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Myelodysplastic syndrome (MDS), diagnosis, prognosis and the best available treatment

Jalil Ur Rehman

Department of Oncology, King Faisal Specialist Hospital and Research Centre, Saudi Arabia

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Al Johani NI

Department of Oncology, King Faisal Specialist Hospital and Research Centre, Saudi Arabia

Mahnoor Jalil

Medical Student, CMH Lahore Medical College, Pakistan

DOI: 10.15761/ICST.1000320

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Introduction

Myelodysplastic syndrome (MDS) is a stem cell disorder characterized by ineffective hematopoiesis and bone marrow dysplasia that, in many cases, progresses to acute myeloid leukemia [1]. Treatment for MDS is variable and applied according to the risk classification based on the International Prognostic Scoring System (IPSS) [2,3]. Approximately 10–20% of patients with myelodysplastic syndrome (MDS) present with autoimmune diseases (AD) which can be challenging to recognize. The autoimmunity is believed to be triggered by the increased apoptosis in the dysplastic bone marrow. Recent evidence suggests that both diseases are characterized by dendritic and T-cell abnormalities. AD presentation varies from clinical syndromes such as vasculitis, lupus and rheumatoid arthritis to laboratory abnormalities such as thrombocytopenia, hemolytic anemia and autoantibodies [4]. The association of AIM and MDS was first described in 1982 as AIHA one year after the diagnosis of MDS. 6 Subsequently, multiple cases and studies have been published emphasizing the relationship between autoimmunity and MDS [5].

Prognostic markers and survival benefit

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q is part of a group of clonal disorders in myeloid stem cells with ineffective hematopoiesis which is manifested by morphologic dysplasia in hematopoietic cells and single or lineage Cytopenias. It is the only MDS subtype defined cytogenetically in the World Health Organization classification system [6].

MDS with isolated Del (5q) is present in <5% of MDS cases, it occurs more often in women than in men, male: female ratio 7: 3, with a median age of diagnosis at 65 to 70 years. Patients suffering from MDS with isolated Del (5q) present with macrocytic anemia, normal or increased platelet count and absence of significant neutropenia in their peripheral blood [7]. The incidence of bleeding and infections is therefore low in these patients because of the absence of significant neutropenia and thrombocytopenia. Blood transfusion dependency is seen in patients with severe anemia at diagnosis but also can develop in other patients. According to the Revised International Prognostic Scoring System (IPSS-R), MDS with isolated Del (5q) are defined as Low- or Intermediate -1- risk subtypes and usually have an indolent course [8].

Trisomy 21 and risk of transformation

Trisomy 21 (+21) is well known in the context of Down’s syndrome, associated with a marked risk to develop AML during childhood. However, besides this hereditary disease, +21 may also occur as a clonal somatic abnormality in several hematologic disorders. In adult de novo AML, trisomy 21 occurs in around 3% of patients. In MDS, +21 as a single abnormality is occurring more rarely. In a series of 968 patients published by Sole et al. [9], isolated +21 was detected in 0.8% of patients and showed a significant association with CMML, where 3.5% of patients showed +21 as sole abnormality. 54 Further publications found a comparable incidence, calculated as 1.1% of patients showing +21 within a non-complex karyotype. Based on a cohort of 2,901 patients, the incidence of +21 as an isolated abnormality was 0.3%, assigning this abnormality to the group of rare abnormalities in MDS. Based on nine patients, the authors described an association with a low ANC (median 1.9/nl) and a slightly decreased platelet (median 105/nl) and hemoglobin (9.1 g/dl) level. The median blast count in these patients was 6%, indicating an association with higher risk MDS. The median OS was 100.8 months in +21 within a non-complex karyotype. Other publications stated a median OS of 13.9 months and 21.5 months respectively, for patients showing isolated +21.

The median time to AML evolution was 100.7 months in the publication of Schanz et al. Solé et al. stated a cumulative AML risk of 25% after one year and 50% after five years. Taken these results together, the prognostic impact of an acquired, isolated +21 in patients with MDS remains unclear und has to be stated as intermediate until a higher number of patients were analyzed.

Molecular factor affecting the survival

The molecular background of patients showing +21 in myeloid malignancies remains undefined as yet. RUNX1 (=AML1), located on chromosome 8q22, commonly involved in t (8; 21)/RUNX1-RUNXT1 in AML, was shown to be also point mutated in patients with myeloid malignancies like AML, MDS and MPN with +21. A Japanese group found a poor prognostic impact of intragenic RUNX1 mutations in MDS but did not describe a correlation with +21. [10].

Available treatment modalities

Therefore, these findings suggest that 5--Azacitidine, a cytidine nucleoside analog, is a demethylating agent that was approved by the U.S. Food and Drug Administration for the treatment of high-risk MDS in 2004 [11-13]. In an international multicenter Phase III study (the Aza-001 study), 5-azacitidine was found to achieve a better overall survival in patients with high-risk MDS compared to conventional Therapies [11,14,15]. Almost all patients were treated with more than one cycle and approximately half achieved a first response after two or more cycles [16] Azacitidine therapy should be continued after obtaining a response.

In the post hoc analysis of the AZA-001 study, Silverman et al. reported that a median of two cycles (range, 1-16) of 5-azacitidine treatment was efficacious in achieving a first response with a hematological improvement [17]. Furthermore, The US Cancer and Leukemia Group B reported a median time to the initial response of 64 days for 5-Azacitidine therapy, although the time to a response in the subjects treated with a single cycle of therapy was unclear [10]. Therefore, late responses to 5-azacitidine treatment remain to be investigated.

Currently the only therapy with proven curative potential for MDS is hematopoietic stem cell transplantation (HSCT) [18], with long-term survival rates between 25% and 70%. However, HSCT carries a risk of toxicity and potentially fatal complications, particularly in older patients.

References

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  4. Pilorge S, Doleris LM, Dreyfus F, Park S (2011) The autoimmune manifestations associated with myelodysplastic syndrome respond to 5-azacytidine: A report on three cases. Br J Haematol 153: 664-665. [Crossref]
  5. Chalhoub E, Chalouhy C, Jambeih R, Page SJ (2013) Autoimmune Hemolytic Anemia with Myelodysplastic Syndrome. Kansas Journal of Medicine: 94-97.
  6. Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, et al. (2007) New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients.Blood110: 4385-4395. [Crossref]
  7. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, et al. (2006) Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia.Blood108: 419-425. [Crossref]
  8. Shahmarvand N, Ohgami RS (2017) del (5q) solely in Myelodysplastic syndrome; Atlas Genet Cytogenet Oncol Haematol. [In press].
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  11. Itzykson R, Thépot S, Quesnel B, Dreyfus F, Beyne-Rauzy O, et al. (2011) Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood 117: 403- 411. [Crossref]
  12. Mahesh KKN (2005) Molecules of the Millennium-Azacitidine: A novel drug for myelodysplastic syndrome. Indian J Pharmacol 37: 414- 415.
  13. Tsao CF, Dalal J, Peters C, Gonzalez C, Kearns GL (2007) Azacitidine pharmacokinetics in an adolescent patient with renal compromise.J Pediatr Hematol Oncol29: 330-333. [Crossref]
  14. Uchida T, Ogawa Y, Kobayashi Y, Ishikawa T, Ohashi H, et al. (2011) Phase I and II study of azacitidine in Japanese patients with myelodysplastic syndromes.Cancer Sci102: 1680-1686. [Crossref]
  15. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, et al. (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.Lancet Oncol10: 223-232. [Crossref]
  16. Silverman LR, Fenaux P, Mufti GJ, Santini V, Hellström-Lindberg E, et al. (2011) Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes.Cancer117: 2697-2702. [Crossref]
  17. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, et al. (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B.J Clin Oncol20: 2429-2440. [Crossref]
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Editorial Information

Editor-in-Chief

Hiroshi Miyamoto
University of Rochester Medical Center

Article Type

Mini Review

Publication history

Received: September 18, 2019
Accepted: September 29, 2019
Published: October 03, 2019

Copyright

©2019 Rehman J. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Rehman J, Al Johani NI, Jalil M (2019) Myelodysplastic syndrome (MDS), diagnosis, prognosis and the best available treatment. Integr Cancer Sci Therap 6: DOI: 10.15761/ICST.1000320.

Corresponding author

Jalil Ur Rehman, MBBS (DOW), MRCP (UK) FRCP (LONDON), MBC-J-64

Department of Oncology, King Faisal Specialist Hospital, P.O. Box: 40047, Jeddah 21499, Kingdom of Saudi Arabia, Tel: 00966-555212399.

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

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