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15 pages, 1367 KiB

Open AccessArticle

Clonal Myeloproliferative Disorders in Patients with Down Syndrome—Treatment and Outcome Results from an Institution in Argentina

by Carla L. Pennella, Tamara Muñoz Cassina, Jorge G. Rossi, Edgardo M. Baialardo, Patricia Rubio, María A. Deu, Luisina Peruzzo, Myriam R. Guitter, Cristian G. Sanchez de La Rosa, Elizabeth M. Alfaro and María S. Felice

Cancers 2022, 14(13), 3286; https://doi.org/10.3390/cancers14133286 - 5 Jul 2022

Cited by 3 | Viewed by 2164

Abstract

Children with Down syndrome (DS) are at an increased risk of developing clonal myeloproliferative disorders. The balance between treatment intensity and treatment-related toxicity has not yet been defined. We analyzed this population to identify risk factors and optimal treatment. This single-center retrospective study [...] Read more.

Children with Down syndrome (DS) are at an increased risk of developing clonal myeloproliferative disorders. The balance between treatment intensity and treatment-related toxicity has not yet been defined. We analyzed this population to identify risk factors and optimal treatment. This single-center retrospective study included 78 DS patients <16 years-old with Transient Abnormal Myelopoiesis (TAM, n = 25), Acute Myeloblastic Leukemia (DS-AML, n = 41) of which 35 had classical Myeloid Leukemia associated with DS (ML-DS) with megakaryoblastic immunophenotype (AMKL) and 6 sporadic DS-AML (non-AMKL). Patients with DS-AML were treated according to four BFM-based protocols. Classical ML-DS vs. non-DS-AMKL were compared and the outcome of ML-DS was analyzed according to treatment intensity. Only four patients with TAM required cytoreduction with a 5-year Event-Free Survival probability (EFSp) of 74.4 (±9.1)%. DS-AML treatment-related deaths were due to infections, with a 5-year EFSp of 60.6 (±8.2)%. Megakaryoblastic immunophenotype was the strongest good-prognostic factor in univariate and multivariate analysis (p = 0.000). When compared ML-DS with non-DS-AMKL, a better outcome was associated with a lower relapse rate (p = 0.0002). Analysis of administered treatment was done on 32/33 ML-DS patients who achieved CR according to receiving or not high-dose ARA-C block (HDARA-C), and no difference in 5-year EFSp was observed (p = 0.172). TAM rarely required treatment and when severe manifestations occurred, early intervention was effective. DS-AML good outcome was associated with AMKL with a low relapse-rate. Even if treatment-related mortality is still high, our data do not support the omission of HDARA-C in ML-DS since we observed a trend to detect a higher relapse rate in the arm without HDARA-C. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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9 pages, 607 KiB

Open AccessArticle

Impact of IKZF1 Deletions in the Prognosis of Childhood Acute Lymphoblastic Leukemia in Argentina

by María Sara Felice, Patricia Laura Rubio, Jorge Digiorge, Mariángeles Barreda Frank, Celeste Sabrina Martínez, Myriam Ruth Guitter, Elisa Olga Sajaroff, Cristian Germán Sánchez La Rosa, Carla Luciana Pennella, Luisina Belén Peruzzo, María Alejandra Deu, Elizabeth Melania Alfaro, María Constanza Guardia, Gladys Gutierrez, María Angelica Fernández Barbieri, Ezequiel Recondo, María Soledad Vides Herrera, Vanina Livio, Constanza Arnaiz, Carolina Romero, Cristina Noemi Alonso and Jorge Gabriel Rossi Show full author list Hide full author list

Cancers 2022, 14(13), 3283; https://doi.org/10.3390/cancers14133283 - 5 Jul 2022

Cited by 5 | Viewed by 2352

Abstract

An association of deletions in the IKZF1 gene (IKZF1del) with poor prognosis in acute lymphoblastic leukemia (ALL) has been demonstrated. Additional deletions in other genes (IKZF1plus) define different IKZF1del subsets. We analyzed the influence of IKZF1del and/or IKZF1plus in the survival of children [...] Read more.

An association of deletions in the IKZF1 gene (IKZF1del) with poor prognosis in acute lymphoblastic leukemia (ALL) has been demonstrated. Additional deletions in other genes (IKZF1plus) define different IKZF1del subsets. We analyzed the influence of IKZF1del and/or IKZF1plus in the survival of children with ALL. From October 2009 to July 2021, 1055 bone marrow samples from patients with ALL were processed by Multiplex ligation-dependent probe amplification (MLPA). Of them, 28 patients died during induction and 4 were lost-in-follow-up, resulting in an eligible 1023 cases. All patients were treated according to ALLIC-BFM-2009-protocol. Patients were classified into three subsets: IKZF1not-deleted (IKZFF1not-del), IKZF1deleted (IKZF1del) and IKZF1del plus deletion of PAX5, CDKN2A, CDKN2B and/or alterations in CRLF2 with ERG-not-deleted (IKZF1plus). The LFSp and SE were calculated with the Kaplan–Meier calculation and compared with a log-rank test. From the 1023 eligible patients, 835 (81.6%) were defined as IKZF1not-del, 94 (9.2%) as IKZF1del and 94 (9.2%) as IKZF1plus. Of them, 100 (9.8%) corresponded to Standard-Risk (SRG), 629 (61.5%) to Intermediate-Risk (IRG) and 294 (28.7%) to High-Risk (HRG) groups. LFSp(SE) was 7 5(2)% for IKZF1not-del, 51 (6)% for IKZF1del and 48 (6)% for IKZF1plus (p-value < 0.00001). LFSp(SE) according to the risk groups was: in SRG, 91 (4)% for IKZF1not-del, 50 (35)% IKZF1del and 100% IKZF1plus (p-value = ns); in IRG, 77 (2)% IKZF1not-del, 61 (10)% IKZF1del and 54 (7)% IKZF1plus (p-value = 0.0005) and in HRG, 61 (4)% IKZF1not-del, 38 (8)% IKZF1del and 35 (9)% IKZF1plus (p-value = 0.0102). The IKZF1 status defines a population of patients with a poor outcome, mainly in IRG. No differences were observed between IKZF1del versus IKZF1plus. MLPA studies should be incorporated into the risk-group stratification of pediatric ALL. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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16 pages, 1960 KiB

Open AccessArticle

An Extensive Quality Control and Quality Assurance (QC/QA) Program Significantly Improves Inter-Laboratory Concordance Rates of Flow-Cytometric Minimal Residual Disease Assessment in Acute Lymphoblastic Leukemia: An I-BFM-FLOW-Network Report

by Margarita Maurer-Granofszky, Angela Schumich, Barbara Buldini, Giuseppe Gaipa, Janos Kappelmayer, Ester Mejstrikova, Leonid Karawajew, Jorge Rossi, Adın Çınar Suzan, Evangelina Agriello, Theodora Anastasiou-Grenzelia, Virna Barcala, Gábor Barna, Drago Batinić, Jean-Pierre Bourquin, Monika Brüggemann, Karolina Bukowska-Strakova, Hasan Burnusuzov, Daniela Carelli, Günnur Deniz, Klara Dubravčić, Tamar Feuerstein, Marie Isabel Gaillard, Adriana Galeano, Hugo Giordano, Alejandro Gonzalez, Stefanie Groeneveld-Krentz, Zsuzsanna Hevessy, Ondrej Hrusak, Maria Belen Iarossi, Pál Jáksó, Veronika Kloboves Prevodnik, Saskia Kohlscheen, Elena Kreminska, Oscar Maglia, Cecilia Malusardi, Neda Marinov, Bibiana Maria Martin, Claudia Möller, Sergey Nikulshin, Jorge Palazzi, Georgios Paterakis, Alexander Popov, Richard Ratei, Cecilia Rodríguez, Elisa Olga Sajaroff, Simona Sala, Gordana Samardzija, Mary Sartor, Pamela Scarparo, Łukasz Sędek, Bojana Slavkovic, Liliana Solari, Peter Svec, Tomasz Szczepanski, Anna Taparkou, Montserrat Torrebadell, Marianna Tzanoudaki, Elena Varotto, Helly Vernitsky, Andishe Attarbaschi, Martin Schrappe, Valentino Conter, Andrea Biondi, Marisa Felice, Myriam Campbell, Csongor Kiss, Giuseppe Basso, Michael N. Dworzak and on behalf of I-BFM-FLOW-Network Show full author list Hide full author list

Cancers 2021, 13(23), 6148; https://doi.org/10.3390/cancers13236148 - 6 Dec 2021

Cited by 24 | Viewed by 4657

Abstract

Monitoring of minimal residual disease (MRD) by flow cytometry (FCM) is a powerful prognostic tool for predicting outcomes in acute lymphoblastic leukemia (ALL). To apply FCM-MRD in large, collaborative trials, dedicated laboratory staff must be educated to concordantly high levels of expertise and [...] Read more.

Monitoring of minimal residual disease (MRD) by flow cytometry (FCM) is a powerful prognostic tool for predicting outcomes in acute lymphoblastic leukemia (ALL). To apply FCM-MRD in large, collaborative trials, dedicated laboratory staff must be educated to concordantly high levels of expertise and their performance quality should be continuously monitored. We sought to install a unique and comprehensive training and quality control (QC) program involving a large number of reference laboratories within the international Berlin-Frankfurt-Münster (I-BFM) consortium, in order to complement the standardization of the methodology with an educational component and persistent quality control measures. Our QC and quality assurance (QA) program is based on four major cornerstones: (i) a twinning maturation program, (ii) obligatory participation in external QA programs (spiked sample send around, United Kingdom National External Quality Assessment Service (UK NEQAS)), (iii) regular participation in list-mode-data (LMD) file ring trials (FCM data file send arounds), and (iv) surveys of independent data derived from trial results. We demonstrate that the training of laboratories using experienced twinning partners, along with continuous educational feedback significantly improves the performance of laboratories in detecting and quantifying MRD in pediatric ALL patients. Overall, our extensive education and quality control program improved inter-laboratory concordance rates of FCM-MRD assessments and ultimately led to a very high conformity of risk estimates in independent patient cohorts. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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16 pages, 1744 KiB

Open AccessArticle

Transcriptional and Mutational Profiling of B-Other Acute Lymphoblastic Leukemia for Improved Diagnostics

by Philippe Chouvarine, Željko Antić, Jana Lentes, Charlotte Schröder, Julia Alten, Monika Brüggemann, Enrique Carrillo-de Santa Pau, Thomas Illig, Teresa Laguna, Denis Schewe, Martin Stanulla, Ming Tang, Martin Zimmermann, Martin Schrappe, Brigitte Schlegelberger, Gunnar Cario and Anke K. Bergmann

Cancers 2021, 13(22), 5653; https://doi.org/10.3390/cancers13225653 - 12 Nov 2021

Cited by 11 | Viewed by 3304

Abstract

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common cancer in children, and significant progress has been made in diagnostics and the treatment of this disease based on the subtypes of BCP-ALL. However, in a large proportion of cases (B-other), recurrent BCP-ALL-associated [...] Read more.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common cancer in children, and significant progress has been made in diagnostics and the treatment of this disease based on the subtypes of BCP-ALL. However, in a large proportion of cases (B-other), recurrent BCP-ALL-associated genomic alterations remain unidentifiable by current diagnostic procedures. In this study, we performed RNA sequencing and analyzed gene fusions, expression profiles, and mutations in diagnostic samples of 185 children with BCP-ALL. Gene expression clustering showed that a subset of B-other samples partially clusters with some of the known subgroups, particularly DUX4-positive. Mutation analysis coupled with gene expression profiling revealed the presence of distinctive BCP-ALL subgroups, characterized by the presence of mutations in known ALL driver genes, e.g., PAX5 and IKZF1. Moreover, we identified novel fusion partners of lymphoid lineage transcriptional factors ETV6, IKZF1 and PAX5. In addition, we report on low blast count detection thresholds and show that the use of EDTA tubes for sample collection does not have adverse effects on sequencing and downstream analysis. Taken together, our findings demonstrate the applicability of whole-transcriptome sequencing for personalized diagnostics in pediatric ALL, including tentative classification of the B-other cases that are difficult to diagnose using conventional methods. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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18 pages, 3052 KiB

Open AccessArticle

Recent Advances in the Management of Pediatric Acute Myeloid Leukemia—Report of the Hungarian Pediatric Oncology-Hematology Group

by Zsuzsanna Gaál, Zsuzsanna Jakab, Bettina Kárai, Anikó Ujfalusi, Miklós Petrás, Krisztián Kállay, Ágnes Kelemen, Réka Simon, Gergely Kriván, Gábor T. Kovács, Csongor Kiss and István Szegedi

Cancers 2021, 13(20), 5078; https://doi.org/10.3390/cancers13205078 - 11 Oct 2021

Cited by 1 | Viewed by 2553

Abstract

Outcome measures of pediatric acute myeloid leukemia (AML) improved considerably between 1990 and 2011 in Hungary. Since 2012, efforts of the Hungarian Pediatric Oncology-Hematology Group (HPOG) included the reduction in the number of treatment centers, contemporary diagnostic procedures, vigorous supportation, enhanced access to [...] Read more.

Outcome measures of pediatric acute myeloid leukemia (AML) improved considerably between 1990 and 2011 in Hungary. Since 2012, efforts of the Hungarian Pediatric Oncology-Hematology Group (HPOG) included the reduction in the number of treatment centers, contemporary diagnostic procedures, vigorous supportation, enhanced access to hematopoietic stem cell transplantation (HSCT), and to targeted therapies. The major aim of our study was to evaluate AML treatment results of HPOG between 2012 and 2019 with 92 new patients registered (52 males, 40 females, mean age 7.28 years). Two periods were distinguished: 2012–2015 and 2016–2019 (55 and 37 patients, respectively). During these periods, 2 y OS increased from 63.6% to 71.4% (p = 0.057), and the 2 y EFS increased significantly from 56.4% to 68.9% (p = 0.02). HSCT was performed in 37 patients (5 patients received a second HSCT). We demonstrate advances in the diagnosis and treatment of acute promyelocytic leukemia (APL) in two cases. Early diagnosis and follow-up were achieved by multidimensional flow cytometry and advanced molecular methods. Both patients were successfully treated with all-trans retinoic acid and arsenic-trioxide, in addition to chemotherapy. In order to meet international standards of pediatric AML management, HPOG will further centralize treatment centers and diagnostic facilities and join efforts with international study groups. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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14 pages, 3255 KiB

Open AccessArticle

A Novel Method for the Evaluation of Bone Marrow Samples from Patients with Pediatric B-Cell Acute Lymphoblastic Leukemia—Multidimensional Flow Cytometry

by Bettina Kárai, Katalin Tisza, Orsolya Eperjesi, Attila Csaba Nagy, Anikó Ujfalusi, Ágnes Kelemen, István Szegedi, Csongor Kiss, János Kappelmayer and Zsuzsanna Hevessy

Cancers 2021, 13(20), 5044; https://doi.org/10.3390/cancers13205044 - 9 Oct 2021

Cited by 2 | Viewed by 2383

Abstract

Multicolor flow cytometry (FC) evaluation has a key role in the diagnosis and prognostic stratification of ALL. Our aim was to create new analyzing protocols using multidimensional dot-plots. Seventy-two pediatric patients with ALL were included in this single-center study. Data of a normal [...] Read more.

Multicolor flow cytometry (FC) evaluation has a key role in the diagnosis and prognostic stratification of ALL. Our aim was to create new analyzing protocols using multidimensional dot-plots. Seventy-two pediatric patients with ALL were included in this single-center study. Data of a normal BM sample and three BM samples of patients with BCP-ALL were merged, then all B cell populations of the four samples were presented in a single radar dot-plot, and those parameters and locations were selected in which the normal and pathological cell populations differed from each other the most. The integrated profile of immunophenotype resulted in a simple, rapid, and accurate method. There were no significant differences between the percentages of lymphoblasts in the detection of minimal residual disease (MRD) by multidimensional or conventional FC method (p = 0.903 at Day 15 and p = 0.155 at Day 33). Furthermore, we found associations between the position and the number of clusters of blast cells in the radar plots and cytogenetic properties (p = 0.002 and p < 0.0001 by the position and p = 0.02 by the number of subclones). FC analysis based on multidimensional dot-plots is not only a rapid, easy-to-use method, but can also provide additional information to screen cases which require detailed genetic examination. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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14 pages, 1094 KiB

Open AccessArticle

Impact of KMT2A Rearrangement and CSPG4 Expression in Pediatric Acute Myeloid Leukemia

by Lina Marie Hoffmeister, Eser Orhan, Christiane Walter, Naghmeh Niktoreh, Helmut Hanenberg, Nils von Neuhoff, Dirk Reinhardt and Markus Schneider

Cancers 2021, 13(19), 4817; https://doi.org/10.3390/cancers13194817 - 26 Sep 2021

Cited by 6 | Viewed by 3439

Abstract

KMT2A rearrangements (KMT2A-r) are among the most common structural aberrations in pediatric acute myeloid leukemia (AML) and are very important for the risk group stratification of patients. Here, we report the outcome of 967 pediatric AML patients with a known KMT2A [...] Read more.

KMT2A rearrangements (KMT2A-r) are among the most common structural aberrations in pediatric acute myeloid leukemia (AML) and are very important for the risk group stratification of patients. Here, we report the outcome of 967 pediatric AML patients with a known KMT2A-r status. The large cohort was characterized by morphology, multicolor flow cytometry, classical cytogenetics and mutation analysis via panel sequencing. In total, the blasts of 241 patients (24.9%) showed KMT2A-r. KMT2A-r is associated with FAB M5, a high white blood cell count and younger age at diagnosis. When subgroups were combined, KMT2A-r had no impact on event-free survival (EFS) and overall survival (OS); however, various subgroups showed a different prognosis, ranging from a <50% OS for KMT2A/AFDN (n = 11) to a 100% chance of survival for patients harboring the rare translocation KMT2A/SEPTIN9 (n = 3, follow up of 3.7 to 9.6 years). A positive correlation of KMT2A-r with KRAS mutations (p < 0.001) existed, albeit without any prognostic impact. In addition, FLT3-ITDs were detected less frequently in AML with KMT2A-r (p < 0.001). Furthermore, KMT2A-r were mutually exclusive, with mutations in NPM1 (p = 0.002), KIT (p = 0.036), WT1 (p < 0.001) and CEBPA (p = 0.006), and translocations NUP98/NSD1 (p = 0.009), RUNX1/RUNX1T1 (p = 0.003) and CBFB/MYH11 (p = 0.006). In the 346 patients tested for CSPG4 expression, a correlation between CSPG4 expression and KMT2A-r was confirmed. However, CSPG4 expression also occurred in patients without KMT2A-r and had no significant prognostic impact on EFS and OS. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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19 pages, 2089 KiB

Open AccessArticle

Advances in the First Line Treatment of Pediatric Acute Myeloid Leukemia in the Polish Pediatric Leukemia and Lymphoma Study Group from 1983 to 2019

by Małgorzata Czogała, Walentyna Balwierz, Katarzyna Pawińska-Wąsikowska, Teofila Książek, Karolina Bukowska-Strakova, Wojciech Czogała, Barbara Sikorska-Fic, Michał Matysiak, Jolanta Skalska-Sadowska, Jacek Wachowiak, Małgorzata Moj-Hackemer, Krzysztof Kałwak, Katarzyna Muszyńska-Rosłan, Maryna Krawczuk-Rybak, Dominik Grabowski, Jerzy Kowalczyk, Lucyna Maciejka-Kembłowska, Ninela Irga-Jaworska, Katarzyna Bobeff, Wojciech Młynarski, Renata Tomaszewska, Tomasz Szczepański, Agnieszka Chodała-Grzywacz, Grażyna Karolczyk, Agnieszka Mizia-Malarz, Katarzyna Mycko, Wanda Badowska, Karolina Zielezińska, Tomasz Urasiński, Justyna Urbańska-Rakus, Małgorzata Ciebiera, Radosław Chaber, Natalia Bartoszewicz, Mariusz Wysocki and Szymon Skoczeń Show full author list Hide full author list

Cancers 2021, 13(18), 4536; https://doi.org/10.3390/cancers13184536 - 9 Sep 2021

Cited by 12 | Viewed by 3417

Abstract

Background: From 1983, standardized therapeutic protocols for pediatric acute myeloid leukemia (AML) based on the BFM group experience were introduced in Poland. We retrospectively analyzed the results of pediatric AML treatment in Poland from 1983 to 2019 (excluding promyelocytic, therapy-related, biphenotypic, and Down [...] Read more.

Background: From 1983, standardized therapeutic protocols for pediatric acute myeloid leukemia (AML) based on the BFM group experience were introduced in Poland. We retrospectively analyzed the results of pediatric AML treatment in Poland from 1983 to 2019 (excluding promyelocytic, therapy-related, biphenotypic, and Down syndrome AML). Methods: The study included 899 children suffering from AML treated with the following: AML-PPPLBC 83 (1983–1993, n = 187), AML-PPGLBC 94 (1994–1997, n = 74), AML-PPGLBC 98 (1998–2004, n = 151), AML-BFM 2004 Interim (2004–2015, n = 356), and AML-BFM 2012 (2015–2019, n = 131). Results: The probability of three-year overall survival was 0.34 ± 0.03, 0.37 ± 0.05, 0.54 ± 0.04, 0.67 ± 0.03, and 0.75 ± 0.05; event-free survival was 0.31 ± 0.03, 0.34 ± 0.05, 0.44 ± 0.04, 0.53 ± 0.03, and 0.67 ± 0.05; and relapse-free survival was 0.52 ± 0.03, 0.65 ± 0.05, 0.58 ± 0.04, 0.66 ± 0.03, and 0.78 ± 0.05, respectively, in the subsequent periods. A systematic reduction of early deaths and deaths in remission was achieved, while the percentage of relapses decreased only in the last therapeutic period. Surprisingly good results were obtained in the group of patients treated with AML-BFM 2012 with unfavorable genetic abnormalities like KMT2A-MLLT10/t(10;11)(p12;q23) and DEK-NUP214/t(6;9)(p23;q24), while unsatisfactory outcomes were found in the patients with FLT3-ITD. Conclusions: The use of standardized, systematically modified therapeutic protocols, with the successive consideration of genetic prognostic factors, and advances in supportive care led to a significant improvement in AML treatment outcomes over the last 40 years. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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19 pages, 13740 KiB

Open AccessArticle

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

by Jonathan Lukas Lühmann, Marie Stelter, Marie Wolter, Josephine Kater, Jana Lentes, Anke Katharina Bergmann, Maximilian Schieck, Gudrun Göhring, Anja Möricke, Gunnar Cario, Markéta Žaliová, Martin Schrappe, Brigitte Schlegelberger, Martin Stanulla and Doris Steinemann

Cancers 2021, 13(17), 4388; https://doi.org/10.3390/cancers13174388 - 30 Aug 2021

Cited by 39 | Viewed by 4756

Abstract

Acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer occurring in children. ALL is characterized by structural and numeric genomic aberrations that strongly correlate with prognosis and clinical outcome. Usually, a combination of cyto- and molecular genetic methods (karyotyping, array-CGH, FISH, [...] Read more.

Acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer occurring in children. ALL is characterized by structural and numeric genomic aberrations that strongly correlate with prognosis and clinical outcome. Usually, a combination of cyto- and molecular genetic methods (karyotyping, array-CGH, FISH, RT-PCR, RNA-Seq) is needed to identify all aberrations relevant for risk stratification. We investigated the feasibility of optical genome mapping (OGM), a DNA-based method, to detect these aberrations in an all-in-one approach. As proof of principle, twelve pediatric ALL samples were analyzed by OGM, and results were validated by comparing OGM data to results obtained from routine diagnostics. All genomic aberrations including translocations (e.g., dic(9;12)), aneuploidies (e.g., high hyperdiploidy) and copy number variations (e.g., IKZF1, PAX5) known from other techniques were also detected by OGM. Moreover, OGM was superior to well-established techniques for resolution of the more complex structure of a translocation t(12;21) and had a higher sensitivity for detection of copy number alterations. Importantly, a new and unknown gene fusion of JAK2 and NPAT due to a translocation t(9;11) was detected. We demonstrate the feasibility of OGM to detect well-established as well as new putative prognostic markers in an all-in-one approach in ALL. We hope that these limited results will be confirmed with testing of more samples in the future. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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16 pages, 962 KiB

Open AccessArticle

Copy Number Alteration Profile Provides Additional Prognostic Value for Acute Lymphoblastic Leukemia Patients Treated on BFM Protocols

by Μirella Αmpatzidou, Lina Florentin, Vassilios Papadakis, Georgios Paterakis, Marianna Tzanoudaki, Dimitra Bouzarelou, Stefanos I. Papadhimitriou and Sophia Polychronopoulou

Cancers 2021, 13(13), 3289; https://doi.org/10.3390/cancers13133289 - 30 Jun 2021

Cited by 7 | Viewed by 2614

Abstract

We present our data of a novel proposed CNA-profile risk-index, applied on a Greek ALLIC-BFM-treated cohort, aiming at further refining genomic risk-stratification. Eighty-five of 227 consecutively treated ALL patients were analyzed for the copy-number-status of eight genes (IKZF1/CDKN2A/2B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1). Using the MLPA-assay, patients were [...] Read more.

We present our data of a novel proposed CNA-profile risk-index, applied on a Greek ALLIC-BFM-treated cohort, aiming at further refining genomic risk-stratification. Eighty-five of 227 consecutively treated ALL patients were analyzed for the copy-number-status of eight genes (IKZF1/CDKN2A/2B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1). Using the MLPA-assay, patients were stratified as: (1) Good-risk(GR)-CNA-profile (n = 51), with no deletion of IKZF1/CDKN2A/B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1 or isolated deletions of ETV6/PAX5/BTG1 or ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. (2) Poor-risk(PR)-CNA-profile (n = 34), with any deletion of ΙΚΖF1/PAR1/EBF1/RB1 or any other CNA. With a median follow-up time of 49.9 months, EFS for GR-CNA-profile and PR-CNA-profile patients was 96.0% vs. 57.6% (p < 0.001). For IR-group and HR-group patients, EFS for the GR-CNA/PR-CNA subgroups was 100.0% vs. 60.0% (p < 0.001) and 88.2% vs. 55.6% (p = 0.047), respectively. Among FC-MRD_d15 + patients (MRD_d15 ≥ 10⁻⁴), EFS rates were 95.3% vs. 51.7% for GR-CNA/PR-CNA subjects (p < 0.001). Similarly, among FC-MRD_d33 + patients (MRD_d33 ≥ 10⁻⁴), EFS was 92.9% vs. 27.3% (p < 0.001) and for patients FC-MRD_d33 − (MRD_d33 < 10⁻⁴), EFS was 97.2% vs. 72.7% (p = 0.004), for GR-CNA/PR-CNA patients, respectively. In a multivariate analysis, the CNA-profile was the most important outcome predictor. In conclusion, the CNA-profile can establish a new genomic risk-index, identifying a distinct subgroup with increased relapse risk among the IR-group, as well as a subgroup of patients with superior prognosis among HR-patients. The CNA-profile is feasible in BFM-based protocols, further refining MRD-based risk-stratification. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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16 pages, 1956 KiB

Open AccessArticle

Pharmacogenetics of the Central Nervous System—Toxicity and Relapse Affecting the CNS in Pediatric Acute Lymphoblastic Leukemia

by Judit C. Sági, András Gézsi, Bálint Egyed, Zsuzsanna Jakab, Noémi Benedek, Andishe Attarbaschi, Stefan Köhrer, Jakub Sipek, Lucie Winkowska, Marketa Zaliova, Stavroula Anastasopoulou, Benjamin Ole Wolthers, Susanna Ranta, Csaba Szalai, Gábor T. Kovács, Ágnes F. Semsei and Dániel J. Erdélyi

Cancers 2021, 13(10), 2333; https://doi.org/10.3390/cancers13102333 - 12 May 2021

Cited by 2 | Viewed by 3746

Abstract

Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty [...] Read more.

Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations’ matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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22 pages, 1011 KiB

Open AccessReview

Single-Cell Sequencing: Biological Insight and Potential Clinical Implications in Pediatric Leukemia

by Donát Alpár, Bálint Egyed, Csaba Bödör and Gábor T. Kovács

Cancers 2021, 13(22), 5658; https://doi.org/10.3390/cancers13225658 - 12 Nov 2021

Cited by 6 | Viewed by 3609

Abstract

Single-cell sequencing (SCS) provides high-resolution insight into the genomic, epigenomic, and transcriptomic landscape of oncohematological malignancies including pediatric leukemia, the most common type of childhood cancer. Besides broadening our biological understanding of cellular heterogeneity, sub-clonal architecture, and regulatory network of tumor cell populations, [...] Read more.

Single-cell sequencing (SCS) provides high-resolution insight into the genomic, epigenomic, and transcriptomic landscape of oncohematological malignancies including pediatric leukemia, the most common type of childhood cancer. Besides broadening our biological understanding of cellular heterogeneity, sub-clonal architecture, and regulatory network of tumor cell populations, SCS can offer clinically relevant, detailed characterization of distinct compartments affected by leukemia and identify therapeutically exploitable vulnerabilities. In this review, we provide an overview of SCS studies focused on the high-resolution genomic and transcriptomic scrutiny of pediatric leukemia. Our aim is to investigate and summarize how different layers of single-cell omics approaches can expectedly support clinical decision making in the future. Although the clinical management of pediatric leukemia underwent a spectacular improvement during the past decades, resistant disease is a major cause of therapy failure. Currently, only a small proportion of childhood leukemia patients benefit from genomics-driven therapy, as 15–20% of them meet the indication criteria of on-label targeted agents, and their overall response rate falls in a relatively wide range (40–85%). The in-depth scrutiny of various cell populations influencing the development, progression, and treatment resistance of different disease subtypes can potentially uncover a wider range of driver mechanisms for innovative therapeutic interventions. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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14 pages, 975 KiB

Open AccessReview

The Microbiome in Childhood Acute Lymphoblastic Leukemia

by Marina Oldenburg, Nadine Rüchel, Stefan Janssen, Arndt Borkhardt and Katharina L. Gössling

Cancers 2021, 13(19), 4947; https://doi.org/10.3390/cancers13194947 - 30 Sep 2021

Cited by 19 | Viewed by 4969

Abstract

For almost 30 years, the term “holobiont” has referred to an ecological unit where a host (e.g., human) and all species living in or around it are considered together. The concept highlights the complex interactions between the host and the other species, which, [...] Read more.

For almost 30 years, the term “holobiont” has referred to an ecological unit where a host (e.g., human) and all species living in or around it are considered together. The concept highlights the complex interactions between the host and the other species, which, if disturbed may lead to disease and premature aging. Specifically, the impact of microbiome alterations on the etiology of acute lymphoblastic leukemia (ALL) in children is not fully understood, but has been the focus of much research in recent years. In ALL patients, significant reductions in microbiome diversity are already observable at disease onset. It remains unclear whether such alterations at diagnosis are etiologically linked with leukemogenesis or simply due to immunological alteration preceding ALL onset. Regardless, all chemotherapeutic treatment regimens severely affect the microbiome, accompanied by severe side effects, including mucositis, systemic inflammation, and infection. In particular, dominance of Enterococcaceae is predictive of infections during chemotherapy. Long-term dysbiosis, like depletion of Faecalibacterium, has been observed in ALL survivors. Modulation of the microbiome (e.g., by fecal microbiota transplant, probiotics, or prebiotics) is currently being researched for potential protective effects. Herein, we review the latest microbiome studies in pediatric ALL patients. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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13 pages, 814 KiB

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Pediatric Mixed-Phenotype Acute Leukemia: What’s New?

by Sandeep Batra and Anthony John Ross

Cancers 2021, 13(18), 4658; https://doi.org/10.3390/cancers13184658 - 16 Sep 2021

Cited by 13 | Viewed by 6230

Abstract

Mixed-phenotype acute leukemias (MPAL) are rare in children and often lack consensus on optimal management. This review examines the current controversies and emerging paradigms in the management of pediatric MPAL. We examine risk stratification, outcomes of recent retrospective and prospective collaborative trials, and [...] Read more.

Mixed-phenotype acute leukemias (MPAL) are rare in children and often lack consensus on optimal management. This review examines the current controversies and emerging paradigms in the management of pediatric MPAL. We examine risk stratification, outcomes of recent retrospective and prospective collaborative trials, and the role of transplantation and precision genomics, and outline emerging targets and concepts in this rare entity. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric Acute Leukemia)

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