Myelodysplastic syndromes and overlap syndromes

Yoon Hwan Chang

doi:10.5045/br.2021.2021010

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Blood Res 2021; 56(S1):

Published online April 30, 2021

https://doi.org/10.5045/br.2021.2021010

Myelodysplastic syndromes and overlap syndromes

Yoon Hwan Chang

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Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Korea

Correspondence to : Yoon Hwan Chang, M.D., Ph.D.
Department of Laboratory Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: cyh1969@snu.ac.kr

Received: January 18, 2021; Revised: March 9, 2021; Accepted: March 10, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological neoplasms characterized by ineffective hematopoiesis, morphologic dysplasia, and cytopenia. MDS overlap syndromes include various disorders, such as myelodysplastic/myeloproliferative neoplasms and hypoplastic MDS with aplastic anemia characteristics. MDS overlap syndromes share the characteristics of other diseases, which make differential diagnoses challenging. Advances in genomic studies have led to the discovery of frequent mutations in MDS and overlap syndromes; however, most of the mutations are not specific for the diagnosis of these diseases. The molecular characteristics of the overlap syndromes usually do not show a just “in-between” form but rather heterogeneous features. Established diagnostic criteria for these diseases based on clinical, morphologic, and laboratory features are still useful when combined with genomic data. It is expected that further studies for MDS and overlap syndromes will place emphasis on the roles of mutations as therapeutic targets and prognostic indicators.

Keywords Myelodysplastic syndromes, Overlap syndromes, Myelodysplastic/myeloproliferative neoplasms, Hypoplastic MDS, Genomic, Mutation

Article

Review Article

Blood Res 2021; 56(S1): S51-S64

Published online April 30, 2021 https://doi.org/10.5045/br.2021.2021010

Myelodysplastic syndromes and overlap syndromes

Yoon Hwan Chang

Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Korea

Correspondence to:Yoon Hwan Chang, M.D., Ph.D.
Department of Laboratory Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: cyh1969@snu.ac.kr

Received: January 18, 2021; Revised: March 9, 2021; Accepted: March 10, 2021

Abstract

Keywords: Myelodysplastic syndromes, Overlap syndromes, Myelodysplastic/myeloproliferative neoplasms, Hypoplastic MDS, Genomic, Mutation

Abstract

Table 1 . Diagnostic criteria for myelodysplastic syndrome (MDS) entities [5, 6]..

Name	Dysplastic lineages	Cytopenias^a)	RS (%)^b)	BM and PB blasts (%)	Cytogenetics^c)
MDS-SLD	1	1 or 2	<15/<5^d)	BM <5, PB <1, no Auer rods	Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS-MLD	2 or 3	1–3	<15/<5^d)	BM <5, PB <1,no Auer rods	Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS-RS
MDS-RS-SLD	1	1 or 2	≥15/≥5^d)	BM <5, PB <1,no Auer rods	Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS-RS-MLD	2 or 3	1–3	≥15/≥5^d)	BM <5, PB <1,no Auer rods	Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS with isolated del(5q)	1-3	1–2	None or any	BM <5, PB <1, no Auer rods	del(5q) alone or with 1 additional abnormality except -7 or del(7q)
MDS-EB
MDS-EB-1	0–3	1–3	None or any	BM 5–9 or PB 2–4, no Auer rods	Any
MDS-EB-2	0–3	1–3	None or any	BM 10–19 or PB 5–19 or Auer rods	Any
MDS-U
1% blood blasts	1–3	1–3	None or any	BM <5, PB=1^e), no Auer rods	Any
SLD and pancytopenia	1	3	None or any	BM <5, PB <1,no Auer rods	Any
Defining cytogenetic abnormality	0	1–3	<15^f)	BM <5, PB <1,no Auer rods	MDS-defining abnormality^g)
Refractory cytopenia of childhood	1–3	1–3	None	BM <5, PB <2	Any

^a)Cytopenias defined as hemoglobin concentration <10 g/dL, platelet count <100×10⁹/L, and absolute neutrophil count <1.8×10⁹/L, although MDS can present with mild anemia or thrombocytopenia above these levels; PB monocytes must be <1×10⁹/L. ^b)Ring sideroblasts as the percentage of marrow erythroid elements. ^c)Cytogenetics by conventional karyotype analysis. ^d)If SF3B1 mutation is present. ^e)1% PB blasts must be recorded on ≥2 separate occasions. ^f)Cases with ≥15% ring sideroblasts by definition have significant erythroid dysplasia and are classified as MDS-RS-SLD. ^g)See Table 2..

Abbreviations: BM, bone marrow; EB, excess blasts; MDS-U, MDS, unclassifiable; MLD, multilineage dysplasia; PB, peripheral blood; RS, ring sideroblasts; SLD, single lineage dysplasia..

Table 2 . Recurrent chromosomal abnormalities and their frequencies in myelodysplastic syndrome (MDS) at diagnosis [5, 14]..

Chromosomal abnormality	Frequency		Prognosis^b)

	MDS overall	Therapy-related MDS
Unbalanced
Gain of chromosome 8^a)	10%		Intermediate
Loss of chromosome 7 or del(7q)	10%	50%	Intermediate
del(5q)	10%	40%	Good
del(20q)^a)	5–8%		Good
Loss of Y chromosome^a)	5%		Very good
Isochromosome 17q or del(17p)	3–5%	25–30%	Intermediate
Loss of chromosome 13 or del(13q)	3%		Intermediate
del(11q)	3%		Very good
del(12p) or t(12p)	3%		Good
del(9q)	1–2%		Intermediate
idic(X)(q13)	1–2%		Intermediate
Balanced
t(11;16)(q23.3;p13.3)		3%	Intermediate
t(3;21)(q26.2;q22.1)		2%	Poor
t(1;3)(p36.3;q21.2)	1%		Poor
t(2;11)(p21;q23.3)	1%		Intermediate
inv(3)(q21.3q26.2)/t(3;3)(q21.3;q26.2)	1%		Poor
t(6;9)(p23;q34.1)	1%		Intermediate

^a)As a sole cytogenetic abnormality in the absence of morphological criteria, gain of chromosome 8, del(20q) and loss of Y chromosome are not considered definitive evidence of MDS; in the setting of persistent cytopenia of undetermined origin, the other abnormalities shown in this table are considered as presumptive evidence of MDS, even in the absence of definitive morphological features. ^b)Normal karyotype: Good; Double including del(5q): Good; Double including -7/del(7q): Poor; Any other double: Intermediate; Complex karyotype (3 abnormalities): Poor; Complex karyotype (>3 abnormalities): Very poor..

Table 3 . Gene mutation profiles for MDS/MPNs, MDS, and MPN [modified from 5, 27, 28]..

Functional class	Gene	CMML	JMML	aCML	MDS/MPN-RS-T	MDS/MPN-U	MDS	MPN
Epigenetic regulation	TET2^a)	50–60%	0	20–40%	10–25%	20–25%	20–30%	10–20%
	DNMT3A^a)	<5%	Rare	∼5%	∼15%	5–10%	∼10%	5–10%
	ASXL1^a)	40–45%	∼5%	∼30%	15–30%	30–50%	15–20%	PMF 25%,
	ASXL1^a)	40–45%	∼5%	∼30%	15–30%	30–50%	15–20%	ET/PV 1–3%
	EZH2	5–10%	<5%	∼20%	∼5%	∼15%	5–10%	PMF 5–10%
	IDH1	<5%	0	<5%		<5%	∼5% (IDH1/2)	1–3%
	IDH2	∼5%	0	<5%	<5%	<5%	∼5% (IDH1/2)	1–3%
RNA splicing	SRSF2^a)	45–50%	0	30–40%	5–10%	∼25%	∼15%	PMF 10–15%,
	SRSF2^a)	45–50%	0	30–40%	5–10%	∼25%	∼15%	ET <2%
	SF3B1^a)	∼5%		5–10%	80–90%	10–15%	20–30%	ET <3%
	U2AF1^a)	5–10%		5–10%	∼5%	10–15%	5–10%	PMF 10–15%
	ZRSR2	5–10%	<5%	<5%	<5%	5–10%	5–10%
Cell signaling	N/KRAS	20–30%	25–35%	25–35%	Rare	10–15%	∼5% (NRAS)	NRAS: PMF Rare
	JAK2	5–10%	0	∼5%	∼50%	∼25%		PV 95%,
	JAK2	5–10%	0	∼5%	∼50%	∼25%		PMF and ET 50–60%
	JAK3		5–15%
	CBL^a)	10–20%	10–15%	5–10%	<5%	∼5%	∼5%	PMF 4%
	PTPN11	<5%	35–45%	<5%		<5%
	NF1	Rare	10–15%	Rare				PMF Rare
	CALR	Rare			<5%	∼5%		PMF 25–30%,
	CALR	Rare			<5%	∼5%		ET 20–25%
	MPL				<5%	∼5%		ET 2–3%,
	MPL				<5%	∼5%		PMF 3–5%
	CSF3R	<5%		5–10%	Rare	<5%
	FLT3	<5%		<5%		<5%		<3%
Transcription	RUNX1	10–20%	<5%	10–20%	<5%	5–10%	∼10%	<3% (sAML 10%)
	CEBPA	<5%		4%		<5%
	ETV6	<5%			<5%	<5%		<3%
	TP53^a)	Rare		Rare	Rare	8–9%	5–10%	<5% (sAML 20%)
	WT1	Rare
Cohesin complex	STAG2	<10%				5–10%	5–7%
Others	ETNK1	<5%		∼8%	Rare	<5%
	SETBP1	5–10%	5–15%	25–40%	∼10%	10–15%
	NPM1	<5%		Rare	0	<5%

^a)These genes are also reported to be mutated in clonal hematopoietic cells in a subset of healthy individuals (clonal hematopoiesis of indeterminate potential)..

Abbreviations: aCML, atypical chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; ET, essential thrombocythemia; JMML, juvenile myelomonocytic leukemia; MDS, myelodysplastic syndrome; MDS/MPN, myelodysplastic/myeloproliferative neoplasm; MDS/MPN-RS-T, MDS/MPN with ring sideroblasts and thrombocytosis; MDS/MPN-U, MDS/MPN unclassifiable; MPN, myeloproliferative neoplasm; PMF, primary myelofibrosis; PV, polycythemia vera; sAML, secondary acute myeloid leukemia..

Unknown < 10% 10-20% 20-30% 30-50% >50%.

Table 4 . Proposed diagnostic criteria for the myelodysplastic syndrome (MDS) with mutated SF3B1 [6]..

Cytopenia defined by standard hematologic values

Somatic SF3B1 mutation

Isolated erythroid or multilineage dysplasia^a)

Bone marrow blasts <5% and peripheral blood blasts <1%

WHO criteria for MDS with isolated del(5q), MDS/MPN-RS-T or other MDS/MPNs, and primary myelofibrosis or other MPNs are not met

Normal karyotype or any cytogenetic abnormality other than del(5q); monosomy 7; inv(3) or abnormal 3q26, complex (≥3)

Any additional somatically mutated gene other than RUNX1 and/or EZH2^b)

^a)RS are not required for the diagnosis. ^b)Additional JAK2V617F, CALR, or MPL mutations strongly support the diagnosis of MDS/MPN-RS-T..

Table 5 . Diagnostic criteria for chronic myelomonocytic leukemia (CMML) [5, 39]..

1. Persistent peripheral blood monocytosis (≥1×10⁹/L) with monocytes accounting for ≥10% of the leukocytes

2. WHO criteria for BCR-ABL1-positive chronic myeloid leukemia, primary myelofibrosis, polycythemia vera, and essential thrombocythemia^a) are not met

3. No rearrangement of PDGFRA, PDGFRB or FGFR1 and no PCM1-JAK2 (which should be specifically excluded in cases with eosinophilia)

4. Blasts^b) constitute <20% of the cells in the peripheral blood and bone marrow

5. Dysplasia involving ≥1 myeloid lineages orIf myelodysplasia is absent or minimal, criteria 1-4 are met and:

-An acquired, clonal cytogenetic or molecular genetic abnormality is present in hematopoietic cells^c) or

-Monocytosis has persisted for ≥3 months and all other causes of monocytosis (e.g., malignancy, infection, and inflammation) have been excluded.

^a)Myeloproliferative neoplasms (MPN) can be associated with monocytosis or it can develop during the course of the disease; such cases can mimic CMML. In these rare instances, a documented history of MPN excludes CMML, whereas the presence of MPN features in the bone marrow and/or MPN-associated mutations (in JAK2, CALR, or MPL) tends to support MPN with monocytosis rather than CMML. ^b)Blasts and blast equivalents include myeloblasts, monoblasts, and promonocytes. Promonocytes are monocytic precursors with abundant light-grey or slightly basophilic cytoplasm with a few scattered fine lilac-colored granules, finely distributed stippled nuclear chromatin, variably prominent nucleoli, and delicate nuclear folding or creasing. Abnormal monocytes, which can be present in both the peripheral blood and the bone marrow are excluded from the blast count. Abnormal monocytes show convoluted nuclei as mature monocytes, but less clumped chromatin, minute nucleoli, and more basophilic cytoplasm. ^c)In the appropriate clinical context, mutations in genes often associated with CMML (e.g., TET2, SRSF2, ASXL1 and SETBP1) support the diagnosis. However, some of these mutations can be age-related or present in other neoplasms; therefore, these genetic findings must be interpreted with caution..

Table 6 . Diagnostic criteria for atypical chronic myeloid leukemia, BCR-ABL1-negative (aCML) [5]..

- Peripheral blood leukocytosis ≥13×10⁹/L, due to increased numbers of neutrophils and their precursors (i.e., promyelocytes, myelocytes, and metamyelocytes), with neutrophil precursors constituting ≥10% of the leukocytes

- Dysgranulopoiesis, which may include abnormal chromatin clumping

- No or minimal absolute basophilia; basophils constitute <2% of the peripheral blood leukocytes

- No or minimal absolute monocytosis; monocytes constitute <10% of the peripheral blood leukocytes

- Hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia, with or without dysplasia in the erythroid and megakaryocytic lineages

- <20% blasts in the blood and bone marrow

- No evidence of PDGFRA, PDGFRB, or FGFR1 rearrangement, or of PCM1-JAK2

- The WHO criteria for BCR-ABL1-positive chronic myeloid leukemia, primary myelofibrosis, polycythemia vera, or essential thrombocythemia^a) are not met.

^a)Myeloproliferative neoplasms (MPNs), in particular those in the accelerated phase and/or in post-polycythemia vera or post-essential thrombocythemia myelofibrosis, if neutrophilic, may simulate aCML. A history of MPN, the presence of MPN features in the bone marrow, and/or MPN-associated mutations (in JAK2, CALR, or MPL) tend to exclude the diagnosis of aCML; conversely, the diagnosis is supported by the presence of SETBP1 and/or ETNK1 mutations. CSF3R mutation is uncommon and, if detected, should prompt careful morphological review to exclude an alternative diagnosis of chronic neutrophilic leukemia or another myeloid neoplasm..

Table 7 . Diagnostic criteria for juvenile myelomonocytic leukemia (JMML) [5, 87]..

Clinical and hematological criteria (all 4 criteria are required)

- Peripheral blood monocyte count ≥1×10⁹/L

- Blast percentage in peripheral blood and bone marrow of <20%

- Splenomegaly

- No Philadelphia (Ph) chromosome or BCR-ABL1 fusion

Genetic criteria (any 1 criterion is sufficient)

- Somatic mutation^a) in PTPN11, KRAS, or NRAS

- Clinical diagnosis of neurofibromatosis type 1 or NF1 mutation

- Germline CBL mutation and loss of heterozygosity of CBL^b)

Other criteria

Cases that do not meet any of the genetic criteria above must meet the following criteria in addition to the clinical and hematological criteria above:

- Monosomy 7 or any other chromosomal abnormality or

- ≥2 of the following:

- Increased hemoglobin F for age

- Myeloid or erythroid precursors on peripheral blood smear

- Granulocyte-macrophage colony-stimulating factor (also called CSF2) hypersensitivity in colony assay

- Hyperphosphorylation of STAT5

^a)If a mutation is found in PTPN11, KRAS, or NRAS, it is essential to consider that it might be a germline mutation and the diagnosis of transient abnormal myelopoiesis of Noonan syndrome must be considered. ^b)Occasional cases have heterozygous splice-site mutations..

Table 8 . Diagnostic criteria for myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) [5]..

- Anemia associated with erythroid-lineage dysplasia, with or without multilineage dysplasia; ≥15% ring sideroblasts^a), <1% blasts in the peripheral blood, and <5% blasts in the bone marrow

- Persistent thrombocytosis, with platelet count ≥450×10⁹/L

- SF3B1 mutation or, in the absence of SF3B1 mutation, no history of recent cytotoxic or growth factor therapy that could explain the myelodysplastic/myeloproliferative features^b)

- No BCR-ABL1 fusion; no rearrangement of PDGFRA, PDGFRB or FGFR1; no PCM1-JAK2and no t(3;3)(q21.3;q26.2), inv(3)(q21.3q26.2), or del(5q)^c)

- No history of myeloproliferative neoplasm, myelodysplastic syndrome (except myelodysplastic syndrome with ring sideroblasts), or other myelodysplastic/myeloproliferative neoplasm

^a)≥15% ring sideroblasts is a required criterion even if SF3B1 mutation is detected. ^b)The diagnosis of myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis is strongly supported by the presence of SF3B1 mutation together with a JAK2 V617F, CALR, or MPL mutation. ^c)In a case that otherwise meets the diagnostic criteria for myelodysplastic syndrome with isolated del(5q)..

Table 9 . Diagnostic criteria for myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) [5]..

Myeloid neoplasm with mixed myeloproliferative and myelodysplastic features at onset, not meeting the WHO criteria for any other myelodysplastic/myeloproliferative neoplasm, myelodysplastic syndrome, or myeloproliferative neoplasm - <20% blasts in the peripheral blood and bone marrow

- Clinical and morphological features of one of the categories of myelodysplastic syndrome^a)

- Clinical and morphological myeloproliferative features manifesting as a platelet count of ≥450×10⁹/L associated with bone marrow megakaryocytic proliferation and/or a white blood cell count of ≥13×10⁹/L^a)

- No history of recent cytotoxic or growth factor therapy that could explain the myelodysplastic/myeloproliferative features

- No PDGFRA, PDGFRB, or FGFR1 rearrangement and no PCM1-JAK2

^a)Cases that meet the criteria for myelodysplastic syndrome with isolated del(5q) are excluded irrespective of the presence of thrombocytosis or leukocytosis..

Table 10 . Semiquantitative comparison of laboratory and genetic features among hMDS, AA, and normo/hypercellular MDS (modified from 117)..

Properties	Normo/hypercellular MDS	hMDS	AA
Laboratory features
Cytopenia and macrocytosis	+	++	++
LDH	+/-	+	++
BM blasts	=/+	-	--
Associated conditions
PNH clone	+/	+	++
LGL clone	+	++	+/-
Extrahematologic autoimmunity	-	++	+/-
Cytogenetic abnormalities	++	+/-	Rare
Somatic mutations
Splicing: SF3B1, SRSF2, U2AF1, ZRSR2	+++	+	+/-
DNA methylation: DNMT3A, TET2, IDH1, IDH2	++	+	+/-
Chromatin modification: ASXL1, EZH2, KDM6A	++	+	+/-
Cohesin: STAG2	+	+/-	Rare
Tumor suppressor: TP53	+	+/-	Rare
Signaling: CBL, FLT3, JAK2, KIT, NRAS, KRAS	+/-	+/-	Rare
Transcription: RUNX1, CEBPA, ETV6, GATA2, NPM1	RUNX1 =/++; others = +/-	+/-	Rare
Pathogenic germline RTEL1 mutations	-	+/-	+

Abbreviations: AA, aplastic anemia; BM, bone marrow; hMDS, hypoplastic myelodysplastic syndrome; LDH, lactate dehydrogenase; LGL, large granular lymphocytes; MDS, myelodysplastic syndrome; PNH, paroxysmal nocturnal hemoglobinuria..