By WHO , Chronic disease:

A disease that persists for a long time.

... Chronic diseases generally cannot
be prevented by vaccines or cured by
medication

CLONAL BLOOD STEM CELL DISORDER

normal number of WBCs in the blood is

4,500 to 11,000 WBC per microliter
 BCR-ABL1 gene ( chimeric –
identical genotype )
  the course of CML may be
 biphasic or triphasic, with an early indolent or chronic phase, followed
 often by an accelerated phase and a terminal blastic phase.
criteria used to define
accelerated phase in all the
studies with interferon and
tyrosine kinase inhibitors
include the presence of any
one of the following factors:
blasts > 15%, blasts plus
promyelocytes > 30%,
basophils > 20%, platelets <
100 × 109/L unrelated to
therapy or cytogenetic clonal
evolution.
accelerated phase is more
frequently symptomatic,
and it includes the
development of fever, night
sweats, weight loss, and
progressive splenomegaly.
blastic phase morphologically resembles acute leukemia.
Its diagnosis requires the presence of at least 30% blasts
in the bone marrow or peripheral blood. The World Health
Organization (WHO) has proposed the diagnosis of blast
phase if there are at least 20%
In some patients, the blastic phase is characterized by
extramedullary deposits of leukemic cells, most
frequently in the central nervous system (CNS), lymph
nodes, skin, or bones.
Historically, patients in the blastic phase usually die
within 3 to 6 months
Patients in the blastic phase are more likely to
experience symptoms, including weight loss, fever, night
sweats, and bone pain. Symptoms of anemia, infectious
complications, and bleeding are common. Subcutaneous
nodules or hemorrhagic tender skin lesions,
lymphadenopathy, and signs of CNS leukemia may also
occur
 CML accounts for 15% of all cases of
leukemia.
 slight male preponderance (male:female ratio
1.6:1)
 median age at diagnosis is 55–65 years. It is
uncommon in children; only 3% of patients
with CML are younger than 20 years. CML
incidence increases slowly with age, with a
steeper increase after the age of 40–50 years.
 Annual incidence of CML is 1.5 cases per 100,000
individuals In the United States, this translates into 4500–
5000 new cases per year.
 The incidence of CML has not changed over several
decades. worldwide annual incidence of CML is about
100,000 cases
 median survival of 6 years before 2000, the disease
prevalence in the United States was 20,000–30,000 cases.
 With TKI therapy, the annual mortality has been reduced
from 10–20% to about 2%. Therefore, the prevalence of
CML in the United States is expected to continue to
increase (about 80,000 in 2013) and reach a plateau of
approximately 180,000 cases around 2030.
 Ideally, with full TKI treatment penetration,the worldwide
prevalence should plateau at 35 times the incidence, or
around 3 million patients.
 no familial associations in CML
 No etiologic agents are incriminated, and no associations
exist with exposures to benzene or other toxins,
fertilizers, insecticides, or viruses.
 CML is not a frequent secondary leukemia following
therapy of other cancers with alkylating agents and/or
radiation.
 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
 Median time to development of CML among atomic bomb
survivors was 6.3 years. Following the Chernobyl accident,
the incidence of CML did not increase, suggesting that
only large doses of radiation can cause CML
 t(9;22) (q34;q11.2) is present in more than 90% of classical CML
 It is present in hematopoietic cells (myeloid, erythroid, megakaryocytes, and
monocytes; less often mature B lymphocytes; rarely mature T lymphocytes, but
not stromal cells), but not in other cells in the human body.
 BCR-ABL1 fusion gene codes for a novel oncoprotein of molecular weight 210
kDa, referred to as p210BCR-ABL1
 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. Over time, normal hematopoiesis is
suppressed, but normal stem cells can persist and may reemerge following
effective therapy, for example with TKIs
 In Ph-positive acute lymphocytic leukemia (ALL) and in rare cases of CML, the
breakpoint in BCR is more centromeric, in a region called the minor BCR region
(mBCR). As a result, a shorter sequence of BCR is fused to ABL1, with a consequent
smaller BCR-ABL1 oncoprotein, p190BCR-ABL1.
 A third rare breakpoint in BCR occurs telomeric to the major BCR region and is
called micro-BCR (μ-BCR). It juxtaposes a larger fragment of the BCR gene to ABL1
and produces a larger p230BCR-ABL1 oncoprotein, which is associated with a
more indolent CML course
 Autophosphorylation and activation of multiple downstream pathways
 that modify gene transcription, apoptosis, skeletal organization, and degradation
of inhibitory proteins.
 These transduction pathways may involve RAS, mitogenactivated protein (MAP)
kinases, signal transducers and activators of transcription (STAT),
phosphatidylinositol-3-kinase (PI3k), MYC, and others.
 These interactions are mostly mediated through tyrosine phosphorylation and
require binding of BCR-ABL1 to adapter proteins such as GRB-2, CRK, CRK-like
(CRK-L) protein, and Src homology containing proteins (SHC).
 plethora of signaling pathways have been implicated in BCR-ABL1-mediated
cellular transformation. The emerging picture is a complex and redundant
transformation network
 An additional layer of complexity is related to differences in signal transduction
between CML differentiated cells and early progenitors. Beta-catenin, Wnt1,
Foxo3a, transforming growth factor β, interleukin-6, PP2A, SIRT1, and others have
been implicated in CML stem cell survival.
 Experimental models have established the causal relationship between the Ph-
related BCR-ABL1 molecular events and the development of CML. In animal
models, expression of BCR-ABL1 in normal hematopoietic cells produced CML-
like disorders or lymphoid leukemia, demonstrating the leukemogenic potential of
BCR-ABL1 as a single oncogenic abnormality.
TKIs bind to the BCR-ABL1 kinase
domain (KD), preventing the activation
of transformation pathways and
inhibiting downstream signaling. As a
result, proliferation of CML cells
is inhibited and apoptosis induced,
leading to the reemergence of normal
hematopoiesis.
 this molecular abnormality in the blood of up
to 25% of normal adults and 5% of infants,
but 0% of cord blood samples. This suggests
that BCR-ABL1 is not sufficient to cause overt
CML in the overwhelming majority of
individuals in whom it occurs. Because CML
develops in only 1.5 of 100,000 individuals
annually, it is evident that additional
molecular events or poor immune recognition
of the rearranged cells are needed to cause
overt CML.
 In some patients with a typical morphologic picture of CML, the
Ph abnormality is not detectable by standard cytogenetic
analysis, but fluorescence in situ hybridization (FISH) and
molecular studies (polymerase chain reaction [PCR]) detect BCR-
ABL1. These patients have a course similar to Ph-positive CML
and respond to TKI therapy.
 Many of the remaining patients have atypical morphologic or
clinical features and belong to other diagnostic groups, such as
atypical CML or chronic myelomonocytic leukemia. These
individuals do not respond to TKI therapy and have a poor
prognosis with a median survival of about 2–3 years.
 Detection of mutations in the granulocyte colony-stimulating
factor receptor (CSF3R) in chronic neutrophilic leukemia and in
some cases of atypical CML and of mutations in SETBP1 in
atypical CML confirmed that they are distinct entities.
 often associated with characteristic chromosomal
abnormalities such as a double Ph, trisomy 8,
isochromosome 17 or deletion of 17p(loss of TP53),
20q–, and others. Molecular events associated with
transformation include mutations in TP53,
retinoblastoma 1 (RB1),myeloid transcriptions factors
like Runx1, and cell cycle regulators like p16. A
plethora of other mutations or functional
abnormalities have been implicated in blastic
transformation, but no unifying theme has emerged
other than that
 BCR-ABL1 itself induces genetic instability that leads
to the acquisition of additional mutations and
eventually to blastic transformation.
 In the United States, because of the easy
access to health care screening and physical
exams, 50–60% of patients are diagnosed on
routine blood tests and have minimal
symptoms at presentation,such as fatigue
 In geographic locations where access to
healthcare is more limited, patients often
present with high CML burden including
splenomegaly, anemia, and related symptoms
(abdominal pain, weight loss, fatigue), as well
as a higher frequency of high-risk CML
 Most patients with CML (90%) present in the indolent or chronic phase
 Depending on the timing of diagnosis, patients are often asymptomatic
(if the diagnosis is discovered during health care screening tests).
 Common symptoms, when present, are manifestations of anemia and
splenomegaly. These may include fatigue, malaise, weight loss (if high
leukemia burden), or early satiety and left upper quadrant pain or
masses (from splenomegaly
 Less common presenting findings include thrombotic or vasoocclusive
events (from severe leukocytosis or thrombocytosis). These include
priapism ( prolonged erection of penis without sexual arousal ) ,
cardiovascular complications, myocardial infarction, venous thrombosis,
visual disturbances, dyspnea and pulmonary insufficiency, drowsiness,
loss of coordination, confusion, or cerebrovascular accidents. Bleeding
diatheses ( tendency to bleed easily ) findings include retinal
hemorrhages, gastrointestinal bleeding,and others.
 Patients who present with, or progress to, the accelerated or blastic
phases have additional symptoms including unexplained fever,
significant weight loss, severe fatigue, bone and joint aches, bleeding
and thrombotic events, and infections.
 Splenomegaly is the most common physical
finding,occurring in 20–70% of patients depending on
health care screening frequency.
 Other less common findings include hepatomegaly
(10–20%), lymphadenopathy (5–10%), and
extramedullary disease (skin or subcutaneous
lesions).
 latter indicates CML transformation if a biopsy
confirms the presence of sheets of blasts
 Other physical findings are manifestations of
complications of high tumor burdendescribed earlier
(e.g., cardiovascular, cerebrovascular, bleeding)
 High basophil counts may be associated with
histamine overproduction causing pruritus, diarrhea,
flushing, and even gastrointestinal ulcers
 In untreated CML, leukocytosis ranging from 10–500
× 109/L is common
 peripheral blood differential shows left-shifted
hematopoiesis with predominance of neutrophils and
the presence of bands, myelocytes, metamyelocytes,
promyelocytes, and blasts (usually ≤5%).
 Basophils and/or eosinophils are frequently increased
 Thrombocytosis is common, 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.
 Cyclic oscillations of counts are noted in 25% of
patients without treatment.
 include a low leukocyte alkaline phosphatase
score and high levels of vitamin B12, uric
acid, lactic dehydrogenase, and lysozyme.
The presence of unexplained and sustained
leukocytosis, with or without splenomegaly,
should lead to a marrow examination and
cytogenetic analysis
 bone marrow is hypercellular with marked myeloid
hyperplasia and a high myeloid-to-erythroid ratio of 15–
20:1. Marrow blasts are 5% or less; when higher, they carry
a worse prognosis or represent acceleration (if they are
≥15%).
 Increased reticulin fibrosis (by Snook’s silver stain) is
common, with 30–40% of patients demonstrating grade 3–
4 reticulin fibrosis. This was considered adverse in the
pre-TKI era. With TKI therapy, reticulin fibrosis resolves in
most patients and is not an indicator of poor prognosis.
 Collagen fibrosis (Wright-Giemsa stain) is rare at
diagnosis.
 Disease progression with a “spent phase”of myelofibrosis
(myelophthisis, or burnt-out marrow) was common with
busulfan therapy (20–30%) but is rare with TKI therapy
 depends on documenting t(9;22)(q34;q11.2), which is found in
90% of cases – ph chromosome.
 Some patients may have complex translocations (variant Ph)
involving three or more translocations that include chromosomes
9 and 22 and one or more other chromosomes
 Others may have a “masked Ph,” involving translocations
between chromosome 9 and a chromosome other than 22.
 The prognosis of these patients and their response to TKI
therapy are similar to those in patients with Ph
 5–10% of patients may have additional chromosomal
abnormalities in the Ph-positive cells. These usually involve
trisomy 8, a double Ph, isochromosome 17 or 17p deletion, 20q–
, or others. This is referred to as clonal evolution and was
historically a sign of adverse prognosis, particularly when
trisomy 8, double Ph, or chromosome 17 abnormalities were
noted
 are now used to aid in the diagnosis of CML.
They are more sensitive approaches to estimate
the CML burden in patients on TKI therapy. They
can be done on peripheral samples, and thus are
less painful and more convenient. Patients with
CML at diagnosis should have a FISH analysis to
quantify the percentage of Ph-positive cells, if
FISH is used to replace marrow cytogenetic
analysis in monitoring response to therapy. FISH
may not detect additional chromosomal
abnormalities (clonal evolution); thus, a
cytogenetic analysis is usually recommended at
the time of diagnosis
 BCR-ABL1 RNA message is usually one of two variants: e13a2 (formerly
b2a2) and e14a2 (formerly b3a2).
 About 2–5% of patients may have other RNA fusion types (e.g., e1a2,
e13a3, or e14a3). In these patients, the routine PCR primers may not
amplify the BCR-ABL1 transcripts, thus leading to false-negative results.
Therefore, molecular studies at diagnosis are important to document the
type and presence of BCR-ABL1 transcripts to avoid erroneously
“undetectable” BCRABL1 transcripts on follow-up studies, with the
misconception of a complete molecular response.
 Both FISH and PCR studies can be falsely positive at low levels or falsely
negative because of technical issues. Therefore, a diagnosis of CML must
always rely on a marrow analysis with routine cytogenetics. The
diagnostic bone marrow confirms the presence of the Ph chromosome,
detects clonal evolution, i.e., chromosomal abnormalities in the Ph-
positive cells (which may be prognostic), and also quantifies the
percentage of marrow blasts and basophils. In 10% of patients, the
percentage of marrow blasts and basophils can be significantly higher
than in the peripheral blood, suggesting poorer prognosis or even
disease transformation
 Progression of CML is usually associated with leukocytosis
resistant to therapy, increasing anemia, fever and
constitutional symptoms, and increased blasts and
basophils in the peripheral blood or marrow.
 Criteria of accelerated-phase CML, historically associated
with median survival of less than 1.5 years, include the
presence of 15% or more peripheral blasts, 30% or more
peripheral blasts plus promyelocytes, 20% or more
peripheral basophils, cytogenetic clonal evolution
(presence of chromosomal abnormalities in addition to
Ph), and thrombocytopenia <100 × 109/L (unrelated to
therapy )
 About 5–10% of patients present with de novo accelerated
phase or blastic phase
 Blastic-phase CML is defined by the presence of 30% or more
peripheralvor marrow blasts or the presence of sheets of blasts
in extramedullary disease (usually skin, soft tissues, or lytic bone
lesions).
 Blastic phase CML is commonly myeloid (60%) but can present
uncommonly as erythroid, promyelocytic, monocytic, or
megakaryocytic.
 Lymphoid blastic phase occurs in about 25% of patients.
Lymphoblasts are terminal deoxynucleotide transferase positive
and peroxidase negative (although occasionally with low
positivity up to 3–5%) and express lymphoid markers (CD10,
CD19, CD20, CD22). However, they also often express myeloid
markers (50–80%), resulting in diagnostic confusion. This is
important because, unlike other morphologic blastic phases,
lymphoid blastic-phase CML is quite responsive to anti- ALL-
type chemotherapy (e.g., hyper-CVAD [cyclophosphamide,
vincristine, doxorubicin, and dexamethasone]) in combination
with TKIs.
 Before the imatinib era, the annual mortality in CML was 10% in the first 2 years and 15–20%
thereafter
 median survival time in CML was 3–7 years (with hydroxyurea-busulfan and interferon α).
 Without a curative option of allogeneic SCT, the course of CML was inexorable toward
transformation to, and death from, accelerated or blastic phases. The disease stability was
unpredictable, with some patients demonstrating sudden transformation to a blastic phase
 With imatinib therapy, the annual mortality in CML has decreased to 2% in the first 12 years of
observation.
 estimated 8- to 10-year survival rate is now 85%, or 93% if only CML-related deaths are
considered
 course of CML has also become quite predictable. In the first 2 years of TKI therapy, rare
sudden transformations are still noted (1–2%), usually lymphoid blastic transformations that
respond to combinations of chemotherapy and TKIs followed by allogeneic SCT. These may be
explained by the intrinsic mechanisms of sudden transformation already existing in the CML
clones before the start of therapy that were not amenable to TKI inhibition, in particular
imatinib. Second-generation TKIs (nilotinib , dasatinib) used as frontline therapy have reduced
the incidence of transformation in the first 2–3 years from 6–8% with imatinib to 2–4% with
nilotinib or dasatinib.
 Disease transformation to accelerated or blastic phase is rare on continued TKI therapy,
estimated at <1% annually in years 4–8 of follow-up on the original imatinib trials
 Patients usually develop resistance in the form of cytogenetic relapse, followed by hematologic
relapse and subsequent transformation, rather than the previously feared sudden
transformations without the warning signals of cytogenetic-hematologic relapse.
 Before the imatinib era, several pretreatment prognostic factors predicted for worse outcome
in CML and have been incorporated into prognostic models and staging systems. These have
included older age, significant splenomegaly, anemia, thrombocytopenia or thrombocytosis,
high percentages of blasts and basophils (and/or eosinophils), marrow fibrosis, deletions in
the long arm of chromosome 9, clonal evolution, and others.
 As with the introduction of cisplatin into testicular cancer therapy, the introduction of TKIs into
CML therapy has nullified or lessened the prognostic impact of most of these prognostic
factors and the significance of the CML models (e.g., Sokal, Hasford, European Treatment and
Outcome Study [EUTOS]).
 Treatment-related prognostic factors have emerged as the most important prognostic factors
in the era of imatinib therapy.
 Achievement of complete cytogenetic response has become the major therapeutic endpoint
and is the only endpoint associated with improvement in survival.
 Achievement of a major molecular response is associated with decreased risk of events
(relapse) and CML progression, may predict for differences in event-free survival (depending
on the definition of an event) and for small differences in transformation rates,but has not
been associated with survival prolongation. Among patients in complete cytogenetic response,
survival is similar independent of whether they achieve a major molecular response or not. This
may be due to the efficacy of salvage TKI therapies, which are and should be implemented at
the first evidence of cytogenetic relapse. Achievement of complete molecular response
(undetectable BCR-ABL1 transcripts), particularly when durable (>2 years), may offer the
possibility of durable molecular response (molecular cure rather than functional cure) in the
context of investigational trials and may allow temporary therapy interruption in women eager
to have babies. The lack of achievement of major or complete molecular responses should not
be considered as “failure” of a particular TKI therapy and/or an indication to change the TKI or
to consider allogeneic SCT
 Pretreatment prognostic factors and
prognostic models have lost much of their
clinical relevance to define prognosis and to
select different therapies.
 However TKI-associated therapeutic
responses have gained major clinical
relevance and dictate appropriate and careful
monitoring of patients to optimize their
treatment.
 introduction of TKI therapy, first in the form of
imatinib mesylate in 2001
 Before 2000, allogeneic SCT was frontline
therapy, when available
 Otherwise, patients were offered interferon α
therapy (approved for the treatment of CML in
1986), which had modest benefits (improving
survival from a median of 3–4 years with
hydroxyurea-busulfan to a median of 6–7 years),
but also significant side effects
 With TKI therapy, the estimated 10-year survival
in CML is 85%
 Imatinib 400 mg orally daily, nilotinib 300 mg orally twice a day (on an empty
stomach), and dasatinib 100 mg orally daily are approved for frontline therapy of
CML
 All three are also approved for salvage therapy ( given after an ailment does not
respond to standard therapy) (nilotinib 400 mg twice daily), in addition to
bosutinib (500 mg daily) and ponatinib (45 mg daily).
 Imatinib, dasatinib (140 mg daily), bosutinib, and ponatinib are also approved for
the treatment of CML transformation (accelerated and blastic phase), whereas
 nilotinib is only approved for chronic and accelerated phase
 Dasatinib, nilotinib, and bosutinib are referred to as second generation TKIs;
ponatinib is referred to as a third-generation TKI.

 sixth approved agent is omacetaxine (Synribo), a protein synthesis inhibitor with

presumed more selective inhibition of the synthesis of the BCR-ABL1 oncoprotein.
It is approved for the treatment of chronic- and accelerated-phase CML after
failure of two or more TKIs, at 1.25 mg/m2 subcutaneously twice a day for 14
days for induction and for 7 days for consolidation-maintenance.
 Nilotinib is similar in structure to imatinib but
30 times more potent.
 Dasatinib and bosutinib are dual SRC-ABL1
TKIs (dasatinib is reported to be 300 times
more potent and bosutinib 30–50 times more
potent than imatinib).
 Ponatinib is effective against wild-type and
mutant BCRABL1 clones. It is unique in being
the only currently available BCRABL1 TKI that
is active against T315I, a gatekeeper mutant
resistant to the other four TKIs
effect of TKIs is their ability to stabilize the CML genome, leading
to a much reduced transformation rate. In particular, the previously
observed sudden blastic transformations (i.e., abrupt transformation
to blastic phase in a patient who had been in cytogenetic response)
have become uncommon, occurring rarely in younger patients in the
first 1–2 years of TKI therapy (usually sudden lymphoid blastic transformations).
 Before
Sudden transformations beyond the third year of TKI
 the era of selective BCR-ABL1 tyrosine kinase inhibitors (TKIs),
therapy are rare in patients who continue on TKI therapy. Moreover,
the median
initial experience survivalthat
suggests in CML was 3–7
the course of years,
CML hasand the 10-year
become significantly
survival
more indolent, even without cytogenetic responses, in
 rate was 30% or less. Introduced into CML therapy in 2000, TKIs
patientshaveon TKI-based therapy compared to previous experience with
hydroxyurea/busulfan.
 revolutionized the treatment, natural history, and prognosis of
CML.
 Today, the estimated 10-year survival rate with imatinib
mesylate, the
 first BCR-ABL1 TKI approved, is 85%. Allogeneic stem cell
transplantation
 (SCT), a curative but risky treatment approach, is now offered
 as second- or third-line therapy after failure of TKIs.
 most clinically relevant one is the development of
different ABL1 kinase domain mutations that
prevent the binding of TKIs to the catalytic site
(ATP binding site) of the kinase
 More than 100 BCR-ABL1 mutations have now
been described, many of which confer relative or
absolute resistance to imatinib
 resulted in the development of second-
generation TKIs (i.e., dasatinib, nilotinib,
bosutinib) and of a third-generation TKI
(ponatinib) with selective efficacy against T315I,
a mutation of the gatekeeper residue of the
kinase that causes resistance to all other TKIs.
It is thus important to recognize the comparability of these
measures in monitoring response. A partial cytogenetic response is
defined as the presence of 35% less Ph-positive metaphases by routine
cytogenetic analysis. This is roughly equivalent to BCR-ABL1
transcripts by the International Scale (IS) of 10% or less. A complete
cytogenetic response refers to the absence of Ph-positive metaphases
(0% Ph positivity). This is approximately equivalent to BCR-ABL1
transcripts (IS) of 1% or less. A major molecular response refers to
BCR-ABL1 transcripts (IS) ≤0.1%, or roughly a 3-log or greater reduction
of CML burden from baseline. A complete molecular response
usually refers to BCR-ABL1 transcripts (IS) <0.0032% (undetectable by
current techniques), roughly equivalent to a more than 4.5-log reduction
of CML burden from baseline.
prognosis of de novo accelerated
phase
with TKI therapy has improved
significantly, with an estimated 8-year
survival rate of 75%. The median
survival of accelerated phase evolving
from chronic phase has also improved
from a historical median survival
of 18 months to an estimated 4-year
survival rate of 70% on TKI
therapy. Therefore, the criteria for
accelerated-phase CML should be
revisited because most have lost much
of their prognostic significance.