Disease of older males. The Philadelphia chromosome - BCR-ABL gene and it’s Tyrosine kinase protein – central to the pathogenesis. Occurs in 3 phases Imatinib has revolutionized the management

1. CHRONIC
MYELOGENOUS
LEUKEMIA

2. Definition, History & Epidemiology
Etiology and Pathogenesis
Clinical Features
Diagnosis
Course and special clinical situations
Differential Diagnosis
Risk assessment and Therapy
2

3. The World Health Organization Classification
System for Myeloproliferative Neoplasms

4. DEFINITION
• Chronic myelogenous leukemia (CML) - pluripotential stem
cell disease characterized by
• Anemia
• Extreme blood granulocytosis and granulocytic immaturity
• Basophilia
• Thrombocytosis
• Splenomegaly
• Characteristic genetic change - Reciprocal translocation
between chromosomes 9 and 22 (Philadelphia (Ph)
chromosome)
4

5. HISTORY
• In 1845, Bennett in Scotland and Virchow in Germany
described splenic enlargement, severe anemia, and
leukocytosis at autopsy
• Virchow proposed the term leukämie
• In 1878, Neumann proposed – marrow origin for leukemia –
myelogene (myelogenus)
• Nowell and Hungerford in 1960 identified the culprit gene at
the Perelman School of Medicine, Philadelphia
• Dr. Rowley identified the BCR-ABL translocation
• 1998 – Discovery of targeted TKI therapy
5

6. EPIDEMIOLOGY
• CML - 15 %of all cases of Leukemia
• US Incidence ~ 2 per lakh persons for men and 1.1 per lakh
persons for women
• Sparse Indian data - 0.8–2.2/lakh in men and 0.6–1.6/lakh in
women
• 50-70% of leukemias in Indian adults
• Male predominance (1.4:1)
• Average age at presentation – 50 yrs
• Incidence is least in Swedes
6

7. EPIDEMIOLOGY
7

8. ETIOPATHOGENESIS
1. Environmental Leukemogens
• Very high doses of ionizing radiation*
• Chemical leukemogens - benzene and alkylating agents – are
not causative – increased incidence of AML
• No concordance of the disease between identical twins
• Several large studies – no links with smoking/diet/lifestyle
8

9. Etiopathogenesis
9
2. The stem cell

10. 2. The stem cell
Etiopathogenesis
10
CML Stem Cell

11. 2. The stem cell
• Acquisition of the BCR-ABL fusion gene in a single
multipotential hematopoietic cell  CML stem cell
• Majority of these cells would be in G0 phase of the cell cycle
• These BCR-ABL stem cells favor differentiation over self-
renewal
• Ph chromosome is found on myeloid, monocytic, erythroid,
megakaryocytic, B-cells and sometimes T-cell proof that CML
derived from pluripotent stem cell
Etiopathogenesis
11

12. 2. The stem cell
• The CML stem cells have
no regulation of
proliferation
• Mediated by IL3 – GCSF
autocrine loop
• Immature granulocytes
>> mature granulocytes
Etiopathogenesis
12

13. 3. BCR-ABL protein (Tyrosine Kinase)
• BCR (breakpoint cluster region) gene on chromosome 22
fused to the ABL (Ableson leukemia virus) gene on
chromosome 9
• The fusion protein derived from the BCR-ABL gene is a
tyrosine kinase enzyme
• This particular protein is seen in small amounts normally*
• The ABL gene  regulated tyrosine kinase
• BCR-ABL  unregulated tyrosine kinase
Etiopathogenesis
13

14. 3. BCR-ABL (Tyrosine Kinase)
Etiopathogenesis
14
Altered adhesion
• No adhesion to
marrow stroma
• Reduced regulation
by marrow factors
Mitogenic
activation
• Activation of various
pathways 
proliferation
Inhibition of
apoptosis
• Upregulation of Bcl-
2
• Uninhibited
proliferation

15. CLINICAL FEATURES
A. Symptoms
• At diagnosis – 70% symptomatic
• Easy fatigability
• Loss of sense of well-being
• Decreased tolerance to exertion
• Anorexia
• Abdominal discomfort
• Early satiety *
• Weight loss
• Excessive sweating
15

16. A. Symptoms
• Uncommon symptoms
• Night sweats
• Heat intolerance
• Gouty arthitis
• Left upper-quadrant and left shoulder pain*
• Urticaria
• Hyperleukocytic Syndrome —dyspnea, tachypnea, hypoxia,
lethargy, slurred speech
Clinical features
16
Mimics thyrotoxicosis

17. Clinical features
17
Acute febrile neutrophilic
dermatosis (Sweet syndrome)
A. Symptoms

18. B. Signs
• Pallor
• Splenomegaly
• Sternal tenderness
• Rarely hepatomegaly,
lymphadenopathy – Poor
prognostic indicators
Clinical features
18

19. DIAGNOSIS
A. Laboratory studies
Blood counts and blood smear
• Hemoglobin concentration - decreased
• Nucleated red cells in blood film
• Leukocyte count above 25,000/μl (> 1,00,000/μl)
• Hypersegmented neutrophils
• Basophil and eosinophil counts - increased (Absolute)
• The platelet count - normal or increased
• Blast cells ~ 3 % (<10% in the chronic phase)
19

20. A. Laboratory studies
Diagnosis
20
Peripheral smear

21. A. Laboratory studies
Diagnosis
21
Bone marrow
Hypercellular
Replacement of fat
Granulopoiesis
Megakaryocytopoiesis
Erythropoiesis

22. A. Laboratory studies
Bone Marrow studies
• Mitotic figures are increased
• Macrophages that mimic
Gaucher cells *
• Macrophages - engorged with
lipids - yield ceroid pigment -
imparting a granular and bluish
cast - sea-blue histiocytes
• Increased reticulin fibrosis
(Collagen type III) *
• Angiogenesis
Diagnosis
22

23. A. Laboratory studies
Other lab features :
• Neutrophil Alkaline Phosphatase reduced
• Serum B12 and transcobalamin increased (>10 ULN)
• Serum uric acid increased
• Lactate dehydrogenase increased
• Mean histamine levels increased
Diagnosis
23

24. B. Cytogenetics
• Study of the number and structure of chromosomes
• Samples from bone marrow myeloid cells
• The presence of the Philadelphia chromosome – shortened
chromosome 22*
• Cytogenetics cannot identify complex translocations
Diagnosis
24

25. B. Cytogenetics
Diagnosis
25
90%

26. C. Molecular Probes
i. FISH (Fluorescence In Situ Hybridization)
• Detect the BCR-ABL fusion gene on chromosome 22
• Qualitative
Diagnosis
26

27. C. Molecular Probes
ii. PCR (Polymerase Chain Reaction)
• Most sensitive test to identify and measure the BCR-ABL gene
(Quantitative)
• Can be performed on blood/marrow cells
• Amplifies the BCR-ABL derived abnormal mRNA
• One abnormal cell in one million cells can be detected
Diagnosis
27

28. COURSE OF THE DISEASE
• CML has 3 phases
28
I. Chronic Phase
• Most patients are asymptomatic
• Incidental leukocytosis/splenomegaly
• Bleeding and infectious complications are uncommon in the
chronic phase

29. II. Accelerated phase
defined by
• 10%–19% blasts in blood or bone marrow
• >20% basophils in blood or bone marrow
• Thrombocytosis, thrombocytopenia unrelated to therapy (<1
lakh or >10 lakh)
• New clonal chromosome abnormalities
• Anemia progresses and cause fatigue, loss of sense of well-
being
• Splenomegaly
• Ranges from 4-5 years before progressing
Course of the disease
29

30. III. Blast Crisis
defined by
• ≥20% blasts in blood or bone marrow
• Extramedullary blastic infiltration (Chloroma)
• Resembles acute leukemia
• 2/3 transform to myeloid blastic phase and 1/3 to lymphoid blastic
phase
• Infection and bleeding common
• Abdominal pain, bone pain
• Survival is 6-12 months (worse for myeloid phenotype)
Course of the disease
30

31. Special Clinical situations
Neutrophilic CML
• A rare variant of BCR-ABL–positive CML – leukocytosis
principally of mature neutrophils
• WBC count lower than that of classic CML
• Basophilia, myeloid immaturity in the blood, prominent
splenomegaly, or low leukocyte alkaline phosphatase scores –
all absent!
• Larger fusion protein than in classic CML
• Usually has an indolent course
• Now classified separately
Course of the disease
31

32. Special Clinical situations
Hyperleukocytosis (15% of cases)
• Intravascular flow-impeding effects of white cell counts greater
than 3,00,000/µL (upto 8 lakh)
• Impaired circulation of the lung, central nervous system,
special sensory organs, and penis
• resulting in some combination of
• Tachypnea, dyspnea, cyanosis,
• Dizziness, slurred speech, delirium, stupor,
• Visual blurring, diplopia, retinal vein distention, retinal
hemorrhages, papilledema,
• Tinnitus, impaired hearing,
• And priapism
Course of the disease
32

33. Special Clinical situations
Concurrence of Lymphoid Malignancies
1. CML - years after irradiation of non-Hodgkin or Hodgkin
lymphoma
2. Accelerated phase  dedifferentiation of the CML clone 
acute lymphoblastic transformation
3. Plasmacytic malignancies – positive association
4. Patients may present with Ph+ ALL, after chemotherapy-
induced remission, develop features of typical CML
Course of the disease
33

34. DIFFERENTIAL DIAGNOSIS
• Polycythemia vera
• Essential thrombocythemia
• Primary myelofibrosis
• Leukemoid reactions
34

35. RISK ASSESSMENT
• 3 scores
1. Sokal score - 1984
2. Euro (Hasford) score – 1998
3. European Treatment and Outcome Study (EUTOS) –
2011
35

36. 1. Sokal score
• Age
• Spleen size
• Platelet count
• Peripheral blood blast percentage
• Was used in busulphan or hydroxyurea based therapy
• Low risk - <0.8
• Intermediate risk – 0.8 – 1.2
• High risk - >1.2
Risk assessment
36

37. 2. Hasford score
• Age
• Spleen size
• Platelets
• Blast cell percentage
• Eosinophil percentage
• Was used in interferon based therapy
• Low risk - <780
• Intermediate - 780-1480
• High risk >1480
Risk assessment
37

38. 3. The European Treatment and Outcome Study
(EUTOS) risk score
• Low risk - <87
• High risk - >87
• Also proposed a formula for predicting probability of
no CCyR at 18 months
• Presently used – ‘Imatinib era’
Risk assessment
38
(7 x basophil [%]) + (4 x spleen size)

39. TREATMENT
1. Initial Cytoreduction Therapy
2. Tyrosine Kinase Inhibitor Therapy
3. Interferon therapy
4. Chemotherapy
5. Allogeneic Stem Cell Transplantation
6. Treatment of accelerated/blast phases
7. Treatment of CML in pregnancy
8. Treatment cessation
39

40. 1. Initial therapy
• Allopurinol 300 mg/day orally with adequate hydration 
Rasburicase 0.2 mg/kg i.v (one doses) for Hyperuricemia*
• Leukapheresis – helps reduce leucocyte burden, only in
conjunction with definitive therapy
• Hydroxyurea - Reversible suppression of hematopoiesis
1 to 6 g/day orally (titre based on counts)
• Anagrelide – to reduce the platelet burden
Treatment
40

41. 2. Tyrosine Kinase inhibitor therapy
Treatment
41
First generation Second generation
Imatinib
Dasatinib
Nilotinib
Bosutinib
Ponatinib
Bafetinib

42. 2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
• Approved for use in Ph+ CML in 2001
• Preliminary studies showed a remarkable cytogenic
remission
• Hematological remission was seen in 95%
• Now the treatment of choice for CML
Treatment
42

43. 2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
43

44. 2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
• Dosage –400 mg/day orally  400 mg BD
• Well tolerated
• Myelosuppression is common in CML patients
• Elevated hepatic transaminases (Acute liver failure described)
• Periorbital edema
• Cutaneous reactions
• Osteoporosis
Treatment
44

45. 2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
45

46. 2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
46
90-96%

47. 2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
47
~63%

48. 2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
48
National Comprehensive Cancer Network

49. 2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Treatment
49
European Leukemia Net

50. 2. Tyrosine Kinase inhibitor therapy
Imatinib Mesylate
Four mechanisms of resistance
(1) Gene amplification
(2) Mutations at the kinase site
(3) Enhanced expression of multidrug exporter proteins
(4) Alternative signaling pathways compensating imatinib-
sensitive mechanisms.
Treatment
50

51. 2. Tyrosine Kinase inhibitor therapy
2nd Generation TKI
1. Dasatinib
• Used in imatinib resistance or intolerance
• 325-fold more potent than imatinib
• 100 mg/day, administered in chronic phase CML
• Unlike imatinib, dasatinib penetrates the blood–brain barrier
• Cytopenia, followed by fluid retention, diarrhea, and skin rash
Treatment
51

52. 2. Tyrosine Kinase inhibitor therapy
2nd Generation TKI
2. Nilotinib
• Used in imatinib resistance or intolerance
• 30 times more potent than imatinib
• ATP-competitive inhibitor of BCR-ABL
• 400 mg every 12 hours
• Neutropenia, hyperbilirubinemia, hypophosphatemia, QT
interval prolongation
• Imatinib and nilotinib in combination may have additive or
synergistic effects
Treatment
52

53. 3. Interferon α
• IFNα was the initial therapy before TKI therapy
• Complete cytogenetic response – uncommon (13%)
• 50% responders – long term survival
• 3-5 million units/m2 five times per week
• Neurotoxicity, thrombocytopenia, fatigue, and liver
dysfunction  dose limiting effects
• Single dose of 450 µg pegylated IFNα – comparable
• IFNα was combined with Cytarabine
• Some patients intolerant to a Imatinib may be treated
successfully with INFα
Treatment
53

54. 4. Chemotherapeutic Agents and other modalities
i. Cytarabine
• IFNα combined with cytarabine (20 mg/m2/day -10 days
per month  better than IFN alone
• Replaced by TKI
ii. Busulfan
• Once the mainstay of treatment – now almost never used
• Use limited to the preparative regimen for allografting or
autografting
Treatment
54

55. 4. Chemotherapeutic Agents and other modalities
iii. Splenectomy*
• Delay the onset of the accelerated phase
• Enhance sensitivity to chemotherapy
• Prolong survival of patients
• But, does not prolong the chronic phase
iv. Radiotherapy
• Splenic irradiation - extreme splenomegaly with splenic
pain, perisplenitis
• may be useful for extramedullary tumors (bone/soft tissue)
Treatment
55

56. 4. Chemotherapeutic Agents and other modalities
v. Omacetaxine (formerly Homoharringtonine)
• Protein translation inhibitor
• Still in Phase 2 trials
• Showed promise in TKI intolerant/resistant cases
• 18% major cytogenetic response in TKI failed cases
vi. Experimental
• Lonafarnib and tipifarnib
• Berbamine
• Adaphostin
• Third-generation TKIs
Treatment
56

57. 5. Allogeneic Stem Cell Transplantation
• Allogeneic HSCT - complicated by mortality owing to the
procedure
(1) The patient
(2) The type of donor
(3) The preparative regimen (myeloablative or reduced-
intensity)
(4) Graft versus Host Disease
(5) Post-transplantation treatment
Treatment
57

58. 6. Treatment of accelerated/blast phases
• Goal  achieve remission
• Else aim to reduce to chronic phase
• TKI – bridging therapy to permit allogenic SCT
• Dasatinib and nilotinib achieve better molecular remission in
accelerated phase
• Imatinib+mitoxantrone+etoposide
• Imatinib+cytarabine
• Ultimately – Stem cell transplant
Treatment
58
Blast crisis

59. 7. Treatment of CML in pregnancy
• Untreated CML  placental insufficiency (leukostasis)
• Risk of teratogenicity with Imatinib
• IFN is safe – can be used
• Leukapheresis – 1st trimester
• Hydroxyurea – 2nd and 3rd trimester
• Restart TKI therapy soon after delivery
Treatment
59

60. 8. Treatment cessation
• Despite achieving deep and lasting remissions
• CML is not curable
• Patients with remissions - have residual CML cells (PCR)
• Evidence suggests - people who receive TKIs may remain in
remission for very long periods
• Research still underway
Treatment
60

61. 61
Treatment

62. CONCLUSION
• Disease of older males
• The Philadelphia chromosome  BCR-ABL gene and it’s
Tyrosine kinase protein – central to the pathogenesis
• Occurs in 3 phases
• Most patients in the chronic phase - asymptomatic
62

63. CONCLUSION
• Imatinib has revolutionized the management of CML
• Long term survival is a reality now
• TKI therapy is still not curative
• 3rd generation TKI and newer drugs in the pipeline show
some promise at achieving a possible cure
63