Chronic Myeloid Leukemia

AGHA MUHAMMAD HAMMAD KHAN

HOUSE OFFICER
ONCOLOGY (WARD- 4)

Hematopoietic Progenitors

Leukemias:
What are Leukemias?

Neoplasm of white blood cell and its

precursor.
Clonal proliferations and
accumulation of cells in marrow.
Classify as:
Acute leukemias
Chronic leukemias

Types of Leukemia

Acute

: No
Maturation beyond
blast
Lymphocytic (B or T
lineage)

Myeloid granulocytes
Erythroids
Monocytes
Platelets

Chronic :

Maturation beyond
blast

ALL CLL

AML CML

What is CML?
Chronic Myelogenous Leukemia (CML) is

defined as,
a malignant cancer of the bone marrow.
It causes rapid growth of the bloodforming cells (known as myeloid
precursors) in the bone marrow, peripheral
blood, and body tissues.

Epidemiology of CML
Approximately 5,050 cases in the U.S. in 2009 (11%
of all leukemias) with an incidence that increases
significantly with age (median age ~ 55)
Risk Factors include:
prior high dose radiation exposure
exposure to certain organic solvents (benzene)
age
gender (male > female)
A very small percentage (< 0.1%) of individuals can
express Bcr-Abl but not develop CML (wrong cell
of origin, multiple genetic mutations leading to
non-viability, immune surveillance)

CML Pathophysiology
the Philadelphia Chromosome
CML was the first
malignancy to be linked
to a clear genetic
abnormality, the
chromosomal
translocation known as
the Philadelphia
chromosome. This
chromosomal
abnormality is so
named because it was
first discovered and
described in 1960

Chronic Myeloid Leukemia

Clinical Presentation
Asymptomatic (~ 30%)
Fatigue, weight loss, fever
Easy bruising and purpura

Abdominal fullness, pain and/or early

satiety due to splenomegaly (~ 50-90%)

DIAGNOSIS

CML Peripheral Blood and BM

Findings
Peripheral smear can

only give a presumptive

1) leukocytosis with a
left shift
2) normocytic anemia.
3) thrombocytosis in
50% of pts.
4) absolute
eosinophilia with a
normal % of Eos.
5) absolute and relative
increase in basophils

Bone marrow
Bone marrow
Hypercellular

(reduced fat
spaces).
Myeloid:erythroid
ratio 10:1 to 30:1
(N : 2:1).
Myelocyte
predominant cell,
blasts less 10%.
Megakaryocytes
increased &
dysplastic.
Increase reticulin
fibrosis in 30-40%.

Diagnosing Chronic Myeloid

Leukemia

Karyotyping in CML : (1-10%).

Fluorescence in-situ
hybridization(FISH): (0.5-5%).
Quantitative RT-PCR for Bcr-Abl: (0.0001-

0.001%)

Diagnostic Criteria for the 3

Phases of the Disease
Patients who have CML are said to be in one of
the following three phases (in order of
occurrence):
the chronic phase (between 1 and 15%
blasts)
the accelerated phase (between 15% - 30%
blasts)
the blast phase (more than 30% blasts).

PHASES

Chronic phase
85% of patients with CML are in the chronic

phase at the time of diagnosis.

Asymptomatic or have only mild symptoms
of fatigue, left side pain, joint and/or hip
pain, or abdominal fullness.
myleoblast cell <10% in blood or
bonemarrow.
Philadelphia chromosome (POSITIVE)

Accelerated phase
Median duration is 3.5 5 yrs before

evolving to more aggressive phases.

Clinical features
Increasing splenomegaly refractory to
chemo
Increasing chemotherapy requirement
Lab features: (WHO CRITERIA)
1. 1019% myeloblasts in the blood or bone
marrow.
2. >20% basophils in the blood or bone marrow.
3. Platelet count <100,000, unrelated to therapy.
4. Platelet count >1,000,000, unresponsive to
therapy.
5. Cytogenetic evolution with new
abnormalities in addition to the Philadelphia

Blastic Phase
Resembles acute leukaemia.

Diagnosis requires > 30% blast in

Large clusters of blasts in the bone

marrow on biopsy.
Development of a chloroma (solid
focus of leukemia outside the bone
marrow).

General Management
Discussion with family
The disease & diagnosis
Prognosis

Choices of treatment

CML - principles of treatment

1. Relieve symptoms of

hyperleukocytosis, splenomegaly and

thrombocytosis.
Hydration
Chemotherapy (bulsuphan,
Hydoxyurea)
2. Control and prolong chronic phase
(non-curative).
alpha interferon+chemotherapy
Imatinib mesylate
Chemotherapy (hydroxyurea)

CML - principles of treatment

3) Eradicate malignant clone
(curative).
Allogeneic transplantation
Imatinib mesylate/STI 571
(Thyrosine kinase inhibitor)

Treatment Milestones for CML

Definitions of Responses to Treatments

Hematologic Response
Complete Hematologic response
1) Normal PB counts (WBC < 10 and plt < 450)
2) Normal WBC differential
3) No Dz symptoms
4) Normalization of the size of the liver and spleen
Cytogenetic Responses: Ph+ Metaphases
1) complete: 0%
2) partial: 1% - 35%
3) minor: 36% - 65%
4) minimal: 66% - 95%
5) none: 96% - 100%
Molecular Responses: ratio of Bcr-Abl/Abl
Major Molecular Response
3-log10 reduction from initial diagnosis sample
(i.e. 25 0.025)

Chemotherapy
Busulphan
Alkylating agent
Preferred in older pts (not candidate

for transplant)
Side effect :
prolonged myelosuppression
Pulmonary fibrosis
Skin pigmentation
infertility

Chemotherapy
Hydoxyures
Fewer side effect
Acts by inhibiting the enzyme

ribonucleotide reductase
Haematological remissions obtain in
80% for both drugs
However disease progression not
altered and persistence of Ph
chromosome containing clone

Chemotherapy
Recombinant human - Interferon
Prolong chronic phase and increase

survival
Haematogical and cytogenetic
remission
Side effect
Flu like symptoms
Fever and chills
Anorexia
Depression

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

Imatinib has Revolutionized

the Treatment of CML
IRIS Trial

Imatinib Mesylate in Chronic

Phase CML Following IFN-
Failure: Overall Survival*
Seventy-five percent of patients remain alive

on imatinib mesylate therapy after a median

follow-up of 45 months.
Patients who received imatinib mesylate had
significantly improved survival rates, with an
estimated 4-year survival rate of 86% vs 43%
(P<0.0001). The estimated 4-year
transformation-free survival was 80%.

Treatment Options for Resistant

Disease
1) Dose Escalation of imatinib
2) Second Generation TKIs

3) Bone Marrow Transplant

Dose Escalation of imatinib

START-R Trial
Patients resistant to 400mg-600 mg of imaitnib were
treated with either 70 mg BID of dasatinib or 800 mg of
imaitnib
primary endpoint of the trial was the rate of
MCyR(major cytogenetic response )at 12 weeks and
this was equal
(D=36%; IM=29%; p=.40)
At a minimum follow-up of 2 years, dasatinib
demonstrated higher rates of:
complete hematologic response (93% vs 82%; P
= .034)
major cytogenetic response (MCyR) (53% vs
33%; P = .017)
complete cytogenetic response (44% vs 18%; P =
.0025)
The depth of the previous response to imatinib may be
associated with the proportion of patients responding
to dose escalation. Patients having achieved a prior
major cytogenetic response (MCyR) with imatinib
reported a greater than 50% chance of reachieving that
response with high-dose imaitnib, yet only 7% of

Second Generation
Tyrosine Kinase Inhibitors (TKIs)
The FDA has approved 2 additional oral TKIs for the treatment
of
imatinib relapsed/refractory or imatinib intolerant CML

1. Dasatinib
2. Nilotinib

Bone Marrow Transplantation

Allogeneic bone marrow transplant remains the only
known curative option in CML
Associated with an increased morbidity and mortality.
Therefore, not typically applied for upfront therapy for
CML
considered only in cases of matched-related
extremely young pts (pediatrics)
However, often considered in those with
relapsed/refractory disease to TKI based therapies
efficacy of the transplant dependent upon the
phase of the disease at the time of the
transplant: CP>AP>BP

CML - prognosis
Median survival

3.5 yrs (range 2-8 yrs).

Interferon + chemotherapy :6 years.
Transplant :
5+ years.
Imatinib mesylate : 8.9 years.(5yr: 86%;
10yr:68%).

THANK YOU