (ALL) should receive systemic combination chemotherapy together with some form of CNS prophylaxis.
Because the CNS is a sanctuary site (i.e., an anatomical space that is poorly penetrated by many of the systemically administered chemotherapy agents typically used to treat ALL), specific CNS-directed therapies must be instituted early in treatment to eliminate clinically evident CNS disease at diagnosis and to prevent CNS relapse in all patients. Historically, survival rates for children with ALL improved dramatically after CNS-directed therapies were added to treatment regimens.
Standard treatment options for CNS-directed therapy include the following:
Intrathecal chemotherapy.
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CNS-directed systemic chemotherapy.
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Cranial radiation therapy.
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All of these treatment modalities have a role in the treatment and prevention of CNS leukemia. The combination of intrathecal chemotherapy plus CNS-directed systemic chemotherapy is standard. Cranial radiation is reserved for select situations.[1]
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The type of CNS-therapy that is used is based on a patient’s risk of CNS-relapse, with higher-risk patients receiving more intensive treatments. Data suggest that the following groups of patients are at increased risk of CNS relapse:
Patients with 5 or more WBC/µL and blasts in the cerebrospinal fluid (CSF) (CNS3), obtained at diagnosis.
Patients with blasts in the CSF but fewer than 5 WBC/µL (CNS2) may be at increased risk of CNS relapse,[2] although this risk appears to be nearly fully abrogated if they receive more doses of intrathecal chemotherapy, especially during the induction phase.[3]
Patients with T-ALL, especially those with high presenting peripheral blood leukocyte counts.
Patients who have a traumatic lumbar puncture showing blasts at the time of diagnosis may have an increased risk of CNS relapse. These patients receive more intensive CNS-directed therapy on some treatment protocols.[3,4]
CNS-directed treatment regimens for newly diagnosed childhood ALL are presented in Table 11.
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| Disease Status | Standard Treatment Options | |
|---|---|---|
| ALL = acute lymphoblastic leukemia; CNS = central nervous system; CNS3 = cerebrospinal fluid with ≥5 white blood cells/µL, cytospin positive for blasts, or cranial nerve palsies. | ||
| aThe 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 and very 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 therapy | ||
A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurological toxic effects and other late effects.
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Preserved source evidence · Not medical advice