Chronic myeloid leukemia (CML) is a stem cell disorder caused by the Philadelphia chromosome, which results from the fusion of the BCR gene on chromosome 22 and the ABL gene on chromosome 9. This fusion produces the BCR-ABL protein which exhibits uncontrolled tyrosine kinase activity, driving excessive proliferation of CML cells. CML progresses through chronic, accelerated and blast crisis phases as additional genetic mutations accumulate. Tyrosine kinase inhibitors (TKIs) target the BCR-ABL protein and have significantly improved survival, with a 10-year survival of 85% with TKI therapy. Monitoring response through cytogenetics, FISH and molecular testing guides treatment decisions such as changing or adding other TKIs.

1. CHRONIC MYELOID LEUKEMIA
(Notes from Harrison’s 20th
Ed by Col Bharat Malhotra)
DEFINE
 Proliferation of Primitive Myeloid Stem Cells
 Maturation of cells proceed fairly.
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative
stem cell disorder resulting in proliferation of all haematopoietic
lineages but manifesting predominantly in the granulocytic series.
The disease is driven by the BCR-ABL1 chimeric gene product, that
codes for a constitutively active tyrosine kinase, resulting from a
reciprocal balanced translocation between the long arms of
chromosomes 9 and 22, t(9;22), known as the Philadelphia
chromosome (Ph)
ETIOPATHOGENESIS
The defining characteristic of CML is the chromosome
abnormality known as thePhiladelphia (Ph) chromosome. BCR gene
on chromosome 22 fuses with ABL gene on chromosome 9. BCR-
ABL fusion gene encodes protein with tyrosine kinase activity
This BCR-ABL1 oncoprotein exhibits constitutive kinase activity
that leads to excessive proliferation and reduced apoptosis of CML
cells, endowing them with a growth advantage over their normal
counterparts.
Other rare rearrangements:
There can be rarely a Variant Ph, Masked Ph
There are no familial associations in CML.
No etiologic agents are incriminated.
Exposure to ionized radiation may increase risk.
The cause of the BCR-ABL1 molecular rearrangement is unknown
BLAST PHASE
Theevents associated with the transition of CMLfrom a chronic to
accelerated-blastic phaseare poorly understood. BCR-ABL1 itself
induces genetic instability that favors the acquisition of additional
molecular events/mutations and eventually to blastic
transformation
RESISTANCE TO TKIs
Among patients developing resistance to TKIs, several resistance
mechanisms have been observed. The most clinically relevant one
is thedevelopment of different ABL1 kinase domain mutations that
may prevent thebinding of TKIs to the catalyticsite (ATP-binding
site) of the kinase or maintain the kinase activity despite the
presence of a TKI. Morethan 100 BCR-ABL1 mutations have now
been described, many of which confer relative or absolute
resistance to imatinib. This has resulted in the development of
second-generation TKIs (i.e., dasatinib, nilotinib, bosutinib) and of
a third-generation TKI (ponatinib) with significant efficacy against
T315I, a “gatekeeper” mutation that prevents binding of and causes
resistance to all other TKIs.
SURVIVAL
Median Survival without Rx:
3-7 years (30%)
Median survival with TKI: (85%)
EPIDEMIOLOGY
Account for 15% of all leukemias.
Median age: 55-65 years
Incidence increases steeply over 40-
50 years
In children < 20 years is 3%

2. NATURAL HISTORY
The disease has 3 phases
Peripheral blood
< 5% Blast 5- 10% Blast
Basophilia
--
Bone Marrow
< 10% Blast 10-20% Blast > 20% Blast
Myeloid/ Lymphoid
-- --
Extramedullary
proliferationof blasts
in spleen, liver, lymph node,
soft tissue and becomes
refractory to Rx
Responseto Rx Unresponsive
to Rx
Transforms into acute
leukemia
SUSPECT CML IN
 Massivesplenomegaly
 PBS shows: Myeloproliferativedisorder, high thrombocytosis,
Full range of granulocyte precursors, usually myelocytes and
neutrophils (blast <10%)
 Unexplained metabolic/oncology emergencies
CLINICAL FEATURES
Chronic Phase
Indolent or chronic onset - usually asymptomatic
Usually diagnosed on routine blood test with fatigue
symptom
40 – 70 years usually around 50 years
 Asymptomatic – abnormal high WBC count/ Platelets
 Anaemia- Fatigue, malaise
 Palpable splenomegaly – massive (50%) early satiety
and left upper quadrant pain or mass (from
splenomegaly)
 Thrombotic or Vaso-occlusive events (from severe
leucocytosis or thrombocytosis) - priapism, MI,
venous thrombosis,visual disturbances, pulmonary
insufficiency, drowsiness,loss of coordination,
confusion,or CVA)
 Bleeding diatheses findings include retinal
haemorrhages, gastrointestinalbleeding
 Atypical –
Weight loss, night sweats (if high burden)
Markedthrombocytosis without leucocytosis
5% diagnosedin acceleratedor blast phase
High basophil count may produce histamine causingpruritis, flushing
Splenomegaly is the most common physical finding
Splenic enlargement in Chronic Phase is due to infiltration ofthe red pulp cords by
mature and immature granulocytes. A similar infiltrate can be seen in hepatic sinuses
and portal areas.
Other less common findings include hepatomegaly (5–10%),
lymphadenopathy (5–10%)
Accelerated or Blast phase
Unexplained fever, significant weight loss,infections,
bleeding & thrombotic events.
Extramedullary disease is usually seen
INVESTIGATIONS
Spleen size Palpation and by USS abdomen
Hb
CBC
Low
--
TLC DLC 10000 to 600000 /cumm
(Usually 25000-80000 /cumm)
unexplained and sustained leucocytosis
Platelets Thrombocytosis
PBS
(essential)
Hypercellular – myeloidhyperplasia
Bands, promyelocytes, Myelocytes,
segmentedneutrophils,
Blast < 5% (usually <2%)
Philadelphia chromosome present
Basophilia as the disease progresses
Significant granulocyte dysplasia absent
LAP Score Increased in leukemoid reaction (Normal cells)
Not required in AML(cells immature)
Decreasedin CML (Cell mature but not
normal)
Serum
Uric Acid
High (rapid cell turnover)
Serum LDH High (rapid cell turnover)
Blood or BM
(essential)
Quantitative RT-PCR (qPCR) using
international scaleorFISH for BCR-ABL1
Bone Marrow
Aspiration &
Biopsy
(Not
essential)
BM is hypercellular, marked myeloid
hyperplasiaand blast < 5% with no dysplasia
BMA is essential for complete karyotype
for morphological evaluation to confirm the
phase of disease
Chromosomal abnormalities –
Ph chromosome cytogenetics by karyotyping
FISH method if cytogenetics is not available

3. Confirmatory
test
CBC, Spleen size
Conventional karyotyping
Detect fusion BCR-ABL1
 RT-PCR to detect BCR-ABL1
 FISH when Ph -ve
BM Exam- for phase of disease
Biochem profile and viral markers
Advanced
CML
Flow Cytometry to determine cell lineage
Mutational analysis – by molecular test
HLA testing – for considering allogenic HCT
PET CT: Extramedullary disease in blast crisis
PERIPHERAL SMEAR IN CHRONIC PHASE
BCR ABL1
Qualitative RT PCR
(in PB & BM)
FISH
(In Selected cases)
Ph Chromosome Quicker then RTPCR
Also picks other BCR-ABL1
fusion patterns like m-bcr,
micro-bcr
BONE MARROW EXAM – Required to decide phase of disease but for
initial diagnosisit is not essential as Ph Chromosome can be testedin
peripheral blood.
MONITORING PATIENTS ON TKI THERAPY
03 monthly
Monitoring is by cytogenetics, FISH, and molecular
studies has become an important standardpractice to
assess response to therapy, emphasize compliance,
evaluate possible treatment resistance, identify the
need to change TKI therapy, and determine the need
to assess for kinase domain mutations.
ACCELERATED PHASE CML
> 15% peripheralblast cells
Increase in basophils
Thrombocytopenia
Cytogenetic clonal evolution
BLAST CRISIS CML
>30% peripheralor marrow blast
Sheets of blast in extramedullary disease
(Extramedullary disease occurs usually in blast crises)
DIFFERENTIAL DIAGNOSIS
1. LEUKEMOID REACTION
2. BCR-ABL1 NEGATIVE MPN
3. MDS-MPN
BLAST < 5% Myeloid bulge
Significant
Leukocytosis

4. TREATMENT
TYROSINE KINASE INHIBITORS
Estimated 10-year survival in CML is 85% with TKI therapy.
Imatinib All phases (first line)
Dasatinib All phases (second line) (potent)
Nilotinib All phases (second line) (potent)
(Except B Phase)
Bosutinib All phases (second line) (potent)
Ponatinib All phase – for mutant clones
Reduce dose later
Protein synthesis inhibitor with selective inhibition of
BCR-ABL1 oncogene
Omacetaxine After failure of > 2 TKI
Imatinib, nilotinib, and dasatinib are all acceptable frontline
therapies in CML. The long-term results of imatinib are very
favorable.
Salvage therapy in chronic phase with dasatinib, nilotinib,
bosutinib is associated with complete cytogenetic response
rates of 30–60%, depending on the salvage status
(cytogenetic vs hematologic relapse), prior response to other
TKIs, and the mutations at the time of relapse.
Ponatinib is the only TKI active in the setting of T315I
mutation, with complete cytogenetic response rates of 50–
70% among patients who have received 2 or more TKI.
AIM OF THERAPY
CML is now considered an indolent disease, which, with
appropriate continuous TKI therapy, treatment compliance,
careful monitoring, and early change to other TKIs as
indicated, can be associated with close to normal survival.
Therefore, in standard practice, achievement and
maintenance of a complete cytogenetic response are the
aims of therapy because complete cytogenetic response is the
only outcome associated with survival prolongation.
Molecular cures (off TKI therapy) are estimated to be about
15% post-imatinib therapy and 20–25% post–second-
generation TKIs by obtaining undetectable BCR-ABL1
transcripts for > 2 years.
INDICATOR OF FAILURE OF TKI
A general practice rule is to continue the particular TKI
chosen at the most tolerable dose schedule not associated with
grade 3–4 side effects or with bothersome chronic side
effects, for as long as possible,until either cytogenetic relapse
or the persistence of unacceptable side effects. These two
factors (i.e., cytogenetic relapse and intolerable side effects as
judged by the patient and treating physician)are the indicators
of “failure” of a particular TKI therapy
ALLOGENEIC STEM CELL
TRANSPLANT
Allogeneic SCT, a curative modality in CML, is associated
with long-term survival rates of 40–60% when implemented
in the chronic phase. It is associated with early (1-year)
mortality rates of 5–30%. Although the 5- to 10-year survival
rates were reported to be around 50–60% (and considered as
cure rates), about 10–15% of patients die in the subsequent
1–2 decades from subtle long-term complications of the
transplant (rather than from CML relapse). These are related
to chronic graft-versus-host disease (GVHD), organ
dysfunction.
The maturing positive experience with TKIs has now
relegated SCT use to after first-line TKI failures. Among
patients who present with or evolve to blastic phase,
combinations of chemotherapy and TKIs should be used to
induce remission, followed by allogeneic SCT as soon as
possible.
OTHER THERAPIES – used earlier
HYDROXYUREA
Hydroxyurearemainsasafe andeffectiveagent(at
dailydosesof 0.5–10 g) to reduce initial CMLburden,
as a temporarymeasure inbetweendefinitive
therapies,orincombination withTKIstosustain
complete hematologicorcytogeneticresponses.
INTERFERON α
Interferonα isconsideredincombinationwithTKIs
(an investigational approach),sometimesafterCML
failure onTKIs.
TREATMENT OF
ACCELERATED AND BLASTIC PHASES
Patients in accelerated or blastic phase may receive therapy
with TKIs, preferably second- or third-generation TKIs
(dasatinib, nilotinib, bosutinib, ponatinib), alone or in
combination with chemotherapy, to reduce the CML burden,
before undergoing allogeneic SCT.
SUPPORTIVE
Anaemia, Bleeding
Metabolic problem, Nutrition, Renal assessment
Manage hyperuricemia – IV hydration, Allopurinol
Identify and manage thrombotic and veno-occlusive disease
PROGNOSIS
In the current era of TKI therapy, the most important prognostic
indicator is response to treatment at the haematological, cytogenetic,
and molecular level. However, therisk scores based on clinical and
haematological findings (the Sokol score and EUTOS score are also
valid).
Overall, the completecytogenetic responserate tofirst-lineTKIis 70―90%,
with 5-year progression-free and overall survival rates of 80-95%.