Received: 23 November 2022 Revised: 19 December 2022 Accepted: 21 December 2022

DOI: 10.1002/ajh.26828

ANNUAL CLINICAL UPDATES IN

HEMATOLOGICAL MALIGNANCIES

Atypical chronic myeloid leukemia and myelodysplastic/

myeloproliferative neoplasm, not otherwise specified: 2023
update on diagnosis, risk stratification, and management

Mrinal M. Patnaik | Ayalew Tefferi

Division of Hematology, Department of

Internal Medicine, Mayo Clinic, Rochester, Abstract
Minnesota, USA
Disease Overview: Atypical chronic myeloid leukemia (aCML) and myelodysplastic/
Correspondence myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are
Mrinal M. Patnaik, Division of Hematology,
MDS/MPN overlap neoplasms characterized by leukocytosis, in the absence of
Mayo Clinic, 200 First Street SW, Rochester,
MN, 55905, USA. monocytosis and eosinophilia, with <20% blasts in the blood and bone marrow.
Email: patnaik.mrinal@mayo.edu
Diagnosis: aCML, previously known as aCML, BCR::ABL1 negative, was renamed as
aCML by the ICC classification, and as MDS/MPN with neutrophilia by the 5th edition
of the WHO classification. This entity is characterized by dysplastic neutrophilia with
immature myeloid cells comprising ≥10% of the white blood cell count, with prominent
dysgranulopoiesis. MDS/MPN-NOS consists of MDS/MPN overlap neoplasms not
meeting criteria for defined categories such as chronic myelomonocytic leukemia
(CMML), MDS/MPN-ring sideroblasts-thrombocytosis (MDS/MPN-RS-T), and aCML.
Mutations and Karyotype: Cytogenetic abnormalities are seen in 40–50% of patients
in both categories. In aCML, somatic mutations commonly encountered include
ASXL1, SETBP1, ETNK1, and EZH2 whereas MDS/MPN-NOS can be further stratified
by mutational profiles into CMML-like, MDS/MPN-RS-T-like, aCML-like, TP35-
mutated, and “others”, respectively.
Risk Stratification: The Mayo Clinic aCML model stratifies patients based on age
>67 years, hemoglobin <10 g/dl, and the presence of TET2 mutations into low-risk
(0–1 points) and high-risk (>2 points) groups, with median survivals of 18 and
7 months, respectively. MDS/MPN-NOS patients have traditionally been risk strati-
fied using MDS risk models such as IPSS and IPSS-R.
Treatment: Leukocytosis and anemia are managed like lower risk MPN and MDS.
DNMT inhibitors have been used in both entities with suboptimal response rates.
Allogeneic stem cell transplant remains the only curative strategy but is associated
with high morbidity and mortality.

1 | D I S E A S E OV E R V I E W

Myelodysplastic syndromes (MDS)/myeloproliferative overlap neo-

Tweetable Summary: Atypical chronic myeloid leukemia and myelodysplastic/
plasms are unique myeloid neoplasms with overlapping features of
myeloproliferative neoplasm, not otherwise specified: 2023 update on diagnosis, risk-
stratification, and management. MDS and MPN.1,2 The 4th edition of the World Health Organization

Am J Hematol. 2023;98:681–689. wileyonlinelibrary.com/journal/ajh © 2023 Wiley Periodicals LLC. 681

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682 PATNAIK AND TEFFERI

(WHO) classification schema (2016–2017) included five entities in this given that all MDS/MPN overlap neoplasms mandate the exclusion of
subgroup; chronic myelomonocytic leukemia (CMML), atypical chronic BCR::ABL1 for their diagnosis, with the 5th edition of the WHO system
myeloid leukemia (aCML), BCR::ABL1 negative, juvenile myelomonocytic opting to rename aCML as MDS/MPN with neutrophilia (Table 1: Dif-
leukemia (JMML), MDS/MPN-ring sideroblasts and thrombocytosis ferences between the ICC and WHO classification schema for aCML).4,5
2,3
(MDS/MPN-RS-T), and MDS/MPN-unclassifiable (MDS/MPN-U). In Until there is consensus in nomenclature, for the purposes of this
2022, there emerged two competing schemata for myeloid neoplasms review, we will refer to this entity as aCML. Atypical CML is commonly
classification, including the International Consensus Classification (ICC) seen in the elderly (median age at diagnosis: 70–74 years), with a male
and the 5th edition of the WHO classification.4,5 Both classification preponderance, with an estimated frequency of 1–2 cases for every
schemata eliminated JMML from the category of overlap neoplasms, 100 cases of BCR::ABL1 rearranged CML.6,7 Patients present with leu-
given that JMML is a pediatric-onset entity with germline predisposition kocytosis and neutrophilia, with immature myeloid cells (IMC) including
(germline PTPN11, CBL, and NF1 mutations) and has predominant mye- promyelocytes, myelocytes, and metamyelocytes comprising ≥ 10% of
loproliferative features. While both classification schemata have white blood cells (WBC).6 The characteristic feature that distinguishes
retained core essential features for the diagnosis of overlap neoplasms, aCML from other related MDS/MPN overlap neoplasms and MPN,
there are subtle divergences and semantic differences, with potential to such as chronic neutrophilic leukemia (CNL), is the presence of marked
impact patient care. In this review, we focus on aCML and dysgranulopoiesis, along with a high percentage of circulating IMC,
MDS/MPN-U, which has been renamed as MDS/MPN-not otherwise without monocytosis, eosinophilia, and basophilia.1,4 The disease is
specified (NOS), by both classification schema. associated with poor outcomes (median survival 10–29 months), with
high rates of leukemic transformation (10–20% over 5 years).6,8,9

1.1 | Atypical CML, BCR::ABL1 negative

1.1.1 | Diagnostic criteria
Atypical CML is an MDS/MPN overlap neoplasm characterized by dys-
plastic neutrophilia occurring in the absence of monocytosis and eosin- The diagnostic hallmark for aCML, as defined by the ICC and WHO, is
ophilia.1 The ICC schemata has dropped the term BCR::ABL1 negative, the presence of leukocytosis ≥13  109/L, with circulating IMC

TABLE 1 Comparison between the 5th edition of the WHO and the 2022 ICC schema for atypical CML

Criteria International consensus classification 5th edition of the WHO classification

Nomenclature Atypical chronic myeloid leukemia Myelodysplastic/myeloproliferative neoplasm
with neutrophilia
White blood cell count ≥13  109/L with immaturea myeloid cells ≥13  109/L with neutrophilia, with immaturea
constituting ≥10% of WBC myeloid cells constituting ≥10% of WBC
Cytopenia MDSb-qualifying thresholds Not specifically mentioned in the WHO criteria
Peripheral blood and bone marrow blasts <20% <20%
Dysplasia Dysgranulopoiesis; hyposegmented or Circulating immaturea myeloid cells
hypersegmented neutrophils, with or without constituting≥10% of WBC, with neutrophilic
abnormal chromatin clumping dysplasia
Eosinophils <10% Not specifically mentioned
Monocytes <10% <10%
Bone marrow cellularity and hematopoiesis Hypercellular with granulocytic hyperplasia and Hypercellular with granulocytic hyperplasia and
granulocytic dysplasia, with or without granulocytic dysplasia, with or without
involvement of other lineages involvement of other lineages
Molecular exclusionary criteria BCR::ABL1 or tyrosine kinase fusions associated BCR::ABL1 or tyrosine kinase fusions associated
with myeloid/lymphoid neoplasms with with myeloid/lymphoid neoplasms with
eosinophilia. eosinophilia.
JAK2, MPL, and CALR mutations JAK2, MPL, and CALR mutations.
CSF3R mutations
MDS/MPN-RS-T with SF3B1 mutations
Next generation sequencing datac Desirable to document presence of ASXL1 and Desirable to document presence of SETBP1
SETBP1 mutations. and/or ETNK1 mutations

Abbreviations: ICC, International Consensus Classification; NGS, next generation sequencing; WHO, World Health Organization; WBC, white blood cell
count; MDS, myelodysplastic syndromes.
a
Immature myeloid cells include promyelocytes, myelocytes, and metamyelocytes.
b
MDS-defining cytopenias include Hb <13 g/dl in males and <12 g/dl in females, neutropenia with absolute neutrophil count <1.8  109/L, and
thrombocytopenia with platelet counts <150  109/L.
c
Supportive and desirable criteria.
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PATNAIK AND TEFFERI 683

F I G U R E 1 Peripheral blood (PB) and bone marrow findings in a patient with atypical chronic myeloid leukemia (aCML). (A) Wright Giemsa
stain (200) demonstrating dysplastic neutrophilia. Thin arrows demonstrate dysplastic granulocytes with one nuclear lobe, two nuclear lobes
and characteristically clumped chromatin (right upper granulocyte in PB), along with dyserythropoiesis (black arrow), (B) Wright Giemsa stain
(600) demonstrating bone marrow dysplasia. The thick arrow shows two dysplastic megakaryocytes with small hypolobated forms.

comprising ≥10% of the WBC differential, with <20% blasts in the ASXL1 mutations being the most common (60–90%), followed by TET2,
peripheral blood and bone marrow (note: only the ICC requires periph- SRSF2, and SETBP1 mutations (all approximately 20–40%).6,10–14 Other
eral blood cytopenias, with similar thresholds as MDS, for a diagnosis of mutational categories involve signaling pathways (e.g., CBL, NRAS, and
aCML).1,4,5 In addition, peripheral blood monocytes and eosinophils JAK2), pre-mRNA splicing (e.g., U2AF1, SF3B1, ZRSR2), transcription
should be <10% of the WBC differential without basophilia, helping to factors (e.g., RUNX1, CUX1, and GATA2), metabolic enzymes (ETNK1),
differentiate aCML from CMML, chronic eosinophilic leukemia, and and epigenetic regulator genes (DNTM3A, IDH1/2, and EZH2).6,10–14
CML, respectively. Bone marrow biopsies are typically hypercellular Clonal structural inferences suggest that ETKN1 and ASXL1 mutations
with granulocytic hyperplasia and dysplasia, with or without dysplasia are early events in aCML, with RAS, CBL, TET2, SRSF2, and SETBP1
involving other lineages.1,4,5 Prominent dysgranulopoiesis can be seen mutations representing secondary events, with a strong tendency for
in the peripheral blood and in bone marrow aspirates. Dysgranulopoi- CBL mutations to reach homozygosity through somatic uniparental dis-
esis can be defined by the presence of hyposegmented and/or hyper- omy (copy neutral-loss of heterozygosity) (Figure 2).
segmented neutrophils with or without abnormal chromatin clumping In a large study including 71 patients with aCML, ASXL1 muta-
(Figure 1). Acquired Pelger–Huët anomaly, or other nuclear abnormali- tions were seen in 65 (92%) patients and were characterized as being
ties, such as hypersegmentation with abnormally clumped nuclear chro- ancestral in 79%, with SETBP1 (38%) mutations being frequent and
matin, or bizarrely segmented nuclei, abnormal cytoplasmic granularity, either co-ancestral or occurring secondary to ASXL1 mutations.9 No
and multiple nuclear projections, may be observed in neutrophils. Mega- patients were found to have ancestral SETBP1 and secondary ASXL1
karyopoiesis can be quantitatively normal or increased with dysmega- mutations, suggesting that, in patients with this combination, ASXL1
karyopoiesis, including micromegakaryocytes and small megakaryocytes mutations are usually acquired early on during the evolutionary pro-
with hypolobated nuclei, being commonly encountered. The circulating cess (Figure 2). Ancestral somatic mutations are defined as somatic
and bone marrow blast % should be <20%. Finally, defined and recur- pathogenic variants (single nucleotide variants and indels) that occur
rent genetic abnormalities must be excluded, such as BCR::ABL1 fusion early during clonal evolution in hematopoietic stem and progenitor
and myeloid and lymphoid neoplasms with eosinophilia and cells, enhancing clonal fitness, with secondary mutations over time,
tyrosine kinase gene fusions (MLN-TK e.g., PDGFRA, PDGFRB, FGFR1, often resulting in disease progression. On bulk sequencing, ancestral
PCM1::JAK2, FLT3, and ETV6::ABL1 fusions). The ICC has added sup- mutations are identified by their higher variant allele fractions
portive criteria, including the absence of MPN-associated driver muta- (approximate), while on single-cell sequencing, they are identified by
tions and the presence of somatic mutations involving ASXL1 and their early occurrence in mapped clonal trajectories.
4
SETBP1. The 5th edition of the WHO criteria for aCML outline sup- Two genes whose somatic mutations are enriched in aCML
portive somatic mutations, such as ASXL1 and ETNK1, while highlighting include ETNK1 (13–15%) and SETBP1. ETNK1 kinase results in phos-
that it is desirable to document the absence of MPN-associated driver phorylation of ethanolamine (Et) to phosphoethanolamine (P-Et), with
mutations such as JAK2, CALR, MPL, and CSF3R.5 P-Et being a key component of the Kennedy pathway, representing the
main metabolic route by which mammalian cells synthesize critical cell
membrane phospholipids.14 ETNK1 mutations are not specific to aCML
1.1.2 | Cytogenetics, gene mutations, and prognosis and have been annotated in 5% of patients with CMML and 20% of
patients with systemic mastocytosis and eosinophilia.10,15 ETNK1 muta-
Cytogenetic abnormalities are seen in approximately 40% of patients, tions are thought to be ancestral, resulting in a mutator phenotype, and
with trisomy 8 being the most common, followed by 7/del7q.6,7,9–11 have also been shown to increase mitochondrial activity, ROS (reactive
Gene mutations are present in almost all patients with aCML, with oxygen species) production, and H2AX phosphorylation.14 In myeloid
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684 PATNAIK AND TEFFERI

F I G U R E 2 Clonal hierarchy and disease progression patterns in atypical CML demonstrating stochastic and then sequential acquisition of
somatic mutations and somatic copy number alterations resulting in disease progression to acute myeloid leukemia. AML, acute myeloid
leukemia; CMP, common myeloid progenitors; GMP, granulocyte monocyte progenitors; HSC, hematopoietic stem cell; SCNA, somatic copy
number alterations.

neoplasms, ETNK1 mutations tend to cluster in the following hot spot multivariable analysis, advanced age (p = .003) [age > 67: HR 10.1, 95% CI
regions in the ETNK1 catalytic domain, impairing enzymatic activity: 1.3–119], low hemoglobin (p = .008) [HB < 10 gm/dl: HR 8.2, 95% CI
H243Y, N244S/T/K, and G245V/A, respectively. 14,15
SETBP1 muta- 1.6–23.2]; and TET2 mutations (p = .01) [HR 8.8, 95% CI 1.6–47.7] were
tions, on the other hand, are seen in 15–25% of patients with independently prognostic.6 We then used age > 67 years, hemoglobin
aCML.6,10,16 These somatic mutations cluster between amino acids <10 gm/dl, and the presence of TET2 mutations (each counted as one
858–871, with the most common mutation being SETBP1 p.Gly870Ser, risk factor) to create a hazard ratio weighted prognostic model, effec-
known to abrogate the ubiquitination site for the protein, leading to tively stratifying patients into two risk categories, low (0–1 risk factor)
higher SETBP1 and SET protein levels, decreasing the PP2a activity, and high (≥2 risk factors), with median OS of 18 and 7 months, respec-
and resulting in a proliferative phenotype.17,18 SETBP1 also forms a tively.6 In a larger series of 71 patients, ASXL1 mutations were once
multimeric complex (with HCF1/KMT2A/PHF8) involved in gene tran- again not found to be prognostic (given their ubiquitous distribution of
scription and histone modification (H3K4me2 and H3K9ac), with higher approximately 90%), while SRSF2 and SETBP1 mutations were associ-
protein levels leading to upregulation of several genes, including ated with better outcomes, and RUNX1, CUX1, and NRAS mutations
MECOM.17,18 CSF3R mutations, which have been documented in aCML, were associated with shortened overall survivals.9 In a large series of
are thought to be infrequent in the context of an accurate morphologi- 134 patients, 65 (49%) with aCML and 69 (51%) with MDS/MPN-U,
19
cal diagnosis (<10%) and are actually relatively specific to CNL, with there was a clear survival difference between the two entities
the 5th edition of the WHO classification schema highlighting that the (12.4 months for aCML vs 21.8 months for MDS/MPN-U; p = .004),
absence of these mutations is desirable for a diagnosis of aCML.5,8 with the negative impact on survival being driven by leukocytosis and
circulating IMC and not by dysgranulopoiesis, justifying the ongoing dis-
tinction between aCML and MDS/MPN-U (MDS/MPN-NOS).8
1.1.3 | aCML risk stratification

Given the rarity of the disease, there is no consensus on risk stratifica- 1.1.4 | Risk-adapted therapy
tion, except for the fact that, in general, outcomes are very
poor (median OS: 10–29 months). The Mayo Clinic prognostic There is no prospective data on the management of patients with
model was developed in 2017, on a dataset of 25 patients. In aCML. Proliferative features, including leukocytosis, splenomegaly,
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PATNAIK AND TEFFERI 685

TABLE 2 Comparison of classification criteria between the 2022 ICC and the 5th edition of the WHO classification for MDS/MPN-NOS

Criteria International Consensus Classification 5th edition of the WHO Classification

Nomenclature Myelodysplastic/myeloproliferative neoplasm not otherwise Myelodysplastic/myeloproliferative neoplasm not
specified otherwise specified
Peripheral blood Platelet count ≥450  109/L and/or WBC ≥13  109/L A combination of cytopenia(s) and proliferative
feature(s)
Cytopenia MDS-defining cytopenias
Peripheral blood and bone <20% <20%
marrow blasts
Bone marrow findings Presence of clonality: Demonstration of a clonal cytogenetic A combination of cell dysplasia and proliferative
abnormality and/or somatic mutations. If clonality cannot be features.
determined other causes should be excluded.
Exclusions Myeloid/lymphoid neoplasms with eosinophilia and tyrosine Therapy-related myeloid neoplasms.
kinase gene fusions. Disease defining gene fusions: BCR::ABL1 or fusions/
t(3;3)(q21.3;q26.2) and inv (3)(q21.3q26.2) rearrangements of PDGFRA, PDGFRB, JAK2 or FGFR1
Isolated del(5q) (myeloid/lymphoid neoplasms with eosinophilia and
tyrosine kinase gene fusions).
Other MDS/MPN entities, including CMML, MDS/MPN
with neutrophilia, MDS/MPN-with SF3B1 mutations,
and thrombocytosis

Abbreviations: ICC, International Consensus Classification; MDS, myelodysplastic syndrome; WBC, White blood cell count; WHO, World Health
Organization.

and related constitutional symptoms, can be effectively controlled for median age was 46 years, and the median time from diagnosis to HCT
a short duration of time with hydroxyurea.20 Interferon alpha has was 7 months. 64% underwent a matched sibling donor HCT, while
been used in the past, with durable responses in small number of 24% received a reduced intensity of conditioning. At 5 years, the
patients.20 Agents such as thalidomide and lenalidomide have been relapse-free survival was 36%, non-relapse mortality 24%, and relapse
6
tried with limited success. Management of anemia and red blood cell occurred in 40% of patients.24 Patient age and EBMT score (age, dis-
transfusion dependency is similar to that of MDS, with the use of ease stage, time interval from diagnosis to HCT, donor type, and
erythropoiesis-stimulating agent therapy and red blood cell transfu- donor–recipient sex mismatch) were the only factors that impacted
sions. DNA methyltransferase inhibitors (DNMTi) such as azacitidine survival.24 ABNL-MARRO (A Basket study of Novel therapy for
and decitabine have also been used anecdotally in this disease, with untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes)
limited success.6,21 In the Mayo Clinic series, five patients received is an international trial developed by the MDS/MPN IWG, providing
DNMTi (median number of cycles 5, range 1–40), with the best the framework for collaborative studies to advance treatment of
response being stable disease in 40%.6 CSF3R mutations are infre- MDS/MPN.25 AM-001 is an open-label, randomly allocated, phase
quently encountered in aCML (<10%), with the T618I, T615A [mem- 1/2 study that will test novel treatment combinations in MDS/MPNs,
brane-proximal mutations] and the T640N [transmembrane domain beginning with the novel targeted agent Itacitinib, a selective JAK1
mutation] mutations resulting in ligand-independent dimerization and inhibitor, combined with ASTX727, a fixed-dose oral combination of
activation of CSF3R, leading to constitutive JAK–STAT signaling that the DNMTi decitabine and the cytidine deaminase inhibitor cedazuri-
19
can be blocked with Ruxolitinib. In a prospective phase II study that dine.25 This trial will also prospectively validate the 2015 IWG
enrolled 23 patients with aCML, 6 (26.1%) patients had CSF3R muta- MDS/MPN response criteria specifically developed for overlap
tions, with 11 (47.8%) going on to receive >6 cycles of therapy with neoplasms.23
Ruxolitinib. In the aCML cohort, the responses to Ruxolitinib were dis-
mal, with only 2 patients (8.7%) meeting partial response criteria by
study protocol and zero patients meeting response criteria by the 1.2 | MDS/MPN-NOS
International Working Group (IWG) criteria for MDS/MPN overlap
neoplasms, highlighting the relative inefficacy of the drug.22,23 This category of overlap neoplasms demonstrates features of MDS
Allogeneic hematopoietic stem cell transplant (HCT) remains the and MPN, not otherwise meeting criteria for defined overlap neo-
only curative strategy for affected patients. This, however, is not an plasms, such as CMML, aCML, MDS/MPN-RS-T, MDS, and MPN.4,5
option for the vast majority due to increased age at presentation and Affected patients usually present with MDS-defining cytopenias,
comorbidities. The largest series published to date, validating the use <20% peripheral blood and BM blasts, have features of myeloproli-
of allogeneic HCT for aCML is from the European Society of Blood feration (platelet count ≥450 000/L and/or WBC ≥13  109/L), either
and Bone Marrow Transplantation (EBMT), where 42 patients had clonal cytogenetic changes or myeloid somatic mutations, or, in the
available data on transplant outcomes for aCML(1997–2006).24 The absence of clonal markers, an exhaustive exclusion of other reactive
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686 PATNAIK AND TEFFERI

causes that can give rise to features of MDS and MPN.4,5 Prime having the worst outcomes (median 5.2 months).9 In the large Mayo
among the conditions that can mimic MDS/MPN-NOS is accelerated Clinic-Moffitt Cancer Center study (n = 140), using the same molecu-
phase MPN, where apart from the increased blasts, there can be lar stratification schema, the median survival for individual categories
prominent features of atypia/dysplasia concomitant to the myeloproli- was MDS/MPN-RS-T-like 170 months (range: 1, 170), CMML-like
feration.26 Hence, the presence of MPN-associated driver mutations, 44 months (range: 12, median NR), others 28 months (range: 24, 35),
such as JAK2, MPL, and CALR, particularly with high variant allele frac- aCML-like 19 months (range: 1, 23), and TP53mt 10.5 months (range:
tions, should always initiate a search into a preexistent MPN. The 5th 4, 24), respectively.27
edition of the WHO classification also calls for the exclusion of While molecular risk stratification is useful for prognostication,
therapy-related myeloid neoplasms and disease defining gene fusions, MDS-risk models, such as the International Prognostic Scoring System
such as BCR::ABL1 or MLN-TK.5 The ICC schema calls for the exclu- (IPSS), Revised-IPSS (IPSS-R), and the Global MD Anderson Prognostic
sion of BCR::ABL1 rearrangements, MLN-TK fusions and in addition, Scoring System, have all been used comparably to risk stratify
also ask for the exclusion of t(3;3)(q21.3;q26.2) and inv (3) patients, with the IPSS-R being particularly effective in risk stratifying
(q21.3q26.2) in patients that otherwise meet criteria for MDS-NOS, patients belonging to the “Others” category.27,28,33,34 Of note, the
and isolated del(5q) in patients that otherwise meet criteria for MDS ICC and the 5th edition of the WHO classification have included oli-
with del(5q), respectively (Table 2: Differences in classification schema gomonocytic CMML (absolute monocyte count ≥0.5 and <1  109/
between the ICC and the 5th edition of the WHO classification for L, with monocytes ≥10% of WBC differential) as bona fide CMML, as
MDS/MPN-NOS).4 long as clonal cytogenetic or molecular abnormalities are documen-
ted, with the WHO calling for the concomitant presence of bone
marrow dysplasia (necessary) and an expansion of classical mono-
1.2.1 | Cytogenetic abnormalities and gene cytes (CD14+/CD16 ; M01 fraction) >94%; a modification that
mutations may lead to a reduction in the number of CMML-like cases in the
MDS/MPN-NOS category.35
Cytogenetic abnormalities can be seen in 40–50% of patients, with
frequent aberrations being +8, 7q / 7, monosomal karyotype, com-
plex karyotype, and 12p / 12, followed by isochromosome 17q 1.2.3 | Risk-adapted therapy
(now considered a provisional category by the ICC schema).27–29
In a large Mayo Clinic-Moffit Cancer Center study, somatic muta- We encourage further molecular categorization of patients with
tions identified included ASXL1 (58%), SRSF2 (37%), SETBP1 (19%), MDS/MPN-NOS, using somatic mutational data, to classify patients
JAK2 (18%), TET2 (15%), NRAS (13%), EZH2 (12%), RUNX1 (10%), into the above-mentioned overlap neoplasm-like categories. Patients
SF3B1 (10%), GATA2 (9%), TP53 (7%), STAG2 (7%), ZRSR2 (6%), CBL with CMML-like, aCML-like, and MDS/MPN-RS-T-like overlap neo-
(6%), MPL, FLT3, and IDH1 (4% each), and U2AF1 (3%), respectively. plasms are best managed with care algorithms designed for these enti-
Of note, somatic TP53 mutations are very uncommon in MDS/MPN ties and discussed elsewhere.30,31 Given the highly aggressive nature
overlap neoplasms and, if seen, are largely restricted to MDS/MPN- of TP53 mutant cases, allogeneic HCT should be encouraged in appro-
NOS and therapy-related CMML.30–32 priate recipients. The Mayo Clinic-Moffitt Cancer Center study
assessed 59 patients who received DNMTi, with a median of 5 cycles
(range 1–24). Twenty-seven of these patients went on to receive
1.2.2 | Molecular stratification and prognostication ≥6 cycles of therapy and were considered for response assessment. In
this group, only 1 (4%) patient achieved a complete remission, with
Patients with MDS/MPN-NOS can be further stratified based on their 2 (7%) partial remissions, 3 (11%) marrow remissions, and only 1 (4%)
somatic mutation profile and phenotype into five categories: patient achieving a complete cytogenetic response; underscoring
(a) CMML-like (biallelic TET2, TET2/SRSF2 and RUNX1/SRSF2 muta- the poor responses of these patients to DNMTi.28 In this study,
tions), (b) aCML-like (ASXL1/SETBP1, ASXL1/SRSF2, ASXL1/EZH2 and 8 (6%) patients underwent allogeneic HCT, with 63% being alive at
RUNX1/EZH2 mutations), (c) MDS/MPN-RS-T-like (SF3B1, DNMT3A/ last follow-up (median follow-up 61 months).28 Patients
SF3B1, SF3B1/JAK2 and DNMT3A/JAK2 mutations), (d) TP53 mutant with MDS/MPN-NOS will also be eligible for participation in the
(monoallelic and multi-hit TP53 states), and (e) others (CBL and STAG2) ABNL-MARRO clinical trial.25
(Figure 3).9,27 In a large study that included 106 patients, this system
effectively stratified patients into CMML-like 17%, aCML-like 33%,
MDS/MPN-RS-T like 12%, TP53 mutant (13%), and others (26%), 1.2.4 | MDS/MPN with isolated
respectively.9 This stratification resulted in survival rates similar to isochromosome 17q
individual overlap entities, with MDS/MPN-RS-T-like patients having
the best outcomes (median not reached), followed by CMML-like This is a provisional entity that has been proposed by the ICC for
patients (median not reached), others (median 80.3 months), and overlap neoplasms that do not meet criteria for other defined
aCML-like patients (median 18.8 months), with TP53 mutant cases MDS/MPN overlap neoplasms and demonstrate either an isolated
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PATNAIK AND TEFFERI 687

F I G U R E 3 Molecular
stratification of MDS/MPN-not
otherwise specified. Schema
demonstrating the use of
morphology and somatic next
generation sequencing patterns to
further classify MDS/MPN-NOS into
CMML-like, MDS/MPN-RS-T-like,
aCML-like, TP53-mutant, and
“others” category. HSPC,
hematopoietic stem and progenitor
cells.

T A B L E 3 International Consensus Classification (ICC) diagnostic

criteria for myelodysplastic/myeloproliferative neoplasm with isolated MPL, and CALR (especially with variant allele fractions ≥25%).36 Reac-
isochromosome (17q) [MDS/MPN with i(17q)] tive causes of bone marrow overlap features, especially concomitant
administration of growth factors, which must be factored in and serve
Need to meet the general criteria for a diagnosis of MDS/MPN, NOS
as exclusionary criteria. The formation of i(17q) is associated with loss
• Leukocytosis of ≥13  109/L
of 17p and loss of 1 TP53 allele at 17p13.1.37 In a multi-institutional
• MDSa-defining cytopenias
study that included 29 patients with MDS/MPN and isolated i(17q),
• Blasts <20% of the cells in blood and bone marrow
19 patients had i(17q) at baseline and 10 acquired this at progression
• Dysgranulopoiesis with non-segmented or Pseudo-Pelger Huët
(median 13 months). Compared to MDS/MPN-NOS, MDS/MPN with
neutrophils
i(17q) had a higher prevalence of splenomegaly and increased periph-
• An i(17q), either isolated or occurring with one other additional
eral blood blasts. Somatic mutational profiling identified a high fre-
abnormality [other than 7/del(7q)]
quency of SETBP1 (69%), ASXL1 (67%), and SRSF2 (63%) mutations,
• No BCR::ABL1 or genetic abnormalities of myeloid/lymphoid
neoplasms with eosinophilia and tyrosine kinase gene fusions with SETBP1 and SRSF2 mutations being statistically enriched in
MDS/MPN with i(17q).36 Interestingly, only 1 patient had a somatic
• Absence of MPN-associated driver mutations (JAK2, CALR and MPL)
TP53 mutation with a VAF of 4.48%, indicating that in most cases
• No history of recent cytotoxic or growth factor therapy that could
explain the MDS/MP features these patients have monoallelic inactivation of TP53. The median sur-
vival for this group was a dismal 11 months. Further prospective vali-
Abbreviations: MDS, myelodysplastic syndrome; MPN, myeloproliferative
dation of this category is needed.
neoplasm; NOS, not otherwise specified.
a
MDS-defining cytopenias include Hb <13 g/dl in males and <12 g/dl in
females, neutropenia with absolute neutrophil count <1.8  109/L, and
thrombocytopenia, with platelet counts <150  109/L. 1.3 | Summary

Atypical CML and MDS/MPN-NOS are rare overlap neoplasms that

isochromosome 17q [i(17q)], or i(17q) with an additional cytogenetic are generally associated with poor outcomes. Atypical CML results in
abnormality with the exception of 7/del7q (Table 3).4 Whether this dysplastic neutrophilia in the absence of monocytosis and eosinophilia
is a distinct entity or falls into the spectrum of aCML, with which it and is associated with a high rate of transformation to AML. ASXL1
shares a similar molecular signature, remains to be elucidated. mutations are common, with the disease displaying a higher fre-
Affected patients typically present with a WBC ≥13  109/L, with quency of ETNK1, SETBP1, and EZH2 mutations in comparison to
MDS-defining cytopenias, and with <20% peripheral blood and bone other MDS/MPN overlap neoplasms. Response to DNMTi is subop-
marrow blasts. Bone marrow aspirates typically demonstrate dysgra- timal and allogeneic HCT remains the only curative modality for
nulopoiesis. BCR::ABL1 fusions and MLN-TK fusions must be affected patients. MDS/MPN-NOS can be molecularly further strati-
excluded, along with MPN-associated driver mutations such as JAK2, fied based on somatic mutation profiles into CMML-like, aCML-like,
 10968652, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26828 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [05/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
688 PATNAIK AND TEFFERI

MDS/MPN-RS-T-like, TP53 mutant, and an “others” category, with 5. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World
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myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):
TP53 mutant patients. Molecular categorization into MDS/MPN
1703-1719.
overlap-like categories, followed by appropriate risk-adapted ther- 6. Patnaik MM, Barraco D, Lasho TL, et al. Targeted next generation
apy, is strongly recommended for these patients. While the ICC sequencing and identification of risk factors in World Health Organi-
schema and the 5th edition of the WHO criteria do have minor zation defined atypical chronic myeloid leukemia. Am J Hematol.
2017;92(6):542-548.
semantic and structural differences, they have retained core diag-
7. Breccia M, Latagliata R, Mengarelli A, Biondo F, Mandelli F,
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866-868.
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ACKNOWLEDGMENTS 12. Patnaik MM, Lasho T. Myelodysplastic syndrome/myeloproliferative
This Study is supported in part by grants from the “The Henry neoplasm overlap syndromes: a focused review. Hematology Am Soc
J. Predolin Foundation for Research in Leukemia, Mayo Clinic, Hematol Educ Program. 2020;2020(1):460-464.
13. Meggendorfer M, Jeromin S, Haferlach C, Kern W, Haferlach T. The
Rochester, MN, USA.”
mutational landscape of 18 investigated genes clearly separates four
The authors would like to thank Drs. Min Shi and Kaaren Reichard for subtypes of myelodysplastic/myeloproliferative neoplasms. Haemato-
providing images for atypical CML. logica. 2018;103(5):e192-e195.
14. Fontana D, Mauri M, Renso R, et al. ETNK1 mutations induce a muta-
tor phenotype that can be reverted with phosphoethanolamine. Nat
CONF LICT OF IN TE RE ST
Commun. 2020;11(1):5938.
Ayalew Tefferi has served on the ICC panel for classification of mye- 15. Lasho TL, Finke CM, Zblewski D, et al. Novel recurrent mutations in
loid neoplasms. ethanolamine kinase 1 (ETNK1) gene in systemic mastocytosis with
Mrinal Patnaik has served on the 2022 WHO panel for classification eosinophilia and chronic myelomonocytic leukemia. Blood Cancer J.
2015;5:e275.
of MDS/MPN overlap neoplasms.
16. Laborde RR, Patnaik MM, Lasho TL, et al. SETBP1 mutations in
Mrinal Patnaik has also received research funding from Stem Line 415 patients with primary myelofibrosis or chronic myelomonocytic
Pharmaceuticals and Kura Oncology. leukemia: independent prognostic impact in CMML. Leukemia. 2013;
27(10):2100-2102.
17. Piazza R, Valletta S, Winkelmann N, et al. Recurrent SETBP1 muta-
DATA AVAI LAB ILITY S TATEMENT
tions in atypical chronic myeloid leukemia. Nat Genet. 2013;45(1):
This is a review article and there is no original data to share
18-24.
18. Piazza R, Magistroni V, Redaelli S, et al. SETBP1 induces transcription
ORCID of a network of development genes by acting as an epigenetic hub.
Mrinal M. Patnaik https://orcid.org/0000-0001-6998-662X Nat Commun. 2018;9(1):2192.
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Ayalew Tefferi https://orcid.org/0000-0003-4605-3821
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