Chronic Myeloid Leukemia in India: A Review
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International Journal of Science and Healthcare Research
Vol.5; Issue: 1; Jan.-March 2020
Website: www.ijshr.com
Review Article ISSN: 2455-7587
Chronic Myeloid Leukemia in India: A Review
Namrata Bhutani
Senior Resident, Department of Biochemistry, Vardhaman Mahavir Medical College & Safdarjung Hospital,
New Delhi.
ABSTRACT 1973, Janet D. Rowley at the University of
Chicago identified the mechanism by which
Chronic myeloid leukemia (CML) is a clonal Philadelphia chromosome arises as a
myeloproliferative disorder of a pluripotent stem translocation.
cell. CML is the commonest adult leukaemia in
Epidemiology of Chronic Myeloid
India and the annual incidence ranges from 0.8–
2.2/100,000 population in males and 0.6–
Leukemia
1.6/100,000 population in females in India. The Global burden of Chronic Myeloid
median age of diagnosis is 38-40 years. Chronic Leukemia:
myeloid leukemia is divided into three phases The incidence of CML around the
based on clinical characteristics and laboratory world varies by a factor of approximately
findings. CML prognostic scoring systems twofold. The lowest incidence is in Sweden
stratify patients into risk groups based on patient and China (approximately 0.7 per 100,000
and disease related characteristics at diagnosis . persons), and the highest incidence is in
With the introduction of the Tyrosine Kinase Switzerland and the United States
Inhibitor, imatinib, the treatment and natural (approximately 1.5 per 100,000 persons). [2]
history of CML has changed dramatically in CML accounts for approximately 15
recent years, with an improvement in the 5-year
percent of all cases of leukemia, or
survival rate from little more than 20% to over
90%.This article presents a brief review about approximately 5000 new cases per year in
chronic myeloid leukemia and its therapy. the United States. The age-adjusted
incidence rate in the United States is
Keywords: Chronic myeloid leukemia, CML, approximately 2.0 per 100,000 persons for
pluripotent stem cell, leukaemia in India. men and approximately 1.1 per 100,000
persons for women. The age-specific
INTRODUCTION incidence rate for CML in the United States
Chronic myeloid leukemia (CML) is increases from approximately 0.2 per
a clonal myeloproliferative disorder of a 100,000 persons younger than 20 years to a
pluripotent stem cell. It is characterized by rate of approximately 10.0 per 100,000
the Philadelphia (Ph) chromosome, which octogenarians per year. [3]
occurs due to a balanced reciprocal Although CML occurs in children
translocation between chromosome 9 and 22 and adolescents, less than 10 percent of all
t(9;22)(q34.1;q11.2). It was the first cases occur in subjects between 1 and 20
malignancy that had a specific chromosomal years old. CML represents approximately 3
abnormality uniquely linked to it. This percent of all childhood leukemias. Multiple
chromosomal abnormality is so named occurrences of CML in families are rare. No
because it was first discovered and concordance of the disease between
described in 1960 by two scientists from identical twins has been found. Analytical
Philadelphia, Pennsylvania: Peter Nowell of epidemiologic evidence for a familial
the University of Pennsylvania and David predisposition in CML has also not been
Hungerford of the Fox Chase Cancer Center found. [4]
at Temple University.(Nowell-PC). [1] In Chronic myeloid leukemia in INDIA
International Journal of Science and Healthcare Research (www.ijshr.com) 6
Vol.5; Issue: 1; January-March 2020Namrata Bhutani. Chronic myeloid leukemia in India: a review
CML is the commonest adult phase, and in acute lymphoid and myeloid
leukaemia in India and the annual incidence leukemias. [6]
ranges from 0.8–2.2/100,000 population in Minor (m-BCR): The breakpoint in the m-
males and 0.6–1.6/100,000 population in BCR region results in an e1a2 junction
females in India. The median age of which is translated into a p190 BCR-ABL
diagnosis is 38-40 years. This is a decade protein. Some acute lymphoblastic leukemia
earlier than the median incidence in the (ALL) are induced by this protein. [7]
western world. Though CML is Micro(μ-BCR): There is a third BCR-ABL
predominantly a disease affecting adults, a protein: p230. It consists of more than 90%
minority of patients are children and young of p160 because the breakpoint is located in
adults. [5] the 3-end of the BCR gene, in the -BCR
BCR-ABL Transcripts region. Its transcript contains a e19a2
The BCR/ABL fusion oncogene, the junction. The micro breakpoint position has
product of the t(9;22) Philadelphia been associated mainly with a mild form of
chromosome (Ph), exists in three principal CML, defined as Philadelphia chromosome-
forms (P190, P210 and P230). These positive chronic neutrophilic leukaemia
proteins arise from distinct breakpoints in (Phpositive CNL). [8]
the BCR gene on chromosome 22. This BCR-ABL AND SIGNAL
occurs due to autosplicing, which causes TRANSDUCTION [9]
translocation of BCR exon 1, exons 1-12/13, The tyrosine phosphoprotein kinase
or exons 1-19, respectively, to the c-ABL activity of p210BCR-ABL has been
gene on chromosome 9.These different causally linked to the development of Ph-
genes give rise to three distinct fusion chromosome–positive leukemia in man.
proteins of molecular mass 190, 210 and p210BCR-ABL is, unlike the ABL protein
230kD. These proteins contain the same that is located principally in the nucleus,
portion of the c-ABL tyrosine kinase in the located in the cytoplasm making it
COOH terminus but include different accessible to a large number of interactions,
amounts of Bcr sequence at the NH2 especially components of signal
terminus. transduction pathways. It binds and/or
Major (M-BCR): The e13a2 phosphorylates more than 20 cellular
(b2a2)/e14a2 (b3a2) fusion transcripts proteins in its role as an oncoprotein. The
encode for a 210-kDa protein. pathways and interactions invoked by BCR-
Minor (m-BCR): The e1a2 encodes for ABL acting on mitogen-activated protein
a 190-kDa protein (P190BCR-ABL). kinases are multiple and complex. [10]
Micro ( -BCR): The e19a2 encodes for A subunit of phosphatidylinositol 3'-
a 230-kDa protein (P230BCR-ABL) kinase (PI3K) associates with p210BCR-
Major BCR-ABL (M-BCR): More than ABL; this interaction is required for the
95% Ph-positive CML patients present with proliferation of BCR-ABL–dependent cell
a breakpoint in the M-BCR region. The lines and primary CML cells.
[11]
most common BCR-ABL transcripts in p210BCRABL regulates an RAF-
CML are e13a2 (b2a2) and e14a2 (b3a2). encoded serine-threonine kinase.
Two major breakpoints are found after the Downregulation of RAF expression is found
13th exon resulting in a b2a2 (e13a2) fusion to inhibit BCR-ABL–dependent growth of
or after the 14th exon resulting in a b3a2 CML. [12] Cell transformation by BCR-ABL
(e14a2) fusion. Both of these fusion is affected by an adaptor protein that can
mRNAs are translated into p210BCR-ABL relate tyrosine kinase signals to RAS. This
protein. The P210 form of BCR/ABL is involves growth factor receptor bound
found in hematopoietic cells of patients with protein-2 (GRB2). p210BCR-ABL has been
chronic myeloid leukemia (CML) in stable found to activate multiple alternative
pathways of RAS. PI3K is constitutively
International Journal of Science and Healthcare Research (www.ijshr.com) 7
Vol.5; Issue: 1; January-March 2020Namrata Bhutani. Chronic myeloid leukemia in India: a review
activated by BCR-ABL, generates inositol phosphorylates the common subunit of the
lipids, and is dysregulated by the IL-3 and GMCSF receptors and JAK2. Both
downregulation by BCR-ABL of ABL and BCR are also multifunctional
polyinositol phosphate tumor suppressors, regulators of the GTP-binding protein
such as PTEN and SHIP. [13] family Rho and the growth factor-binding
The adaptor molecule CRKL is a protein GRB2, which links tyrosine kinases
major in vivo substrate for p210BCR-ABL to RAS and forms a complex with BCR-
as it acts to relate p210BCR-ABL to ABL and the nucleotide exchange factor Sos
downstream effectors. CRKL is a linker that leads to activation of RAS. The
protein that has homology to the v-crk p210BCR-ABL activates Jun kinase and
oncogene product. Antibodies to CRKL can requires Jun for transformation.
immunoprecipitated paxillin. Paxillin is a Reactive oxygen species are
focal adhesion protein [14] that is increased in BCR-ABL–transformed cells.
phosphorylated by p210BCR-ABL. The These act as a second messenger to
p210BCR-ABL may be physically linked to modulate enzymes regulated by the redox
paxillin by CRKL. CRKL binds to CBL, an equilibrium. An increase in these reactive
oncogene product that induces B cell and oxygen products is also believed to play a
myeloid leukemias in mice. The Src role in the acquisition of additional
homology 3 domains of CRKL do not bind mutations through the chronic phase,
to CBL, but they do bind BCR-ABL. contributing to the progression to
Therefore, CRKL mediates the oncogenic accelerated phase. [16]
signal of BCR-ABL to CBL. The p210BCR-
ABL may, therefore, induce the formation STAGING OF CML
of multimeric complexes of signaling Chronic myeloid leukemia is divided into
proteins. These complexes contain paxillin three phases based on clinical characteristics
and talin and explain some of the adhesive and laboratory findings. In the absence of
defects of CML cells. intervention, CML typically begins in the
Hef2 also binds to CRKL in leukemic chronic phase and over the course of several
tissues of p190BCR-ABL transgenic mice. years progresses to an accelerated phase and
Hef2 is involved in the integrin signaling ultimately to a blast crisis.
pathway [15] and encodes a protein that Chronic phase: Approximately 85% of
accelerates GTP hydrolysis of RAS-encoded patients with CML are in the chronic
proteins and neurofibromin. The latter phase at the time of diagnosis. During
negatively regulates granulocyte-monocyte this phase, patients are usually
colony-stimulating factor (GM-CSF) asymptomatic or have only mild
signaling through RAS in hematopoietic symptoms of fatigue or abdominal
cells. Nuclear factor (NF)-B activation is fullness. The duration of chronic phase
also required for p210BCR-ABL mediated is variable and depends on how early the
transformation. Expression of p210BCR- disease was diagnosed as well as the
ABL leads to activation of NF B–dependent therapies used. Ultimately, in the
transcription via nuclear translocation. absence of curative treatment the disease
Cell lines that express p210BCR- progresses to an accelerated phase. It is
ABL also demonstrate constitutive characterized by peripheral blood blasts
activation of Janus-associated kinases fewer than 10% in the blood and bone
(JAKs) and signal transducers and activators marrow.
of transcription (STATs), usually STAT5. Accelerated phase: [16] WHO criteria
STAT5 is also activated in primary mouse define accelerated phase by
marrow cells acutely transformed by the Blasts in blood or marrow 10-19%
BCR-ABL. p210BCR-ABL co- Basophils in blood ≥ 20%
immunoprecipitates with and constitutively
International Journal of Science and Healthcare Research (www.ijshr.com) 8
Vol.5; Issue: 1; January-March 2020Namrata Bhutani. Chronic myeloid leukemia in India: a review
Persistent thrombocytopenia rapid progression and short survival.
9
(˂100˟10 /L) unrelated to therapy Blast crisis is diagnosed by the
CCA/Ph1 on treatment following criteria:
Thrombocytosis (˃1000 ˟ 109 /L) Blasts in blood or marrow ≥ 20%
unresponsive to therapy Extramedullary blast proliferation,
Increasing spleen size and increasing apart from spleen
white blood cell count unresponsive Large foci or clusters of blasts in the
to therapy. The accelerated phase is bone marrow biopsy
significant because it signals that the
disease is progressing and PROGNOSTIC SCORES
transformation to blast crisis is CML prognostic scoring systems stratify
imminent. patients into risk groups based on patient
Blast crisis in CML: [16] Blast crisis is and disease related characteristics at
the final phase in the evolution of CML diagnosis. [17] The table below mentions two
and behaves like an acute leukemia with of these prognostic scores.
TABLE 1: PROGNOSTIC SCORES FOR CML
S.NO. SCORE CALCULATION RISK DEFINITION BY CALCULATION
1. SOKAL Exp[0.0116*(age- Low risk ˂ 0.8
2
43.4)]+(0.0345*spleen size7.51)+[0.188*(platelet /700) )- Intermediate risk : 0.8-1.2
0.563]+[0.087*(blasts-2.10)] High risk : > 1.2
2. EUTOS Spleen*4+ basophils*7 Low risk ≤87 High risk ˃87
(European
Treatment and
Outcome Study)
THERAPY OF CHRONIC MYELOID statistically significantly higher with
LEUKEMIA [18] imatinib compared with the IFN–cytarabine
Before the advent of TKIs, treatment combination (87.1% vs 34.7%, respectively;
options included cytotoxic chemotherapy P< 0.001). The rate of freedom from
(cytarabine, busulfan, hydroxyurea) or IFN- progression to the accelerated phase at 18
α. These treatments are still valuable and months was also significantly higher in
potentially curative for patients who do not patients treated with imatinib than in those
respond to newer therapies. With the who received the IFN-α/ cytarabine
introduction of the Tyrosine Kinase combination (96.7% vs 91.5%, respectively;
Inhibitor, imatinib, the treatment and natural P< 0.001). Six- and eight-year follow-up of
history of CML has changed dramatically in patients who received imatinib in the IRIS
recent years, with an improvement in the 5- trial demonstrated an overall survival (OS)
year survival rate from little more than 20% rate of 88% and 85%, respectively. An
to over 90%.Imatinib was first approved in evaluation of data from the Imatinib
the USA in 2001 for the treatment of the LongTerm Side Effects trial has shown that
advanced phases of CML, although for patients who achieve a stable
guidelines currently recommend therapy to cytogenetic response (CyR) with imatinib,
be continued indefinitely. Imatinib was OS is 95.2% at 8 years and is not
established as the standard of care for statistically significantly different from that
patients with CP-CML based on the results of the general population.
of the International Randomized Study of Unfortunately, a significant
Interferon and STI571 (IRIS) trial. This trial proportion of patients respond suboptimally
included 1,106 patients newly diagnosed or have no response to imatinib and they
with CML who were randomized to either require an alternative treatment strategy to
imatinib or IFN plus cytarabine. After a prevent progression to the accelerated
median follow-up of 19 months, the major phase. In IRIS for example, at the 8-year
cytogenetic response (MCyR) rate was data cut-off 16% of patients had
International Journal of Science and Healthcare Research (www.ijshr.com) 9
Vol.5; Issue: 1; January-March 2020Namrata Bhutani. Chronic myeloid leukemia in India: a review
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