CD371-positive pediatric B-cell acute lymphoblastic leukemia: propensity to lineage switch and slow early response to treatment

Author:

Buldini Barbara12ORCID,Varotto Elena1ORCID,Maurer-Granofszky Margarita3,Gaipa Giuseppe4,Schumich Angela3,Brüggemann Monika5ORCID,Mejstrikova Ester6,Cazzaniga Giovanni47ORCID,Hrusak Ondrej6ORCID,Szczepanowski Monika5,Scarparo Pamela1,Zimmermann Martin8,Strehl Sabine3ORCID,Schinnerl Dagmar3,Zaliova Marketa6ORCID,Karawajew Leonid9ORCID,Bourquin Jean-Pierre10,Feuerstein Tamar11,Cario Gunnar12,Alten Julia12,Möricke Anja12,Biffi Alessandra12ORCID,Parasole Rosanna13ORCID,Fagioli Franca14,Valsecchi Maria Grazia7,Biondi Andrea15ORCID,Locatelli Franco1617,Attarbaschi Andishe3,Schrappe Martin12,Conter Valentino15ORCID,Basso Giuseppe1,Dworzak Michael N.318

Affiliation:

1. 1Pediatric Hematology, Oncology and Stem Cell Transplant Division, Maternal and Child Health Department, University of Padua, Padua, Italy

2. 2Pediatric Onco-Hematology, Stem Cell Transplant and Gene Therapy Laboratory, Istituto di Ricerca Pediatrica, Città della Speranza, Padua, Italy

3. 3St. Anna Children’s Cancer Research Institute, Vienna, Austria

4. 4Tettamanti Center, IRCCS San Gerardo dei Tintori, Monza, Italy

5. 5Department of Internal Medicine I, Hematology Laboratory, University Medical Center Schleswig-Holstein, Kiel, Germany

6. 6Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic

7. 7School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy

8. 8Hannover Medical School, Hannover, Germany

9. 9Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin, Berlin, Germany

10. 10Division of Oncology and Children’s Research Center, University Children’s Hospital, University of Zurich, Zurich, Switzerland

11. 11Immune Phenotype Laboratory, Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel

12. 12Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany

13. 13Department of Oncology, Hematology and Cellular Therapy, Santobono-Pausilipon Children’s Hospital, Naples, Italy

14. 14Pediatric Onco-Hematology, City of Science and Health of Turin, Regina Margherita Children’s Hospital, Turin, Italy

15. 15Pediatrics, IRCCS San Gerardo dei Tintori, Monza, Italy

16. 16Department of Pediatric Hematology/Oncology, Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, Rome, Italy

17. 17Department of Health Science and Public Health, Catholic University of the Sacred Heart, Rome, Italy

18. 18St. Anna Children’s Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

Abstract

Abstract 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.

Publisher

American Society of Hematology

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