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Hematologic Malignancies: Challenges from Diagnosis to Treatment

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 30 April 2024 | Viewed by 14036

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Special Issue Editors

Dr. Ioanna Sakellari

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Guest Editor

Hematology Department—BMT Unit, G. Papanicolaou Hospital, 57010 Thessaloniki, Greece
Interests: hematopoietic cell transplantation; cell therapy; acute myeloid leukemia; graft-versus-host-disease

Dr. Eleni Gavriilaki

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Guest Editor

Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
Interests: hematologic malignancies; thrombosis; complement; cellular therapy; lymphoma; myeloma; COVID-19
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hematologic malignancies represent a constantly changing landscape with emerging diagnostic and treatment modalities. Emerging challenges in the field involve not only new treatments and appropriate patient selection but also unprecedented worldwide changes, such as COVID-19.

Therefore, this Special Issue aims to highlight basic, translational, and clinical research in the field, gathering both original research and review articles. We welcome physicians and scientists to share their valuable research with us.

Dr. Ioanna Sakellari
Dr. Eleni Gavriilaki
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

hematopoietic cell transplantation
cell therapy
acute myeloid leukemia
graft-versus-host-disease
hematologic malignancies
thrombosis
complement
lymphoma
myeloma
COVID-19

Published Papers (10 papers)

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Research

Jump to: Review

17 pages, 3465 KiB

Open AccessArticle

Immune Checkpoint Pathway Expression in Lymphocyte Subpopulations in Patients with Common Variable Immunodeficiency and Chronic Lymphocytic Leukemia

by Paulina Mertowska, Sebastian Mertowski, Konrad Smolak, Aleksandra Kita, Gabriela Kita, Katarzyna Guz, Marcin Pasiarski and Ewelina Grywalska

Cancers 2023, 15(21), 5184; https://doi.org/10.3390/cancers15215184 - 28 Oct 2023

Viewed by 911

Abstract

This study aims to gain a deeper understanding of chronic lymphocytic leukemia (CLL) and common variable immunodeficiency (CVID) by studying immune cells and specific immune checkpoint signaling pathways. The analysis of the percentage of selected immune points and their ligands (PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200) on peripheral blood lymphocyte subpopulations was performed using flow cytometry, and additional analyses determining the serum concentration of the above-mentioned molecules were performed using enzyme immunoassay tests. The obtained results indicate several significant changes in the percentage of almost all tested molecules on selected subpopulations of T and B lymphocytes in both CVID and CLL patients in relation to healthy volunteers and between the disease subunits themselves. The results obtained were also supported by the analysis of the serum concentration of soluble molecules tested. By uncovering valuable insights, we hope to enhance our comprehension and management of these conditions, considering both immunodeficiencies and hematological malignancies. Understanding the role of these signaling pathways in disease development and progression may lead to the development of modern, personalized diagnostic and therapeutic strategies. Ultimately, this knowledge may enable the monitoring of the immune system in patients with CVID and CLL, paving the way for improved patient care in the future. Full article

(This article belongs to the Special Issue Hematologic Malignancies: Challenges from Diagnosis to Treatment)

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11 pages, 35284 KiB

Open AccessArticle

Reducing Chemotherapy Waiting Times in the Ambulatory Setting of a Tertiary Cancer Centre Using a Design Thinking Approach

by Wei-Ying Jen, Zhi Yao Chan, Yee Mei Lee, Noel Ng, Belinda Tan, Constance Teo, Yuet Peng Wong, Cheng Ean Chee and Yen-Lin Chee

Cancers 2023, 15(18), 4625; https://doi.org/10.3390/cancers15184625 - 19 Sep 2023

Cited by 1 | Viewed by 1214

Abstract

Introduction: Chemotherapy is complex. We hypothesized that a design thinking approach could redesign preparatory processes and reduce wait times. Methods: A multidisciplinary process mapping exercise was undertaken to understand the current processes, followed by proposing and testing solutions. Proposals were selected based on desirability and feasibility. These focused on starting the morning treatments on time and scheduling pre-made regimens in these slots. The primary outcome measure was the time from the appointment to starting treatment. Treatments in the post-intervention study group were compared against a historical control group. Results: The median time to start morning treatment decreased by 46%, from 83 min (with an interquartile range 50–127) in the control group to 45 min (with an interquartile range of 24–81 min) in the study group (p < 0.001). This translated into an overall improvement for the day, with the median time to start treatment decreasing from 77 min (with an interquartile range of 40–120 min) to 47 min (with an interquartile range of 20–79 min) (p < 0.001). Pre-makes increased by 258%, from 908 (28.5%) to 2340 (71.7%) regimens (p < 0.001). The number of patients starting treatment within an hour of their appointment increased from 1688 (32.8%) to 3355 (62.3%, p < 0.001). Conclusion: We have shown that a data-driven, design thinking approach can improve waiting times. This can be adapted to improve other processes in an empathetic, sustainable manner. Full article

(This article belongs to the Special Issue Hematologic Malignancies: Challenges from Diagnosis to Treatment)

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13 pages, 1608 KiB

Open AccessArticle

The Relative Dose Intensity Changes during Cycles of Standard Regimens in Patients with Diffuse Large B-Cell Lymphoma

by Shin Lee, Kei Fujita, Tetsuji Morishita, Eiju Negoro, Hikaru Tsukasaki, Kana Oiwa, Takeshi Hara, Hisashi Tsurumi, Takanori Ueda and Takahiro Yamauchi

Cancers 2023, 15(18), 4458; https://doi.org/10.3390/cancers15184458 - 07 Sep 2023

Viewed by 836

Abstract

No studies have focused on the trajectory of the average relative dose intensity (ARDI) during cycles of first-line chemotherapy for patients with diffuse large B-cell lymphoma. To evaluate the impact of attenuating ARDI during cycles on overall survival, we conducted a multi-centre, longitudinal, observational retrospective study. A total of 307 analysable patients were enrolled. Multivariate Cox hazards modelling with restricted cubic spline models revealed prognostic benefits of higher ARDI up to, but not after, cycle 6. According to group-based trajectory modelling, patients were classified into five groups depending on the pattern of ARDI changes. Among these, two groups in which ARDI had fallen significantly to less than 50% by cycles 4–6 displayed significantly poorer prognosis, despite increased ARDI in the second half of the treatment period (log-rank p = 0.02). The Geriatric Nutritional Risk Index offered significant prediction of unfavourable ARDI changes (odds ratio 2.540, 95% confidence interval 1.020–6.310; p = 0.044). Up to cycle 6, maintenance of ARDI in all cycles (but particularly in the early cycles) is important for prognosis. Malnutrition is a significant factor that lets patients trace patterns of ARDI changes during cycles of chemotherapy associated with untoward prognosis. Full article

(This article belongs to the Special Issue Hematologic Malignancies: Challenges from Diagnosis to Treatment)

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12 pages, 1981 KiB

Open AccessArticle

Divergent Oxidative Stress in Normal Tissues and Inflammatory Cells in Hodgkin and Non-Hodgkin Lymphoma

by Cecilia Marini, Vanessa Cossu, Francesco Lanfranchi, Sonia Carta, Francesca Vitale, Francesca D’Amico, Matteo Bauckneht, Silvia Morbelli, Maria Isabella Donegani, Silvia Chiola, Stefano Raffa, Luca Sofia, Tania Di Raimondo, Filippo Ballerini, Chiara Ghiggi, Paolo Durando, Silvia Ravera, Mattia Riondato, Anna Maria Orengo, Silvia Bruno, Sabrina Chiesa and Gianmario Sambuceti Show full author list Hide full author list

Cancers 2023, 15(13), 3533; https://doi.org/10.3390/cancers15133533 - 07 Jul 2023

Viewed by 927

Abstract

Background: Previous studies reported mitochondrial and endoplasmic reticulum redox stress in peripheral blood mononucleated cells (PBMCs) of treatment-naïve Hodgkin lymphoma (HL) patients. Here, we assessed whether this response also applies to non-HL (NHL) patients, and whether the oxidative damage is a selective feature of PBMCs or, rather, also affects tissues not directly involved in the inflammatory response. Methods: Isolated PBMCs of 28 HL, 9 diffuse large B cell lymphoma, 8 less aggressive-NHL, and 45 controls underwent flow cytometry to evaluate redox stress and uptake of the glucose analogue 2-NBDG. This analysis was complemented with the assay of malondialdehyde (MDA) levels and enzymatic activity of glucose-6P-dehydrogenase and hexose-6P-dehydrogenase (H6PD). In all lymphoma patients, ¹⁸F-fluoro-deoxyglucose uptake was estimated in the myocardium and skeletal muscles. Results: Mitochondrial reactive oxygen species generation and MDA levels were increased only in HL patients as well as H6PD activity and 2-NBDG uptake. Similarly, myocardial FDG retention was higher in HL than in other groups as opposed to a similar tracer uptake in the skeletal muscle. Conclusions: Redox stress of PBMCs is more pronounced in HL with respect to both NHL groups. This phenomenon is coherent with an increased activity of H6PD that also extends to the myocardium. Full article

(This article belongs to the Special Issue Hematologic Malignancies: Challenges from Diagnosis to Treatment)

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12 pages, 467 KiB

Open AccessArticle

Risk Factors, Prevalence, and Outcomes of Invasive Fungal Disease Post Hematopoietic Cell Transplantation and Cellular Therapies: A Retrospective Monocenter Real-Life Analysis

by Eleni Gavriilaki, Panagiotis Dolgyras, Sotiria Dimou-Mpesikli, Aikaterini Poulopoulou, Paschalis Evangelidis, Nikolaos Evangelidis, Christos Demosthenous, Evangelia Zachrou, Panagiotis Siasios, Despina Mallouri, Anna Vardi, Zoi Bousiou, Alkistis Panteliadou, Ioannis Batsis, Marianna Masmanidou, Chrysavgi Lalayanni, Evangelia Yannaki, Damianos Sotiropoulos, Achilles Anagnostopoulos, Timoleon-Achilleas Vyzantiadis and Ioanna Sakellari Show full author list Hide full author list

Cancers 2023, 15(13), 3529; https://doi.org/10.3390/cancers15133529 - 07 Jul 2023

Cited by 1 | Viewed by 1002

Abstract

(1) Background: Autologous, allogeneic hematopoietic cell transplantation (HCT) and other cellular therapies, including CAR T cell and gene therapy, constitute a cornerstone in the management of various benign and malignant hematological disorders. Invasive fungal infections (IFD) remain a significant cause of morbidity and mortality in HCT recipients. Therefore, we investigated the prevalence and risk factors of IFD following HCT and other cellular therapies in an era of novel antifungal prophylaxis. (2) Methods: In this study, we retrospectively enrolled adult HCT recipients who were treated at our JACIE-accredited center according to standard operating procedures over the last decade (2013–2022). (3) Results: 950 patients who received cellular therapies were studied. None of the 19 CAR T cell and neither of the two gene therapy recipients developed IFD whereas 3/456 autologous HCT recipients who suffered from primary refractory/relapsed lymphomas presented with probable IFD. Overall, 11 patients who received allogeneic HCT experienced probable IFD, possible IFD was found in 31/473, and IFD was proven in 10/473. A second IFD episode was present in three patients. Four-year OS was significantly lower in proven compared to probable IFD (p = 0.041) and was independently associated with HCT-CI (p = 0.040) and chronic GVHD (p = 0.045). (4) Conclusions: In this real-world cohort, the prevalence of proven and probable IFD in an era of novel antifungal prophylaxis was found to be relatively low. However, IFDs were associated with poor outcomes for patients who received allogeneic HCT. Full article

(This article belongs to the Special Issue Hematologic Malignancies: Challenges from Diagnosis to Treatment)

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12 pages, 2098 KiB

Open AccessArticle

TP53 Mutations in AML Patients Are Associated with Dismal Clinical Outcome Irrespective of Frontline Induction Regimen and Allogeneic Hematopoietic Cell Transplantation

by Davidson Zhao, Mojgan Zarif, Qianghua Zhou, José-Mario Capo-Chichi, Andre Schuh, Mark D. Minden, Eshetu G. Atenafu, Rajat Kumar and Hong Chang

Cancers 2023, 15(12), 3210; https://doi.org/10.3390/cancers15123210 - 16 Jun 2023

Cited by 4 | Viewed by 1676

Abstract

TP53 mutations are associated with extremely poor outcomes in acute myeloid leukemia (AML). The outcomes of patients with TP53-mutated (TP53^MUT) AML after different frontline treatment modalities are not well established. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative procedure for AML; however, long-term outcomes among patients with TP53^MUT AML after allo-HCT are dismal, and the benefit of allo-HCT remains controversial. We sought to evaluate the outcomes of patients with TP53^MUT AML after treatment with different frontline induction therapies and allo-HCT. A total of 113 patients with TP53^MUT AML were retrospectively evaluated. Patients with TP53^MUT AML who received intensive or azacitidine-venetoclax induction had higher complete remission rates compared to patients treated with other hypomethylating-agent-based induction regimens. However, OS and EFS were not significantly different among the induction regimen groups. Allo-HCT was associated with improved OS and EFS among patients with TP53^MUT AML; however, allo-HCT was not significantly associated with improved OS or EFS in time-dependent or landmark analysis. While the outcomes of all patients were generally poor irrespective of therapeutic strategy, transplanted patients with lower TP53^MUT variant allele frequency (VAF) at the time of diagnosis had superior outcomes compared to transplanted patients with higher TP53 VAF. Our study provides further evidence that the current standards of care for AML confer limited therapeutic benefit to patients with TP53 mutations. Full article

(This article belongs to the Special Issue Hematologic Malignancies: Challenges from Diagnosis to Treatment)

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17 pages, 1792 KiB

Open AccessArticle

Azacitidine Post-Remission Therapy for Elderly Patients with AML: A Randomized Phase-3 Trial (QoLESS AZA-AMLE)

by Esther Natalie Oliva, Anna Candoni, Prassede Salutari, Giuseppe A. Palumbo, Gianluigi Reda, Giuseppe Iannì, Giovanni Tripepi, Maria Cuzzola, Debora Capelli, Corrado Mammì, Caterina Alati, Maria Concetta Cannatà, Pasquale Niscola, Bianca Serio, Pellegrino Musto, Ernesto Vigna, Antonio Volpe, Lorella Maria Antonia Melillo, Maria Teresa Arcadi, Donato Mannina, Maria Elena Zannier and Roberto Latagliata Show full author list Hide full author list

Cancers 2023, 15(9), 2441; https://doi.org/10.3390/cancers15092441 - 24 Apr 2023

Viewed by 1312

Abstract

This phase-3 randomized multicenter trial evaluated the efficacy of subcutaneous azacitidine (AZA) post-remission therapy vs. best supportive care (BSC) in elderly acute myeloid leukemia (AML) patients. The primary endpoint was the difference in disease-free survival (DFS) from complete remission (CR) to relapse/death. Patients with newly diagnosed AML aged ≥61 years received two courses of induction chemotherapy (“3+7” daunorubicin and cytarabine) followed by consolidation (cytarabine). At CR, 54 patients were randomized (1:1) to receive BSC (N = 27) or AZA (N = 27) at a dose of 50 mg/m² for 7 days every 28 days and the dose increased after the 1st cycle to 75 mg/m² for a further 5 cycles, followed by cycles every 56 days for 4.5 years. At 2 years, median DFS was 6.0 (95% CI: 0.2–11.7) months for patients receiving BSC vs. 10.8 months (95% CI: 1.9–19.6, p = 0.20) months for AZA. At 5 years, DFS was 6.0 (95% CI: 0.2–11.7) months in the BSC arm vs. 10.8 (95% CI: 1.9–19.6, p = 0.23) months in the AZA arm. Significant benefit was afforded by AZA on DFS at 2 and 5 years in patients aged >68 years (HR = 0.34, 95% CI: 0.13–0.90, p = 0.030 and HR = 0.37, 95% CI: 0.15–0.93, p = 0.034, respectively). No deaths occurred prior to leukemic relapse. Neutropenia was the most frequent adverse event. There were no differences in patient-reported outcome measures between study arms. In conclusion, AZA post-remission therapy was found to provide benefit in AML patients aged >68 years. Full article

(This article belongs to the Special Issue Hematologic Malignancies: Challenges from Diagnosis to Treatment)

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Review

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26 pages, 1699 KiB

Open AccessReview

EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets

by Ioanna E. Stergiou, Stavros P. Papadakos, Anna Karyda, Ourania E. Tsitsilonis, Meletios-Athanasios Dimopoulos and Stamatios Theocharis

Cancers 2023, 15(15), 3963; https://doi.org/10.3390/cancers15153963 - 04 Aug 2023

Cited by 2 | Viewed by 1260

Abstract

Erythropoietin-producing hepatocellular carcinoma receptors (EPHs) represent the largest family of receptor tyrosine kinases (RTKs). EPH interaction with ephrins, their membrane-bound ligands, holds a pivotal role in embryonic development, while, though less active, it is also implicated in various physiological functions during adult life. In normal hematopoiesis, different patterns of EPH/ephrin expression have been correlated with hematopoietic stem cell (HSC) maintenance and lineage-committed hematopoietic progenitor cell (HPC) differentiation, as well as with the functional properties of their mature offspring. Research in the field of hematologic malignancies has unveiled a rather complex involvement of the EPH/ephrinsignaling pathway in the pathophysiology of these neoplasms. Aberrations in genetic, epigenetic, and protein levels have been identified as possible players implicated both in tumor progression and suppression, while correlations have also been highlighted regarding prognosis and response to treatment. Initial efforts to therapeutically target the EPH/ephrin axis have been undertaken in the setting of hematologic neoplasia but are mainly confined to the preclinical level. To this end, deciphering the complexity of this signaling pathway both in normal and malignant hematopoiesis is necessary. Full article

(This article belongs to the Special Issue Hematologic Malignancies: Challenges from Diagnosis to Treatment)

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13 pages, 624 KiB

Open AccessReview

Myeloid Leukemia of Down Syndrome

by Aikaterini Kosmidou, Athanasios Tragiannidis and Eleni Gavriilaki

Cancers 2023, 15(13), 3265; https://doi.org/10.3390/cancers15133265 - 21 Jun 2023

Cited by 4 | Viewed by 1710

Abstract

Myeloid leukemia of Down syndrome (ML-DS) is characterized by a distinct natural history and is classified by the World Health Organization (WHO) as an independent entity, occurring with unique clinical and molecular features. The presence of a long preleukemic, myelodysplastic phase, called transient abnormal myelopoiesis (TAM), precedes the initiation of ML-DS and is defined by unusual chromosomal findings. Individuals with constitutional trisomy 21 have a profound dosage imbalance in the hematopoiesis-governing genes located on chromosome 21 and thus are subject to impaired fetal as well as to neonatal erythro-megakaryopoiesis. Almost all neonates with DS develop quantitative and morphological hematological abnormalities, yet still only 5–10% of them present with one of the preleukemic or leukemic conditions of DS. The acquired mutations in the key hematopoietic transcription factor gene GATA1, found solely in cells trisomic for chromosome 21, are considered to be the essential step for the selective growth advantage of leukemic cells. While the majority of cases of TAM remain clinically ‘silent’ or undergo spontaneous remission, the remaining 20% to 30% of them progress into ML-DS until the age of 4 years. The hypersensitivity of ML-DS blasts to chemotherapeutic agents, including but not limited to cytarabine, and drugs’ increased infectious and cardiac toxicity have necessitated the development of risk-adapted treatment protocols for children with ML-DS. Recent advances in cytogenetics and specific molecular mechanisms involved in the evolution of TAM and ML-DS are reviewed here, as well as their integration in the improvement of risk stratification and targeted management of ML-DS. Full article

(This article belongs to the Special Issue Hematologic Malignancies: Challenges from Diagnosis to Treatment)

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15 pages, 1807 KiB

Open AccessReview

Spatially Guided and Single Cell Tools to Map the Microenvironment in Cutaneous T-Cell Lymphoma

by Eirini Kalliara, Emma Belfrage, Urban Gullberg, Kristina Drott and Sara Ek

Cancers 2023, 15(8), 2362; https://doi.org/10.3390/cancers15082362 - 18 Apr 2023

Cited by 3 | Viewed by 1927

Abstract

Mycosis fungoides (MF) and Sézary syndrome (SS) are two closely related clinical variants of cutaneous T-cell lymphomas (CTCL). Previously demonstrated large patient-to-patient and intra-patient disease heterogeneity underpins the importance of personalized medicine in CTCL. Advanced stages of CTCL are characterized by dismal prognosis, and the early identification of patients who will progress remains a clinical unmet need. While the exact molecular events underlying disease progression are poorly resolved, the tumor microenvironment (TME) has emerged as an important driver. In particular, the Th1-to-Th2 shift in the immune response is now commonly identified across advanced-stage CTCL patients. Herein, we summarize the role of the TME in CTCL evolution and the latest studies in deciphering inter- and intra-patient heterogeneity. We introduce spatially resolved omics as a promising technology to advance immune-oncology efforts in CTCL. We propose the combined implementation of spatially guided and single-cell omics technologies in paired skin and blood samples. Such an approach will mediate in-depth profiling of phenotypic and molecular changes in reactive immune subpopulations and malignant T cells preceding the Th1-to-Th2 shift and reveal mechanisms underlying disease progression from skin-limited to systemic disease that collectively will lead to the discovery of novel biomarkers to improve patient prognostication and the design of personalized treatment strategies. Full article

(This article belongs to the Special Issue Hematologic Malignancies: Challenges from Diagnosis to Treatment)

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