View source for HAEM4Backup:Myelodysplastic/Myeloproliferative Neoplasms with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T)

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==Primary Author(s)*==

Anamaria Munteanu, MD, Ph.D, Harbor-UCLA Medical Center, Fabiola Quintero-Rivera, University of California Irvine

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==Cancer Category/Type==

Tumors of hematopoietic and lymphoid tissue

==Cancer Sub-Classification / Subtype==

MDS/MPN overlap syndromes

==Definition / Description of Disease==

MDS/MPN-RS-T is a MDS/MPN with more than 15% ring sideroblasts and persistent thrombocytosis (more than 450 x 10 <sup>9</sup>/L platelets). It generally presents with anemia and erythroid dysplasia and SF3B1 mutation is present in 80% of cases. Other diagnosis criteria consider the number of blasts:  <1% peripheral blood leukocytes and <5% of nucleated cells in bone marrow. For diagnosis of MDS/MPN-RS-T we must exclude cases with prior diagnosis of MDS, MPN or MDS/MPN, as well as therapy related myeloid neoplasm. Exception are cases of MDS-RS which transform in MDS/MPN RS-T<ref name=":0">Arber DA, et al., (2017). MDS/MPN with ring sideroblasts and thrombocytosis, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p93-94</ref><ref name=":1">Bone Marrow Pathology. Kathryn Foucar, Kaaren Reichard, David Czuchlewski, ASCP Press, 2020, Calssification of MDS/MPN, MDS/MPN with ring sideroblasts and thrombocytosis p383-384.</ref>

Specific genetic alterations must also be absent: BCR-ABL1 fusion, PDGFRA, PDGFRB, FGFR1, PCM1-JAK2 rearrangements, t(3;3)(q21q26), inv(3)(q21q26) or del(5q).

==Synonyms / Terminology==

Older terminology includes: Refractory anemia with ring sideroblasts and marked thrombocytosis

==Epidemiology / Prevalence==

Median patient age is 71-75 years old at diagnosis, with slight female prevalence.

==Clinical Features==

Symptoms and clinical features are related to anemia, iron overload and thrombocytosis. Thrombocytemia manifests with thrombosis/hemorrhage. Differential diagnosis for thrombocytosis is Essential Thromocytopenia (ET) or reactive thrombocytosis. 

For the presence of ring sideroblasts differential diagnosis includes alcohol, toxins such as lead or zinc, drugs such as isoniazid, chloramphenicol linezolid, penicillamine and other conditions such as pyridoxine deficiency, copper deficiency, or hereditary sideroblastic anemia<ref name=":2">{{Cite journal|last=Mm|first=Patnaik|last2=A|first2=Tefferi|date=2019|title=Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis: "2019 Update on Diagnosis, Risk-stratification, and Management"|url=https://pubmed.ncbi.nlm.nih.gov/30618061/|language=en|doi=10.1002/ajh.25397|pmc=PMC6408294|pmid=30618061}}</ref>.

Ring sideroblasts are abnormal erythroid lineage precursors with increased mitochondrial iron deposits forming siderotic granules. A minimum of five distinct siderotic granules must be present, involving at least one third of the nuclear circumference.

==Sites of Involvement==

Peripheral blood and bone marrow involvement are consistently present, splenic and hepatic involvement are less frequent.

==Morphologic Features==

Peripheral blood<ref name=":0" /><ref name=":1" />: 

Normochromic macrocytic anemia, 

Thrombocytosis with anisocytosis

Erythroid lineage dysplasia-nuclear segmentation, or megaloblastoid features; 

Hemosiderin laden macrophages. 

Blast count: Less than 1% peripheral blood leukocytes.    

Bone marrow <ref name=":0" /><ref name=":1" />:

Increased erythroid precursors with ineffective erythropoiesis

Increased number of large mature megakaryocytes with dysplastic features and hyperlobulated nuclei

Bone marrow fibrosis

More than 15% ring sideroblasts

Blast count <5% of nucleated cells in bone marrow

==Immunophenotype==

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||Ring sideroblasts positive with Prussian-blue
|}

==Chromosomal Rearrangements (Gene Fusions)==

No chromosomal rearrangements for MDS/MPN-RS-T
==Characteristic Chromosomal Aberrations / Patterns==

No recurrent chromosomal aberrations for MDS/MPN-RS-T. However, abnormalities have been reported in 10% of patients. Trisomy 8 and loss of Y are the most common changes.<ref name=":3" /> 

==Genomic Gain/Loss/LOH==

No genomic gain/loss for MDS/MPN-RS-T
==Gene Mutations (SNV/INDEL)==

The presence of concomitant  mutations in SF3B1 and JAK2 V617F support the diagnosis of MDS/MPN-RS-T; less commonly encountered are SF3B1 and CALR or SF3B1 and MPL <ref>{{Cite journal|last=S|first=Jeromin|last2=T|first2=Haferlach|last3=S|first3=Weissmann|last4=M|first4=Meggendorfer|last5=C|first5=Eder|last6=N|first6=Nadarajah|last7=T|first7=Alpermann|last8=A|first8=Kohlmann|last9=W|first9=Kern|date=2015|title=Refractory anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in SF3B1 or other spliceosome genes accompanied by JAK2V617F and ASXL1 mutations|url=https://pubmed.ncbi.nlm.nih.gov/25527566/|language=en|doi=10.3324/haematol.2014.119032|pmc=PMC4380732|pmid=25527566}}</ref><ref name=":3">{{Cite journal|last=L|first=Palomo|last2=M|first2=Meggendorfer|last3=S|first3=Hutter|last4=S|first4=Twardziok|last5=V|first5=Adema|last6=I|first6=Fuhrmann|last7=F|first7=Fuster-Tormo|last8=B|first8=Xicoy|last9=L|first9=Zamora|date=2020|title=Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/32573691/|language=en|pmid=32573691}}</ref>.

{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|SF3B1|| ||RNA splicing|| ||85-97%
|-
|JAK2
|
|Cell signaling
|
|37-50%
|-
|TET2
|
|Epigenetic regulator
|
|25%
|-
|DNMT3A
|
|Epigenetic regulator
|
|15%
|-
|ASXL1
|
|Epigenetic regulator
|
|10-20%
|-
|IDH2
|
|Epigenetic regulator
|
|
|}	
		
===Other Mutations===
In less than 10%, SRSF2, U2AF1, ZRSR2, EZH2, IDH2, ETV6, RUNX1, SETBP1, HEPHL1 and PAFAH2
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||SF3B1 and  JAK2 V617F; SF3B1 and CALR; SF3B1 and MPL; SF3B1-DNMT3A
|-
|Founder mutations||SF3B1, DNMT3A
|-
|Secondary Mutations
|JAK2, SH2B3, MPL
|-
|Mutually Exclusive||JAK2, CALR, MPL
|}

==Epigenomics (Methylation)==

Put your text here

==Genes and Main Pathways Involved==

SF3B1 gene mutations are present in over 80% of patients <ref name=":2" />. Somatic mutation in SF3B1 leads to abnormal ABCB7 protein, accumulation of mitochondrial iron and ineffective erythropoiesis, with formation of ring sideroblasts<ref>{{Cite journal|last=M|first=Cazzola|last2=M|first2=Rossi|last3=L|first3=Malcovati|date=2013|title=Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/23160465/|language=en|doi=10.1182/blood-2012-09-399725|pmc=PMC3790951|pmid=23160465}}</ref>. Mutations in JAK2 correlate with increased platelet count.<ref name=":3" /> 

==Diagnostic Testing Methods==

Gene sequencing. 

Flow cytometry to identify abnormal erythroid precursors

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

The presence of SF3B1 and JAK2 mutations is correlated with better prognosis and longer survival. Mutations in ASXL1, SETBP1 and EZH2 have negative prognostic significance <ref name=":2" /><ref name=":3" />. Abnormal karyotypes, although rare, correlate with very poor outcome <ref name=":3" />. Disease outcome: overall survival is better than in patients with MDS-RS-SLD, but worse than in patients with MPN-ET. There is low risk of converging to leukemic forms.<ref name=":0" /><ref name=":2" />

Treatment: transfusions, recombinant human erythropoietin for anemia. The use of Lenalidomide is controversial, while,  the use of Luspatercept- a novel erythroid maturation agent is not an established treatment option. Aspirin for thrombocytosis. Hydroxyurea is the preferred  cytoreductive agent <ref name=":2" />

==Familial Forms==

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==Other Information==

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==Links==

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==References==
<references />
==Notes==
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