PAX5-altered acute lymphoblastic leukemia (PAX5-alt ALL) is a recently recognized molecular subtype of B-ALL characterized by a distinct transcriptional signature and frequent PAX5 fusions (PAX5-r). Although PAX5-alt ALL is associated with intermediate outcomes, clinical data specifically investigating pediatric PAX5-r ALL remain limited. We analyzed 159 pediatric patients with PAX5-r ALL treated between 2001 and 2024 in Associazione Italiana di Ematologia Oncologia Pediatrica–Berlin-Frankfurt-Münster (AIEOP-BFM) ALL studies across Italy, Germany, and Austria, revealing high-risk (HR) clinical features. Comparative analyses of patients consecutively enrolled in the AIEOP-BFM ALL 2017 study (PAX5-r, n = 96, vs non-PAX5-r, n = 1948) confirmed higher rates of hyperleukocytosis at diagnosis (22.9% vs 8%; P < .001) and enrichment of IKZF1plus profile (14.7% vs 7.8%; P = .0015) in patients with PAX5-r. No relevant differences in terms of minimal/measurable residual disease (MRD)–based treatment response and risk-group stratification were observed. Patients with PAX5-r had a 4-year event-free survival (EFS) and overall survival of 72.6% ± 5.7% and 95.4% ± 2.3%, respectively. Four-year EFS were 100%, 63.4% ± 9.7%, and 63.3% ± 10% for standard-risk, medium-risk (MR), and HR groups, respectively, indicating that the poor prognostic impact of PAX5-r applies only when end-of-induction MRD is positive (MR/HR). Whole-transcriptome sequencing revealed high FLT3 median expression in PAX5-r ALL, and high-throughput drug screening of patient-derived xenografts (PDXs) showed marked sensitivity to several FLT3 inhibitors. Gilteritinib showed potent ex vivo cytotoxicity and synergism with dexamethasone in PAX5-r PDX models. Collectively, this study investigated clinical and biological features of pediatric PAX5-r ALL, highlighting its unfavorable, MRD-dependent prognosis and identifying FLT3 overexpression as a novel, potential therapeutic target.
Peccatori, N., Curto, A., Silvestri, D., Rebellato, S., Antic, Z., Nebral, K., et al. (2026). Measurable residual disease–dependent unfavorable outcomes in pediatric PAX5-rearranged B-acute lymphoblastic leukemia. BLOOD [10.1182/blood.2026033546].
Measurable residual disease–dependent unfavorable outcomes in pediatric PAX5-rearranged B-acute lymphoblastic leukemia
Peccatori N.;Curto A.;Saitta C.;Sarno J.;Balduzzi A.;Valsecchi M. G.;Biondi A.;Cazzaniga G.;Fazio G.
2026
Abstract
PAX5-altered acute lymphoblastic leukemia (PAX5-alt ALL) is a recently recognized molecular subtype of B-ALL characterized by a distinct transcriptional signature and frequent PAX5 fusions (PAX5-r). Although PAX5-alt ALL is associated with intermediate outcomes, clinical data specifically investigating pediatric PAX5-r ALL remain limited. We analyzed 159 pediatric patients with PAX5-r ALL treated between 2001 and 2024 in Associazione Italiana di Ematologia Oncologia Pediatrica–Berlin-Frankfurt-Münster (AIEOP-BFM) ALL studies across Italy, Germany, and Austria, revealing high-risk (HR) clinical features. Comparative analyses of patients consecutively enrolled in the AIEOP-BFM ALL 2017 study (PAX5-r, n = 96, vs non-PAX5-r, n = 1948) confirmed higher rates of hyperleukocytosis at diagnosis (22.9% vs 8%; P < .001) and enrichment of IKZF1plus profile (14.7% vs 7.8%; P = .0015) in patients with PAX5-r. No relevant differences in terms of minimal/measurable residual disease (MRD)–based treatment response and risk-group stratification were observed. Patients with PAX5-r had a 4-year event-free survival (EFS) and overall survival of 72.6% ± 5.7% and 95.4% ± 2.3%, respectively. Four-year EFS were 100%, 63.4% ± 9.7%, and 63.3% ± 10% for standard-risk, medium-risk (MR), and HR groups, respectively, indicating that the poor prognostic impact of PAX5-r applies only when end-of-induction MRD is positive (MR/HR). Whole-transcriptome sequencing revealed high FLT3 median expression in PAX5-r ALL, and high-throughput drug screening of patient-derived xenografts (PDXs) showed marked sensitivity to several FLT3 inhibitors. Gilteritinib showed potent ex vivo cytotoxicity and synergism with dexamethasone in PAX5-r PDX models. Collectively, this study investigated clinical and biological features of pediatric PAX5-r ALL, highlighting its unfavorable, MRD-dependent prognosis and identifying FLT3 overexpression as a novel, potential therapeutic target.
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