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Challenges in the Treatment of Myelodysplastic Syndrome
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Challenges in the Treatment of Myelodysplastic Syndrome

A special issue of Hemato (ISSN 2673-6357). This special issue belongs to the section "Chronic Myeloid Disease".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 28425

Special Issue Editors

Prof. Dr. Valeria Santini

E-Mail Website
Guest Editor
AOU Careggi, University of Florence, Florence, Italy
Interests: myelodyspalstic syndromes; acute and chronic myeloid leukemias
Dr. Marie Robin

E-Mail Website
Guest Editor
1. Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, Université de Paris, Paris, France
2. Bone Marrow Transplantation Department, French Reference Center for Aplastic Anemia and PNH, Paris, France
Interests: allogeneic stem cell transplantation; graft-versus-host disease; immune defect and other post-transplant complications; myelodysplastic syndrome; myeloproliferative disorders; aplastic anemia

Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to “MDS from Bench to Bedside”, and is conceived under the direction of Pierre Fenaux who has made efforts to continuously contribute to the field over the last 35 years.

During the last decade, the explosion of molecular techniques has enabled better understanding of MDS and AML pathogenetic mechanisms, clonal heterogeneity, and individual diversity. Based on recent findings, new MDS entities have emerged. Alterations in hematopoietic processes, from clonal hematopoiesis of indeterminate potential to lower- and higher-risk MDS have been characterized and analyzed. Molecular signatures of MDS have been used to identify innovative and effective target therapy. While stem cell transplant is still the only curative approach for MDS, combining therapies with different targets and mechanisms of action may be promising to relieve symptoms related to MDS or to decrease the risk of progression to AML.

In this Special Issue, we aim to highlight some of the most important and topical issues, including recent advances, controversies, and challenges in the treatment of MDS.

Prof. Dr. Valeria Santini
Dr. Marie Robin
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. Hemato is an international peer-reviewed open access quarterly 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 1000 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

  • MDS
  • genomic
  • targeted therapy
  • transplantation

Published Papers (6 papers)

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Review

10 pages, 545 KiB  
Review
Treatment of Lower Risk Myelodysplastic Syndromes
by Valeria Santini
Hemato 2022, 3(1), 153-162; https://doi.org/10.3390/hemato3010013 - 08 Feb 2022
Viewed by 3847
Abstract
Purpose of review: Management and Optimization of therapy for lower-risk myelodysplastic syndromes will be reviewed here. Recent findings: Lower-risk MDS typically present with clinical manifestations of anemia, which is the most frequently encountered cytopenia in this setting. While therapy with erythropoietic stimulating agents [...] Read more.
Purpose of review: Management and Optimization of therapy for lower-risk myelodysplastic syndromes will be reviewed here. Recent findings: Lower-risk MDS typically present with clinical manifestations of anemia, which is the most frequently encountered cytopenia in this setting. While therapy with erythropoietic stimulating agents (ESAs) is used in the vast majority of cases, if correctly selected, some patients do not respond, or become irresponsive to ESAs. Novel agents with very different modes of action show promising clinical results in anemic LR-MDS refractory/relapsed after ESAs. Luspatercept, a TGFbeta family ligand trap, induces nearly 50% of transfusion independence in LR MDS. Another investigational agent showing efficacy and possibly disease modifying activity is the telomerase inhibitor imetelstat. Modulation of dose and schedule of hypomethylating agents, both injectable and oral, is currently being explored, and preliminary results are positive. There is still no standard therapeutic approach for thrombocytopenic and neutropenic LR MDS, although they do represent a smaller proportion of cases. Immunosuppressive treatments, as well as TPO mimetics, could represent a good option in selected MDS cases. Summary: At present, the availability of novel active agents allows the planning of sequential therapy, especially for anemic LR MDS. Better diagnosis and prognostic stratification may allow a more precise and personalized treatment. Full article
(This article belongs to the Special Issue Challenges in the Treatment of Myelodysplastic Syndrome)
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21 pages, 612 KiB  
Review
Aetiology of MDS: With a Focus on Hereditary Predisposition
by Anjum B. Khan and David Bowen
Hemato 2022, 3(1), 17-37; https://doi.org/10.3390/hemato3010003 - 24 Dec 2021
Viewed by 3087
Abstract
Myelodysplastic syndromes affect an older age group with a median age at onset in the eighth decade of life. As such, there is a relationship between the pathogenesis of MDS and age-related processes affecting haematopoietic stem/progenitor cells and/or the bone marrow microenvironment. MDS [...] Read more.
Myelodysplastic syndromes affect an older age group with a median age at onset in the eighth decade of life. As such, there is a relationship between the pathogenesis of MDS and age-related processes affecting haematopoietic stem/progenitor cells and/or the bone marrow microenvironment. MDS with an onset in younger people may be associated with recognised hereditary myeloid malignancy syndromes, and ‘forme fruste’ presentations of inherited syndromes in later life are now increasingly recognised such as germline mutations in DDX41. The considerable clinical and research interest in hereditary disorders is reflected in the relative emphasis within our manuscript. Prior chemo/radiotherapy is a clear cause of MDS but the predisposition factors for therapy-related MDS remain unclear. Clonal haematopoiesis is common in older people and may evolve to MDS, although once again, the biological factors driving this evolution are largely unknown. Finally, environmental exposure to genotoxic agents is likely to play only a minor role in the contemporary occupational/recreational setting. Full article
(This article belongs to the Special Issue Challenges in the Treatment of Myelodysplastic Syndrome)
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11 pages, 770 KiB  
Review
Allogeneic Stem Cell Transplantation for MDS
by Sara Villar and Marie Robin
Hemato 2021, 2(3), 545-555; https://doi.org/10.3390/hemato2030034 - 25 Aug 2021
Cited by 3 | Viewed by 4817
Abstract
Myelodysplastic syndromes are clonal disorders with morphological dysplasia, a variable degree of cytopenia and a risk of transformation to acute myeloid leukemia. Prognosis is very variable and is defined by blast count, cytopenia, cytogenetics and more recently by somatic mutations, with IPSS or [...] Read more.
Myelodysplastic syndromes are clonal disorders with morphological dysplasia, a variable degree of cytopenia and a risk of transformation to acute myeloid leukemia. Prognosis is very variable and is defined by blast count, cytopenia, cytogenetics and more recently by somatic mutations, with IPSS or revised IPSS score being the most widely used to assess disease risk. HSCT remains the only curative treatment to date, with high-risk patients obtaining the biggest benefit. However, NRM should be carefully assessed before indicating the transplant in this usually old population, where organ toxicity and comorbid conditions are to be considered. Multi-domain assessment tools, such as CGA (comprehensive geriatric assessment) and EBMT score, are useful in this context and might guide physician decisions regarding the transplant. Indeed, with the development of reduced intensity conditioning regimens, the number of patient candidates for an HSCT has increased. Regarding pre-transplant treatment, patients with a blast excess > 10% might be treated with HMAs or chemotherapy, although there are no randomized trials confirming the benefit of this approach, even when achieving a complete response. Concerning donor choice, matched sibling donors continue to be the first option, although matched unrelated donors, and more recently haploidentical donors, have proven to be valid options and should be offered in the absence of a related donor. Relapse remains the main cause of transplantation failure. MRD assessment and pre-emptive or prophylactic use of HMA or other targeted inhibitors with or without DLI are accepted strategies to reduce relapse risk, but the prognosis in this context remains dismal, and is the subject for several ongoing clinical protocols. Full article
(This article belongs to the Special Issue Challenges in the Treatment of Myelodysplastic Syndrome)
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19 pages, 1691 KiB  
Review
Pathophysiology of Myelodysplastic Syndromes
by Michaela Fontenay, Batoul Farhat and Ismael Boussaid
Hemato 2021, 2(3), 477-495; https://doi.org/10.3390/hemato2030030 - 26 Jul 2021
Cited by 2 | Viewed by 6327
Abstract
Ineffective hematopoiesis is the major characteristic of early myelodysplastic syndromes. Its pathophysiology relies on a diversity of mechanisms supported by genetic events that develop in aging hematopoietic stem cells. Deletion and mutations trigger epigenetic modifications, and co-transcriptional and post-transcriptional deregulations of gene expression. [...] Read more.
Ineffective hematopoiesis is the major characteristic of early myelodysplastic syndromes. Its pathophysiology relies on a diversity of mechanisms supported by genetic events that develop in aging hematopoietic stem cells. Deletion and mutations trigger epigenetic modifications, and co-transcriptional and post-transcriptional deregulations of gene expression. Epistatic interactions between mutants may aggravate the phenotype. Amplification of minor subclones containing mutations that promote their growth and suppress the others drives the clonal evolution. Aging also participates in reprogramming the immune microenvironment towards an inflammatory state, which precedes the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressive cells that alters the anti-tumor response of effector cells. Integrating biomarkers of transcription/translation deregulation and immune contexture will help the design of personalized treatments. Full article
(This article belongs to the Special Issue Challenges in the Treatment of Myelodysplastic Syndrome)
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26 pages, 1785 KiB  
Review
Chronic Myelomonocytic Leukemia Gold Jubilee
by Eric Solary and Raphael Itzykson
Hemato 2021, 2(3), 403-428; https://doi.org/10.3390/hemato2030026 - 01 Jul 2021
Viewed by 3964
Abstract
Chronic myelomonocytic leukemia (CMML) was named 50 years ago to describe a myeloid malignancy whose onset is typically insidious. This disease is now classified by the World Health Organisation as a myelodysplastic syndrome (MDS)-myeloproliferative neoplasm (MPN) overlap disease. Observed mostly in ageing people, [...] Read more.
Chronic myelomonocytic leukemia (CMML) was named 50 years ago to describe a myeloid malignancy whose onset is typically insidious. This disease is now classified by the World Health Organisation as a myelodysplastic syndrome (MDS)-myeloproliferative neoplasm (MPN) overlap disease. Observed mostly in ageing people, CMML is characterized by the expansion of monocytes and, in many cases, granulocytes. Abnormal repartition of circulating monocyte subsets, as identified by flow cytometry, facilitates disease recognition. CMML is driven by the accumulation, in the stem cell compartment, of somatic variants in epigenetic, splicing and signaling genes, leading to epigenetic reprogramming. Mature cells of the leukemic clone contribute to creating an inflammatory climate through the release of cytokines and chemokines. The suspected role of the bone marrow niche in driving CMML emergence and progression remains to be deciphered. The clinical expression of the disease is highly diverse. Time-dependent accumulation of symptoms eventually leads to patient death as a consequence of physical exhaustion, multiple cytopenias and acute leukemia transformation. Fifty years after its identification, CMML remains one of the most severe chronic myeloid malignancies, without disease-modifying therapy. The proliferative component of the disease that distinguishes CMML from severe MDS has been mostly neglected. This review summarizes the progresses made in disease understanding since its recognition and argues for more CMML-dedicated clinical trials. Full article
(This article belongs to the Special Issue Challenges in the Treatment of Myelodysplastic Syndrome)
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18 pages, 397 KiB  
Review
Inflammatory and Immune Disorders Associated with Myelodysplastic Syndromes
by Vincent Jachiet, Pierre Fenaux, Anna Sevoyan, Yervand Hakobyan, Lionel Ades, Olivier Fain, Arsène Mekinian and on behalf of the MINHEMON and GFM
Hemato 2021, 2(2), 329-346; https://doi.org/10.3390/hemato2020019 - 24 May 2021
Cited by 4 | Viewed by 5317
Abstract
Systemic auto-inflammatory or autoimmune diseases (SIADs) develop in up to a quarter of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). With or without the occurrence of SIADs, the distribution of MDS subtypes and the international or CMML-specific prognostic scoring systems [...] Read more.
Systemic auto-inflammatory or autoimmune diseases (SIADs) develop in up to a quarter of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). With or without the occurrence of SIADs, the distribution of MDS subtypes and the international or CMML-specific prognostic scoring systems have been similar between MDS/CMML patients. Moreover, various SIADs have been described in association with MDS, ranging from limited clinical manifestations to systemic diseases affecting multiple organs. Defined clinical entities including systemic vasculitis, connective tissue diseases, inflammatory arthritis and neutrophilic diseases are frequently reported; however, unclassified or isolated organ impairment can also be seen. Although the presence of SIADs does not impact the overall survival nor disease progression to acute myeloid leukemia, they can help with avoiding steroid dependence and make associated adverse events of immunosuppressive drugs challenging. While therapies using steroids and immunosuppressive treatment remain the backbone of first-line treatment, increasing evidence suggests that MDS specific therapy (hypomethylating agents) and sparing steroids may be effective in treating such complications based on their immunomodulatory effect. The aim of this review was to analyze the epidemiological, pathophysiological, clinical and therapeutic factors of systemic inflammatory and immune disorders associated with MDS. Full article
(This article belongs to the Special Issue Challenges in the Treatment of Myelodysplastic Syndrome)
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