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Fozza C, Murtas A, Caocci G, La Nasa G. Autoimmune disorders associated with myelodysplastic syndromes: clinical, prognostic and therapeutic implications. Leuk Res 2022; 117:106856. [PMID: 35525186 DOI: 10.1016/j.leukres.2022.106856] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/29/2022]
Abstract
Around one third of patients with myelodysplastic syndromes (MDS) suffer from concomitant autoimmune disorders (AD). However the actual burden of such an association appears to be quite heterogeneous in different studies probably due to variable criteria in selecting both MDS patients and subtypes of AD. Moreover, both the prognostic implications and the potential applications of specific therapeutic approaches in this patient subgroup are still at least partially under debate. The present review will try to shed some further light on the clinical association between MDS and AD in order to better delineate its prognostic significance and to suggest potential therapeutic algorithms available for these patients.
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Affiliation(s)
- Claudio Fozza
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 12, 07100 Sassari, Italy
| | - Andrea Murtas
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 12, 07100 Sassari, Italy
| | - Giovanni Caocci
- Department of Medical Sciences, University of Cagliari, Cagliari, Italy
| | - Giorgio La Nasa
- Department of Medical Sciences, University of Cagliari, Cagliari, Italy
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Hypoplastic Myelodysplastic Syndromes: Just an Overlap Syndrome? Cancers (Basel) 2021; 13:cancers13010132. [PMID: 33401595 PMCID: PMC7795441 DOI: 10.3390/cancers13010132] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 12/29/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Hypoplastic myelodysplastic syndromes (hMDS) represent a diagnostic conundrum. They share morphologic and clinical features of both MDS (dysplasia, genetic lesions and cytopenias) and aplastic anemia (AA; i.e., hypocellularity and autoimmunity) and are not comprised in the last WHO classification. In this review we recapitulate the main clinical, pathogenic and therapeutic aspects of hypo-MDS and discuss why they deserve to be distinguished from normo/hypercellular MDS and AA. We conclude that hMDS may present in two phenotypes: one more proinflammatory and autoimmune, more similar to AA, responding to immunosuppression; and one MDS-like dominated by genetic lesions, suppression of immune surveillance, and tumor escape, more prone to leukemic evolution. Abstract Myelodysplasias with hypocellular bone marrow (hMDS) represent about 10–15% of MDS and are defined by reduced bone marrow cellularity (i.e., <25% or an inappropriately reduced cellularity for their age in young patients). Their diagnosis is still an object of debate and has not been clearly established in the recent WHO classification. Clinical and morphological overlaps with both normo/hypercellular MDS and aplastic anemia include cytopenias, the presence of marrow hypocellularity and dysplasia, and cytogenetic and molecular alterations. Activation of the immune system against the hematopoietic precursors, typical of aplastic anemia, is reckoned even in hMDS and may account for the response to immunosuppressive treatment. Finally, the hMDS outcome seems more favorable than that of normo/hypercellular MDS patients. In this review, we analyze the available literature on hMDS, focusing on clinical, immunological, and molecular features. We show that hMDS pathogenesis and clinical presentation are peculiar, albeit in-between aplastic anemia (AA) and normo/hypercellular MDS. Two different hMDS phenotypes may be encountered: one featured by inflammation and immune activation, with increased cytotoxic T cells, increased T and B regulatory cells, and better response to immunosuppression; and the other, resembling MDS, where T and B regulatory/suppressor cells prevail, leading to genetic clonal selection and an increased risk of leukemic evolution. The identification of the prevailing hMDS phenotype might assist treatment choice, inform prognosis, and suggest personalized monitoring.
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Fozza C, La Nasa G, Caocci G. The Yin and Yang of myelodysplastic syndromes and autoimmunity: The paradox of autoimmune disorders responding to therapies specific for MDS. Crit Rev Oncol Hematol 2019; 142:51-57. [PMID: 31376677 DOI: 10.1016/j.critrevonc.2019.07.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/25/2019] [Accepted: 07/22/2019] [Indexed: 12/16/2022] Open
Abstract
The biological milieu and clinical picture of myelodysplastic syndromes (MDS) is characterised by a variety of immune mechanisms and manifestations, including an increased frequency of autoimmune disorders. The present review will try to shed some light on the potential clinical and pathogenetic implications of these immune processes in MDS by focusing on the beneficial effects exerted by some MDS-modifying therapies on autoimmune manifestations.
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Affiliation(s)
- Claudio Fozza
- Hematology Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 12, 07100 Sassari, Italy.
| | - Giorgio La Nasa
- Hematology Unit, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
| | - Giovanni Caocci
- Hematology Unit, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
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Fozza C. Deciphering the prognostic significance of autoimmune disorders in myelodysplastic syndromes. Ann Hematol 2019; 98:1025-1026. [PMID: 30310984 DOI: 10.1007/s00277-018-3514-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 10/04/2018] [Indexed: 11/27/2022]
Affiliation(s)
- Claudio Fozza
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 12, 07100, Sassari, Italy.
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Retuning the immune system in myelodysplastic syndromes: from immunomodulatory approaches to vaccination strategies and non myeloablative hemopoietic cell transplant. Crit Rev Oncol Hematol 2019; 133:112-119. [DOI: 10.1016/j.critrevonc.2018.11.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 08/09/2018] [Accepted: 11/05/2018] [Indexed: 12/24/2022] Open
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Daitoku S, Aoyagi T, Takao S, Tada S, Kuroiwa M. Successful Treatment of Hemophagocytic Lymphohistiocytosis Associated with Low-risk Myelodysplastic Syndrome by Azacitidine. Intern Med 2018; 57:2995-2999. [PMID: 29780114 PMCID: PMC6232014 DOI: 10.2169/internalmedicine.0497-17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome that occurs as a complication in many clinical settings. Malignancy-associated HLH develops in patients with hematopoietic neoplasms, particularly in those with lymphoma, and its development in those with myelodysplastic syndrome (MDS) is uncommon. We herein report a case of HLH in a patient with low-risk MDS that was successfully treated with azacitidine. The prevalence of immune abnormalities among MDS patients and the immune effects of azacitidine have recently been elucidated, suggesting that MDS-associated HLH occurs as a result of immune impairment, and azacitidine improves this condition by restoring the immune system.
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Affiliation(s)
- Shinya Daitoku
- Department of Hematology, National Hospital Organization Fukuoka Higashi Medical Center, Japan
| | - Tomomi Aoyagi
- Department of Gastroenterology and Hepatology, National Hospital Organization Fukuoka Higashi Medical Center, Japan
| | - Shinichiro Takao
- Department of Gastroenterology and Hepatology, National Hospital Organization Fukuoka Higashi Medical Center, Japan
| | - Seiya Tada
- Department of Gastroenterology and Hepatology, National Hospital Organization Fukuoka Higashi Medical Center, Japan
| | - Mika Kuroiwa
- Department of Hematology, National Hospital Organization Fukuoka Higashi Medical Center, Japan
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Wang C, Yang Y, Gao S, Chen J, Yu J, Zhang H, Li M, Zhan X, Li W. Immune dysregulation in myelodysplastic syndrome: Clinical features, pathogenesis and therapeutic strategies. Crit Rev Oncol Hematol 2018; 122:123-132. [DOI: 10.1016/j.critrevonc.2017.12.013] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 11/26/2017] [Accepted: 12/18/2017] [Indexed: 12/16/2022] Open
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8
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Fozza C. The burden of autoimmunity in myelodysplastic syndromes. Hematol Oncol 2017; 36:15-23. [PMID: 28449370 DOI: 10.1002/hon.2423] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 03/30/2017] [Accepted: 03/31/2017] [Indexed: 12/19/2022]
Abstract
The clinical history of patients with myelodysplastic syndromes (MDS) is characterised by bone marrow insufficiency as well as by the possible evolution into acute leukaemia. However a number of reports highlight the frequent occurrence of autoimmune manifestations involving different sites and organs. The present review will first describe the clinical pictures most often observed in MDS patients. The actual burden of autoimmunity will be then addressed by focusing on the few available registry studies. Finally, the potential collateral impact of specific treatments for MDS on the evolution of autoimmune disorders will be considered.
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Affiliation(s)
- Claudio Fozza
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
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Fozza C, Crobu V, Isoni MA, Dore F. The immune landscape of myelodysplastic syndromes. Crit Rev Oncol Hematol 2016; 107:90-99. [PMID: 27823655 DOI: 10.1016/j.critrevonc.2016.08.016] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 08/15/2016] [Accepted: 08/31/2016] [Indexed: 12/25/2022] Open
Abstract
Even though the pathogenesis of myelodysplastic syndromes (MDS) is dominated by specific molecular defects involving hematopoietic precursors, also immune mechanisms seem to play a fundamental functional role. In this review we will first describe the clinical and laboratory autoimmune manifestations often detectable in MDS patients. We will then focus on studies addressing the possible influence of different immune cell subpopulations on the disease onset and evolution. We will finally consider therapeutic approaches based on immunomodulation, ranging from immunosuppressants to vaccination and transplantation strategies.
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Affiliation(s)
- Claudio Fozza
- Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 12, 07100 Sassari, Italy.
| | - Valeria Crobu
- Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 12, 07100 Sassari, Italy
| | - Maria Antonia Isoni
- Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 12, 07100 Sassari, Italy
| | - Fausto Dore
- Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 12, 07100 Sassari, Italy
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Fozza C, Corda G, Barraqueddu F, Virdis P, Contini S, Isoni A, Dore F, Podda L, Longinotti M. Evidence of a skewed T-cell repertoire in patients with light chain amyloidosis. Hematol Oncol 2016; 36:492-494. [PMID: 26857096 DOI: 10.1002/hon.2281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 12/15/2015] [Accepted: 12/22/2015] [Indexed: 11/10/2022]
Affiliation(s)
- Claudio Fozza
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Giovanna Corda
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | | | - Patrizia Virdis
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Salvatore Contini
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Antonella Isoni
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Fausto Dore
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Luigi Podda
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
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Fozza C, Corda G, Barraqueddu F, Virdis P, Contini S, Galleu A, Isoni A, Dore F, Angelucci E, Longinotti M. Azacitidine improves the T-cell repertoire in patients with myelodysplastic syndromes and acute myeloid leukemia with multilineage dysplasia. Leuk Res 2015. [DOI: 10.1016/j.leukres.2015.06.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Fozza C, Corda G, Virdis P, Contini S, Barraqueddu F, Galleu A, Isoni A, Cossu A, Dore F, Careddu MG, Bonfigli S, Giannico B, Longinotti M. Derangement of the T-cell repertoire in patients with B-cell non-Hodgkin's lymphoma. Eur J Haematol 2014; 94:298-309. [DOI: 10.1111/ejh.12417] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2014] [Indexed: 02/02/2023]
Affiliation(s)
- Claudio Fozza
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
| | - Giovanna Corda
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
| | - Patrizia Virdis
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
| | - Salvatore Contini
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
| | | | - Antonio Galleu
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
| | - Antonella Isoni
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
| | - Antonella Cossu
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
| | - Fausto Dore
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
| | - Maria G. Careddu
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
| | - Silvana Bonfigli
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
| | - Barbara Giannico
- Department of Biomedical Sciences; University of Sassari; Sassari Italy
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Frietsch JJ, Dornaus S, Neumann T, Scholl S, Schmidt V, Kunert C, Sayer HG, Hochhaus A, La Rosée P. Paraneoplastic inflammation in myelodysplastic syndrome or bone marrow failure: case series with focus on 5-azacytidine and literature review. Eur J Haematol 2014; 93:247-59. [DOI: 10.1111/ejh.12311] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2014] [Indexed: 12/14/2022]
Affiliation(s)
- Jochen J. Frietsch
- Klinik für Innere Medizin II; Hämatologie und internistische Onkologie; Universitätsklinikum Jena; Jena Germany
| | - Sebastian Dornaus
- Klinik für Innere Medizin II; Hämatologie und internistische Onkologie; Universitätsklinikum Jena; Jena Germany
| | - Thomas Neumann
- Klinik für Innere Medizin III; Universitätsklinikum Jena; Jena Germany
| | - Sebastian Scholl
- Klinik für Innere Medizin II; Hämatologie und internistische Onkologie; Universitätsklinikum Jena; Jena Germany
| | - Volker Schmidt
- Klinik für Innere Medizin II; Hämatologie und internistische Onkologie; Universitätsklinikum Jena; Jena Germany
| | - Christa Kunert
- Klinik für Innere Medizin II; Hämatologie und internistische Onkologie; Universitätsklinikum Jena; Jena Germany
| | - Herbert G. Sayer
- Klinik für Innere Medizin II; Hämatologie und internistische Onkologie; Universitätsklinikum Jena; Jena Germany
| | - Andreas Hochhaus
- Klinik für Innere Medizin II; Hämatologie und internistische Onkologie; Universitätsklinikum Jena; Jena Germany
| | - Paul La Rosée
- Klinik für Innere Medizin II; Hämatologie und internistische Onkologie; Universitätsklinikum Jena; Jena Germany
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14
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Parikh AR, Olnes MJ, Barrett AJ. Immunomodulatory treatment of myelodysplastic syndromes: antithymocyte globulin, cyclosporine, and alemtuzumab. Semin Hematol 2013; 49:304-11. [PMID: 23079060 DOI: 10.1053/j.seminhematol.2012.07.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
It is now well accepted that a subgroup of patients with myelodysplastic syndromes (MDS) can recover from pancytopenia following immunosuppressive treatment (IST). For many years immunosuppression with antilymphocyte antibodies has been a standard treatment approach for patients with severe aplastic anemia (SAA). The initial concept of using immunosuppression to treat pancytopenic patients with MDS was based on the premise that MDS might share with SAA an autoimmune basis for the bone marrow failure common to both conditions. The idea was supported by reports of favorable outcomes in occasional cases of MDS treated with antithymocyte globulin (ATG). Today, various forms of IST have been successfully used to restore hematopoiesis in MDS in many centers worldwide. In this review we outline the rationale for use of IST in MDS, and describe studies which help to define the patients with MDS likely to respond to IST. We summarize 18 published clinical trials using IST for MDS and discuss how these studies have helped to define the MDS subgroups likely to respond to treatment, the nature and durability of the response, the impact of IST on long-term outcome, and the best treatment approach.
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Affiliation(s)
- Ankur R Parikh
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1202, USA
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Fozza C. Emerging immunological concepts in the pathogenesis of myelodysplastic syndromes. World J Hematol 2013; 2:13-15. [DOI: 10.5315/wjh.v2.i2.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 02/06/2013] [Accepted: 03/27/2013] [Indexed: 02/05/2023] Open
Abstract
The involvement of T-lymphocytes in the pathogenesis of myelodysplastic syndromes (MDS) is now well documented by relevant clinical and experimental findings. This brief review will focus on the T-cell repertoire pattern typical of MDS patients as well as on the potential role exerted by specific T-cell subsets in this context. Future investigations should further explore the specific role played by different T-cell subsets in the bone marrow milieu typical of MDS, further clarifying which of the described changes represent either an epiphenomenon or rather a real causative factor in the pathogenesis of these disorders.
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IL10 inversely correlates with the percentage of CD8+ cells in MDS patients. Leuk Res 2013; 37:541-6. [DOI: 10.1016/j.leukres.2013.01.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 01/04/2013] [Accepted: 01/25/2013] [Indexed: 12/24/2022]
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Fozza C, Longinotti M. The role of T-cells in the pathogenesis of myelodysplastic syndromes: passengers and drivers. Leuk Res 2012; 37:201-3. [PMID: 23218025 DOI: 10.1016/j.leukres.2012.11.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 11/12/2012] [Accepted: 11/13/2012] [Indexed: 12/23/2022]
Abstract
Although a burden of clinical and experimental data suggest the involvement of T-lymphocytes in the pathogenesis of myelodysplastic syndromes (MDS), the actual weight exerted by T-cells in this scenario is yet to be conclusively dissected. This brief review will try to further address this point, by running through the most relevant studies exploring the T-cell repertoire of MDS patients as well as the potential role of specific T-cell subsets such as regulatory T-cells and Th17 T-cells.
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Affiliation(s)
- Claudio Fozza
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
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Giagounidis A. Introduction: application of new therapies to myelodysplastic syndrome. Semin Hematol 2012; 49:285-6. [PMID: 23079057 DOI: 10.1053/j.seminhematol.2012.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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