Bailey.Glen: Created page with "==Primary Author(s)*== Ruth MacKinnon PhD Victorian Cancer Cytogenetics Service Melbourne, Australia TOC ==Cancer Category/Type== Myelodysplastic/Myeloproliferative N..."

2023-11-03T17:29:48Z

Created page with "==Primary Author(s)*== Ruth MacKinnon PhD Victorian Cancer Cytogenetics Service Melbourne, Australia __TOC__ ==Cancer Category/Type== Myelodysplastic/Myeloproliferative N..."

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==Primary Author(s)*==
Ruth MacKinnon PhD

Victorian Cancer Cytogenetics Service

Melbourne, Australia

__TOC__

==Cancer Category/Type==

Myelodysplastic/Myeloproliferative Neoplasm (MDS/MPN)

==Cancer Sub-Classification / Subtype==

Myelodysplastic / myeloproliferative neoplasm, unclassifiable (MDS/MPN-U)

==Definition / Description of Disease==

MDS/MPN-U are a heterogeneous group of myeloid neoplasms meeting the criteria for MDS/MPN at onset, without the defining features of one of the other categories of MDS/MPN, i.e. chronic myelomonocytic leukaemia (CMML) juvenile myelomonocytic leukaemia (JMML), atypical chronic myeloid leukaemia, ''BCR-ABL1''-negative (aCML) or myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). <ref name=":0">Orazi A, et al., (2017). Myelodysplastic / myeloproliferative neoplasm, unclassifiable, 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, p95-96.</ref><ref name=":1">{{Cite journal|last=Ti|first=Mughal|last2=Nc|first2=Cross|last3=E|first3=Padron|last4=Rv|first4=Tiu|last5=M|first5=Savona|last6=L|first6=Malcovati|last7=R|first7=Tibes|last8=Rs|first8=Komrokji|last9=Jj|first9=Kiladjian|date=2015|title=An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/26341525/|language=en|doi=10.3324/haematol.2014.114660|pmc=PMC4800699|pmid=26341525}}</ref>

MDS/MPN-U is the most poorly characterised of the MDS/MPN subgroups <ref name=":2">{{Cite journal|last=P|first=Bose|last2=A|first2=Nazha|last3=Rs|first3=Komrokji|last4=Kp|first4=Patel|last5=Sa|first5=Pierce|last6=N|first6=Al-Ali|last7=A|first7=Sochacki|last8=A|first8=Shaver|last9=W|first9=Ma|date=2018|title=Mutational landscape of myelodysplastic/myeloproliferative neoplasm-unclassifiable|url=https://pubmed.ncbi.nlm.nih.gov/30242087/|language=en|doi=10.1182/blood-2018-05-848473|pmc=PMC6236463|pmid=30242087}}</ref>.

*< 20% blasts in the peripheral blood and bone marrow
*Clinical and morphological features of a category of MDS
**'''excluding''' any case meeting the criteria for MDS with isolated del(5q)
*Platelet count of ≥ 450 ×10/L with bone marrow megakaryocytic proliferation and/or a white bood cell count of ≥ 13 × 109/L
*Myelodysplastic / myeloproliferative features not explained by recent cytotoxic or growth factor therapy
*Excludes cases with ''PDGFRA'', ''PDGFRB'' and ''FGFR1'' rearrangement and ''PCM1-JAK2'' <ref name=":0" />

When an underlying MPN has not been identified, the category of MDS/MPN-U is appropriate. <ref name=":0" />

Cases with features of MDS/MPN-U may arise due to prior exposure to treatment and are included in the [[Therapy-Related Myeloid Neoplasms|Therapy-related myeloid neoplasms]] (t-MN).

Well-defined MPN which subsequently develop dysplastic features and progress to a more aggressive phase are excluded from this category.

Palomo ''et al.'' <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> proposed sub-categories of MDS/MPN-U based on the molecular signature. See [[Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN), Unclassifiable#Gene Mutations .28SNV.2FINDEL.29|Gene Mutations]] below.

==Synonyms / Terminology==

*Chronic myelodysplastic / myeloproliferative disease (no longer used)
*Mixed myeloproliferative / myelodysplastic syndrome, unclassifiable
*Overlap syndrome, unclassifiable <ref name=":0" /><ref name=":1" />

==Epidemiology / Prevalence==

*Less than 5% of myeloid malignancies<ref>{{Cite journal|last=L|first=Cannella|last2=M|first2=Breccia|last3=R|first3=Latagliata|last4=A|first4=Frustaci|last5=G|first5=Alimena|date=2008|title=Clinical and prognostic features of patients with myelodysplastic/myeloproliferative syndrome categorized as unclassified (MDS/MPD-U) by WHO classification|url=https://pubmed.ncbi.nlm.nih.gov/17709138/|language=en|pmid=17709138}}</ref>
*Median age: reports vary from 70 <ref name=":1" /> to 75 <ref name=":2" />
*Male:female ratio 2:1 <ref name=":1" /><ref name=":3" />

==Clinical Features==

*Overlap with [[Myelodysplastic Syndromes (MDS)|MDS]] and [[Myeloproliferative Neoplasms (MPN)|MPN]] <ref name=":0" />
*Clinically the most heterogeneous of the MDS/MPN <ref name=":3" />
*Does not have features that define it as belonging to any of the other categories of MDS/MPN <ref name=":0" /><ref name=":1" />

==Sites of Involvement==

*Peripheral blood and bone marrow always involved
*Extramedullary tissues may be involved <ref name=":0" />

==Morphologic Features==

Co-occurrence of myeloid lineages with (i) ineffective and/or dysplastic proliferation and (ii) effective proliferation with or without dysplasia

*Usually with anaemia, with or without macrocytosis
*Thrombocytosis (platelets ≥ 450 x 109/L) or leucocytosis (white blood cells ≥ 13 x 109/L)
*Dysgranulopoiesis in about 50% of cases
*Giant or hypogranular platelets in some
*Dysmegakaryopoiesis with megakaryocytes resembling those in MDS in >50% of cases, otherwise varying proportions of MDS-like and MPN-like megakaryocytes
*No dysmegakaryopoiesis in <10% of cases
*Blasts < 20% in bone marrow and peripheral blood
*Proliferation in any or all of myeloid lineages in bone marrow biopsy
*≥ 10% of at least one cell line <ref name=":0" />

Palomo ''et al.''<nowiki/>'s MDS/MPN-U sub-categories defined by molecular profile <ref name=":3" /> (see Gene Mutations below) tend to have:

*CMML-like: higher monocyte count
*aCML-like: higher white blood cell count
*MDS/MPN-RS-T-like: higher ring sideroblast percentage
*''TP53'': more anaemia and higher blast percentage
*other: ''JAK2'' mutations correlated with thrombocytosis

==Immunophenotype==

May be similar to that of [[Myelodysplastic Syndromes (MDS)|MDS]] or [[Myeloproliferative Neoplasms (MPN)|MPN]] <ref name=":0" />

==Chromosomal Rearrangements (Gene Fusions)==

*None identified
*''BCR-ABL1'' fusion should be excluded
*Absence of ''PDGFRA'', ''PDGFRB'' and ''FGFR1'' rearrangements, absence of ''PCM1-JAK2'' fusion <ref name=":0" />

==Characteristic Chromosomal Aberrations / Patterns==

*None specific to MDS/MPN-U
*Abnormal karyotype 43% across four studies (11/38 <ref>{{Cite journal|last=M|first=Meggendorfer|last2=S|first2=Jeromin|last3=C|first3=Haferlach|last4=W|first4=Kern|last5=T|first5=Haferlach|date=2018|title=The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/29700173/|language=en|doi=10.3324/haematol.2017.183160|pmc=PMC5927999|pmid=29700173}}</ref>; 48/102 <ref name=":3" />; 23/65 <ref name=":4">{{Cite journal|last=Sa|first=Wang|last2=Rp|first2=Hasserjian|last3=Ps|first3=Fox|last4=Hj|first4=Rogers|last5=Jt|first5=Geyer|last6=D|first6=Chabot-Richards|last7=E|first7=Weinzierl|last8=J|first8=Hatem|last9=J|first9=Jaso|date=2014|title=Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/24627528/|language=en|doi=10.1182/blood-2014-02-553800|pmc=PMC4067498|pmid=24627528}}</ref>; 43/85 <ref name=":5">{{Cite journal|last=Cd|first=DiNardo|last2=N|first2=Daver|last3=N|first3=Jain|last4=N|first4=Pemmaraju|last5=C|first5=Bueso-Ramos|last6=Cc|first6=Yin|last7=S|first7=Pierce|last8=E|first8=Jabbour|last9=Je|first9=Cortes|date=2014|title=Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy|url=https://pubmed.ncbi.nlm.nih.gov/24492324/|language=en|doi=10.1038/leu.2014.8|pmc=PMC3981947|pmid=24492324}}</ref>)
*Complex karyotype 10% across three studies (12/102 <ref name=":3" />; 2/65 <ref name=":4" />; 10/85 <ref name=":5" />)
*Specific abnormalities:
**Isochromosome of 17q (commonly referred to as i(17q) but correctly written as i(17)(p11.2)) has gain of 17q, gain of 17p from the 17p11.2 breakpoint to the centromere; and loss of 17p from the telomere to the 17p11.2 breakpoint, including ''TP53'' <ref>{{Cite journal|last=Barbouti|first=Aikaterini|last2=Stankiewicz|first2=Pawel|last3=Nusbaum|first3=Chad|last4=Cuomo|first4=Christina|last5=Cook|first5=April|last6=Höglund|first6=Mattias|last7=Johansson|first7=Bertil|last8=Hagemeijer|first8=Anne|last9=Park|first9=Sung-Sup|date=2004|title=The Breakpoint Region of the Most Common Isochromosome, i(17q), in Human Neoplasia Is Characterized by a Complex Genomic Architecture with Large, Palindromic, Low-Copy Repeats|url=https://linkinghub.elsevier.com/retrieve/pii/S0002929707619399|journal=The American Journal of Human Genetics|language=en|volume=74|issue=1|pages=1–10|doi=10.1086/380648|pmc=PMC1181896|pmid=14666446}}</ref> <ref>{{Cite journal|last=T|first=Fioretos|last2=B|first2=Strömbeck|last3=T|first3=Sandberg|last4=B|first4=Johansson|last5=R|first5=Billström|last6=A|first6=Borg|last7=Pg|first7=Nilsson|last8=H|first8=Van Den Berghe|last9=A|first9=Hagemeijer|date=1999|title=Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations|url=https://pubmed.ncbi.nlm.nih.gov/10381517/|language=en|pmid=10381517}}</ref>. It is the only cytogenetic abnormality mentioned in the MDS/MPN-U section of the 2016 edition of the WHO classification <ref name=":0" />. It is well documented in MDS/MPN <ref>{{Cite journal|last=R|first=Kanagal-Shamanna|last2=Ce|first2=Bueso-Ramos|last3=B|first3=Barkoh|last4=G|first4=Lu|last5=S|first5=Wang|last6=G|first6=Garcia-Manero|last7=S|first7=Vadhan-Raj|last8=D|first8=Hoehn|last9=Lj|first9=Medeiros|date=2012|title=Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53|url=https://pubmed.ncbi.nlm.nih.gov/22038701/|language=en|pmid=22038701}}</ref><ref>{{Cite journal|last=McClure|first=R. F.|last2=Dewald|first2=G. W.|last3=Hoyer|first3=J. D.|last4=Hanson|first4=C. A.|date=1999|title=Isolated isochromosome 17q: a distinct type of mixed myeloproliferative disorder/myelodysplastic syndrome with an aggressive clinical course|url=http://doi.wiley.com/10.1046/j.1365-2141.1999.01537.x|journal=British Journal of Haematology|language=en|volume=106|issue=2|pages=445–454|doi=10.1046/j.1365-2141.1999.01537.x|issn=0007-1048}}</ref> with some cases meeting the criteria for atypical CML (aCML), and others justifying an MDS/MPN-U classification <ref name=":0" />. Data on incidence are rare; one case in 65 was reported in one study (1.5%) <ref name=":4" />. Six cases were reported in a series of 551 MDS/MPN which included both aCML and MDS/MPN-U . Meggendorfer et al <ref name=":7">{{Cite journal|last=M|first=Meggendorfer|last2=U|first2=Bacher|last3=T|first3=Alpermann|last4=C|first4=Haferlach|last5=W|first5=Kern|last6=C|first6=Gambacorti-Passerini|last7=T|first7=Haferlach|last8=S|first8=Schnittger|date=2013|title=SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations|url=https://pubmed.ncbi.nlm.nih.gov/23628959/|language=en|pmid=23628959}}</ref> found a highly significant association between i(17q) and ''SETBP1'' mutations. ''SETBP1'' mutation is strongly correlated with aCML <ref name=":3" /> <ref name=":7" />, and was found in about a third of the aCML-like subcategory of MDS/MPN-U <ref name=":3" />.
**+ 8
***23% across two studies (26/102 <ref name=":3" />; 12/65 <ref name=":4" />)
***isolated +8, 16% across two studies (17/102 <ref name=":3" />; 13/85 <ref name=":5" />)
**-7/del(7q)
***10% across two studies (12/102 <ref name=":3" />; 4/65 <ref name=":4" />)
***isolated -7/del(7q), 5% (5/102 <ref name=":3" />)

*Excludes any case with isolated del(5q) (even if ''JAK2'' is mutated) <ref name=":0" /> - these should be classified as MDS with isolated del(5q).

==Genomic Gain/Loss/LOH==

One study identified very few recurrent gains and losses below the level of cytogenetic detection <ref name=":3" />.

==Gene Mutations (SNV/INDEL)==

Amongst the MDS/MPN subtypes, MDS/MPN-U has the most heterogeneous mutation profile. In one study it was most strongly correlated with ''U2AF1'' and ''TP53'' mutations <ref name=":3" />.

No mutations are specific for any MDS/MPN, including MDS/MPN-U <ref name=":3" />.

The WHO in 2017 <ref name=":0" /> listed ''TET2'', ''NRAS'', ''RUNX1'', ''CBL'', ''SETBP1'' and ''ASXL1'' as having relatively high mutation frequencies. Frequencies* of these and the other most common mutations given in recent publications are:

*''ASXL1:'' 29%* <ref name=":2" />; 53% <ref name=":3" />
*''TET2:'' 27% <ref name=":2" />; 37% <ref name=":3" />
*''JAK2:'' 25% <ref name=":2" />; 25% <ref name=":3" />
**V617F <ref name=":2" />; 18% <ref name=":4" />
*''SRSF2:'' 23% <ref name=":2" />; 23% <ref name=":3" />
**P95 residue <ref name=":2" />
*''EZH2:'' 17% <ref name=":2" />; 25% <ref name=":3" />
*''U2AF1:'' 13% <ref name=":2" />;19% <ref name=":3" />
**most mutatons in Q157 <ref name=":2" />
*''RUNX1:'' 13% <ref name=":2" />; 17% <ref name=":3" />
*''SF3B1:'' 12% <ref name=":2" />11% <ref name=":3" />
*''ZRSR2:'' 11% <ref name=":2" />'';'' 5% <ref name=":3" />
*''SETBP1:'' 11% <ref name=":2" />;12% <ref name=":3" />
*''NRAS:'' 10% <ref name=":2" />; 4% <ref name=":3" />
*''DNMT3A:'' 9% <ref name=":2" />'';'' 13% <ref name=":3" />
*''TP53:'' 8% <ref name=":2" />;12% <ref name=":3" />
*''STAG2:'' 5% <ref name=":2" />; 16% <ref name=":3" />
*''CSF3R:'' 5% <ref name=":2" />'';'' 5% <ref name=":3" />
*''ZBTB33:'' 5% <ref name=":3" />
**novel to MDS/MPN-U
*''CBL:'' 4% <ref name=":2" />; 6% <ref name=":3" />

<nowiki>*</nowiki>Frequencies from Figure 1 in <ref name=":2" /> are given, since the list in the text does not include all of these genes (the values in the text do not match the values in Figure 1).

Palomo ''et al'' identified specific mutation combinations that mimicked the other MDS/MPN subtypes and allowed MDS/MPN-U to be assigned to one of five MDS/MPN-U sub-categories <ref name=":3" />:

(The first three are most similar to one of the three other adult subgroups of MDS/MPN)

#CMML-like (''TET2/SRSF2'')
#aCML-like (''ASXL1/EZH2'')
#MDS/MPN-RS-T-like (''SF3B1'' or ''DNMT3A/SF3B1'')
#TP53 sub-category (mono- or bi-allelic ''TP53'' mutation; more anaemia and higher blast count)
#other (no distinctive signature but enriched for ''U2AF1, JAK2, ASXL1'' mutations; ''JAK2'' mutations correlated with thrombocytosis)

===Other Mutations===
The presence of ''TET2'', ''NRAS'', ''RUNX1'', ''CBL'', ''SETBP1'' or ''ASXL1'' mutation may help confirm a suspected diagnosis <ref name=":0" />.

If a ''SF3B1'' mutation is present, consider whether it is MDS/MPN-RS-T or progression from MDS with ring sideroblasts <ref name=":0" />.

MPN driver mutations (e.g. ''JAK2'', ''MPL'' or ''CALR'' mutation'')'' may be present, but if pre-existing MPN is not documented, an MDS/MPN-U designation is justified <ref name=":0" />.

There is a significant likelihood of AML developing if there is ''ASXL1'' and ''SRSF2'' co-mutation <ref name=":2" />.

==Epigenomics (Methylation)==

Not known

==Genes and Main Pathways Involved==

*Major drivers / early mutations in epigenetic regulators (''ASXL1, TET2)'' and splicing factors (''SRSF2'') <ref name=":2" /> <ref name=":3" />
*Secondary mutations in signaling pathway genes (''JAK2'') <ref name=":3" />

==Diagnostic Testing Methods==

*Bone marrow aspirate
*Full blood count
*Cytogenetics

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

*Prognosis is variable and not well documented <ref name=":0" />
*There are few data regarding an appropriate prognostic scoring system <ref name=":0" />, but IPSS-R <ref name=":2" />or IPSS <ref name=":5" /> have been prognostically useful
*Median overall survival (OS) from various reports: 80 months <ref name=":3" />; 21.8 months <ref name=":4" />; 12 months <ref name=":2" />
*Leukaemia-free survival: 18.9 months <ref name=":4" />; 10.8 months <ref name=":2" />
*Leukaemic transformation: 10% <ref name=":3" />; 16% after a median of 10.8 months <ref name=":2" />;
**ASXL1/SRSF2 co-mutation is a significant risk factor <ref name=":2" />
*Abnormal karyotype associated with inferior OS <ref name=":3" />
*''ASXL1, EZH2, STAG2'' mutations associated with shorter OS <ref name=":2" /><ref name=":3" />
*Targeted sequencing may be useful for assessing prognostic impact and making clinical decisions <ref name=":3" />.
**Molecular classification into sub-categories had the strongest prognostic impact in a study by Palomo ''et al.'' <ref name=":3" />:
***MDS/MPN-RS-T-like: most favourable prognosis
***aCML-like: high risk
***"TP53": least favourable prognosis
*“Treatment is based on therapies used for MDS or MPN and is guided by symptoms and/or cytopenias” and can include growth factors for leukocytosis or cytoreductive therapies for cytopenias <ref name=":0" />.

==Familial Forms==

Not known

==Other Information==

Refractory anemia with ring sideroblasts and thrombosis (RARS-T) fell within this category prior to the 2016 WHO edition <ref name=":0" /><ref name=":6">{{Cite journal|last=A|first=Orazi|last2=U|first2=Germing|date=2008|title=The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features|url=https://pubmed.ncbi.nlm.nih.gov/18480833/|language=en|pmid=18480833}}</ref> but now forms a distinct category, MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

==Links==

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==References==
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==Notes==
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HAEM4Backup:Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN), Unclassifiable - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== Ruth MacKinnon PhD Victorian Cancer Cytogenetics Service Melbourne, Australia __TOC__ ==Cancer Category/Type== Myelodysplastic/Myeloproliferative N..."

Bailey.Glen: Created page with "==Primary Author(s)*== Ruth MacKinnon PhD Victorian Cancer Cytogenetics Service Melbourne, Australia TOC ==Cancer Category/Type== Myelodysplastic/Myeloproliferative N..."