SHUMAYLA ASLAM-FAIZ, MD
SHUMAYLA ASLAM-FAIZ, MD
DEPARTMENT OF INTERNAL MEDICINE
DEPARTMENT OF INTERNAL MEDICINE
Edition, Ch 101, Pg 746-757
American Cancer Society
from any of these
Development of myeloid and lymphoid leukemias within the context of hematopoietic cell hierarchy.
Hematopoietic stem cells (HSCs; S) produce granulocytic (G) and lymphocytic (L) precursors, which then go on
to generate smaller differentiated cells. Genetic and/or epigenetic aberrancies (striped) in stem or progenitor
cells lead to a neoplastic accumulation of cells due to hyperproliferation and decreased apoptosis.
• CML is defined by the presence of BCR-ABL1 fusion gene in a
patient with a myeloproliferative neoplasm.
•Philadelphia chromosome (Ph)
• 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)(q34.1;q11.2)
INCIDENCE AND EPIDEMIOLOGY
• CML accounts for 15% of all cases of leukemia
• The annual incidence of CML is 1.5 cases per 100,000 individuals
• Male : female ratio 1.6:1
• The median age at diagnosis is 55–65 years.
• It is uncommon in children; only 3% of patients with CML are younger
than 20 years.
• the median survival in CML was 3–7 years but, with introduction
of TKI therapy (tyrosine kinase inhibitors) imatinib mesylate, the
first BCR-ABL1 TKI approved, is 85%.
• The annual mortality has been reduced from 10–20% to about
• No familial associations in CML
• Exposure to ionizing radiation (e.g., nuclear accidents,
radiation treatment for ankylosing spondylitis or cervical
cancer) has increased the risk of CML, which peaks at 5–10
years after exposure and is dose-related (larger dose)
• Because of adequate protection, the risk of CML is not
increased in individuals working in the nuclear industry or
among radiologists in recent times.
and reduced apoptosis
PATHOPHYSIOLOGY OF CML
Phases of chronic myeloid leukemia
• The phases are based mainly on the number of immature WBC (blasts
blasts) in the
blood or bone marrow.
1. Chronic phase
• less than 10% blasts in their blood or bone marrow.
• fairly mild symptoms (if any) and usually respond to standard treatments.
• Most patients are diagnosed in the chronic phase.
2. Blast phase (aka acute phase or blast crisis)
• 20% or more blasts
• Large clusters of blasts are seen in the bone marrow.
• The blast cells have spread to tissues and organs beyond the bone marrow.
These patients often have fever, poor appetite, and weight loss. In this phase,
the CML acts a lot like an acute leukemia.
3. Accelerated phase
Patients are considered to be in accelerated phase if any of the following are
•15% or more, but less than 30% blasts
•Basophils make up 20% or more of the blood
•Blasts and promyelocytes combined make up 30% or more of the blood
•Very low platelet counts (100 x 1,000/mm3
or less) that are not caused by
•New chromosome changes in the leukemia cells with the Philadelphia
•symptoms such as fever, poor appetite, and weight loss. CML in the
accelerated phase doesn't respond as well to treatment as CML in the
CML in Accelarated Phase
• Healthcare available areas 50–60% of patients are diagnosed
on routine blood tests and have minimal symptoms at
presentation, such as fatigue.
• locations where access to health care is more limited,
patients often present with high CML burden including
splenomegaly, anemia, and related symptoms (abdominal
pain, weight loss, fatigue
pain, weight loss, fatigue), which translate into a higher
frequency of high-risk CML.
• Less common presenting findings include thrombotic or
hyperviscosity-related events (from severe leukocytosis or
• cardiovascular complications, MI, VTE, visual disturbances, dyspnea and
pulmonary insufficiency, drowsiness, loss of coordination, confusion, or
• Manifestations of bleeding diatheses include retinal hemorrhages,
gastrointestinal bleeding, and others.
• Patients who present with, or progress to, the accelerated or blastic
phases frequently have additional symptoms including unexplained
fever, significant weight loss, severe fatigue, bone and joint pain,
bleeding and thrombotic events, and infections.
Hematologic and Marrow Findings
• leukocytosis ranging from 10–500 × 109/L.
• predominance of neutrophils and the presence of bands
• Basophils and/or eosinophils are frequently increased
• but thrombocytopenia is rare and, when present, suggests a worse prognosis, disease
acceleration, or an unrelated etiology
• Anemia is present in one-third of patients.
• left-shifted hematopoiesis with predominance of neutrophils and the
presence of bands, myelocytes, metamyelocytes, promyelocytes, and blasts
(usually ≤5%). Anemia is present in one-third of patients.
• Bone Marrow
• hypercellular with marked myeloid hyperplasia and a high
myeloid-to-erythroid ratio of 15–20:1.
• Marrow blasts are <5%; when >15 they carry a worse prognosis or
represent transformation to accelerated phase.
• Increased reticulin fibrosis (by Snook’s silver stain) is common,
with 30–40% of patients demonstrating grade 3–4 reticulin
• With TKI therapy, reticulin fibrosis resolves in most patients and is not an
indicator of poor prognosis
• Biochemical abnormalities include a low leukocyte alkaline
phosphatase score and high levels of vitamin B12, uric acid, lactic
dehydrogenase, and lysozyme.
Cytogenetic and Molecular Findings
• The diagnosis of CML is straightforward and depends on documenting
the t(9;22)(q34.1;q11.2), which is identified by G-banding in 90% of
• Techniques such as FISH and PCR are now used to aid in the diagnosis
• Both FISH and PCR studies can be falsely positive because of technical
issues. Therefore, a diagnosis of CML must always rely on a marrow
analysis with routine cytogenetics.
• Serious side effects occur in <5–10% of patients.
• With imatinib therapy, common mild to moderate side effects include
fluid retention, weight gain, nausea, diarrhea, skin rashes, periorbital
edema, bone or muscle aches, fatigue, and others (rates of 10–20%).
• In general, second-generation TKIs are associated with lower rates of
these bothersome adverse events.
• Allogeneic SCT, a
curative modality in
CML, is associated
survival rates of 40–
implemented in the
OTHER TREATMENTS AND SPECIAL
• Chemotherapeutic Agents
• Hydroxyurea remains a safe and effective agent (at daily doses of
0.5–10 g) to reduce initial CML burden, as a temporary measure in
between definitive therapies in combination with TKIs to sustain
complete hematologic or cytogenetic responses.
• Busulfan is often used in allogeneic SCT preparative regimens.
Because of its side effects (delayed myelosuppression, Addison-
like disease, pulmonary and cardiac fibrosis, myelofibrosis), it is
now only rarely used in the chronic management of CML.
• Interferon α: Interferon α is considered in combination with TKIs,
sometimes after CML failure on TKIs, occasionally in patients during
pregnancy, or as part of investigational strategies with TKIs to
eradicate residual molecular disease.
• Others Splenectomy is now seldom considered to alleviate symptoms
of massive splenomegaly and/or hypersplenism. Splenic irradiation is
rarely used, if at all, because of the postirradiation adhesions and
MONITORING THERAPY IN CML
• Achievement of complete cytogenetic response by 12 months
12 months of
• Failure to achieve a complete cytogenetic response by 12 months or
occurrence of later cytogenetic or hematologic relapse are
considered as treatment failure and an indication to change therapy.
• Patients on frontline imatinib therapy should be closely monitored
until documentation of complete cytogenetic response, every 6
months with peripheral blood FISH and PCR studies (to check for
concordance of results), or more frequently (every 3 months) if there
are concerns about changes in BCR-ABL1 transcripts
Discontinuation of TKIs and
Treatment-Free Remissions or
• Several studies have confirmed that TKI discontinuation among
patients who achieve undetectable BCR-ABL1 transcripts for longer
than 2–3 years can result in treatment-free remission rates of 40–
• low Sokal-risk CML in first chronic phase (no evidence of
Sokal Index for Chronic Myelogenous
Leukemia (CML) survival
• Sokal Score = exp[0.0116 × (age in years – 43.4)] + [0.0345 × (spleen
size in cm – 7.51)] + [0.188 x ((platelets in 109
/L / 700)2
– 0.563)] +
[0.0887 × (blasts in % – 2.10)]
PROGNOSIS AND CML COURSE
• Before the TKI therapy, imatinib era, the annual mortality in CML was
10% in the first 2 years and 15–20% thereafter. The median survival
time in CML was 3–7 years (with hydroxyurea-busulfan and interferon
• Without a curative option of allogeneic SCT, the course of CML was
toward transformation to, and death from, accelerated or blastic
Adverse prognostic factors:
• Accelerated phase or blast phase
• Enlarged spleen
• Areas of bone damage from growth of leukemia
• Increased number of basophils and eosinophils (certain types of
granulocytes) in blood samples
• Very high or very low platelet counts
• Age 60 years or older
• Multiple chromosome changes in the CML cells
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