Cns Prophylaxis

Although only 2-10% of adults with ALL present with CNS involvement at diagnosis,63 50-75% of patients will relapse in the CNS at 1 year in the absence of CNS-directed therapy.64 65 The diagnosis of CNS leukemia requires the presence of more than five leukocytes per microliter in the cerebrospinal fluid (CSF) and the identification of lymphoblasts in the CSF differential.66 Patients with CSF involvement may be asymptomatic, or can present with headache, meningismus, malaise, fever, or cranial nerve palsies. False-negative CSF results may occur in patients with predominantly cranial nerve involvement. Mature B-cell ALL, high serum lac-tate dehydrogenase (LDH) levels, and high proliferative index (more than 14% of lymphoblasts in the G2M/S

phase of the cell cycle at diagnosis) have been associated with a higher risk of CNS disease in adult ALL.63

There is no consensus regarding the best approach for CNS prophylaxis in adult ALL. Concomitant use of cranial irradiation and IT therapy is often toxic and may result in delays in delivery of postremission intensification therapy. Alternative strategies have included triple IT therapy with MTX, cytarabine, and a corticosteroid without cranial irradiation,67 or IT therapy combined with high-dose systemic therapy with CSF-pene-trating drugs, including MTX, cytarabine, L-asparaginase, and corticosteroids. Systemic administration of dexam-ethasone achieves higher CSF levels than of prednisone and has a longer half-life in the CSF than prednisone.68 As discussed previously, in a randomized pediatric trial, dexamethasone resulted in a lower incidence of CNS relapse compared to prednisone.39 Although some studies suggest that CNS relapse rates of less than 5% can be achieved in adults with ALL using combination IT and high-dose systemic chemotherapy without cranial irradiation,42 63 69 in the GMALL studies, attempts to omit or postpone CNS irradiation led to higher CNS relapse rates.70 The omission of CNS irradiation may be of particular concern for patients with precursor T ALL; the pediatric oncology groups in the United States have generally continued to use prophylactic irradiation for high-risk patients with T-lineage disease. Future trials may explore a risk-oriented approach to CNS prophylaxis, with the goals of minimizing toxicity and optimizing efficacy.

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