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Recent Developments of Hematologic Diagnostics in the Interplay with Evolving Treatment Developments

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 24329

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Special Issue Editors

Prof. Dr. Vera Ulrike Bacher

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Guest Editor

Department of Hematology, University Hospital Bern, 3010 Bern, Switzerland
Interests: hematologic diagnostics; flow cytometry; cytomorphology; molecular genetics; measurable disease diagnostics; acute leukemias; chronic leukemias; lymphomas; myeloma; personalized therapies; interaction of diagnostics and therapies in hematology; prognosis; predictive markers
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Thomas Pabst

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Guest Editor

Department of Oncology, Inselspital Bern, University of Bern, Freiburgstrasse 41G, CH-3010 Bern, Switzerland
Interests: hemato-oncologic diagnostics; myeloid malignancies; plasma cell disorders; leukemia and myeloma therapy; CAR-T cell therapy

Special Issue Information

Dear Colleagues,

Hematologic diagnostics underwent a rapid expansion in recent years, mainly due to the introduction of next-generation sequencing (NGS) and improved minimal residual disease (MRD) strategies. At the same time, with the expansion of therapeutic options for hematologic malignancies by kinase inhibitors, monoclonal antibodies, as well as novel immunotherapeutic approaches by CAR-T cells and bispecific antibodies, individualized treatment strategies become increasingly available for patients both at diagnosis or at relapse with myeloid or lymphoproliferative malignancies. This specific issue illustrates the current landscape of diagnostic options for patients with hemato-oncologic malignancies at first manifestation and at follow-up, and it provides insights into the interaction of these emerging diagnostic possibilities together with established and novel therapeutic options. Future perspectives for further optimizing this interplay between diagnostics and therapeutic options are discussed.

Prof. Dr. Ulrike Bacher
Prof. Dr. Thomas Pabst
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

hematologic diagnostics
next-generation sequencing (NGS)
flow cytometry
therapeutic targets
hemato-oncologic therapy
interaction

Published Papers (7 papers)

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Research

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17 pages, 2459 KiB

Open AccessArticle

The Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP, and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib

by Pawel Robak, Dariusz Jarych, Damian Mikulski, Izabela Dróżdż, Edyta Węgłowska, Aleksandra Kotkowska, Małgorzata Misiewicz, Piotr Smolewski, Konrad Stawiski, Wojciech Fendler, Janusz Szemraj and Tadeusz Robak

Cancers 2021, 13(5), 951; https://doi.org/10.3390/cancers13050951 - 25 Feb 2021

Cited by 8 | Viewed by 2799

Abstract

Proteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM); however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The aim of our study is to assess the expression of previously described genes that may influence the resistance to bortezomib treatment at the mRNA level (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1) and prognosis of MM patients. mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. RPL5 was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of PSMB5 and CXCR and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of POMP and RPL5 was associated with shorter overall survival. Full article

(This article belongs to the Special Issue Recent Developments of Hematologic Diagnostics in the Interplay with Evolving Treatment Developments)

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16 pages, 2856 KiB

Open AccessArticle

BMI1-Inhibitor PTC596 in Combination with MCL1 Inhibitor S63845 or MEK Inhibitor Trametinib in the Treatment of Acute Leukemia

by Katja Seipel, Basil Kopp, Ulrike Bacher and Thomas Pabst

Cancers 2021, 13(3), 581; https://doi.org/10.3390/cancers13030581 - 02 Feb 2021

Cited by 12 | Viewed by 3007

Abstract

Purpose: Prognosis for acute myeloid leukemia (AML) patients is poor, particularly in TP53 mutated AML, secondary, relapsed, and refractory AML, and in patients unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting the stem cell oncoprotein BMI1 and activating the tumor suppressor protein p53 may represent a promising novel treatment option for poor risk AML patients. Experimental Design: The BMI1 inhibitor PTC596, MCL1 inhibitor S63845, and MEK inhibitor trametinib, as well as the p53 activator APR-246 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including FLT3-ITD and FLT3 wild type, NPM1 mutant and wild type, as well as TP53 mutant and wild type AML cell lines and a variety of patient derived AML cells. Results: AML cell lines were variably susceptible to PTC596 and to combination treatments with PTC596 and MCL1 inhibitor S63845, MEK inhibitor trametinib, or TP53 activator APR-246, independent of TP53 mutational status. Susceptibility of patient samples for PTC596 in combination with S63845 or trametinib was significant for the majority of adverse risk primary and secondary AML with minimal efficacy in favorable risk AML, and correlated significantly with CD34 positivity of the samples. BMI1 and MN1 gene expression, and MCL1 and MEK1 protein levels were identified as biomarkers for response to PTC596 combination treatments. Conclusions: The combination of PTC596 and S63845 may be an effective treatment in CD34+ adverse risk AML with elevated MN1 gene expression and MCL1 protein levels, while PTC596 and trametinib may be more effective in CD34+ adverse risk AML with elevated BMI1 gene expression and MEK protein levels. Full article

(This article belongs to the Special Issue Recent Developments of Hematologic Diagnostics in the Interplay with Evolving Treatment Developments)

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13 pages, 5093 KiB

Open AccessArticle

Automated Early Detection of Myelodysplastic Syndrome within the General Population Using the Research Parameters of Beckman–Coulter DxH 800 Hematology Analyzer

by Noémie Ravalet, Amélie Foucault, Frédéric Picou, Martin Gombert, Emmanuel Renoult, Julien Lejeune, Nicolas Vallet, Sébastien Lachot, Emmanuelle Rault, Emmanuel Gyan, Marie C. Bene and Olivier Herault

Cancers 2021, 13(3), 389; https://doi.org/10.3390/cancers13030389 - 21 Jan 2021

Cited by 11 | Viewed by 2536

Abstract

The incidence of myelodysplastic syndrome increases with aging and the early diagnosis enables optimal care of these diseases. The DxH 800 hematology analyzer measures and calculates 126 cytological parameters, but only 23 are used for routine CBC assessment. The goal of this study was to use the 103 unexploited “research parameters” to develop an algorithm allowing for an early detection of subclinical MDS patients by triggering morphological analysis. Blood sample parameters from 101 MDS patients and 88 healthy volunteers were analyzed to identify the critical “research parameters” with: (i) the most significant differences between MDS patients and healthy volunteers, (ii) the best contributions to principal component analysis (PCA), first axis, and (iii) the best correlations with PCA, first two axes (cos² > 0.6). Ten critical “research parameters” of white blood cells were identified, allowing for the calculation of an MDS-likelihood score (MDS-LS), based on logistic regression. Automatic calculation of the MDS-LS is easily implementable on the middleware system of the DxH 800 to generate a flag for blood smear review, and possibly early detection of MDS patients in the general population. Full article

(This article belongs to the Special Issue Recent Developments of Hematologic Diagnostics in the Interplay with Evolving Treatment Developments)

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9 pages, 1753 KiB

Open AccessArticle

Detection of Pathogenic Isoforms of IKZF1 in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15

by Weiqiang Zhao, Ying Li, Chenjiao Yao, Guojuan Zhang, Kevin Y. Zhao, Wei Chen, Peng Ru, Xiaokang Pan, Huolin Tu and Daniel Jones

Cancers 2020, 12(11), 3161; https://doi.org/10.3390/cancers12113161 - 28 Oct 2020

Cited by 2 | Viewed by 2326

Abstract

Leukemia-associated alternative splicing of IKZF1 can result in proteins with loss of one to four copies of its N-terminal zinc finger domains (N-ZnF). The best characterized pathogenic splice isoforms, Ik-6 and Ik-8, have been commonly found in BCR-ABL1+ acute lymphoblastic leukemia (ALL) and a subset of BCR-ABL1-like ALL. Infantile and childhood ALL that express these pathogenic IKZF1 isoforms have shown inferior clinical outcomes and can be resistant to tyrosine kinase inhibitors. Using ALL cell lines, we designed and validated a method to detect abnormal IKZF1 transcripts. In the SUP-B15 leukemia cell line, we noted novel IKZF1 transcripts that include both an Ik-6 splice and a transcript with a 14 base pair insertion at the C-terminus. There was also increased IKZF2 protein in SUP-B15 as compared to other ALL lines. Expression of Ik-6 could be suppressed by treatment with the pro-apoptotic type II histone deacetylase inhibitor givinostat. In 17 adult ALL samples, we noted the Ik-6 isoforms in 6 of 15 BCR-ABL1⁻, and 1 of 2 BCR-ABL1⁺ cases, with Ik-8 also expressed in one case. Cases with Ik-6 expression showed inferior survival as well as older age at presentation, lower expression of CD10 and more commonly a diploid karyotype. Full article

(This article belongs to the Special Issue Recent Developments of Hematologic Diagnostics in the Interplay with Evolving Treatment Developments)

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18 pages, 1519 KiB

Open AccessArticle

The Value of Serum MicroRNA Expression Signature in Predicting Refractoriness to Bortezomib-Based Therapy in Multiple Myeloma Patients

by Paweł Robak, Izabela Dróżdż, Dariusz Jarych, Damian Mikulski, Edyta Węgłowska, Monika Siemieniuk-Ryś, Małgorzata Misiewicz, Konrad Stawiski, Wojciech Fendler, Janusz Szemraj, Piotr Smolewski and Tadeusz Robak

Cancers 2020, 12(9), 2569; https://doi.org/10.3390/cancers12092569 - 09 Sep 2020

Cited by 19 | Viewed by 3425

Abstract

Bortezomib is the first-in-class proteasome inhibitor, commonly used in the treatment of multiple myeloma (MM). The mechanisms underlying acquired bortezomib resistance in MM are poorly understood. Several cell-free miRNAs have been found to be aberrantly regulated in MM patients. The aim of this pilot study was to identify a blood-based miRNA signature that predicts bortezomib-based therapy efficacy in MM patients. Thirty MM patients treated with bortezomib-based regimens were studied, including 19 with refractory disease and 11 who were bortezomib sensitive. Serum miRNA expression patterns were identified with miRCURY LNA miRNA miRNome PCR Panels I+II (Exiqon/Qiagen). Univariate analysis found a total of 21 miRNAs to be differentially expressed in patients with MM according to bortezomib sensitivity. Multivariate logistic regression was created and allowed us to discriminate refractory from sensitive patients with a very high AUC of 0.95 (95%CI: 0.84–1.00); sensitivity, specificity and accuracy were estimated as 0.95, 0.91, and 0.93. The model used expression of 3 miRNAs: miR-215-5p, miR-181a-5p and miR-376c-3p. This study is the first to demonstrate that serum expression of several miRNAs differs between patients who are bortezomib refractory and those who are sensitive which may prove useful in studies aimed at overcoming drug resistance in MM treatment. Full article

(This article belongs to the Special Issue Recent Developments of Hematologic Diagnostics in the Interplay with Evolving Treatment Developments)

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12 pages, 2336 KiB

Open AccessArticle

Accurate In-Vivo Quantification of CD19 CAR-T Cells after Treatment with Axicabtagene Ciloleucel (Axi-Cel) and Tisagenlecleucel (Tisa-Cel) Using Digital PCR

by Anita Badbaran, Carolina Berger, Kristoffer Riecken, Anne Kruchen, Maria Geffken, Ingo Müller, Nicolaus Kröger, Francis A. Ayuk and Boris Fehse

Cancers 2020, 12(7), 1970; https://doi.org/10.3390/cancers12071970 - 20 Jul 2020

Cited by 22 | Viewed by 6415

Abstract

Immunotherapy with CD19-specific chimeric antigen receptor (CAR-) T cells has shown excellent efficacy in relapsed/refractory B-cell cancers. The in vivo expansion and persistence of CAR-T cells after infusion are important response- and toxicity-determining variables, but diagnostic tools are largely missing. We showed previously for axi-cel that digital PCR (dPCR) is excellently suited to monitoring CAR-T cells in vivo. Here, we aimed to develop an analogous dPCR assay for tisa-cel. To do so, we cloned and sequenced the CAR construct from the lentiviral tisa-cel vector and designed primers and Black hole quencher (BHQ) probes complimentary to sequences present in the FMC63 scFv part of axi-cel (assay A), tisa-cel (T), and both constructs (U = “universal”). In conjunction with excellent specificity, all assays have a detection limit of one single CAR copy, corresponding to a sensitivity of approximately 1 in 5000 cells (0.02%) for 100 ng genomic DNA (for one vector copy per transduced cell). The new universal assay was first validated using patient samples previously quantified with the axi-cel-specific dPCR and thereafter applied to quantify and monitor adoptively transferred axi-cel and tisa-cel T cells in post-infusion samples (peripheral blood, bone marrow, liquor, and ascites). Actual CAR-T counts per µl were calculated, taking into account vector copy and peripheral blood mononuclear cell (PBMC) numbers, and showed very good correlation with flow cytometry results. We conclude that our novel dPCR assay is optimally suited to monitoring tisa-cel and axi-cel CAR-T cells in real-time in various body fluids. Full article

(This article belongs to the Special Issue Recent Developments of Hematologic Diagnostics in the Interplay with Evolving Treatment Developments)

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Review

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14 pages, 3074 KiB

Open AccessReview

Recent Advances in Molecular Diagnostics and Targeted Therapy of Myeloproliferative Neoplasms

by Simona Stivala and Sara C. Meyer

Cancers 2021, 13(20), 5035; https://doi.org/10.3390/cancers13205035 - 09 Oct 2021

Cited by 1 | Viewed by 2826

Abstract

Somatic mutations in JAK2, calreticulin, and MPL genes drive myeloproliferative neoplasms (MPN), and recent technological advances have revealed a heterogeneous genomic landscape with additional mutations in MPN. These mainly affect genes involved in epigenetic regulation and splicing and are of diagnostic and prognostic value, predicting the risk of progression and informing decisions on therapeutic management. Thus, genetic testing has become an integral part of the current state-of-the-art laboratory work-up for MPN patients and has been implemented in current guidelines for disease classification, tools for prognostic risk assessment, and recommendations for therapy. The finding that JAK2, CALR, and MPL driver mutations activate JAK2 signaling has provided a rational basis for the development of targeted JAK2 inhibitor therapies and has fueled their translation into clinical practice. However, the disease-modifying potential of JAK2 inhibitors remains limited and is further impeded by loss of therapeutic responses in a substantial proportion of patients over time. Therefore, the investigation of additional molecular vulnerabilities involved in MPN pathogenesis is imperative to advance the development of new therapeutic options. Combination of novel compounds with JAK2 inhibitors are of specific interest to enhance therapeutic efficacy of molecularly targeted treatment approaches. Here, we summarize the current insights into the genetic basis of MPN, its use as a diagnostic and prognostic tool in clinical settings, and the most recent advances in targeted therapies for MPN. Full article

(This article belongs to the Special Issue Recent Developments of Hematologic Diagnostics in the Interplay with Evolving Treatment Developments)

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