Measurable Residual Disease-Dependent Unfavorable Outcomes in Pediatric PAX5-Rearranged B-Acute Lymphoblastic Leukemia.
In 159 pediatric PAX5-rearranged B-ALL cases, unfavorable event-free survival was concentrated among patients with positive end-of-induction MRD, while transcriptomic analysis and PDX drug screening identified high FLT3 expression and sensitivity to FLT3 inhibitors, including gilteritinib with dexamethasone.
Open original publication →What the AI sees
In 159 pediatric PAX5-rearranged B-ALL cases, unfavorable event-free survival was concentrated among patients with positive end-of-induction MRD, while transcriptomic analysis and PDX drug screening identified high FLT3 expression and sensitivity to FLT3 inhibitors, including gilteritinib with dexamethasone.
Research significance
The supplied evidence shows FLT3 overexpression and ex vivo FLT3-inhibitor sensitivity in PAX5-rearranged PDX models; it therefore supports—but does not clinically establish—the hypothesis that adding an FLT3 inhibitor such as gilteritinib could improve outcomes in MRD-positive pediatric PAX5-rearranged B-ALL.
Source 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). While PAX5-alt ALL has been associated with intermediate outcomes, clinical data specifically investigating pediatric PAX5-r ALL remain limited. We collected and analyzed 159 pediatric cases of PAX5-r ALL treated between 2001-2024 within AIEOP-BFM ALL studies across Italy, Germany and Austria, revealing high-risk 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<0.001) and enrichment of IKZF1plus profile (14.7% vs. 7.8%, p=0.0015) in PAX5-r patients. No relevant differences in terms of minimal/measurable residual disease (MRD)-based treatment response and risk-group stratification were observed. PAX5-r patients had a 4-year EFS and OS 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 high-risk (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 MRD-dependent unfavorable prognosis and identifying FLT3 overexpression as a novel, potential therapeutic target.