Chapter
2: MYELODYSPLASTIC /
MYELOPROLIFERATIVE
DISEASES
Chronic
Myelomonocytic Leukemia (CMML)
General
Monoclonal hematopoietic disorder of bone marrow stem cells
in which monocytosis is a major defining feature.
Diagnostic criteria
·
Persistent
monocytosis (>1 x 109/L)
in PB
·
No
Ph or BCR/ABL
·
<20% blasts in
PB or BM (CMML Blasts: Myeloblasts, monoblasts and promonocytes)
·
Dysplasia
in one or more myeloid lineages (not necessary)
·
If
dysplasia is minimal or absent, CMML can be diagnosed if:
o
Clonal
cytogenetic abnormality in marrow cells, or
o
Monocytosis
persistent for at least 3 mo, and all
other causes of monocytosis have been excluded (such as tumor, infection, or
inflammation)
Epidemiology
·
3/100,000
over the age of 60, annually
·
Median
age at diagnosis 65-75 years
·
Male
predominance 1.5-3:1
Clinical features
·
Sites
of involvement
o
PB
and BM always involved
o
Most common sites of extramedullary leukemic
infiltration: spleen, liver, skin, and LNs
·
~50%
of patients
o
WBC
count normal or slightly decreased
o
MDS-like
picture
·
~50%
of patients
o
WBC
count increased
o
MPD-like
picture
·
Fatigue,
weight loss, fever, night sweats, infection, and bleeding
Etiology
·
Unknown
·
Occupational
or environmental carcinogens, ionizing irradiation and cytotoxic agents in some
cases
PB Morphology
·
Monocytosis
(>1 x 109/L), hallmark of CMML
·
Monocytes
>10% of WBC
·
Monocytes
are usually mature with unremarkable morphology, but can exhibit:
o
Abnormal
granulation
o
Unusual
nuclear lobation
o
Finely
dispersed chromatin
·
Blasts
<20% of WBC
·
WBC
count decreased, normal, or increased
·
Promyelocytes
and myelocytes <10% of WBC
·
Mild
basophilia
·
Eosinophils
normal or slightly increased.
·
If
>1.5 x 109/L, then DX: CMML with eosinophilia
·
Dysgranulopoiesis
present in most cases, and may be more prominent in cases with normal or low
WBC count
·
Neutrophil
nuclear hypolobation
·
Neutrophil
abnormal cytoplasmic granulation
·
Mild
anemia, common
·
Moderate
thrombocytopenia with atypical platelets often present
BM Morphology
·
Hypercellular
in >75% of cases
·
Granulocytic
proliferation
·
Monocytic
proliferation
o
Alpha
naphthyl acetate esterase
o
Alpha
naphthyl butyrate esterase +/- naphthol ASD chloroacetate esterase
·
Dysgranulopoiesis
in most cases
·
Dyserythropoiesis
(>50% of cases)
o
Megaloblastic
changes, abnormal nuclear contours, ringed-sideroblasts
·
Megakaryocytic
dysplasia (up to 80% of cases)
o
Abnormal
nuclear lobation and micromegs
·
Variable
degree of fibrosis (30% of cases)
Other organ systems
·
Splenic
enlargement
o
Red
pulp infiltration by leukemic cells
·
Lymph
nodes
o
Uncommon
involvement
o
If
seen→ sign of transformation to a more acute phase
o
LN
may be diffusely infiltrated by myeloid blasts
·
Plasmacytoid
monocytes
o
Sometimes
diffusely infiltrate LNs or spleen
o
Generalized
lymphadenopathy due to plasmacytoid monocyte infiltration may be presenting
manifestation of CMML
o
Proposed
to be of monocytic lineage, but not proven to be clonally related to the
neoplastic cells of CMML
Classification
·
CMML-1
o
Blasts
<5% in PB or <10% in BM
·
CMML-2
o
Blasts
5-19% in PB or 10-19% in BM (or Auer rods with <20% blasts in BM or PB)
o
May
be at risk of rapid transformation to acute leukemia and poor prognosis
·
CMML with
eosinophilia:
o CMML
criteria + PB eosinophilia > 1.5 x 109/L
o
May
have extensive tissue damage related to eosinophil degranulation
a/w
t(5;12)
o Tx
with Gleevec
Immunophenotype
·
CD33
and CD13 + , variable CD14, CD64, and CD68
·
Increased
% of CD34+ cells may be associated with early transformation to acute leukemia
·
Plasmacytoid
monocytes
o
Characteristic
phenotype: CD14, CD43, CD56, CD68, and CD4
o
CD2,
CD5 often present, but T-cell derivation disproved
Genetics
Nonspecific cytogenetic abnormalities in 20-40%
·
+8
·
-7/del
(7q)
·
Structural
abnormalities of 12p
·
Abnormalities of
11q23 uncommon (suggest acute leukemia)
·
i(17q)
more aggressive course
·
RAS
point mutations (40%)
·
t(5;12)(q31;p12)
o
-Result
in TEL/PDGFßR abnormal fusion gene
o
-<1-2%
of CMML cases
o
-Marked
eosinophilia
Prognosis/predictive factors
·
Prognosis
o
Median
survival 20-40 months
o
15-30%
progress to acute leukemia
·
Predictive
factors
o
PB
and BM blast % (most imp. survival determinant)
o
Splenomegaly
o
Severity
of anemia
o
Degree
of leukocytosis
Atypical
Chronic Myeloid Leukemia (aCML)
General
·
Leukemic
disorder with MDS and MPD features at initial diagnosis
·
Leukocytosis
with principle involvement of dysplastic immature and mature neutrophils
·
Multilineage
dysplasia common
·
No
Ph or BCR/ABL
Epidemiology
·
Unknown
incidence
·
Estimated
1-2 cases for every 100 cases of Ph+, BCR/ABL+ CML
·
Median
age 7th-8th decades
·
M:F
= 1-2.5:1
Sites of involvement
·
PB
and BM always involved
·
Spleen
and liver involvement common
Clinical features
·
Few
reports
·
Most
patients have symptoms related to
o
Anemia
o
Thrombocytopenia
o
Splenomegaly
Etiology
·
Unknown
Diagnostic criteria
·
PB
leukocytosis (mature and immature neutrophils)
·
Prominent
dysgranulopoiesis (major feature): pseudo Pelger-Huet cells, abnormally condensed nuclear chromatin,
abnormal nuclear segmentation, or abnormal granules.
·
No
Ph or BCR/ABL
·
Neutrophil
precursors (promyelos, myelos, metamyelos) ľ10% of WBC
·
Basophils
<2% of WBC
·
Monocytes
< 10% of WBC
·
Hypercellular
BM with granulocytic proliferation and dysplasia +/- erythroid and
megakaryocytic dysplasia
·
<20%
blasts in PB and BM
BM morphology
·
BM
megakaryopoiesis and erythropoiesis are variable in quantity
·
M:E
>10:1
·
Increased
reticulin fibers at diagnosis or later in course of disease
Cytochemistry/Immunophenotype
·
No
specific abnormalities
Genetics
·
+8, +13, del(20q), i(17q), del(12p)
o
80%
of cases
o
Not
specific
o
No
Ph or BCR/ABL
Course and prognosis
·
Median
survival < 20 months
·
Poor
prognostic factors
o
Thrombocytopenia
o
Marked
anemia
·
25-40%
evolve to acute leukemia
·
Remainder
die of marrow failure
aCML Variant: Syndrome of abnormal chromatin clumping
·
PB
morphology
o
High % of
immature and mature neutrophils with exaggerated clumping of chromatin
o
Nuclear
hypolobation and cytoplasmic hypogranularity are common
o
WBC count usually
increased
o
Severe anemia and
thrombocytopenia
·
BM
morphology
o
Hypercellular
o
Granulocytic
proliferation with nuclear abnormalities similar to PB
o
Moderate dysplasia
in erythroid and megakaryocytic lineages
·
Survival
is similar to aCML
Juvenile
Myelomonocytic Leukemia (JMML)
General
·
Monoclonal
hematopoietic disorder of childhood characterized by proliferation of the
granulocytic and monocytic lineages
·
Erythroid
and megakaryocytic abnormalities common
·
Bone
marrow stem cell with multilineage potential in the myeloid series
Diagnostic Criteria
·
PB
monocytosis > 1 x 109/L
·
Blasts
< 20% of WBCs in the blood and of the nucleated bone marrow cells
·
No
Ph chromosome or BCR/ABL
·
Plus
two or more of the following:
o
Hemoglobin
F increased for age
o
Immature
granulocytes in PB
o
WBC>10
x 109/L
o
Monoclonal
chromosomal abnormality
o GM-CSF hypersensitivity of myeloid
progenitors in vitro
Epidemiology
·
1.3
per million children ages 0-14, annually
·
<2-3%
of all childhood leukemias
·
20-30%
of all cases of myeloproliferative and myelodysplastic diseases in patients
less than 14 years old.
·
75%
occur in children <3 years old
·
Male
predominance of ~ 2:1
·
10%
of patients have NF-1
Sites of Involvement
·
PB
and BM always involved
·
Leukemic
infiltration
o
Liver
and spleen, virtually in all cases
o
LN
o
Skin
o
Respiratory
tract
Clinical Features
·
Constitutional
symptoms (including malaise, pallor, and fever or infection)
·
Bleeding
·
Bronchitis
or tonsillitis in (50%)
·
Maculopapular
skin rash (40-50%)
·
Café-au-lait
spots in pts with NF-1
·
Hepatosplenomegaly
(~100%)
Etiology
·
Unknown
·
Some
genetic predisposition
·
Association
with neurofibromatosis type 1
PB Morphology
·
Leukocytosis
o
WBC
25-35 x 109/L
o
>100
x 109/L in 5-10%
o
Neutrophils
(including promyelocytes and myelocytes) and monocytes
o
Blasts
usually < 5%, always < 20%
o
Eosinophilia
and basophilia in minority
·
Anemia
o
nRBCs
frequent
o
RBCs
typically normocytic, but may be microcytic, or macrocytic (a/w monosomy 7)
·
Thrombocytopenia
(may be severe)
BM Morphology
·
Hypercellular
bone marrow
o
Granulocytic
proliferation
o
Monocot’s
usually 5-10%
o
Blasts
< 20%
§
No Auer rods
·
Dyspoiesis/dysplasia
usually minimal
o
Pseudo-Pelger-Huet
neutrophils
o
Hypogranularity
of neutrophil cytoplasm
o
Megaloblastic
changes in erythroid precursors
Morphology
in Other Organs
·
Leukemic
infiltration
o
Skin
§
Superficial and
deep dermis
o
Lung
§
Peribronchial
lymphatics into adjacent alveolar septae
o
Spleen
§
Red pulp
§
Predilection for
trabecular and central arteries
o
Liver
§
Sinusoids and
portal tracts
Cytochemistry/Immunophenotype
·
No
specific abnormalities
·
Lysozyme
should be used for detection
o
Myelo-peroxidase
may be weakly expressed
·
Alpha
naphthyl acetate esterase
·
Butyrate
esterase +/- napthol ASD chloroacetate esterase
·
LAP
scores decreased in 50% of cases, not helpful for Dx
Genetics
·
No
Ph or BCR/ABL
·
Monosomy
7 (30-40%)
·
Point
mutations in RAS (20%)
·
Loss
of NF1 allele
o
Associated
with NF-1
·
Loss
of heterozygosity for NF1
o
Patients
lacking NF-1 phenotype
Prognosis
·
Overall
poor prognosis
·
Better
Prognosis:
o
<1
year of age
·
Worse
prognosis:
o
2
years old
o
PLT
<33 x 109/L
o
Hbg
F >15%
·
If
untreated, 30% die in one year
·
Median
survival from 5 months to 4 years
·
Most
die from organ failure (leukemic infiltration)
·
10-20%
evolve to acute leukemia
·
Response
to chemotherapy often poor
·
BMT
demonstrated to improve survival time
Myelodysplastic/myeloproliferative
disease, unclassifiable
(MDS/MPD,
U)
General
·
Cases
with clinical, laboratory and morphologic features that support a diagnosis of
both MDS and MPD, but do not meet criteria for other entities in the MDS/MPD
category
·
Proliferation
of one or more myeloid lineages that is ineffective and/or dysplastic
and, simultaneously effective proliferation +/- dysplasia
in one or more of the other
lineages
Diagnostic
Criteria
·
Features of MDS (RA, RARS, RCMD, RAEB), and
·
Features of MPD (eg, plt>600k,
WBC≥13k), and
·
No h/o CMPD or MDS, no drug causes, no Ph or
BCR/ABL, del (5q), t(3;3)(q21;q26) or inv(3)(q21q26)
OR
·
Features of MDS and MPD, but cannot be assigned
to any other MDS, CMPD or MDS/MPD
Exclusion
Criteria
·
Patients
with a previous, well-defined myloproliferative disease who develop dysplastic
features associated with transformation to a more aggressive phase
·
Ph,
BCR/ABL
Incidence
·
Unknown
Sites of Involvement
·
BM
and PB always involved
·
Spleen
·
Liver
·
Other
extramedullary tissues
Clinical Findings
·
Similar
to those of both MDS and MPD patients
·
Splenomegaly
and hepatomegaly
Etiology
·
Unknown
PB Morphology
·
Anemia
+/- macrocytosis
o
Dimorphic
RBCs
·
Evidence
of effective proliferation in one or more lineages
o
Thrombocytosis
( > 600 x 109/L)
o
Leukocytosis
( > 13 x 109/L)
·
Dysplasia
·
Giant
or hypogranular platelets
·
Blasts
< 20%
o
>10%
indicates transformation to aggressive phase
BM Morphology
·
Hypercellular
bone marrow
·
Proliferation
of one or all of the myeloid lineages
·
Dysplastic
features present simultaneously in at least one cell line
Provisional
entity: MDS/MPD, U-Refractory anemia with ringed-sideroblasts (RARS) associated
with marked thrombocytosis
·
Clinical
and morphologic features of RARS
·
Markedly
elevated platelet count (>600 x 109/L)
·
BM
Morphology
o
>15%
of erythroid precursors are ringed-sideroblasts
o
Megakaryocytic
proliferation
§
Normal or
enlarged megs, similar to those in ET
·
?
Distinct entity
·
?
Spectrum of RARS
·
?
Simultaneous occurrence of two diseases
·
Disease
entities with similar findings
o
5q-
syndrome
o
MDS
or AML and abnormalities of 3q21q26
§
Thrombocytosis
with micromegs
·
Genetics
o
Not
specific
·
No Ph, BCR/ABL
·
Cell
of origin
o
Unknown
·
Prognosis/predictive
factors
o
Unknown