Myelodysplastic-Myeloproliferative
disorders

Chronic myelomonocytic leukemia
(CMML)
Atypical chronic myeloid leukemia,
BCR-ABL1-negative (aCML)
Myelodysplastic/myeloproliferative
neoplasm with ring sideroblasts and
thrombocytosis (MDS/MPN-RS-T)
Myelodysplastic/myeloproliferative
neoplasm, unclassifiable
(MDS/MPN-U)
Adult MD/MP disorders
Cell of origin:
Hematopoietic stem cell
Invariably involves
blood and bone marrow
Occurs in elderly age
group

Chronic myelomonocytic leukemia
• Introduction: It is a clonal hematopoietic malignancy with features of
both a myeloproliferative neoplasm and a myelodysplastic syndrome
• Incidence: 0.4 cases per 100,000 population
• Age: Elderly (median age 65-75years)
• Male predominance (M:F ~2.5:1)
• Etiology: Primarily de novo
• Exposure to occupational and environmental carcinogens or ionizing irradiation
• Sites for extramedullary leukemic infiltration: spleen, liver, skin and
lymph nodes

Chronic myelomonocytic leukemia
Proliferative
type
Weight
loss
Fever
Night
sweats
Increased
WBC count
Dysplastic
type
Fatigue
Infection
Bleeding
Decreased
WBC count
• Hepatosplenomegaly
• Lymphadenopathy: uncommon
Clinical features:

Chronic myelomonocytic leukemia
Peripheral blood:
• RBC:
• Mild anemia
• Normocytic but sometimes macrocytic
• nRBCs: may be present
• Platelet:
• Variable in number
• Moderate thrombocytopenia
• Atypical and large platelets may be seen

Chronic myelomonocytic leukemia
• WBC:
• Increased/normal/decreased in number
• Monocyte count: always >10%
• Monocytosis (always >1 x 109/L)
• Monocyte morphology: mature but can exhibit unusual nuclear lobulation or
chromatin patterns and abnormal granulation (abnormal monocytes)
• Neutrophil precursors: <10%
• Dysgranulopoiesis: may be seen
• Eosinophil and basophil count: usually normal
• Blasts & promonocytes: <20%

Chronic myelomonocytic leukemia
• Bone marrow aspirate:
• Usually hypercellular
• Increased M:E ratio
• Granulocytic and monocytic
proliferation
• Dysgranulopoiesis &
dysmegakaryopoiesis: ~80%
• Erythroid precursors: often
reduced in number
• Mild Dyserythropoiesis
• Blasts and promonocytes: <20%
• Bone marrow biopsy:
• Mild to moderate fibrosis
• Interstitial nodules composed of
mature plasmacytoid dendritic
cells (~20% cases)

Nodules of mature plasmacytoid dendritic cells
The cells have round nuclei, finely dispersed chromatin,
inconspicuous nucleoli, and a rim of eosinophilic cytoplasm.
The cytoplasmic membrane is usually distinct with well-
defined cytoplasmic borders, imparting a cohesive appearance
to the infiltrating cells.

Chronic myelomonocytic leukemia
• < 2% blasts in the blood and
• < 5% in the bone marrowCMML-0
• 2-4% blasts in the blood and/or
• 5-9% blasts in the bone marrowCMML-1
• 5-19% blasts in the blood and/or
• 10-19% in the bone marrow and/or
• Presence of Auer rods
CMML-2
Based on percentage of blasts and promonocytes in the peripheral blood and bone marrow:

• Cytochemistry:
• Strongly recommended
• Alpha-naphthyl butyrate esterase
(ANBE) staining alone or in
combination with chloroacetate
esterase (CAE) staining
• ANBE: brown reaction product in
monocytes and it’s precursors
• CAE: granular bright blue reaction
product in cells of neutrophil
lineage
• More sensitive than IHC
Chronic myelomonocytic leukemia

• Immunophenotype:
• Blood and marrow cells usually express typical myelomonocytic antigens
(CD33 and CD13) and variably express CD14, CD68 and CD64
• Blood and marrow monocytes: aberrant phenotypes (decreased CD14
expression; overexpression of CD56; aberrant expression of CD2)
• Increased proportion of CD14+/CD16- monocytes
• Mature plasmacytoid dendritic cells: positive for CD123, CD4, CD43, CD45RA,
CD68
Chronic myelomonocytic leukemia

• Genetic profile:
• 20-40% cases have clonal cytogenetic aberrations
• Most common: +8, -Y, del(7q), +21
Chronic myelomonocytic leukemia

• Genetic profile: molecular and epigenetic abnormalities
Patnaik MM, Tefferi A. Cytogenetic and molecular
abnormalities in chronic myelomonocytic leukemia.
Blood Cancer J. 2016 Feb 5;6:e393.

• Prognosis and predictive factors:
• Survival times range from 1 month to >100 months
• Median survival time: 20-40 months
• 15-30% cases progress to AML
• Prognostic factors: serum LDH level, splenomegaly, anaemia,
thrombocytopenia and lymphocytosis
• %age of blasts in blood and BM: most important factor determining survival
Chronic myelomonocytic leukemia

Differential diagnosis of CMML
CMML CML-CP Myeloid neoplasms with
PDGFRB rearrangement
WBC Variable; Monocytosis,
may have left shifted
neutrophilia
Increased; Left shifted
neutrophilia with peaks in
%age of myelocytes and
segmented
neutrophils
Increased; may have left
shifted neutrophilia,
monocytosis, eosinophilia
Blood immature
granulocytes
Usually <10% >10% <10%
Blood monocytes Always >1x103/μL Variable, <1x103/μL Often <1x103/μL
Blood eosinophils Not increased Increased Increased
Blood basophils Not increased Increased Increased
Blood blasts <20% Usually <2% <20%
Granulocytic dysplasia Present Absent Absent
Pseudo-gaucher cells Absent Present Usually absent
BCR-ABL1 fusion gene Absent Present (90-95%) Absent

Differential diagnosis of CMML
• Reactive monocytosis
• Infections: TB, SABE, HIV-1, Infectious mononucleosis, Malaria, Rocky
Mountain spotted fever, Trypanosomiasis, Brucellosis & Cat-scratch disease
• Autoimmune diseases: Vasculitis, SLE, Rheumatoid arthritis, IBD & Sarcoidosis

• Introduction: It is a leukemic disorder with myelodysplastic and
myeloproliferative features present at the time of initial diagnosis
• Incidence: unknown
• ~1-2 aCML cases per 100 cases of BCR-ABL1-positive CML
• Age: Elderly (median age 70-80years)
• Male predominance (M:F ~2.5:1)
• Sites for extramedullary leukemic infiltration: spleen and liver
• C/F: Fatigue, bleeding, hepatosplenomegaly
Atypical chronic myeloid leukemia, BCR-ABL 1-negative

Atypical chronic myeloid leukemia, BCR-ABL 1-negative
Peripheral blood:
• RBC:
• Moderate anemia
• Anisopoikilocytosis
• Dyserythropoiesis may be seen
• Platelets:
• Usually decreased in number
• WBC:
• Increased in number (always >13 x 109/L)
• Neutrophil precursors: >10%
• Monocyte count: may be increased
(<10%)
• Blasts: <5%
• Dysgranulopoiesis: prominent
• Hypersegmentation with abnormally
clumped nuclear chromatin or bizarrely
segmented nuclei, abnormal cytoplasmic
granularity (usually hypogranular) and
multiple nuclear projections
• Basophil count: usually normal

Atypical chronic myeloid leukemia, BCR-ABL 1-negative
• Bone marrow aspirate:
• Usually hypercellular
• Increased M:E ratio
• Granulocytic proliferation
• Dysgranulopoiesis: prominent
• Erythroid precursors: usually decreased in number
• Dyserythropoiesis: seen in 40% cases
• Megakaryocytes: Usually normal/increased in number
• Dysmegakaryopoiesis: often present
• Blasts: <20%
• Bone marrow biopsy:
• Mild fibrosis

• Cytochemistry and immunophenotype:
• No specific cytochemical abnormalities or immunophenotypic characteristics
• Genetic profile:
• ~80% show karyotypic abnormalities
• Most common abnormalities: +8 and del(20q)
• Abnormalities of chromosomes 13, 14, 17, 19 and 12 are also frequent
• SETBP1 and ETNK1 mutations: present in one-third cases
• CSF3R mutation: present in <10% cases
Atypical chronic myeloid leukemia, BCR-ABL 1-negative

• Prognosis and predictive factors:
• Poor prognosis
• Median survival time: 14-29 months
• Adverse prognostic factors: age >65 years, female gender, WBC count >50 x 109/L,
thrombocytopenia and haemoglobin level <10 g/dl
• ~30-40% cases evolves to AML
Atypical chronic myeloid leukemia, BCR-ABL 1-negative

aCML CML-CP CNL
Organomegaly Hepatosplenomegaly Splenomegaly Hepatosplenomegaly
Blood neutrophils &
bands
Not-defined Not-defined >80%
Blood immature
granulocytes
>10% >10% <10%
Blood basophils Minimal or <2% Increased Not increased
Blood myeloblasts <20% Usually <2% <1%
Granulocytic dysplasia Prominent Minimal/absent Minimal/absent
Megakaryocytic dysplasia Usually present Minimal/absent Minimal/absent
Marrow myeloblasts <20% Usually <5% <5%
BCR-ABL1 fusion gene Absent Present (90-95%) Absent
CSF3R mutation <10% Absent Present (>90%)
Differential diagnosis of aCML

• Introduction: It is a definitive entity in the 2016 WHO classification
• Age: Elderly (median age 72-75years)
• Slight female predominance
• Sites for extramedullary involvement: spleen and liver
• C/F: Fatigue, splenomegaly (~40%), hepatomegaly, thrombotic events
(2% to 20%)
Myelodysplastic/myeloproliferative neoplasm
with ring sideroblasts and thrombocytosis

Myelodysplastic/myeloproliferative neoplasm
with ring sideroblasts and thrombocytosis
Peripheral blood:
• RBC:
• Anemia
• Normochromic macrocytic or
normocytic
• Often dimorphic blood picture
• Anisocytosis
• WBC count and DLC:
• Usually normal
• Neutrophils may show mild
dysgranulopoiesis
• Blasts: absent/rare (<1%)
• Platelets:
• Persistant thrombocytosis (>450 x 109/L)
• Anisocytosis
• Tiny forms to atypical large or giant
platelets
• Bizarre shaped or agranular platelets
may also be seen

Myelodysplastic/myeloproliferative neoplasm
with ring sideroblasts and thrombocytosis
• Bone marrow aspirate:
• Usually hypercellular
• Reversal of M:E ratio
• Erythroid hyperplasia
• Dyserythropoiesis: marked
• >15% ring sideroblasts present on Prussian blue stain
• Megakaryocyte hyperplasia
• Megakaryocytes are predominantly large hypersegmented and show focal
clustering
• Multilineage dysplasia may also be seen

MDS/MPN-RS-T: Mutational pathogenesis
Mario Cazzola, Luca Malcovati, Rosangela Invernizzi,
Myelodysplastic/Myeloproliferative Neoplasms,
Hematology Am Soc Hematol Educ Program, 2011

• Genetic profile:
• Cytogenetic abnormalities: ~10% cases
• Somatic mutation involving RNA splicing gene (SF3B1): ~60-90%
• SF3B1 mutation commonly associated with JAK2 V617F mutation
• Rare association of CALR or MPL W515 mutation with SF3B1 has also been reported
• Detection of SF3B1, JAK2 V617F, CALR & MPL W515 mutations are not required for
the diagnosis
• Their presence supports the diagnosis and carry prognostic significance
Myelodysplastic/myeloproliferative neoplasm
with ring sideroblasts and thrombocytosis

Prognosis and predictive factors
• Median overall survival: 76- 128 months
• Prognostic factors: patient age, JAK2 V617F and SF3B1 mutation
• SF3B1 mutation: significantly longer median overall survival
• JAK2 V617F mutation: more favourable outcome
Myelodysplastic/myeloproliferative neoplasm
with ring sideroblasts and thrombocytosis

MDS/MPN-RS-T MDS-RS ET
Median age (in years) 72-75 60-73 ~60
Anemia Present Present Absent
Leukocytosis Not common Not common Not common
Thrombocytosis Present Absent Present
Ring sideroblasts >15% >15%/>5% Absent
Dysplasia Present Present Absent
JAK2 V617F mutation <10% Rare Common (50-60%)
SF3B1 mutation 60-90% 80-90% Absent
Median overall
survival
76-128 months Short (69-108 months) Long (120-180 months)
Myelodysplastic/myeloproliferative neoplasm
with ring sideroblasts and thrombocytosis

Montalban-Bravo G, Garcia-Manero G. MDS/MPN-RS-T justified inclusion as a unique
disease entity? Best Practice and Research: Clinical Haematology. 2020 Jan 1. 101147.

MDS-RS-T MDS-RS ET

• Introduction: It is characterized by dysplastic proliferation of one or more
myeloid lineages and simultaneously effective proliferation of another
myeloid lineages with no history of a preceding MPN
• Age: Elderly (median age ~70years)
• Male predominance
• Sites for extramedullary involvement: spleen and liver may be involved
• C/F: overlap with those of entities in the MDS and MPN
• Weight loss, fever and night sweats: Effective proliferation
• Fatigue, infection and bleeding: Dysplastic proliferation
Myelodysplastic/myeloproliferative neoplasm,
unclassifiable

Myelodysplastic/myeloproliferative neoplasm,
unclassifiable
Peripheral blood:
• RBC:
• Anemia
• Macrocytosis
• nRBCs may be seen
• WBC count:
• Increased in number (~70%)
• Neutrophilic precursors
• Neutrophils may show dysplasia
• Blasts: <20%
• Platelets:
• Increased/decreased in number
• Giant and hypogranular platelets
may be seen

• Bone marrow aspirate:
• Hypercellular
• M:E ratio: increased/decreased
• Proliferation of any or all myeloid lineages
• Significant (>10%) dysplastic features in at least one cell line
• Dysgranulopoiesis and dysmegakaryopoiesis: ~50% cases
• Blasts:<20%
• Bone marrow biopsy:
• Moderate to marked fibrosis (20-30%)
Myelodysplastic/myeloproliferative neoplasm,
unclassifiable

• Cytochemistry and immunophenotype:
• Cytochemical abnormalities or immunophenotypic characteristics are similar
to MDS or MPN
• Genetic profile
• No specific cytogenetic or molecular genetic findings
• High frequencies of TET2, NRAS, RUNX1, CBL, SETBP1 and ASXL 1 mutations
have been reported
Myelodysplastic/myeloproliferative neoplasm,
unclassifiable

• Prognosis and predictive factors
• Median overall survival: ~12-18 months
• AML transformation: ~20-30%
• Thrombocytopenia: negative impact on survival
• Thrombocytosis: favorable predictor for an improved survival
Myelodysplastic/myeloproliferative neoplasm,
unclassifiable

MDS/MPN-RS-T

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