CML
9
9q+
22
Ph
22q-
Translocation
ABL
BCR
ABL
BCR
Transcription and translation
BCR-ABL fusion
protein
Inhibition by
TKI
Constitutive tyrosine kinase
Phosphorylation of multiple substrates
Mitogenic signaling and genomic instability increased
Apoptosis and stromal regulation decreased
CML
 Stem cell disorder
 Characterized by
myeloproliferation
 Well-described
clinical course
*Clonal myeloproliferative disorder resulting
from neoplastic transformation of pluripotent
stem cells (affect myeloid, erythroid &
megakaryocytic lineages)
* proliferation,  apoptosis
*Cytogenetic hallmark: Ph chromosome positivity
*7% to 15% of all adult leukemias (5th leukemia
in USA)
*Median age at diagnosis: 55 years (20% to 30%
of patients ≥ 60 years)
*Fatal disorder with poor prognosis
*Median survival: 3-5 years (2 years without
treatment)
*Allogeneic SCT curative in 40% to 70% of
patients (Associated with mortality and
toxicity)
*Interferon alfa ± cytarabine: CCyR of 20% to
30%
Median survival: 6-7 years
Also associated with adverse events
*Other options: hydroxyurea, busulfan
* The exact cause is not found
* Pathogenesis is well established with
consequences on treatment & prognosis
*Possible association with ionizing radiation &
exposure to industrial benzene
Asymptomatic – accidentally discovered on routine
CBC
Anemia – easy fatigability, malaise, shortness of
breath, chest pain, palpitation
High metabolic rate - weight loss, fever
Lt hypochondrial discomfort, easy satiety
Bleeding- skin ecchymoses, bruises, petechiae
UGI ulceration & bleeding (↑ s histamine due to
basophilia)
Thrombosis – thrombocytosis, leukocytosis
Headache, bone pain, gouty arthritis, leukostasis,
priapism
Pallor, cutaneous bleeding, splenomegaly (one of the
largest spleens)
No lymphadenopathy
Fever
Weight Loss
Hepatomegaly – less common than splenomegaly
*85% of patients diagnosed with chronic-phase
CML
*50% of patients asymptomatic
Symptomatic patients exhibit
Constitutional symptoms
Left upper quadrant discomfort
Early satiety
purpura ,Splenomegaly, hepatomegaly
1- Benign Phase – in which the disease
behavior & response is predictable(Stable
phase)
2- Accelerated phase – tumor burden increases
rapidly with more systemic symptoms &
increasing difficulty in control of disease
3- Acute phase – Blastic crisis may be AML,ALL,
AUL
Patient may present in accelerated or acute
phase for the first time
CBC- Hb↓, PCV↓, WBC↑ > 10000/µl
Differential count – Neutrophilic leukocytosis
different stages seen (blasts, promyelocytes,
myelocytes, metamyelocytes, stab or band
forms), eosinophilia, basophilia
Thrombocytosis or thrombocytopenia
LAP score ↓ or absent
STC I, III ↑, SLDH↑, S histamine↑, S uric acid↑
Bone Marrow Aspirate & Biopsy- hypercellular,
devoid of fat, myeloid hyperplasia, ↑retculin
or collagen fibers, M:E ratio 15-20:1
Cytogenetics- Philadelphia chromosome
positivity 95% (Ph –ve 5%) shortened long arm
of chromosome22
Molecular biology- BCR/ABL gene positive
* Balanced reciprocal translocation between
chromosome 22 & chromosome 9 [t(9;22)]
that brings BCR gene in juxtaposition with
ABL gene forming a new hybrid gene BCR/ABL
that codes for synthesis of a chimeric protein
P210 that shows tyrosine kinase activity
causing uncontrolled proliferation of the
malignant clone
1- Leukemoid reaction rarely WBC count
exceeds 30000, not clonal, BM no blasts
excess, seen in overwhelming sepsis &
disseminated TB.
2- MDS – CMML stage.
3- chronic corticosteroids use (demargination).
4- other MPD.
Parameter
Historical Perspective
(Until 2000)
Modern Perspective
(Since 2000)
Course
Fatal
Indolent
Prognosis
Poor
Excellent
Median survival, yrs
3-6
≥ 25*
Frontline treatment
Allogeneic SCT,
interferon alfa
Imatinib
Second-line treatment
Not established
Allogeneic SCT, novel TKIs
Targeted Therapy1- Imatinib mesylate 400 mg/d
- TKI targets the pathogenetic mechanism
- revolutionized treatment causing CCyR &
CMR
S/E skin rash, edema, myelosuppression,
hepatitis
2- Dasatinib & Nilotinib 2nd line for imatinib
failure or hypersensitivity
3- high dose imatinib 600-800 mg/d
* BMT when enter accelerated phase prior to acute
phase
* Interferon-α + cytosine arabinoside
* Hydroxyurea orally
* Busulfan (myleran) orally – no more used now
because of severe & protracted myelosuppression
12345-
Allopurinol
H-2 blockers
PPI
Blood transfusion
platelet transfusion
It was an inevitably fatal disease
With recent treatment became a curable
disease compatible with long survival
Newer agents are evolving
Improving BMT &SCT results
Once the patient enters the acute phase the
only hope remains in transplantation & TKI
are used as bridging to that
Poor Prognostic Factors in CML
• Older age
• Splenomegaly
• Anemia
• Thrombocytosis, thrombocytopenia
• Blasts, promyelocytes, basophils
• Marrow fibrosis
• Cytogenetic clonal evolution
(Euro), MDACC Prognostic Models: Sokal, Hasford