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Cancers
Special Issues
Hematologic Malignancy
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Hematologic Malignancy

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 58847

Special Issue Editors

Dr. Nicola Stefano Fracchiolla

E-Mail Website
Guest Editor
Hematology - BMT Center, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Via Francesco Sforza 35, 20122 Milan, Italy
Interests: acute leukemias; myelodysplastic syndromes; lymphomas; myelomas; infections in oncohematologic patients
Special Issues, Collections and Topics in MDPI journals
Dr. Francesco Onida

E-Mail Website
Guest Editor
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy
Interests: autologous and allogeneic stem cell transplantation; graft-versus-host disease and other post-transplant complications; myelodysplastic syndromes; chronic myelomonocytic leukemia and other myelodysplastic/myeloproliferative neoplasms; myeloproliferative neoplasms; cutaneous T-cell lymphomas; autologous transplantation in autoimmune diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hematologic malignancies have always represented a highly dynamic field for biologic and translational research, that rapidly impacts the clinical practice.
Recently, the ever more refined risk stratifications, based on molecular biomarkers and minimal residual disease assessment, and the advent of novel targeted agents, have increased the complexity of the clinical approach. Therefore, clinical decision making and patient management has become even more challenging, with particular impact on to allogeneic transplant indications.
The deeper understanding of the biologic characteristics of many hematologic malignancies and in particular of their genomic landscape, allowed the identification of specific therapeutic targets that have profoundly modified the treatment of our patients.
Among these new therapeutic modalities, we can cite in lymphoblastic leukemias and lymphomas the advent of innovative immunologic approaches, such as monoclonal antibodies, Bite, Darts, checkpoint inhibitors and CAR-T cell, while in acute myeloid leukemias the molecular-based therapies and the new cytotoxic formulations, as FLT3 inhibitors, gentuzumab/ozogamycin, CPX351.
In chronic myeloproliferative neoplasms, multiple myeloma and chronic lymphocytic leukemia, a continuous effort is ongoing to tailor the treatment on patients and disease characteristics, to optimize the use of the numerous biologic and targeted therapies
It is therefore a great pleasure to invite you to contribute to the current Special Issue. Its aim is to update biological and clinical aspects of hematologic malignancies, with research as well as review articles addressing the state of the art and the future perspectives of hematologic malignancies, focusing preferentially on innovative research in biology, diagnosis, prognosis and therapy.

Dr. Nicola Stefano Fracchiolla
Prof. Dr. Francesco Onida
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.

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Research

Jump to: Review

11 pages, 955 KiB  
Article
Prognostic Value of FDG-PET/CT Parameters in Patients with Relapse/Refractory Multiple Myeloma before Anti-CD38 Based Therapy
by Guillemette Fouquet, Myriam Wartski, Amina Dechmi, Lise Willems, Bénédicte Deau-Fischer, Patricia Franchi, Justine Descroocq, Paul Deschamps, Estelle Blanc-Autran, Jérôme Clerc, Didier Bouscary, Sylvain Barreau, Nicolas Chapuis, Marguerite Vignon and Anne-Ségolène Cottereau
Cancers 2021, 13(17), 4323; https://doi.org/10.3390/cancers13174323 - 27 Aug 2021
Cited by 3 | Viewed by 1831
Abstract
Although anti-CD38 monoclonal antibodies have improved the prognosis of relapsed/refractory multiple myeloma (RRMM), some patients still experience early relapses with poor outcomes. This present study evaluated the predictive value of FDG PET/CT parameters for RRMM prior to initiating anti-CD38 treatment. We included 38 [...] Read more.
Although anti-CD38 monoclonal antibodies have improved the prognosis of relapsed/refractory multiple myeloma (RRMM), some patients still experience early relapses with poor outcomes. This present study evaluated the predictive value of FDG PET/CT parameters for RRMM prior to initiating anti-CD38 treatment. We included 38 consecutive RRMM patients who underwent a PET/CT scan treated at our institution at relapse. The median PFS was 12.5 months and the median OS was not reached. 42% of the patients had an initial ISS score of 1, 37% of 2, and 21% of 3. The presence of >3 focal lesions (FLs, n = 19) and the ISS score were associated with inferior PFS (p = 0.0036 and p = 0.0026) and OS (p = 0.025 and p = 0.0098). Patients with >3 FLs had a higher initial ISS score (p = 0.028). In multivariable analysis, the ISS score and >3 FLs were independent prognostic factors for PFS (p = 0.010 and p = 0.025 respectively), and combined they individualized a high-risk group with a median PFS and OS of 3.1 months and 8.5 months respectively vs. not reached for the other patients. The presence of >3 FLs on PET was predictive of survival outcomes in patients with RRMM treated using CD38 targeted therapy. Combined with the initial ISS, an ultra-high-risk RRMM population can thus be identified. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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10 pages, 1586 KiB  
Article
An Improved Animal Model of Multiple Myeloma Bone Disease
by Syed Hassan Mehdi, Carol A Morris, Jung Ae Lee and Donghoon Yoon
Cancers 2021, 13(17), 4277; https://doi.org/10.3390/cancers13174277 - 25 Aug 2021
Cited by 3 | Viewed by 3196
Abstract
Multiple myeloma (MM) is a plasma cell malignancy that causes an accumulation of terminally differentiated monoclonal plasma cells in the bone marrow, accompanied by multiple myeloma bone disease (MMBD). MM animal models have been developed and enable to interrogate the mechanism of MM [...] Read more.
Multiple myeloma (MM) is a plasma cell malignancy that causes an accumulation of terminally differentiated monoclonal plasma cells in the bone marrow, accompanied by multiple myeloma bone disease (MMBD). MM animal models have been developed and enable to interrogate the mechanism of MM tumorigenesis. However, these models demonstrate little or no evidence of MMBD. We try to establish the MMBD model with severe bone lesions and easily accessible MM progression. 1 × 106 luciferase-expressing 5TGM1 cells were injected into 8–12 week-old NOD SCID gamma mouse (NSG) and C57BL/KaLwRij mouse via the tail vein. Myeloma progression was assessed weekly via in vivo bioluminescence (BL) imaging using IVIS-200. The spine and femur/tibia were extracted and scanned by the micro-computer tomography for bone histo-morphometric analyses at the postmortem. The median survivals were 56 days in NSG while 44.5 days in C57BL/KaLwRij agreed with the BL imaging results. Histomorphic and DEXA analyses demonstrated that NSG mice have severe bone resorption that occurred at the lumbar spine but no significance at the femur compared to C57BL/KaLwRij mice. Based on these, we conclude that the systemic 5TGM1 injected NSG mouse slowly progresses myeloma and develops more severe MMBD than the C57BL/KaLwRij model. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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11 pages, 1062 KiB  
Article
New Approaches in Characterization of Lesions Dissemination in DLBCL Patients on Baseline PET/CT
by Anne-Ségolène Cottereau, Michel Meignan, Christophe Nioche, Jérôme Clerc, Loic Chartier, Laetitia Vercellino, Olivier Casasnovas, Catherine Thieblemont and Irène Buvat
Cancers 2021, 13(16), 3998; https://doi.org/10.3390/cancers13163998 - 08 Aug 2021
Cited by 12 | Viewed by 2022
Abstract
Dissemination, expressed recently by the largest Euclidian distance between lymphoma sites (SDmax), appeared a promising risk factor in DLBCL patients. We investigated alternative distance metrics to characterize the robustness of the dissemination information. In 290 patients from the REMARC trial (NCT01122472), the Euclidean [...] Read more.
Dissemination, expressed recently by the largest Euclidian distance between lymphoma sites (SDmax), appeared a promising risk factor in DLBCL patients. We investigated alternative distance metrics to characterize the robustness of the dissemination information. In 290 patients from the REMARC trial (NCT01122472), the Euclidean (Euc), Manhattan (Man), and Tchebychev (Tch) distances between the furthest lesions, firstly based on the centroid of each lesion and then directly from the two most distant tumor voxels and the Travelling Salesman Problem distance (TSP) were calculated. For PFS, the areas under the ROC curves were between 0.63 and 0.64, and between 0.62 and 0.65 for OS. Patients with high SDmax whatever the method of calculation or high SD_TSP had a significantly poorer outcome than patients with low SDmax or SD_TSP (p < 0.001 for both PFS and OS), with significance maintained in Ann Arbor advanced-stage patients. In multivariate analysis with total metabolic tumor volume and ECOG, each distance feature had an independent prognostic value for PFS. For OS, only SDmax_Tch, SDmax_Euc _Vox, and SDmax_Man _Vox reached significance. The spread of DLBCL lesions measured by the largest distance between lymphoma sites is a strong independent prognostic factor and could be measured directly from tumor voxels, allowing its development in the area of the deep learning segmentation methods. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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23 pages, 3040 KiB  
Article
Transcript-Level Dysregulation of BCL2 Family Genes in Acute Myeloblastic Leukemia
by Luiza Handschuh, Pawel Wojciechowski, Maciej Kazmierczak and Krzysztof Lewandowski
Cancers 2021, 13(13), 3175; https://doi.org/10.3390/cancers13133175 - 25 Jun 2021
Cited by 7 | Viewed by 2316
Abstract
The expression of apoptosis-related BCL2 family genes, fine-tuned in normal cells, is dysregulated in many neoplasms. In acute myeloid leukemia (AML), this problem has not been studied comprehensively. To address this issue, RNA-seq data were used to analyze the expression of 26 BCL2 [...] Read more.
The expression of apoptosis-related BCL2 family genes, fine-tuned in normal cells, is dysregulated in many neoplasms. In acute myeloid leukemia (AML), this problem has not been studied comprehensively. To address this issue, RNA-seq data were used to analyze the expression of 26 BCL2 family members in 27 AML FAB M1 and M2 patients, divided into subgroups differently responding to chemotherapy. A correlation analysis, analysis of variance, and Kaplan-Meier analysis were applied to associate the expression of particular genes with other gene expression, clinical features, and the presence of mutations detected by exome sequencing. The expression of BCL2 family genes was dysregulated in AML, as compared to healthy controls. An upregulation of anti-apoptotic and downregulation of pro-apoptotic genes was observed, though only a decrease in BMF, BNIP1, and HRK was statistically significant. In a group of patients resistant to chemotherapy, overexpression of BCL2L1 was manifested. In agreement with the literature data, our results reveal that BCL2L1 is one of the key players in apoptosis regulation in different types of tumors. An exome sequencing data analysis indicates that BCL2 family genes are not mutated in AML, but their expression is correlated with the mutational status of other genes, including those recurrently mutated in AML and splicing-related. High levels of some BCL2 family members, in particular BIK and BCL2L13, were associated with poor outcome. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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15 pages, 3199 KiB  
Article
Impact of Mantle Cell Lymphoma Contamination of Autologous Stem Cell Grafts on Outcome after High-Dose Chemotherapy
by Malte Roerden, Stefan Wirths, Martin Sökler, Wolfgang A. Bethge, Wichard Vogel and Juliane S. Walz
Cancers 2021, 13(11), 2558; https://doi.org/10.3390/cancers13112558 - 23 May 2021
Cited by 2 | Viewed by 2011
Abstract
Novel predictive factors are needed to identify mantle cell lymphoma (MCL) patients at increased risk for relapse after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDCT/Auto-HSCT). Although bone marrow and peripheral blood involvement is commonly observed in MCL and lymphoma cell contamination [...] Read more.
Novel predictive factors are needed to identify mantle cell lymphoma (MCL) patients at increased risk for relapse after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDCT/Auto-HSCT). Although bone marrow and peripheral blood involvement is commonly observed in MCL and lymphoma cell contamination of autologous stem cell grafts might facilitate relapse after Auto-HSCT, prevalence and prognostic significance of residual MCL cells in autologous grafts are unknown. We therefore performed a multiparameter flow cytometry (MFC)-based measurable residual disease (MRD) assessment in autologous stem cell grafts and analyzed its association with clinical outcome in an unselected retrospective cohort of 36 MCL patients. MRD was detectable in four (11%) autologous grafts, with MRD levels ranging from 0.002% to 0.2%. Positive graft-MRD was associated with a significantly shorter progression-free and overall survival when compared to graft-MRD negative patients (median 9 vs. 56 months and 25 vs. 132 months, respectively) and predicted early relapse after Auto-HSCT (median time to relapse 9 vs. 44 months). As a predictor of outcome after HDCT/Auto-HSCT, MFC-based assessment of graft-MRD might improve risk stratification and support clinical decision making for risk-oriented treatment strategies in MCL. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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14 pages, 4868 KiB  
Article
High Throughput Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia in the Context of the Prospective Trial 02/06 of the Northern Italy Leukemia Group (NILG)
by Silvia Salmoiraghi, Roberta Cavagna, Pamela Zanghì, Chiara Pavoni, Anna Michelato, Ksenija Buklijas, Lara Elidi, Tamara Intermesoli, Federico Lussana, Elena Oldani, Chiara Caprioli, Paola Stefanoni, Giacomo Gianfaldoni, Ernesta Audisio, Elisabetta Terruzzi, Lorella De Paoli, Erika Borlenghi, Irene Cavattoni, Daniele Mattei, Annamaria Scattolin, Monica Tajana, Fabio Ciceri, Elisabetta Todisco, Leonardo Campiotti, Paolo Corradini, Nicola Fracchiolla, Renato Bassan, Alessandro Rambaldi and Orietta Spinelliadd Show full author list remove Hide full author list
Cancers 2020, 12(8), 2242; https://doi.org/10.3390/cancers12082242 - 11 Aug 2020
Cited by 6 | Viewed by 2880
Abstract
By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. [...] Read more.
By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p < 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p < 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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17 pages, 2560 KiB  
Article
Digital Droplet PCR is a Specific and Sensitive Tool for Detecting IDH2 Mutations in Acute Myeloid LeuKemia Patients
by Susanna Grassi, Francesca Guerrini, Elena Ciabatti, Riccardo Puccetti, Serena Salehzadeh, Maria Rita Metelli, Alessia Di Vita, Cristiana Domenichini, Francesco Caracciolo, Enrico Orciuolo, Matteo Pelosini, Elisa Mazzantini, Pietro Rossi, Francesco Mazziotta, Mario Petrini and Sara Galimberti
Cancers 2020, 12(7), 1738; https://doi.org/10.3390/cancers12071738 - 30 Jun 2020
Cited by 22 | Viewed by 2829
Abstract
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) interfere with cellular metabolism contributing to oncogenesis. Mutations of IDH2 at R140 and R172 residues are observed in 20% of acute myeloid leukemias (AML), and the availability of the IDH2 inhibitor Enasidenib made IDH2 mutational [...] Read more.
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) interfere with cellular metabolism contributing to oncogenesis. Mutations of IDH2 at R140 and R172 residues are observed in 20% of acute myeloid leukemias (AML), and the availability of the IDH2 inhibitor Enasidenib made IDH2 mutational screening a clinical need. The aim of this study was to set a new quantitative polymerase chain reaction (PCR) technique, the drop-off digital droplet PCR (drop-off ddPCR), as a sensitive and accurate tool for detecting IDH2 mutations. With this technique we tested 60 AML patients. Sanger sequencing identified 8/60 (13.5%) mutated cases, while ddPCR and the amplification refractory mutation system (ARMS) PCR, used as a reference technique, identified mutations in 13/60 (21.6%) cases. When the outcome of IDH2-mutated was compared to that of wild-type patients, no significant difference in terms of quality of response, overall survival, or progression-free survival was observed. Finally, we monitored IDH2 mutations during follow-up in nine cases, finding that IDH2 can be considered a valid marker of minimal residual disease (MRD) in 2/3 of our patients. In conclusion, a rapid screening of IDH2 mutations is now a clinical need well satisfied by ddPCR, but the role of IDH2 as a marker for MRD still remains a matter of debate. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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23 pages, 1396 KiB  
Article
Capture-Based Next-Generation Sequencing Improves the Identification of Immunoglobulin/T-Cell Receptor Clonal Markers and Gene Mutations in Adult Acute Lymphoblastic Leukemia Patients Lacking Molecular Probes
by Roberta Cavagna, Marie L. Guinea Montalvo, Manuela Tosi, Michela Paris, Chiara Pavoni, Tamara Intermesoli, Renato Bassan, Andrea Mosca, Alessandro Rambaldi and Orietta Spinelli
Cancers 2020, 12(6), 1505; https://doi.org/10.3390/cancers12061505 - 09 Jun 2020
Cited by 9 | Viewed by 3235
Abstract
The monitoring of minimal residual disease (MRD) in Philadelphia-negative acute lymphoblastic leukemia (ALL) requires the identification at diagnosis of immunoglobulin/T-cell receptor (Ig/TCR) rearrangements as clonality markers. Aiming to simplify and possibly improve the patients’ initial screening, we designed a capture-based next-generation sequencing (NGS) [...] Read more.
The monitoring of minimal residual disease (MRD) in Philadelphia-negative acute lymphoblastic leukemia (ALL) requires the identification at diagnosis of immunoglobulin/T-cell receptor (Ig/TCR) rearrangements as clonality markers. Aiming to simplify and possibly improve the patients’ initial screening, we designed a capture-based next-generation sequencing (NGS) panel combining the Ig/TCR rearrangement detection with the profiling of relevant leukemia-related genes. The validation of the assay on well-characterized samples allowed us to identify all the known Ig/TCR rearrangements as well as additional clonalities, including rare rearrangements characterized by uncommon combinations of variable, diversity, and joining (V-D-J) gene segments, oligoclonal rearrangements, and low represented clones. Upon validation, the capture NGS approach allowed us to identify Ig/TCR clonal markers in 87% of a retrospective cohort (MRD-unknown within the Northern Italy Leukemia Group (NILG)-ALL 09/00 clinical trial) and in 83% of newly-diagnosed ALL cases in which conventional method failed, thus proving its prospective applicability. Finally, we identified gene variants in 94.7% of patients analyzed for mutational status with the same implemented capture assay. The prospective application of this technology could simplify clonality assessment and improve standard assay development for leukemia monitoring, as well as provide information about the mutational status of selected leukemia-related genes, potentially representing new prognostic elements, MRD markers, and targets for specific therapies. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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Review

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18 pages, 695 KiB  
Review
The Impact of Induction Regimes on Immune Responses in Patients with Multiple Myeloma
by Michael A. Firer, Michael Y. Shapira and Galia Luboshits
Cancers 2021, 13(16), 4090; https://doi.org/10.3390/cancers13164090 - 13 Aug 2021
Cited by 4 | Viewed by 2246
Abstract
Current standard frontline therapy for newly diagnosed patients with multiple myeloma (NDMM) involves induction therapy, autologous stem cell transplantation (ASCT), and maintenance therapy. Major efforts are underway to understand the biological and the clinical impacts of each stage of the treatment protocols on [...] Read more.
Current standard frontline therapy for newly diagnosed patients with multiple myeloma (NDMM) involves induction therapy, autologous stem cell transplantation (ASCT), and maintenance therapy. Major efforts are underway to understand the biological and the clinical impacts of each stage of the treatment protocols on overall survival statistics. The most routinely used drugs in the pre-ASCT “induction” regime have different mechanisms of action and are employed either as monotherapies or in various combinations. Aside from their direct effects on cancer cell mortality, these drugs are also known to have varying effects on immune cell functionality. The question remains as to how induction therapy impacts post-ASCT immune reconstitution and anti-tumor immune responses. This review provides an update on the known immune effects of melphalan, dexamethasone, lenalidomide, and bortezomib commonly used in the induction phase of MM therapy. By analyzing the actions of each individual drug on the immune system, we suggest it might be possible to leverage their effects to rationally devise more effective induction regimes. Given the genetic heterogeneity between myeloma patients, it may also be possible to identify subgroups of patients for whom particular induction drug combinations would be more appropriate. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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30 pages, 20553 KiB  
Review
Transcription/Replication Conflicts in Tumorigenesis and Their Potential Role as Novel Therapeutic Targets in Multiple Myeloma
by Laure Dutrieux, Yea-Lih Lin, Malik Lutzmann, Raphaël Rodriguez, Michel Cogné, Philippe Pasero and Jérôme Moreaux
Cancers 2021, 13(15), 3755; https://doi.org/10.3390/cancers13153755 - 27 Jul 2021
Cited by 7 | Viewed by 3955
Abstract
Plasma cells (PCs) have an essential role in humoral immune response by secretion of antibodies, and represent the final stage of B lymphocytes differentiation. During this differentiation, the pre-plasmablastic stage is characterized by highly proliferative cells that start to secrete immunoglobulins (Igs). Thus, [...] Read more.
Plasma cells (PCs) have an essential role in humoral immune response by secretion of antibodies, and represent the final stage of B lymphocytes differentiation. During this differentiation, the pre-plasmablastic stage is characterized by highly proliferative cells that start to secrete immunoglobulins (Igs). Thus, replication and transcription must be tightly regulated in these cells to avoid transcription/replication conflicts (TRCs), which could increase replication stress and lead to genomic instability. In this review, we analyzed expression of genes involved in TRCs resolution during B to PC differentiation and identified 41 genes significantly overexpressed in the pre-plasmablastic stage. This illustrates the importance of mechanisms required for adequate processing of TRCs during PCs differentiation. Furthermore, we identified that several of these factors were also found overexpressed in purified PCs from patients with multiple myeloma (MM) compared to normal PCs. Malignant PCs produce high levels of Igs concomitantly with cell cycle deregulation. Therefore, increasing the TRCs occurring in MM cells could represent a potent therapeutic strategy for MM patients. Here, we describe the potential roles of TRCs resolution factors in myelomagenesis and discuss the therapeutic interest of targeting the TRCs resolution machinery in MM. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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31 pages, 1152 KiB  
Review
Rapid Progress in Immunotherapies for Multiple Myeloma: An Updated Comprehensive Review
by Hiroko Nishida
Cancers 2021, 13(11), 2712; https://doi.org/10.3390/cancers13112712 - 31 May 2021
Cited by 14 | Viewed by 7509
Abstract
Despite rapid advances in treatment approaches of multiple myeloma (MM) over the last two decades via proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs), their efficacies are limited. MM still remains incurable, and the majority of patients shortly relapse and eventually [...] Read more.
Despite rapid advances in treatment approaches of multiple myeloma (MM) over the last two decades via proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs), their efficacies are limited. MM still remains incurable, and the majority of patients shortly relapse and eventually become refractory to existing therapies due to the genetic heterogeneity and clonal evolution. Therefore, the development of novel therapeutic strategies with different mechanisms of action represents an unmet need to achieve a deep and highly durable response as well as to improve patient outcomes. The antibody-drug conjugate (ADC), belanatmab mafadotin, which targets B cell membrane antigen (BCMA) on plasma cells, was approved for the treatment of MM in 2020. To date, numerous immunotherapies, including bispecific antibodies, such as bispecific T cell engager (BiTE), the duobody adoptive cellular therapy using a dendritic cell (DC) vaccine, autologous chimeric antigen (CAR)-T cells, allogeneic CAR-natural killer (NK) cells, and checkpoint inhibitors have been developed for the treatment of MM, and a variety of clinical trials are currently underway or are expected to be planned. In the future, the efficacy of combination approaches, as well as allogenic CAR-T or NK cell therapy, will be examined, and promising results may alter the treatment paradigm of MM. This is a comprehensive review with an update on the most recent clinical and preclinical advances with a focus on results from clinical trials in progress with BCMA-targeted immunotherapies and the development of other novel targets in MM. Future perspectives will also be discussed. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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26 pages, 1646 KiB  
Review
Realizing Innate Potential: CAR-NK Cell Therapies for Acute Myeloid Leukemia
by Mark Gurney and Michael O’Dwyer
Cancers 2021, 13(7), 1568; https://doi.org/10.3390/cancers13071568 - 29 Mar 2021
Cited by 19 | Viewed by 6889
Abstract
Next-generation cellular immunotherapies seek to improve the safety and efficacy of approved CD19 chimeric antigen receptor (CAR) T-cell products or apply their principles across a growing list of targets and diseases. Supported by promising early clinical experiences, CAR modified natural killer (CAR-NK) cell [...] Read more.
Next-generation cellular immunotherapies seek to improve the safety and efficacy of approved CD19 chimeric antigen receptor (CAR) T-cell products or apply their principles across a growing list of targets and diseases. Supported by promising early clinical experiences, CAR modified natural killer (CAR-NK) cell therapies represent a complementary and potentially off-the-shelf, allogeneic solution. While acute myeloid leukemia (AML) represents an intuitive disease in which to investigate CAR based immunotherapies, key biological differences to B-cell malignancies have complicated progress to date. As CAR-T cell trials treating AML are growing in number, several CAR-NK cell approaches are also in development. In this review we explore why CAR-NK cell therapies may be particularly suited to the treatment of AML. First, we examine the established role NK cells play in AML biology and the existing anti-leukemic activity of NK cell adoptive transfer. Next, we appraise potential AML target antigens and consider common and unique challenges posed relative to treating B-cell malignancies. We summarize the current landscape of CAR-NK development in AML, and potential targets to augment CAR-NK cell therapies pharmacologically and through genetic engineering. Finally, we consider the broader landscape of competing immunotherapeutic approaches to AML treatment. In doing so we evaluate the innate potential, status and remaining barriers for CAR-NK based AML immunotherapy. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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19 pages, 906 KiB  
Review
Autoimmune Complications in Hematologic Neoplasms
by Wilma Barcellini, Juri Alessandro Giannotta and Bruno Fattizzo
Cancers 2021, 13(7), 1532; https://doi.org/10.3390/cancers13071532 - 26 Mar 2021
Cited by 37 | Viewed by 6587
Abstract
Autoimmune cytopenias (AICy) and autoimmune diseases (AID) can complicate both lymphoid and myeloid neoplasms, and often represent a diagnostic and therapeutic challenge. While autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are well known, other rarer AICy (autoimmune neutropenia, aplastic anemia, and pure [...] Read more.
Autoimmune cytopenias (AICy) and autoimmune diseases (AID) can complicate both lymphoid and myeloid neoplasms, and often represent a diagnostic and therapeutic challenge. While autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are well known, other rarer AICy (autoimmune neutropenia, aplastic anemia, and pure red cell aplasia) and AID (systemic lupus erythematosus, rheumatoid arthritis, vasculitis, thyroiditis, and others) are poorly recognized. This review analyses the available literature of the last 30 years regarding the occurrence of AICy/AID in different onco-hematologic conditions. The latter include chronic lymphocytic leukemia (CLL), lymphomas, multiple myeloma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, and acute leukemias. On the whole, AICy are observed in up to 10% of CLL and with higher frequencies in certain subtypes of non-Hodgkin lymphoma, whilst they occur in less than 1% of low-risk MDS and CMML. AID are described in up to 30% of myeloid and lymphoid patients, including immune-mediated hemostatic disorders (acquired hemophilia, thrombotic thrombocytopenic purpura, and anti-phospholipid syndrome) that may be severe and fatal. Additionally, AICy/AID are found in about 10% of patients receiving hematopoietic stem cell transplant or treatment with new checkpoint inhibitors. Besides the diagnostic difficulties, these AICy/AID may complicate the clinical management of already immunocompromised patients. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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15 pages, 961 KiB  
Review
Oncogenic Mutations of MYD88 and CD79B in Diffuse Large B-Cell Lymphoma and Implications for Clinical Practice
by Carlo Visco, Ilaria Tanasi, Francesca Maria Quaglia, Isacco Ferrarini, Costanza Fraenza and Mauro Krampera
Cancers 2020, 12(10), 2913; https://doi.org/10.3390/cancers12102913 - 10 Oct 2020
Cited by 24 | Viewed by 4654
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma in adults. Despite the recognition of transcriptional subtypes with distinct functional characteristics, patient outcomes have not been substantially altered since the advent of chemoimmunotherapy (CIT) twenty years ago. Recently, a few pivotal [...] Read more.
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma in adults. Despite the recognition of transcriptional subtypes with distinct functional characteristics, patient outcomes have not been substantially altered since the advent of chemoimmunotherapy (CIT) twenty years ago. Recently, a few pivotal studies added to the disease heterogeneity by describing several activating mutations, which have been associated with disease presentation, B-cell function and behavior, and final outcome. DLBCL arises from antigen exposed B-cells, with the B-cell receptor (BCR) playing a central role. BCR-activity related mutations, such as CD79B and MYD88, are responsible for chronic activation of the BCR in a substantial subset of patients. These mutations, often coexisting in the same patient, have been found in a substantial subset of patients with immune-privileged (IP) sites DLBCLs, and are drivers of lymphoma development conferring tissue-specific homing properties. Both mutations have been associated with disease behavior, including tumor response either to CIT or to BCR-targeted therapy. The recognition of CD79B and MYD88 mutations will contribute to the heterogeneity of the disease, both in recognizing the BCR as a potential therapeutic target and in providing genetic tools for personalized treatment. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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23 pages, 964 KiB  
Review
A Bird’s-Eye View of Cell Sources for Cell-Based Therapies in Blood Cancers
by Benjamin Motais, Sandra Charvátová, Matouš Hrdinka, Michal Šimíček, Tomáš Jelínek, Tereza Ševčíková, Zdeněk Kořístek, Roman Hájek and Juli R. Bagó
Cancers 2020, 12(5), 1333; https://doi.org/10.3390/cancers12051333 - 23 May 2020
Cited by 9 | Viewed by 4494
Abstract
Hematological malignancies comprise over a hundred different types of cancers and account for around 6.5% of all cancers. Despite the significant improvements in diagnosis and treatment, many of those cancers remain incurable. In recent years, cancer cell-based therapy has become a promising approach [...] Read more.
Hematological malignancies comprise over a hundred different types of cancers and account for around 6.5% of all cancers. Despite the significant improvements in diagnosis and treatment, many of those cancers remain incurable. In recent years, cancer cell-based therapy has become a promising approach to treat those incurable hematological malignancies with striking results in different clinical trials. The most investigated, and the one that has advanced the most, is the cell-based therapy with T lymphocytes modified with chimeric antigen receptors. Those promising initial results prepared the ground to explore other cell-based therapies to treat patients with blood cancer. In this review, we want to provide an overview of the different types of cell-based therapies in blood cancer, describing them according to the cell source. Full article
(This article belongs to the Special Issue Hematologic Malignancy)
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