Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. Treatment intensity depends on the initial CNS status.
In trial AIEOP-BFM ALL 2009, patients with cytomorphological detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal methotrexate on systemic toxicity in induction therapy is unknown.
Between June 01, 2010 and February 28, 2017, 6136 patients at the age of 1 to 17 years with ALL were enrolled onto the trial AIEOP-BFM ALL 2009. The effect of three versus five doses of intrathecal methotrexate during induction therapy on the incidence of severe infectious complications was analyzed.
Among 4706 patients treated with three intrathecal methotrexate doses, 77 (1.6%) had a lifethreatening infection during induction as compared to 59 of 1350 (4.4%) patients treated with five doses (p<0.001; Odds ratio 2.86 [95% confidence interval 1.99-4.13]). In a multivariate regression model, treatment with additional intrathecal methotrexate proved to be the strongest risk factor for life-threatening infections (Odds ratio 2.85 [1.96-4.14]). Fatal infections occurred in 16 (0.3%) and 38 (1.6%) patients treated with three or five intrathecal methotrexate doses, respectively (p<0.001).
As the relevance of additional intrathecal MTX in induction for relapse prevention in CN2 patients is unclear, doses of intrathecal therapy have been reduced for these patients consequently. (ClinicalTrials.gov identifier: NCT01117441 and NCT00613457)
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