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 the AIEOP-BFM ALL 2009 trial, patients with cytomorphologic detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate (MTX) in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal (IT) MTX on systemic toxicity in induction therapy is unknown. Between June 1st 2010 and February 28th 2017, a total of 6,136 ALL patients aged 1-17 years were enrolled onto the AIEOP-BFM ALL 2009 trial. The effect of three versus five doses of IT MTX during induction therapy on the incidence of severe infectious complications was analyzed. Among 4,706 patients treated with three IT MTX doses, 77 (1.6%) had a life-threatening infection during induction as compared to 59 of 1,350 (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 IT MTX 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 IT MTX doses, respectively (P<0.001). As the relevance of additional intrathecal MTX in induction for relapse prevention in CNS2 patients is unclear, doses of intrathecal therapy have been reduced for these patients. (Clinicaltrials.gov identifiers: NCT01117441 and NCT00613457).

Children's Cancer Institute Australia University of New South Wales Lowy Cancer Centre Randwick Australia; Kids Cancer Centre Sydney Children's Hospital Randwick Australia

Department of Pediatric Oncology University Children's Hospital Zuerich Switzerland

Department of Pediatrics Christian Albrechts University Kiel and University Medical Center Schleswig Holstein Kiel Germany

Department of Pediatrics St Anna Children's Cancer Research Institute and St Anna Children's Hospital Medical University School Vienna

Hannover Medical School Pediatric Hematology and Oncology Hannover Germany

Pediatric Clinic University Milano Bicocca Fondazione MBBM San Gerardo Hospital Monza Italy

Pediatric Clinic University Milano Bicocca Fondazione MBBM San Gerardo Hospital Monza Italy; University of Milano Bicocca Center of Biostatistics for Clinical Epidemiology Department of Health Science Milan Italy

Pediatric Hematology Oncology Schneider Children's Medical Center and Sackler Faculty of Medicine Aviv University Aviv Israel

The Children's Hospital at Westmead Department of Oncology Westmead Australia

University Hospital Motol Department of Pediatric Hematology Oncology Prague Czech Republic

University of Milano Bicocca Center of Biostatistics for Clinical Epidemiology Department of Health Science Milan Italy

Haematologica. 2023 Dec 01;108(12):3193-3194. doi: 10.3324/haematol.2023.283275. PubMed

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ClinicalTrials.gov
NCT00613457, NCT01117441