case presentation

2. CASE PRESENTATION
Marwa Mahmoud Khalifa , MS
Hematology Department
AMUH

3.  56 year old male patient from El
beheira, married , with 4 offsprings ,
farmer , smoker.
 Presented with abdominal pain in Rt
hypochondrium , fatty dyspepsia &
jaundice.
 He sought medical advice , US
abdomen and routine laboratory Ix were
done.
 Past Hx : Splenectomy 10 years ago

4. US abdomen & pelvis
1. Chronic calcular cholecystitis, no
intra / extrahepatic biliary dilatation.
2. Mild hepatomegaly, mild periportal
fibrosis, no focal hepatic lesion.
3. Normal PV caliber with hepatopedal
blood flow.
4. Spleen surgically removed with
splenule at its bed.

6. CBC

13. Disease overview
The 2008 WHO classification of myeloid
neoplasms defines chronic
myelomonocytic leukemia (CMML) as a
clonal hematopoietic stem cell disorder
that is characterized by:
1. Presence of an absolute monocytosis
(>1 × 109/L) in the peripheral blood.
2. Presence of myelodysplastic and
myeloproliferative features in the
bone marrow.

14. Classification
 WHO created two separate categories
of CMML:
(a) CMML-1 (<5% peripheral blasts
including promonocytes and <10%
bone marrow blasts).
(b) CMML-2 (5–19% peripheral blasts
including promonocytes or 10–19%
bone marrow blasts including
promonocytes or presence of Auer
rods).

15. Epidemiology
 The incidence and prevalence of
CMML are unknown. Large population
based studies estimate CMML
constitutes ∼10% of all cases of MDS.
 Median age at diagnosis varies
between 65 and 75 years, and there is
a 2:1 male predominance.

16. Clinical manifestations
 The presenting symptoms of CMML are variable.
 Anemia, infection and bleeding are typical.
 Weight loss, night sweats, and abdominal discomfort
from splenomegaly may be the presenting
manifestations.
 Vast majority of patients are discovered incidentally
when a complete blood count is obtained for
unrelated reasons.
 Occasionally, skin infiltration with abnormal
monocytes (leukemia cutis) has been reported as the
initial manifestation.
 Some patients may directly present in the blastic
phase of CMML as acute myeloid leukemia (AML).

17. Diagnosis
 The diagnosis of CMML rests on a
combination of morphologic, histopathologic
and chromosomal abnormalities in the bone
marrow.
 It is important to exclude other
myeloproliferative neoplasms and
infectious/autoimmune conditions that can
cause monocytosis.
 Infectious etiologies such as tuberculosis,
chronic fungal infections, infective
endocarditis, viral, and protozoal infections;
connective tissue disorders such as
systemic lupus erythematosus and
sarcoidosis, and lipid storage disorders.

19. Diagnostic Features of Chronic
Myelomonocytic Leukemia
1. Peripheral blood monocytosis of >1 × 10
9
/L
2. No Philadelphia Chromosome or BCR-
ABL1 fusion gene
3. No rearrangement of the PDGFRA
or PDGFRB
4. Less than 20% blasts in the peripheral blood
and bone marrow
5. Dysplasia present in one or more myeloid
lineages.
If myelodysplasia is minimal or absent, CMML
can still be diagnosed if: an acquired, clonal
cytogenetic or molecular cytogenetic abnormality
is demonstrated in the hematopoietic stem cell
“OR” monocytosis has persisted for greater than

20. Dysplastic versus proliferative
CMML: phenotypic and
molecular differences
In a study in Mayo clinic :
 139 (53%) patients had proliferative
and 122 (47%) dysplastic subtypes.
 There was no difference between the
CMML subtypes in terms of age and
gender distribution, hemoglobin level,
platelet count or BM blast content.
 Patients with proliferative CMML had
higher absolute monocyte counts ,
circulating immature myeloid cells,
circulating blasts and serum LDH
levels.

21.  The following gene mutations were more
common in proliferative vs dysplastic
CMML: ASXL1 (54% vs 37%,
p=0.009), JAK2 (11% vs 3%, p=0.01)
and CBL (11% vs 8%,
p=0.047); SF3B1 mutations were more common
in dysplastic CMML (8% vs 1%, p=0.02).
 There was no difference in the incidence
of TET2, DNMT3A and SRSF2 mutations
 whereas there was a trend towards a higher
prevalence of NRAS (p=0.06)
and CSF3R (p=0.06) mutations in proliferative
CMML.
 Cytogenetic abnormalities (p=0.03), including
higher risk categories were more common in
proliferative CMML.

22. Flow cytometry
 Human monocytes can be divided into
three subsets: CD14+/CD16− (classical),
CD14+/CD16+(intermediate) and
CD14low/CD16+ (nonclassical), with
different gene expression profiles,
chemokine receptor expressions and
phagocytic activities. The classical
monocytes constitute majority of the
human monocytes (∼85%) in healthy
conditions.
 CMML patients demonstrate an increase
in the fraction of classical monocytes
(CD14+/CD16−) [cutoff value 94%]

23. Histopathology
 The bone marrow is generally hypercellular in
the vast majority of the patients.
 There is predominance of the granulocytic
lineage, with dysplasia being a defining feature
of the disease. There is also an increase in the
number of monocytes.
 Eosinophilia is not as striking in patients with
CMML as it is in CML.
 Erythropoiesis is generally decreased and there
may be accompanying abnormal nuclear
contours, ring sideroblasts, and megaloblastoid
changes in red cell precursors.
 Megakaryocytes are generally small and may
have hypolobulated nuclei. Bone marrow
fibrosis may be present in up to 30% of patients
with CMML.

24. Immuohistochemistry
 The peripheral blood and bone marrow
monocytes usually express CD33 and CD13,
the typical antigens on myelocytes. There
may be variable expression of CD68, CD14,
and CD64.
 Markers of aberrant expression include CD2,
CD15, CD56 and decreased expression of
CD14, CD13, HLA-DR, CD64, or CD36. The
presence of myeloblasts can be detected by
expression of CD34.
 The most reliable markers on
immunohistochemistry include CD68R and
CD163.

25. Chromosomal abnormalities
 Clonal cytogenetic abnormalities are seen
in ∼20–30% of CMML patients.
 Common alterations include; trisomy 8,—Y,
abnormalities of chromosome 7
(monosomy 7 and del7q), trisomy 21, and
complex karyotypes.
 The Spanish cytogenetic risk stratification
system categorizes patients in to three
groups; high risk (trisomy 8, chromosome 7
abnormalities, or complex karyotype),
intermediate risk (all chromosomal
abnormalities, except for those in the high
and low risk categories), and low risk
(normal karyotype or –Y).

26. Molecular abnormalities
 These can broadly be divided into the
following categories:
(a) mutations in epigenetic control of
transcription, such as histone modification
(EZH2, ASXL140%, UTX), DNA
methylation (TET2 60%, DNMT3A), or
both (IDH1, IDH2)
(b) mutations in the spliceosome machinery
(SF3B1, SRSF2 45%, U2AF1, ZRSR2)
(c) mutations in genes that regulate cytokine
signaling (JAK2, RAS 30%, CBL,
and FLT3)
(d) mutations in transcription factors and
nucleosome assembly

27. Risk stratification
 Several CMML-specific prognostic
models incorporating novel mutations
have been recently reported.

29. Risk-Adapted Therapy
 Guidelines for supportive care measures
such as the use of erythropoietin analogs
for the treatment of anemia, prophylactic
antibiotics for isolated neutropenia and
iron chelators for Patients with heavy
transfusion burdens.
 One of the earliest reported randomized
trials for CMML, Wattel et al. compared
1000 mg/day of oral hydroxyurea to 150
mg/week of oral etoposide in 105 patients
.After a median follow-up of 11 months,
60% of patients in the hydroxyurea arm
responded compared to 36% in the
etoposide arm. Median OS was

30. Hypomethylating agents
 Azacitidine is the only agent approved
for the treatment of CMML without any
myeloproliferative disorder by the
European Medicine agency (EMA).
The European registration trial
included 358 patients of whom 179
received azacitidine treatment.

31. Others
 A phase 1 study of lenalidomide in
patients with CMML. Ten Austrian
centers recruited 20 patients. Patients
received 5–15 mg lenalidomide daily,
with partial responses and stabilization
of the disease in about half of patients.
 A phase 1 trial of ruxolitinib showed
activity in patients with CMML,
particularly in those having
a myeloproliferative disease type

32. Allogeneic stem cell
transplantation
 Allogeneic stem cell transplantation (HCT)
remains the only curative option for patients
with CMML.
 In general, for younger patients with higher
risk disease and an acceptable co-morbidity
index, allogeneic HCT is the preferred
treatment modality .
 With the advent of reduced intensity
conditioning and alternate donor sources
(haploidentical HCT and double umbilical
cord blood units), an increasing number of
patients have access to HCT. While reduced
intensity conditioning is associated with lower
nonrelapse mortality, disease relapse rates
are higher in comparison to myeloablative
regimens