Chronic myelogenous leukemia ( CML ) Tests to be done in order to differentiate CML from other dieases with common clinical features. It's pathogenesis, clinical presentation and features of diagnostic tests. Methods of treatment. Prognosis of a disease according to "Sokal" score

1. Unexplained leukocytosis in an
adult
Tural Abdullayev

2. History

3. Patient presentation
• 50 year old man
• 2 month history of fatigue and early satiety
• No evidence of acute or chronic infections or
inflammatory conditions that might lead to
reactive granulocytosis and thrombocytosis.

4. Complete Blood Count
• WBC – 75,000/µL (normal range: 4,000-10,000/µL)
• Hgb – 14 g/dL (normal range: 14-16.5 g/dL)
• Hct – 42% (normal range: 42%-50%)
• MCV – 88 fl (normal range: 80-96 fl)
• Platelets – 550,000/µL (normal range: 150,000-400,000/µL)
Differential
• Segmented neutrophils (granulocytes) –33,000/µL (normal range: 1,800-
7,000/µL)
• Bands – 1,500/µL (normal range: 0-700/µL)
• Metamyelocytes –11,000/µL (normal: 0)
• Myelocytes – 7500/µL (normal: 0)
• Basophils – 3,750/µL (normal range: 0-200/µL)
• Lymphocytes – 3,000/µL (normal range 1,000-4,800/µL)
• Monocytes – 750/µL (normal range 0-800/µL)

5. Complete Blood Count
• Based on CBC results:
1. Leukocytosis – ↑ WBC
2. Granulocytosis – ↑ neutrophils
3. Thrombocytosis – ↑ platelets
4. No evidence of Anemia – Normal Hb, Hct, MCV
5. Basophilia – ↑ basophils

6. Physical Examination

7. Physical Examination
• Afebrile
• Head, ears, eyes, nose, throat
– Anicteric (absence of jaundice)
• No lymphadenopathy
• Lungs
– Clear
– No pulmonary signs of infection or malignancy
• Heart
– No murmurs
• Abdomen
– No signs of ascites
– Liver edge is not palpable
– Spleen edge is palpable 4 cm below the left costal margin (Slenomegaly)
• Skin
– No petechiae
– No ecchymoses
– No spider angiomata
• Neurologic exam
– Normal

8. Findings that help to rule out reactive
causes of neutrophilia and
thrombocytosis
1. Afebrile
– Indicates that there is no evidence of
inflammation
2. No lymphadenopathy

9. Splenomegaly
• Possible causes
1. Endothelial or immune system hyperplasia from infections, immune disorders or chronic
hemolysis
2. Infections associated with splenomegaly:
 Bacterial endocarditis
 Malaria
 Schistosomiasis
 TB
3. Immune disorders associated with splenomegaly:
 SLE
 RA
4. Chronic hemolysis associated with splenomegaly:
 Hereditary: thalassemias, spherocytosis, hemoglobin SC disease (note that young children with
sickle cell disease will have splenomegaly, but recurrent infarctions ultimately result in necrosis,
fibrosis and functional asplenia)
 Acquired: autoimmune hemolytic anemia
5. Altered splenic blood flow: cirrhosis; splenic, hepatic or portal vein thrombosis
6. Primary or metastatic malignancies: lymphoma, Hodgkin's disease, chronic lymphocytic
leukemia
7. As a result of extramedullary hematopoiesis (myeloproliferative disorders)
8. Infiltration: amyloid, Gaucher's disease

10. Laboratory Data
• Laboratory and diagnostic studies would be helpful in making a diagnosis
1. Evaluation of peripheral smear
 Help to differentiate CML from leukocytosis of other etiology
 In case of CML, a complete spectrum of myeloid cells is seen in the peripheral blood.
The levels of neutrophils and myelocytes exceed those of blast cells and
promyelocytes
2. Chest X-ray
 In case of suspicion of reactive thrombocytosis and granulocytosis secondary to
infection or to a solid tumor
3. Iron studies
 In case of suspicion of Polycythemia vera
4. Serial stool testing for occult blood – Guaiac tests
 In case of suspicion of reactive thrombocytosis and granulocytosis secondary to a solid
tumor
5. Uric acid
 In CML serum uric acid is usually raised

11. Differential Diagnosis

12. Differential diagnosis
1. Acute myelogenous leukemia
2. Polycythemia vera
3. Essential thrombocythemia
4. Chronic myelogenous leukemia
5. Chronic myelomonocytic leukemia
6. Reactive thrombocytosis and granulocytosis
secondary to infection
7. Reactive thrombocytosis and granulocytosis
secondary to a solid tumor

13. Acute myelogenous leukemia (AML)
• INCORRECT
– Although AML frequently presents with an elevated
total WBC count, the white blood cells are immature
blast forms. This is due to maturation arrest, which is
part of the pathophysiology of acute leukemia.
– Additionally, in acute leukemia, mature white blood
cells such as bands and neutrophils (granulocytes) are
decreased
– Patients with acute leukemia usually have
thrombocytopenia (a decreased platelet count)
– Patients with acute leukemia are typically acutely ill
with fever, anemia, and signs of bleeding.

14. Polycythemia vera
• UNLIKELY
– Polycythemia vera may be associated with the constitutional
symptoms described as well as with splenomegaly, granulocytosis,
basophilia and thrombocytosis.
– However, one of its defining features, an elevated Hct, is not present in
this patient.
– Sometimes, with profound iron deficiency, the hematocrit may not be
elevated. Iron studies would indicate iron deficiency (low serum iron,
elevated total iron binding capacity) and the MCV would be decreased.
This patient has normal iron studies and a normal MCV.
– Mutations in JAK2, a tyrosine kinase involved in the physiology of the
bone marrow response to erythropoietin and in cell proliferation, have
recently been identified in more than 95% of patients with
polycythemia vera (but not in patients with secondary
erythrocytosis).

15. Essential thrombocythemia
• Unlikely
– The prominent feature of essential thrombocythemia is
thrombocytosis
– Granulocytosis and splenomegaly are seen in about 50% of
patients, but there is not typically a marked left shift in the
granulocyte differential, as seen in this patient
– Basophils may be mildly increased
– Mutations in JAK2, a tyrosine kinase involved in the
physiology of the bone marrow response to erythropoietin
and in cell proliferation, have been identified in about 50%
of patients with essential thrombocythemia.

16. Chronic myelogenous leukemia
• Correct! This is the most likely diagnosis
– CML is characterized by granulocytosis with a left
shift, basophilia, thrombocytosis and splenomegaly
– Increasingly patients are being diagnosed while
asymptomatic, on the basis of an elevated WBC count
detected on routine screening
– However, symptoms including fatigue and night
sweats may be seen, secondary to the increased
metabolic state
– Early satiety may occur as a result of splenomegaly.

17. Chronic myelomonocytic leukemia
• Unlikely
– Patients with chronic myelomonocytic leukemia (CMMoL) can
have features of both myelodysplastic and myeloproliferative
disorders
– Although patients with CMMoL may have leukocytosis and
splenomegaly, they are usually older at diagnosis (median age
73) than patients with the classic myeloproliferative disorders,
and they are often symptomatic (weight loss, night sweats)
– By the World Health Organization definition, patients with
CMMoL have a peripheral blood monocytosis (>1,000/µL)
– In contrast to classic myeloproliferative disorders, however,
patients with CMMoL usually have anemia and
thrombocytopenia, secondary to dysplastic and ineffective
hematopoiesis.

18. Reactive thrombocytosis and
granulocytosis secondary to infection
• Unlikely
– The absence of fever, CXR abnormalities (Tb), and
cardiac murmur (endocarditis) makes infection
unlikely
– Patients with reactive thrombocytosis and
granulocytosis secondary to infection would likely
be more ill appearing.

19. Reactive thrombocytosis and
granulocytosis secondary to a solid
tumor
• Unlikely
– The absence of weight loss, cachexia, CXR
abnormalities, gastrointestinal bleeding, and
lymphadenopathy makes a solid tumor unlikely.

20. Diagnostic tests to perform to
make a diagnosis

21. Bone marrow aspiration and biopsy
– Done to evaluate the karyotype as well as
cellularity (usually increased) and extend of
myelofibrosis
– During accelerated phase of disease melofibrosis
may develop and sideroblasts may be seen on
microscopy

22. Bone marrow quantitative
polymerase chain reaction (qPCR)
analysis for BCR-ABL gene
• Presence of the BCR‐ABL1 gene fusion by RT‐PCR analysis and
in 98% of cases Ph chromosome on cytogenetic analysis

23. JAK2 mutation analysis
• The normal JAK2 gene, located on the short arm of chromosome 9
• Is a kinase involved in intracellular signaling following exposure of
hematopoietic cells to cytokines (hematopoietic growth factors
such as erythropoietin, thrombopoietin and granulocyte-
macrophage colony stimulating factor)
• One common mutation in this gene is the result of a single amino
acid substitution of valine to phenylalanine at position 617 (JAK2
V617F).
• The mutated gene may be involved in the pathogenesis of
myeloproliferative disorders by conferring a proliferative and
survival advantage to hematopoietic cells and by making these cells
hypersensitive to the effect of cytokines

24. Flow cytometry of peripheral blood
• Leucocytosis is the main feature and may reach levels greater
than 200× 109 /L (Fig. 14.2). A complete spectrum of myeloid
cells is seen in the peripheral blood. The levels of neutrophils
and myelocytes exceed those of blast cells and promyelocytes

25. Clinical features of the myeloproliferative
disorders and reactive granulocytosis and
thrombocytosis
Disorders RBC WBC PLTS Bone
Marrow
Fibrosis
Spleno
megaly
JAK2
mutation
Ph1
Polycythemia vera Granulocytosis
+/- + 95% -
Essential
thrombocythemia
NI Granulocytosis +/- + 50% -
CML NI Granulocytosis
+/- + - +
Primary
myelofibrosis
Neutropenia +++ ++ 50% -
CMMoL Monocytosis
+/- + - -
Reactive
granulocytosis
NI Granulocytosis NI/ - - - -
Reactive
thrombocytosis
NI NI/
Granulocytosis - - - -

26. Pathophysiology

27. Pathogenesis of CML
• The disease accounts for around 15% of leukaemias and may occur at any
age
• The diagnosis of CML is rarely difficult and is assisted by the characteristic
presence of the Philadelphia (Ph) chromosome
• Philadelphia (Ph) chromosome results from the t(9;22) (q34;q11)
translocation between chromosomes 9 and 22, as a result of which part of
the oncogene ABL1 is moved to the BCR gene on chromosome 22 and part
of chromosome 22 moves to chromosome 9.

28. Pathogenesis of CML
• The abnormal chromosome 22 is the Ph chromosome
• In the Ph translocation 5′ exons of BCR are fused to the 3′ exons of
ABL1
• The resulting chimeric BCR‐ABL1 gene codes for a fusion protein of
size 210kDa (p210)
• This has tyrosine kinase activity in excess of the normal 145‐kDa
ABL1 product
• The Ph translocation is also seen in a minority of cases of acute
lymphoblastic leukaemia (ALL) and in some of these the breakpoint
in BCR occurs in the same region as in CML
• However, in other cases the breakpoint in BCR is further upstream,
in the intron between the first and second exons, leaving only the
first BCR exon intact
• This chimeric BCR‐ ABL1 gene is expressed as a p190 protein which,
like p210, has enhanced tyrosine kinase activity

29. Prognosis and Clinical course

30. Prognosis
• Attempts have been made to stage CML at
presentation in order to predict prognosis. The
most frequently used is the Sokal score, which
takes account of age, blast cell percentage,
spleen size and platelet count. However the
rate of response to a tyrosine kinase inhibitor
is now a more useful measure

31. Sokal score
• Age
• Spleen size ( cm below costal
margin )
• Platelet count
• Platelet count (x 109/L)
• Peripheral blood blasts (% of
leukocytes)
• Peripheral blood eosinophils (%
of leukocytes)
• Peripheral blood basophils (% of
leukocytes)

32. Treatment
• Tyrosine kinase inhibitors
1. Imatinib
2. Nilotinib
3. Dasatinib
4. Bosutinib
5. Ponatinib
• Allogenic stem cell transplantation – for patients reflactory to
frontline therapy
• Splenic radiation – in reflactorycases or in terminal patients with
marked splenomegaly
• Splenectomy – when irradiation/chemotherapy aren’t effective

33. Imatinib + Chemotherapy
• Stage 1
– Imatinib 400mg x 1/d
– If no effect : interferon–α 3 mln IU x 3/week +
hydroxyurea 1 – 2g x 1/d
• Stage 2
– Imatinib 600 – 800mg x 1/d
– Or more aggressive chemotherapy with : Daunorubicin +
Cytarabine
– For older patients: less aggressive chemotherapy with
hyproxyurea + interferon–α
• Stage 3
– Treated like acute leukemia