Chronic myeloid leukemia (CML) is a type of leukemia caused by the BCR-ABL1 fusion gene which results in uncontrolled proliferation of white blood cells. CML progresses through three phases: chronic phase, accelerated phase, and blast crisis. The chronic phase can last 5-6 years before progressing to more advanced phases. CML is diagnosed through blood tests and bone marrow biopsy to detect the Philadelphia chromosome and BCR-ABL1 fusion. Targeted therapy with tyrosine kinase inhibitors such as imatinib have significantly improved outcomes by inhibiting the BCR-ABL1 fusion protein. Resistance can still develop through additional genetic mutations.

1. CHRONIC MYELOID LEUKEMIA
DR. R. RAJKUMAR D.M.
CONSULTANT MEDICAL
ONCOLOGIST

2. Introduction
 CML is a clonal myeloproliferative neoplasm
 Dysregulated production and uncontrolled proliferation
of mature and maturing granulocyte with fairly normal
differentiation
 Fusion of 2 genes: BCR (or chromosome 22) and ABL1
(on chromosome 9), resulting in BCR-ABL1 fusion gene
 Final result: Abnormal chromosome 22 called
Philadelphia (Ph) chromosome
 Final product: BCR-ABL1 fusion protein, a dysregulated
tyrosine kinase

3.  Uncontrolled production of mature and maturing
granulocytes
 Predominantly neutrophils, but also basophils and
eosinophils
 Triphasic or biphasic clinical course
 Chronic phase, accelerated phase, blast crisis
Introduction

4. Phases of CML (before Imatinib)
Chronic phase
Median duration
5–6 years
Accelerated
phase
Median duration
6–9 months
Blast crisis
Median survival
3–6 months
Advanced phases

5. Epidemiology
 Annual incidence: 1 to 2 cases per 100,000
 15% – 20% of all adult leukemias
 Incidence increases significantly with age
– Median age: ~ 55 years
– Prevalence increasing due to current therapy
– Most patients present in CP, 85%
• Majority of CML-related deaths due to progression to AP/BC
– 50% of CML patients are asymptomatic at diagnosis
 Risk factors
– Exposure to ionizing radiation, the only known

6. Molecular Genetics of CML
 The Philadelphia chromosome was originally detected by
workers in Philadelphia.
 The first genetic abnormality to be associated with a
human cancer.
 The result of a balanced translocation between
chromosomes 9 and 22.
 Derivative chromosome 22 is significantly smaller
 Ph chromosome is present in hematopoietic cells from
patients with CML.
 Therefore, the Ph chromosome is acquired and NOT
inherited through the germline.

7. Molecular Genetics of CML
 The development of chronic phase CML appears to be a
direct result of the BCR-ABL1 activity, which promotes
its development by allowing:
I. Uncontrolled proliferation of transformed cells
II. Discordant maturation
III. Escape from apoptosis
IV. Altered interaction with the cellular Matrix
 The progression of CML from chronic phase to accelerated face or
blast crisis is a complex, multistep process (may be related to GMP).
 Also, it appears to involve the constitutive expression of the BCR-
ABL1 tyrosine kinase.

8. Molecular Genetics of CML
BCR
ABL
BCR
ABLBCR{q11
Ph
9q+
22
9
{q34 ABL

9. Philadelphia chromosome
t(9;22)(q34;q11)
22q- = Philadelphia chromosome

10. bcr-abl Gene and Fusion Protein Tyrosine Kinases
p210Bcr-Abl
p185Bcr-Abl2-11
2-11
Chromosome 9
c-bcr
Chromosome 22
c-abl
Exons
Introns
CML Breakpoints
ALL Breakpoints
1
2-11

11. Diagnosis of CML
 Typical findings in the blood and bone marrow
 Requires the detection of the Ph chromosomal or its
product, the BCR-ABL1 fusion mRNA and the BCR-ABL1
protein.
 Conventional cytogenetic analysis (karyotyping) – The first
method
 Florence and in situ hybridization (FISH) analysis
 RT-PCR (The BEST)
 Southern blot techniques – rarely used
 Western Blotting – low sensitivity and labor intensive

12. Accelerated Phase CML
 10-19% blasts in the peripheral blood or bone
marrow
 Peripheral blood basophils ≥20%
 Platelets < 100,000/microL, unrelated to therapy
 Platelets > 1,000,000/microL, unresponsive to
therapy
 Progressive splenomegaly and increasing WBC,
unresponsive to therapy
 Cytogenic evolution

13. Blastic Phase CML
 Blasts in the peripheral blood ≥20% or in the bone
marrow ≥30%
 Large foci or clusters of blasts on the bone marrow
biopsy
 Presence of extramedullary blastic infiltrate (e.g.,
myeloid sarcoma, also known as granulocytic
sarcoma or chloroma)
Blast crisis is generally refractory to treatment, occurs
approximately 3-5 years after the diagnosis of CML and
18 months after the onset of accelerated face

14. Prevalence of the Ph Chromosome
in Hematologic Malignancies
Leukemia % of Ph+ Patients
CML 95
ALL (Adult) 15–30
ALL (Pediatric) 5
AML 2
Faderl S et al. Oncology. 1999;13:169-180.

15. Normal Bcr-Abl Signaling*
• The kinase domain
activates a substrate
protein, eg, PI3
kinase, by
phosphorylation
• This activated
substrate initiates a
signaling cascade
culminating in cell
proliferation and
survival
PP P
ADP P
P
PP P
ATP
SIGNALING
Bcr-Abl
Substrate
Effector
ADP = adenosine diphosphate; ATP = adenosine triphosphate;
P = phosphate.
Savage and Antman. N Engl J Med. 2002;346:683
Scheijen and Griffin. Oncogene. 2002;21:3314.

16. Imatinib Mesylate:
Mechanism of Action*
• Imatinib mesylate
occupies the ATP
binding pocket of
the Abl kinase
domain
• This prevents
substrate
phosphorylation
and signaling
• A lack of signaling
inhibits proliferation
and survival
P
PP P
ATP
SIGNALING
Imatinib
mesylate
Bcr-Abl
Savage and Antman. N Engl J Med. 2002;346:683.

17. Typical Laboratory Parameters
by Phase of CML
Parameter Chronic Accelerated Blast Crisis
WBC count 20 x 109/L — —
Blasts 1%–09% 10-19% 20%
Basophils  20% —
Platelets  or normal  or  
Bone marrow Myeloid hyperplasia
Cytogenetics Ph+
Bcr-Abl + + +
Phase of CML
WBC = white blood cell; Ph+ = Ph chromosome–positive.

18. Molecular Methods for Detecting bcr-abl
at the Ph Chromosome
 Fluorescence in situ hybridization (FISH)
Interphase Metaphase
Courtesy of Charles Sawyers, UCLA.

19. 0%
10%
20%
30%
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60%
70%
80%
90%
100%
0 1 2 3 4 5
Years After Transplant
S
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0%
10%
20%
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40%
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70%
80%
90%
100%
S
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June 2001, based on transplants 1987 - Feb 2001
Chronic Myelogenous Leukemia
Survival by Disease Stage
First Chronic Phase (n=1903)
Accelerated and 2nd CP (n=744)
Blast Phase (n=159)
P=0.0001

20. Other Possible Mechanisms of
Resistance to Imatinib Mesylate
Mechanisms of resistance
 Ph+ cell lines
– Bcr-Abl overexpression
– Gene amplification
– Drug reflux mediated by P-glycoprotein
– Other
 In vivo murine model
– Binding in the plasma of alpha 1-acid
glycoprotein to imatinib mesylate

21. Evolution of Resistance to Imatinib Mesylate in CML
Chronic Phase Blast Crisis Relapse
Ph-positive
Ph-negative
Ph+ blasts
Ph+ imatinib-
resistant blasts
Hematopoietic
differentiation
Bonemarrowtoperipheralblood
Courtesy of Charles L. Sawyers, MD.

22. “MAJOR ROUTE” ACA
Trisomy8
AdditionalPh-chromosome
Isochromosome (17q)
Trisomy 19
“MINOR ROUTE” ACA
Chromosome 3 aberrations,
loss of the Y-chromosome,

23. Prevention of BC by more effective treatment in early CP as shown
by the cumulative incidence of blast crisis (German CML Study
Group experience 1983-2011).
7

24. Survival with BC in the preimatinib and imatinib eras.

25. MANAGEMENT ALGORITHM OF CML-BC.