Page 38 - 2021_06-Haematologica-web

Ferrata Storti Foundation
Haematologica 2021 Volume 106(8):2066-2075
Acute Lymphoblastic Leukemia
DUX4r, ZNF384r and PAX5-P80R mutated B-cell precursor acute lymphoblastic leukemia frequently undergo monocytic switch
Michaela Novakova,1,2,3* Marketa Zaliova,1,2,3* Karel Fiser,1,2* Barbora Vakrmanova,1,2 Lucie Slamova,1,2,3 Alena Musilova,1,2 Monika Brüggemann,4 Matthias Ritgen,4 Eva Fronkova,1,2,3 Tomas Kalina,1,2,3 Jan Stary,2,3 Lucie Winkowska,1,2 Peter Svec,5 Alexandra Kolenova,5 Jan Stuchly,1,2 Jan Zuna,1,2,3 Jan Trka,1,2,3 Ondrej Hrusak1,2,3# and Ester Mejstrikova1,2,3#
1CLIP - Childhood Leukemia Investigation Praguerague, Czech Republic; 2Department of Paediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; 3University Hospital Motol, Prague, Czech Republic; 4Department of Internal Medicine II, University Hospital Schleswig-Holstein, Kiel, Germany and 5Comenius University, National Institute of Children’s Diseases, Bratislava, Slovakia
*MN, MZ and KF contributed equally as co-first authors. #OH and EM contributed equally as co-senior authors.
ABSTRACT
Recently, we described B-cell precursor acute lymphoblastic leukemia (BCP-ALL) subtype with an early switch to the monocyt- ic lineage and the loss of the B-cell immunophenotype, including CD19 expression. Thus far, the genetic background has remained unknown. Among 726 children consecutively diagnosed with BCP-ALL, 8% patients experienced a switch detectable by flow cytometry (FC). Using exome and RNA sequencing, the switch was found to positively correlate with three different genetic subtypes: PAX5-P80R mutation (five cases with switch of five), rearranged (DUX4r) (30 cases of 41) and rearranged (ZNF384r) (four cases of ten). Expression profiles or pheno- typic patterns correlated with genotypes, but within each genotype no cases who subsequently switched could be indentified. If switching was not taken into account, the B-cell-oriented FC assessment underestimat- ed the minimal residual disease level. For patients with PAX5-P80R, a discordance between FC-determined and polymerase chain reaction- determined minimal residual disease was found on day 15, resulting from a rapid loss of the B-cell phenotype. Discordance on day 33 was observed in all the DUX4r, PAX5-P80R and ZNF384r subtypes. Importantly, despite the substantial phenotypic changes, possibly even challenging the appropriateness of BCP-ALL therapy, the monocytic switch was not associated with a higher incidence of relapse and poorer prognosis in patients undergoing standard ALL treatment.
Introduction
We recently described a pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) subtype with an early switch towards the monocytic lineage.1 Such a monocytic switch leads to a variable degree of monocytosis in the early phase of treatment. The switched monocytic cells (“monocytoids”) have significantly dimin- ished expression of immature or lymphoid markers (i.e., CD19 and CD34) and upreg- ulated myeloid markers (i.e., CD33 and CD14) while keeping shared immunoglobu- lin/T-cell receptor (IG/TR) rearrangements with malignant B lymphoblasts. The increase in monocytoid cells was most prominent at days 8 and 15 after the start of therapy, although the proportion differed between the patients. We reported frequent expression of CD2 and a higher prevalence of ERG deletions and IKZF1 gene alter- ations in this leukemia subtype than in other subtypes.1 However, at that time, we
Correspondence:
ESTER MEJSTRIKOVA
ester.mejstrikova@lfmotol.cuni.cz
Received: February 18, 2020. Accepted: June 25, 2020. Pre-published: July 9, 2020.
https://doi.org/10.3324/haematol.2020.250423
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
2066
haematologica | 2021; 106(8)
ARTICLE