Central nervous system (CNS) invasion at initial diagnosis is seen in less than 10% of adults with ALL, mostly in T-lineage or mature ALL, and CNS leukemia is more common in patients with lymph node enlargement, mediastinal masses and extramedullary invasion. Most chemotherapeutic drugs do not penetrate the blood-brain barrier, and factors affecting CNS drug penetration include the physiochemical characteristics of the drug, the degree of protein-drug binding and the adsorption of the drug to the CNS carrier. Desmethoxazole did not show superiority over erythromycin; however, desmethoxazole may overcome P-glycoprotein-mediated multidrug resistance, and the therapeutic effect of the reduced product on CNS leukemia after intravenous application reached measurable levels in the CNS needs further confirmation. Systemic administration of high-dose cytarabine and methotrexate (MTX) overcomes drug resistance on the one hand and achieves therapeutic levels in the cerebrospinal fluid on the other.
High-dose cytarabine was successfully used to induce remission in leukemia with CNS. 3 g/m2 every 12 hours resulted in sustained cytotoxic concentrations of cytarabine in the cerebrospinal fluid, and the clearance half-life of cytarabine was 8 times longer in the cerebrospinal fluid than in plasma. High doses of MTX are equally effective in CNS leukemia, and tetrahydrofolate calcium rescue therapy improves the safety of high doses of MTX and achieves therapeutic concentrations in the cerebrospinal fluid, with studies showing that cytotoxic levels can be achieved in the cerebrospinal fluid when MTX is applied at doses of 6 g/m2.
Intrathecal MTX is the most commonly used method, MTX can be safely applied at 12.5 mg, MTX concentration in CSF is highly variable and more correlated with patient age and body surface area, neurotoxicity is correlated with intrathecal application of MTX and increased MTX concentration in the CNS, MTX can be applied alone or in combination with cytarabine and glucocorticoids, in clinical studies, the combination of three drugs did not shown to be superior to the two-drug combination in clinical studies. Ara-C is the 2nd widely used intrathecal drug, commonly used at a dose of 30 mg/m2, and is converted to the inactive metabolite, ara-C uracil, after intrathecal injection (Ara-C has a prolonged half-life in cerebrospinal fluid relative to plasma due to low cytidine enzyme activity in the intracranial and cerebrospinal fluid). Intrathecal Ara-C is more effective than twice-weekly intrathecal methotrexate injections.
The rate of induced CR in patients with CNS invasion did not differ from that in patients without invasion, except for a small series that reported significantly lower CR rates in patients with a diagnosis of CNS leukemia than in patients without invasion. There is no standard approach to the management of patients with CNS leukemia. Patients with CNS leukemia at diagnosis usually receive more intense intrathecal therapy, which is started early in the induction remission treatment, and it has been suggested that intrathecal chemotherapy be started twice a week at the same time as induction therapy until complete remission is achieved, and then once a week for a total of 12 times. For example, dexamethasone, MTX and Ara-C, or in combination with spinal radiotherapy. Studies in adults with ALL have shown that failure to receive systemic chemotherapy in patients with CNS leukemia can eventually lead to myeloid relapse.
CNS prophylaxis, including intrathecal chemotherapy, spinal cord radiotherapy, and the use of high-dose systemic chemotherapy that can cross the blood-brain barrier, have greatly improved the clinical prognosis of patients. For patients in the high-risk group, early initiation of CNS prophylaxis is important, and the value of CNS prophylaxis in adults with ALL has been demonstrated, although there is no optimal strategy, intrathecal chemotherapy remains the recommended method for CNS prophylaxis, with 4 intrathecal chemotherapy sessions over 4 weeks or 5-drug combination with standard induction, in some cases intrathecal MTX alone, and in other reports with MTX, Ara-C , hormones applied simultaneously, dexamethasone has higher levels and longer half-life than prednisone in CSF, and systemic application of L-mentholatase eliminates L-menthol from the cerebrospinal fluid. Studies have demonstrated that systemic high-dose chemotherapy alone is not sufficient to prevent CNS leukemia, and in high-risk patients, the best prevention method is high-dose chemotherapy combined with intrathecal administration, by which effective prevention results can be obtained even without spinal cord radiation therapy, but requires continuous intrathecal administration during the maintenance period. Although high-dose chemotherapy plus intrathecal chemotherapy is effective in mature B-cell ALL, the combination of spinal radiotherapy and intrathecal chemotherapy is valuable in this subtype.