Chronic Myeloid Leukaemia

1. CHRONIC MYELOID
LEUKEMIA
Dr.A.MEENAKSHI
PROF.S.TITO’S UNIT.
M4

2. Definition
•Chronic myelogenous leukemia is a pluripotent
stem cell disease characterized by
anaemia,extreme blood granulocytosis with
immaturity ,basophilia,thrombocytosis and
splenomegaly.
•The haemtopoietic cell contain a reciprocal
translocation between chromosome 9 and 22
.known as the philadelphia chromosome.
•Occurs more often in men.
•Disease of firsts.
•High doses of ionising radiation can increase the
occurrence of CML.

4. Pathophysiology
•Genetic hallmark of CML is the presence of
BCR-ABLfusion gene product.
•The fusion protein is a result of reciprocal
translocation between the abelson oncogene on
chromosome 9 and break point cluster region on
chromosome 22.
•Fusion genes are generated that encode
190,210,or 230 kda forms of the BCR-ABL
tyrosine kinase.
Other genetic abnormalities
•Trisomy 8,p53 loss.
•Interleukin 1 b involved in the progression of
CML to the blastic phase.

5. Clinical presentation
Symptoms
•Fatigue,malaise
•Weight loss
•Early satiety
•Left upper quadrant pain or mass
•Easy bruising ,bleeding
•Fever
Uncommon presentation
•Acute gouty arthritis,priapism,myocardial
infarction,venous thrombosis,visual
disturbances,sweet syndrome..

6. Signs
•pallor
•Splenomegaly
•Sternal tenderness
•Lymhadenopathy
•Hepatomegaly
•Purpura
•Retinal haemorrhage

7. Diagnostic approach to CML
Peripheral blood
•Granulocytic leukocytosis>50*10p9/l
•Predominance of neutrophils and increased %of
myelocytes.
•Absolute basophilia.
•Platelets are normal or increased in number.
Bone marrow
•Marrow is hypercellular with granulocytic
predominance.
•Megakaryocytes are increased in number with
abnormal morphology.
•Increase in reticulin fibrosis.
•Blasts less than 5%.

8. PERIPHERAL SMEAR PICTURE
Band
forms

9. Band
forms
promyelo
cyte
myelocyte
metam
yelocy
te

10. BONE MARROW PICTURE
megakar
yocyte

11. diagnosis of accelarated phase
•Blasts 10-20% in peripheral blood and or
bone marrow.
•Basophils >20% in peripheral blood.
•Persistent thrombocytopenia.
•Increasing spleen size and white blood
count despite therapy.
•Cytogenetic evidence of clonal evolution.

12. ACCELERATED PHASE
MYELOB
LAST

13. Blast crisis phase
•Blast > 20%
•Extramedullary blast proliferation.
•Large aggregates or clusters of blast in
bone marrow.

14. BLAST CRISIS PHASE
MYELOBL
AST

15. Other abnormalities
There is increase in
•uric acid level
•vitamin B12 level.
•lactate dehydrogenase.
•Increase in the level of angiogenic factors.
•Decrease level of leukocyte alkaline
phosphatase.
•Increase in histamine levels.

16. •Identification of philadelphia chromosome
•Can be done by conventional cytogenetic
karyotyping,FISH,RT-PCR.
Conventional cytogenetics
•Entire chromosomal complement is
evaluated to identify philadelphia
chromosome and other abnormalities.
•Can be done on both peripheral blood and
bone marrow.
Disadvantage
•Presence of cryptic or submicroscopic
BCR-ABL arrangement cannot be
identified

17. Fluorescent insitu hybridisation
Advantage
•Fast results,greater sensitivity than
conventional cytogenetics.
•Submicroscopic or cryptic molecular
alteration can be detected.
Reverse transciptase-PCR
•Detects different length products
corresponding to chimeric BCR-ABL
proteins of 190,210 and 230 kda.
•So helps in distinguishing CML from ALL.

18. Fluorescent insitu hybridisation

19. Prognostic factors
Sokal index
•Percentage of circulating blast,spleen
size,platelet count,age and cytogenetic clonal
evolution.
•Was developed based on chemotherapy treated
patients.
Hassford system
•Developed on interferon alpha treated patients.
•Includes% of circulating blast,spleen
size,platelet count,age,% of eosinophils and
basophils.

20. Treatment
•Drugs
•Stem cell transplant.
•Leukaphresis and splenectomy.
drugs
•Imatinib mesylate,dasatinib,nilotinib
•Hydroxyurea
•busulphan
•Interferon-alpha
•Homoharringtonine
•Anagrelide.
•Cytarabin.

21. Imatinib
•It is an ABL specific tyrosine kinase
inhibitor.
•Imatinib induces apoptosis in cells
expressing BCR/ABL.
•Dose is 400mg/day.
•It should achieve cytogenetic remission
by 6months and molecular remission by
18 months.
•Side effects-edema,pleural and pericardial
effusion,nausea,vomiting,diarrhoea,muscl
e cramps,skin rash,bone pain and
arthralgia.myelosuppression.

23. Criteria for Extent of Imatinib Treatment
Hematologic response -White cell count
<10x109(platelet count <450 x 109/L, no immature
myeloid cells in the blood, and disappearance of all signs
and symptoms related to leukemia (including palpable
splenomegaly) lasting for at least 4 weeks.
•
Major cytogenetic response-Less than 35% of cells
containing the Ph chromosome by cytogenetic analysis
of marrow cells.
•Complete cytogenetic response-No cells containing the
Ph chromosome by cytogenetic analysis of marrow cells.
•Major molecular response-Blood cell BCR-ABL ratio
<0.05% (3-log reduction in PCR signal from mean
pretreatment baseline value)
•.Complete molecular response-Blood cell BCR-ABL
levels undetectable (usually by nested RT-PCR method).

24. Guidelines for response to imatinib
treatment
MMRCcyRnoCcyR18
CcyRMcyRnoMCYR12
McyRmcyRNo mcyR6
CHRpHRNoHR3
Optimal
response
Suboptimal
response
unsatisfact
ory
Time of
observation

30. Newer tyrosine kinase inhibitors
Dasatinib
•Structurally unrelated to imatinib binds to
the ABL kinase domain.
•Side effect-myelosuppression,pleural
effusion,prolongation of QT interval.
Nilotinib
•Structural derivative of imatinib binds to
ABL kinase domain.
•Side effects-rashes,transient elevation of
indirect bilirubin levels and
myelosuppression.

31. Hydroxy urea
•Inhibitor of ribonucleotide reductase.
•Lower the blood counts in 1-2 days.
•Dose is 500-3000 mg/day.
•Side effect-nausea and skin rash.
•Given for patients intolerant to imatinib.
Busulphan
•Gradually lowers the blood counts.
•Dose-6-10 mg/day.
•Should not be used in patients expected
to undergo bonemarrow transplantation.

32. Interferon alpha
•Causes complete haemotologic response
in >70% of patients.
•Dose is 5 million units daily by
subcutaneous administration.
•Hasford score was developed to predict
the survival of patients treated with
interferon alpha.
Homoharringtonine
•it is a plant alkaloid causes cytogenetic
response in patients in late chronic phase.

33. Anagrelide
•It is used for treating elevated platelet
count in CML.especially in presence of
thrombosis and bleeding
Leukapheresis
•Control CMLonly temporarily.
•Used in hyperleucocytic patients where
rapid cytoreduction can reverse the
symptoms.
•Pregnant patient with CML can be
controlled by leukaphresis.

34. Allogenic stem cell transplant
•Outcome depends on patients age,phaseof
disease,type of donor,preparative regimen,graft
vs host disease,post transplantation treatment.
•Patients age should be less than 70
years.transplantation from donor should be HLA
matched.
•Peripheral blood can be used a source of
haemotopoietic progenitor cells.preoperative
regimen like cyclophosphamideplus total body
irradiationis used.
•Complications-graft vs host disease.

35. Differential diagnosis
•Chronic myelomonocytic leukemia
•Juvenile myelomonocytic leukemia
•Chronic neutophilic leukemia
•Atypical CML
•Diseases associated with
hypereosinophilia.

36. Chronic myelomonocytic leukemia
•Anemia, monocytosis >1000/l; blood blasts <10%;
increased plasma and urine lysozyme; BCR
rearrangement absent; uncommon cases with PDGFR-
mutation respond to imatinib.
•Chronic eosinophilic leukemia
•Blood eosinophil count >1500/l; cardiac and neurologic
manifestations common; a proportion of cases have
PDGFR- mutations and are responsive to imatinib
mesylate.
Chronic monocytic leukemia
•Proportion of monocytes elevated; very rare form of
leukemia.
Juvenile myelomonocytic leukemia
•Infants and children <4 years; eczematoid or
maculopapular rash; anemia and thrombocytopenia;
increased HgF in 70% of cases; neurofibromatosis in
10% of cases; BCR rearrangement absent .