CHRONIC MYELOGENOUS LEUKEMIA PROGNOSIS AND EVOLUTION

Abstract

Chronic myelogenous leukemia (CML), a clonal myeloproliferative disorder, is characterized by a biphasic or triphasic course. The disease is diagnosed in chronic phase in over 80% of patients, 10% in accelerated phase and, another10% of patients in blast crisis.Tthe median survival in chronic phase with conventional chemotherapy is 35 to 65 months, being improved by the tyrosine kinase inhibitors-88% of patients at 72 months. The clonal evolution and genetic instability are the main causes of the progression of the disease in accelerated phase or blast crisis, in these conditions the survival rate being significantly lower.

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Bulletin of the Transilvania University of Braşov • Vol. 2 (51) - 2009
Series VI: Medical Sciences
CHRONIC MYELOGENOUS LEUKEMIA
PROGNOSIS AND EVOLUTION
A. ROŞCA1 C. ARION2 A. COLIłĂ2
L. NEDELCU3 C. SCÎRNECIU3
O. ANDREESCU3 I. PANTEA3
Abstract: Chronic myelogenous leukemia (CML), a clonal
myeloproliferative disorder, is characterized by a biphasic or triphasic
course. The disease is diagnosed in chronic phase in over 80% of patients,
10% in accelerated phase and, another10% of patients in blast crisis.Tthe
median survival in chronic phase with conventional chemotherapy is 35 to 65
months, being improved by the tyrosine kinase inhibitors-88% of patients at
72 months. The clonal evolution and genetic instability are the main causes
of the progression of the disease in accelerated phase or blast crisis, in these
conditions the survival rate being significantly lower.
Key words: Chronic Myeloid Leukemia, chronic phase, accelerated phase,
blast crisis, karyotypic/molecular evolution.
1 Doctoral in training of The University of Medicine and Pharmacy “C. Davila“ Bucharest; PDR-MEDIS Brasov.
2 Department of Hematology and Bone Marrow Transplantation “ Stefan Berceanu” – Fundeni Clinical
Institute Bucharest; University of Medicine and Pharmacy “Carol Davila “ Bucharest.
3 Transylvania University of Brasov – Faculty of Medicine.
1. Introduction
The chronic myelogenous leukemia
(CML) is a clonal myeloproliferative
disorder resulting from the neoplasic
transformation of the hematopoietic stem
cell [8]. The marker of the disease is the
reciprocal translocation between the long
arms of chromosomes 9 and 22 – t(9;22)
(q34.1;q11.21)- named the Philadelphia
chromosome, and present at 95% of the
newly diagnosed patients [20]. The
presence of the Philadelphia chromosome
in the cells of the patients diagnosed with
CML was for many years the single
specific cytogenetic anomaly associated
with a neoplastic disease. The result of the
translocation t (9;22) is the hybrid gene
BCR-ABL which codifies the p210 protein
with high level increase of tyrosine kinase
activity compared to the normal
homologue p145, determining an
uncontrolled cellular proliferation,
inhibiting the adherence of cellular
hematopoteic progenitors to the medullar
stroma and blocking the apoptosis [8].
2. Epidemiology
The disease has an incidence of 1-2 cases
at 100000 inhabitants per year in the
Western countries, representing
approximately 15% of the leukemia
incidences at adults. In Romania, there is
estimated to be around 200 new diagnosed
cases per year [4], [19], [20].
The average age at diagnosis is 55-60
years, less than 10% of cases being at
patients under 20 years, CML at children
representing under 2-3% from total
leukemia cases. A slight increase in the
number of the diagnosed patients with ages

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98
over 60 years has been observed lately.
The sex ratio male-female is of 1,3-1,4,
without noticing a difference in evolution
according to sex [8], [19], [20].
3. Diagnosis Evaluation
In order to confirm the diagnosis of chronic
myelogenous leukemia, to stage and estimate
the prognosis, a series of investigations are
essential :full blood count and peripheral film
examination, bone marrow aspirate and bone
marrow trephine biopsy, cytogenetic test (in
order to observe the Philadelphia cr. and the
possible additional chromosomal abnormalities)
and the qualitative and quantitative real time
PCR molecular test made in order to detect the
presence and the level of the BCR-ABL
transcript. The Fish testing is optional, if it is
made presents the advantage that it detects the
BCR-ABL gene by examining a large number
of cells from the peripheral blood, but as a
monitoring method for the therapeutic response
it is indicated only if the RQ-PCR test cannot be
performed [1], [9], [19].
Over 40% of CML cases are diagnosed
on the occasional routine check ups, the
patients being asymptomatic. The most
frequent manifestation in case of
symptomatic patients are: fatigability,
weight loss, nocturnal sweating, sensation
of gastric fullness, anorexia, pain in the left
hypochondrium determined b y the
splenomegaly, purpura [8], [19], [23]. The
typical blood tests modifications in the first
stages of the disease are: leucocytosis with
leukocyte formula deviated up to t he
stadium of myeloblast, anemia and
thrombosis [3], [8], [19].
4. Prognosis Factors
Some clinical factors (age, spleen size) and
laboratory factors (number of platelets and
leucocytes, percentage of blasts, basophiles
and eosinophils) have been included in two
prognosis systems for calculating the relative
risk (RR) from the debut of the disease - RR
Sokal (American prognostic score) and RR
Hasford (European prognostic score).
According to the risk classification – low,
intermediate, high – the cases with
unfavorable evolution may be identified from
the debut [10], [25].
Variables with prognostic significance in CML - After J. Corte, modified Table 1
Clinical Factors Factors Sssociated with the Treatement
Symptoms at diagnosis
Age
Race
Spleen size
Liver size
Hemoglobin level
White blood cell count
Platelet count
% nucleted red blood cells in peripheral blood
% Blasts in peripheral blood or bone marrow
%basophils in peripheral blood or bone marrow
% promyelocytes + % myelocytes in peripheral blood
% eosinophils in peripheral blood
Time from diagnosis
Variant Ph chromosome
Deletion of der(9)
Breakpoint site in the BCR gene
Expression of the BCR/ABL gene
Cytogenetic response
Molecular response
Time to achieve the response
Mielosupresion

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5. Evolution of the Disease
Chronic myelogenous leukemia is
characterized by a biphasic course, initially
a chronic phase and then a blast crisis,
passing from the initial stage to the final
one by an intermediate stage, the
accelerated phase.
The criteria of diagnosis in CML [3], [20] Table 2
CHRONIC PHASE ACCELERATED PHASE BLAST CRISIS
1. Leucocytosis with
leukocyte formula
deviated to the left
2. Absolute basophily ≤ 20%
3. Monocites ≤ 3%
4. Normal no. of
thrombocytes
5.
Minimal or absent
dysplastic modifications
COMPULSORY
CRITERIA
1. Blasts ≤ 15% *
2. Blasts + Promyelocytes ≤
30%*
* in peripheral blood and/or
in bone marrow
1. Non-infectious fever
1. Progressive splenomegaly
2. Anemia and
thrombocytopenia
3. Recurrent thrombocytopenia
4. Dysplastic modifications
5. Myelofibrosis grades I/II
COMPULSORY CRITERIA
1. Blasts 15-29%*
2. Blasts + Promyelocytes ≥
30%*
3. Basophiles ≥ 20%
* in peripheral blood and/or in
bone marrow
1. Fever > 38 C for 7 days
2. Loss of weight > 10%
3. Increase in the size of the
spleen > 25%
4. Anemia <10g/dl
5. Thrombocytopenia <100000/l
6. Leucocytes >50000/l
7. Reticulinic fibrosis in bone
marrow
COMPULSORY CRITERIA
1. Blasts ≥ 30% *
2. Extramedullary blastic tumors
3. Additional cytogenetic
anomalies
* in peripheral blood or in bone
marrow
CML is diagnosed in chronic phase in
over than 80% of cases, 10% representing
patients on accelerated phase at the
moment of diagnosis, while other 10% in
blastic crisis [4], [19], [20].
Survival with CML is determined b y
phase of the disease, but especially by the
risk and therapy factors. After the
progresses achieved in therapy (interferon,
allogeneic hematopoietic stem cell
transplantation, tyrosine-kinase inhibitors)
the evolution of CML has been modified,
and as a consequence must be analyzed
according to treatment.
5. Evolution in Chronic Phase
Under traditional treatment with
hydroxyurea, busulfan and/or cytosar, the
survival in chronic phase is of 35-65
months [4], [8]. On the basis of prognostic
score, the three relative risk groups – low,
intermediate and high – at 48 months with
classic chemotherapy have survival rates
of 62%, 43%, and respectively 33% [11].
Besides the fact that the survival of
patients treated with classic chemotherapy
proved to be similar to the patients that
were not treated or were subject only to
radiation therapy, with these therapies the
evolution of the disease cannot be kept
under control.

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Introduction in the 1980s of the
treatment with interferon alpha, by its
antiviral, immunomodulator,
antiproliferative and antiangiogenetic
effects, has provoked the suppression of
the Ph positive clone. The long term
survival under treatment with interferon
has been observed in cases with normal
values of hemoglobin, normal number of
platelets, low percentage of basophiles and
blastic cells in peripheral blood, normal
spleen size, these parameters being
detected at the moment of diagnosis.
Reported to the 3 relative risks groups
according to Hasford – low, intermediate
and high – the survival rate after 5 years is
of 76%, 55%, and respectively 25% [4],
[16]. Associated to the relative risk group,
the most important predictive factors for
the evolution and survival are the
cytogenetic type and molecular response,
as well as the time interval necessary to
attain these responses. Thus, from the
20-25% of patients with complete
cytogenetic response (CCR), 78% have
survived after 10 years [17]. The
synchronism between cytogenetic response
– molecular response allows an objective
appreciation of the evolution of the
disease. 48% of patients with CCR but
with a level of BCR-ABL/ABL ≥ 0,05%
(less than major molecular response) had a
relapse risk after 48 months [5].
Definition of cytogenetic and molecular responses [6] Table 3
CYTOGENETIC RESPONSE MOLECULAR RESPONSE
MINIMAL CYTOGENETIC RESPONSE
→ 66-95% Ph positive metaphase
MINOR CYTOGENETIC RESPONSE (mCR)
→ 36-65% Ph positive metaphase
PARTIAL CYTOGENETIC RESPONSE (PCR)
→ 1-35% Ph positive metaphase
MAJOR CYTOGENETIC RESPONSE (MCR)
→ 0-35% Ph positive metaphase
COMPLETE CYTOGENETIC RESPONSE
(CCR) → 0% Ph positive metaphase
MAJOR MOLECULAR RESPONSE (MMR):
Decrease with > 3 log in BCR-ABL level
The BCR-ABL/ABL level < 0,05%
COMPLETE MOLECULAR RESPONSE
(CMR)
Negative RT-PCR
The evolution of the CML diagnosed in
chronic phase was significantly modified
once with the discovery of tyrosine-kinase
inhibitors. Imatinib, first tyrosine-kinase
inhibitor used, connects to the inactive
form of ABL gene and acts by a
competitive antagonism of the ATP
binding site located in the tyrosine-kinase
P-loop of BCR-ABL gene, blocking the
transduction signal of cell increase.
According to IRIS trial, administered as
a first line therapy in precocious chronic
phase of CML (first 6 months), an overall
survival of 88% was determined after 72

Roşca, A. et al.: Chronic Myelogenous Leukemia Prognosis and Evolution
101
months of follow up [7]. In late chronic
phase, defined by resistance or intolerance
to rIFN α, the use of imatinib determined a
disease-free survival of 69% after 60
months. A particular aspect observed
during the studies was that in spite of the
CCR was not attained, the use of imatinib
increases the survival rate, even if
introduced in the late phase of the disease
[2]. Despite the efficiency of imatinib, 20-
30% of cases do not respond to this
therapy, the cause being either the primary
resistance to imatinib, or secondary.
According to the mechanism of resistance
– primary, secondary, BCR-ABL
dependent or BCR-ABL independent, the
use of the second line of tyrosine-kinase
inhibitors (dasatinib, nilotinib, bosutinib,
etc.) can stabilize the disease and increase
survival. The presence of T315I mutation,
resistance to the currently used therapies,
influences negatively the evolution of the
disease.
Allogeneic hematopoietic stem cell
transplantation, the only curative t herapy,
determined according to EBMT data
(European Bone Marrow Transplantation
Association) a survival rate of 34% after
20 years of surveillance [2].
6. Evolution of the Disease in
Accelerated Phase and Blast Crisis
Following a normal evolution of 2-4
years in chronic phase, CML progresses
either slowly in accelerated phase, with the
occurrence of medullar failure manifested
through anemia and thrombocytopenia, or
suddenly blast crisis [20]. Two thirds of
cases of blastic crisis are of myeloid type,
while one third is of lymphoid type.
With all the therapeutic progresses made
in the previous years, the advanced phase
of CML is characterized in most of the
cases by a significantly reduced survival
rate, of only 1-2 years in accelerated phase
and of only 3-12 months in blastic crisis
[4], [8]. There has been noted a survival of
51% after 5 years in those cases where
alpha interferon has suppressed the
evolution of the disease [5]. The survival
rate is slightly increased when imatinib in
a dose of 600mg/day induces an early
major cytogenetic response [26].
The evolution of the disease is
determined by the clonal evolution, gene
amplification and the occurrence of new
mutations.
Clonal evolution is present at 20-40% of
patients passing from the chronic phase in
the accelerated phase [4]. Although in
most of the cases, in the chronic phase of
CML the only chromosomal anomaly is t
(9;22), there are 5-10% cases that associate
variants of t(9;22). All the same, derived
deletions of 9 chromosome – der (9) – are
met in 10-15% of patients with CML in
chronic phase and represent modifications
at the level of the long left arm of 9
chromosome, adjacent to the break point
occurred in the t(9;22) translocation. These
anomalies, as well as the persistence and
reoccurrence of the t(9;22) under the
treatment with tyrosine kinase inhibitor,
induce a chromosomal instability correlated
with an increased risk of the disease
transformation and a reduced survival rate
[18]. Most frequent chromosomal
anomalies associated to the clonal evolution
are: trisomy 8 (30-40% of cases),
occurrence of the second Ph chromosome
(20-30% of cases), isochromosome 17 and
other anomalies of 17 chromosome
(15-20% of cases) [4], [18].
The gene amplification and the
occurrence of new punctiform mutations in

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different regions of the tyrosine kinase
domain of BCR-ABL gene are the main
factors which determine the progression of
the disease, the genetic instability
contributing to the increased speed of the
disease transformation [20]. The
expression of the BCR-ABL gene fusion
determines the activation of multiple signal
paths inside the cell, as Ras, Rac, p42 and
p38 MAPK, JNK/SAPK,
PI3K(phosphatidilinositol-3 kinase), Akt,
NF-kB and JAK/STAT [12], [13], [27].
The inactivation of p53, p16 (codified by
CDKN 2A gene, with regulatory role for the
cellular progression) and Rb genes, as well
as the over expression of EVI gene, Ikaros
and PAX5 deletions are correlated with the
progression of CML in accelerated phase
[22]. Modifications in p53 were observed in
5% of cases, N-Ras and Ki-ras mutations
observed in other 5% of cases that evolved to
the acute phase of CML [24]. Ikaros
deletions are frequently met in 60%, in the
Ph+ cells at patients with progression of
disease [20].
The inadequate secretion of growth factors
as IL-1b, IL-6, stimulation factor for the
granulo-monocyte colonies, also contributes
to the unfavorable progression of CML,
determining a decrease in the adherence of
progenitors to medullar stroma.
7. Conclusions
The progression of chronic myelogenous
leukemia has registered modifications once
with the introduction of the therapy with
tyrosine kinase inhibitors. Thus, from a
survival of maximum 65 months in the
past, at the moment the IRIS trial shows a
survival of 88% after 72 months. The
prognosis is still reserved in the advanced
phases of the disease, the progression
leading inexorably to death. The precocious
diagnosis in chronic phase, as well as
identification of risk factors from the debut
of the disease allows an improvement in the
progression and global survival.
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