Measurable Residual Disease-Dependent Unfavorable Outcomes in Pediatric PAX5-Rearranged B-Acute Lymphoblastic Leukemia
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.
Article Details
Authors (35)
Nicolò Peccatori
Tettamanti Center, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy
Alessia Curto
Tettamanti Center, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy
Daniela Silvestri
Clinica Pediatrica - Ospedale San Gerardo, Monza, Italy
Stefano Rebellato
Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Željko Antić
University Hospital Würzburg, Würzburg, Germany
Karin Nebral
Anke Katharina Bergmann
University Hospital Würzburg, Würzburg, Germany
Sabine Strehl
St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
Martin Zimmermann
Hannover Medical School, Hannover, Germany
Claudia Saitta
Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Chiara Palmi
Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Michela Bardini
Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Sanil Bhatia
Arndt Borkhardt
Heinrich-Heine-University, Dusseldorf, Germany
Manuel Quadri
Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Daniela Guardo
IRCCS Istituto Giannina Gaslini, Genoa, Italy
Luca Lo Nigro
Center of Pediatric Hematology Oncology
Rosanna Parasole
AORN Santobono-Pausilipon IRCCS, Naples, Italy
Maria Caterina Putti
Università di Padova, Padova, Italy
Franco Locatelli
IRCCS Ospedale Pediatrico Bambino Gesù Rome, Rome
Julia Alten
Dept. of Pediatrics, UKSH, Kiel, Germany
Martin Stanulla
Hannover Medical School, Hannover, Germany
Barbara Buldini
Jolanda Sarno
Kara L. Davis
Valentino Conter
Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Adriana Cristina Balduzzi
Maria Grazia Valsecchi
Andrea Biondi
Andishe Attarbaschi
Martin Schrappe
Gunnar Cario
University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Carmelo Rizzari
IRCCS San Gerardo dei Tintori, Monza and University of Milano-Bicocca,University of Milano-Bicocca, Monza, Italy
Giovanni Cazzaniga
University of Milano-Bicocca, Monza, Italy
Grazia Fazio
Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy