In the effort to improve immunophenotyping and minimal residual disease (MRD) assessment in acute lymphoblastic leukemia (ALL), the international Berlin-Frankfurt-Münster (iBFM) Flow Network introduced the myelomonocytic marker CD371 for a large prospective characterization with a long follow-up. In the present study, we aimed to investigate the clinical and biological features of CD371-positive (CD371pos) pediatric B-cell precursor ALL (BCP-ALL). From June 2014 to February 2017, 1812 pediatric patients with newly diagnosed BCP-ALLs enrolled in trial AIEOP-BFM ALL 2009 were evaluated as part of either a screening (n = 843, Italian centers) or validation cohort (n = 969, other iBFM centers). Laboratory assessment at diagnosis consisted of morphological, immunophenotypic, and genetic analysis. Response assessment relied on morphology, multiparametric flow cytometry (MFC), and polymerase chain reaction (PCR)-MRD. At diagnosis, 160 of 1812 (8.8%) BCP-ALLs were CD371pos. This correlated with older age, lower ETV6::RUNX1 frequency, immunophenotypic immaturity (all P < .001), and strong expression of CD34 and of CD45 (P < .05). During induction therapy, CD371pos BCP-ALLs showed a transient myelomonocytic switch (mm-SW: up to 65.4% of samples at day 15) and an inferior response to chemotherapy (slow early response, P < .001). However, the 5-year event-free survival was 88.3%. Among 420 patients from the validation cohort, 27 of 28 (96.4%) cases positive for DUX4-fusions were CD371pos. In conclusion, in the largest pediatric cohort, CD371 is the most sensitive marker of transient mm-SW, whose recognition is essential for proper MFC MRD assessment. CD371pos is associated to poor early treatment response, although a good outcome can be reached after MRD-based ALL-related therapies.

Department of Health Science and Public Health Catholic University of the Sacred Heart Rome Italy

Department of Internal Medicine 1 Hematology Laboratory University Medical Center Schleswig Holstein Kiel Germany

Department of Oncology Hematology and Cellular Therapy Santobono Pausilipon Children's Hospital Naples Italy

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology Oncology Cell and Gene Therapy Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital Rome Italy

Department of Pediatric Oncology Hematology Charité Universitätsmedizin Berlin Germany

Department of Pediatrics University Medical Center Schleswig Holstein Kiel Germany

Division of Oncology and Children's Research Center University Children's Hospital University of Zurich Zurich Switzerland

Hannover Medical School Hannover Germany

Immune Phenotype Laboratory Department of Hematology Oncology Schneider Children's Medical Center of Israel Petach Tikva Israel

Pediatric Hematology Oncology and Stem Cell Transplant Division Maternal and Child Health Department University of Padua Padua Italy

Pediatric Onco Hematology City of Science and Health of Turin Regina Margherita Children's Hospital Turin Italy

Pediatric Onco Hematology Stem Cell Transplant and Gene Therapy Laboratory Istituto di Ricerca Pediatrica Città della Speranza Padua Italy

Pediatrics IRCCS San Gerardo dei Tintori Monza Italy

School of Medicine and Surgery University of Milan Bicocca Monza Italy

St Anna Children's Cancer Research Institute Vienna Austria

St Anna Children's Hospital Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Tettamanti Center IRCCS San Gerardo dei Tintori Monza Italy

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