A significance of additional chromosomal aberrations and other variables
on post transplantation outcome of patients with CML*
V. VRANOVÁ1
, S. KATINA2
, G. KIRSCHNEROVÁ1
, M. MISTRÍK3
, J. LAKOTA4
, J. HORÁKOVÁ5
, A. TÓTHOVÁ1
1
Department of Genetics, e-mail: vlavra@post.sk, National Cancer Institute, 833 01 Bratislava, Slovak Republic; 2
Department of
Probability and Mathematical Statistics, Faculty of Mathematics, Physics and CS, Comenius University, Bratislava, 3
Department of
Hematology and Transplantation, University Hospital of st. Cyril and Method, Bratislava, 4
BMT Unit, National Cancer Institute,
Bratislava, and 5
BMT Unit, Children’s Hospital, Bratislava, Slovak Republic
Received February 2, 2005
Chronic myeloic leukemia (CML) is a malignant disease of hematopoietic stem cell characterized by the bcr/abl gene rearrangement.
Allogeneic transplantation of stem cells (SCT) is a routinely used treatment method of patients with this diagnosis
and remains the only curative mode of treatment.
From January 1990 to December 2002 78 patients with CML underwent allogeneic transplantation and were examined at
the Department of Genetics in the National Cancer Institute in Bratislava. Using conventional cytogenetic and FISH 6 patients
(7.7%) showed additional chromosomal changes before SCT. These patients had statistically worse post transplantation
prognosis compared to the patients without additional changes before SCT (mean survival in month ±standard error
(58.08 (±6.70) vs. 5.17 (±0.98), p-value = 0.001), patient mortality (67% vs. 31%)). In addition five other variables were
evaluated for transplant outcome, namely, patient’s age at the time of transplantation, sibling or non-sibling donor, higher
than 1st chronic phase of CML, time from diagnosis to transplantation and sex of donor and recipient. Only the comparison
of HLA-identical sibling transplantation to unrelated donor transplantation was statistically significant (mean survival in
month – 56.6 (±7.2) vs. 13 (±0.0), patient mortality 31% vs. 67%).
Key words: chronic myeloic leukemia (CML), allogeneic stem cell transplantation (SCT), additional chromosomal
aberrations, post transplantation outcome, survival analysis
Chronic myeloid leukemia (CML) is a myeloproliferative
disorder resulting from clonal expansion of the progeny of a
malignant hematopoietic stem cell [37]. It comprises about
15–20% of all leukemias and affects 1–2 people in every
100,000 population per year [5, 10, 37]. In approximately
95% cases it is connected with a Philadelphia (Ph) chromosome
[27], which originates from the reciprocal translocation
of the bcr gene on 22q11 and the abl gene on 9q34 [32]. The
molecular consequence is BCR/ABLfusion protein, which is
a constitutively active cytoplasmic tyrosine kinase [6, 15,
16]. The structure of this protein allows multiple protein-protein
interactions and suggests the involvement of diverse
intracellular pathways [10, 37].
Three to five years after onset, CML progresses from relative
benign chronic phase (CP) to accelerated (AP) and blast
phases (BP) [10, 29, 34]. During the progression a range of
additional chromosomal changes occurs. These additional
abnormalities are very important in disease progression [3,
35] and can be taken as a prognostic indicator – because of
their occurrence before hematological and clinical symptoms
[4, 15]. About 71% of patients in BP have at least one of the
following anomalies: +8, i(17q), +19, +9 or extra Ph-chromosome
[5, 15]. About 15% of patients have –7, –17, +17,
+21, –Y or t(3;21)(q26;q22) [4, 15]. These cytogenetic
changes correlate with changes on the molecular level,
mainly activation of oncogenes and deactivation of tumor-suppressor
genes.
Beside many therapies including conventional chemotherapy
with hydroxyurea or busulfan, interferon alpha (INFα),
STI 571, allogeneic stem cell transplantation (SCT) is routinely
used as therapeutical method for patients with CMLdiagnosis
[9, 19, 40, 41]. Most allogeneic transplantations are
performed from HLA-identical related donors (MSD – match
NEOPLASMA, 52, 5, 2005 381
*
This paper was partially supported by grants from the Slovak Grant
Agency (VEGA, projects 1/7154/20 and 1/0272/03).
sibling donor), HLA-matched unrelated donors (MUD –
match unrelated donor) from transplantation-registries are
also accomplished [25, 30]. Allogeneic transplantation is
connected with many post transplantation complications
(GvHD – Graft vs. Host Disease, rejection of transplantate,
complications associated with immunosuppression), and it’s
successfull performance depends on many risk variables (e.g.
patient’s age in the time of transplantation, phase of CML,
time from diagnosis to transplantation) [13, 33], but it is the
only means of curing CML [2, 8, 11, 12, 33, 36].
In our study we analysed data of 78 CML patients that underwent
allogeneic transplantation examined at Department
of Genetic of National Cancer Institute in Bratislava in
1990–2002 and determined negative influence of additional
chromosomal changes presented before transplantation to
their post transplantation outcome. The transplantation from
sibling donor compare to unrelated donor was registered as a
good prognostic assumption. The age of patient in the time of
transplantation, phase of CML, time from diagnosis to transplantation
and sex of donor and recipient has no statistically
significant value on post transplantation outcome. So we
confirmed the conclusions of many similar studies in our relative
big and long time frame watched set of patients.
Patients and methods
Patient characteristics. Between January 1990 and December
2002, 589 patients with diagnosis CML were examined
at Department of Genetic of National Cancer Institute in
Bratislava. 78 patients were chosen from this group (13.2%)
(75 adults and 3 children) that underwent allogeneic transplantation
of hematopoietic stem cell and whose peripheral
blood (PB) and/or bone marrow (BM) were examined prior
to and after the transplantation. The transplantations were
performed at Hematology and Transplantation Clinic in
Bratislava, at National Cancer Institute in Bratislava and at
2nd Children’s Clinic, Bone Marrow Transplantation unit in
Bratislava.
Methods. Patients were examined at least by one of three
genetic methods – classical cytogenetics, FISH and RT-PCR.
RT-PCR was mainly used to demonstrate t(9;22)(q34;q11.2).
The intervention by RT-PCR and FISH was limited, because
of the later introduction of these methods (in 1995 and 1997)
to our laboratory. Data were collected and evaluated.
Classical cytogenetics. The samples for classical cytogenetics
were cultivated 24 or 72 hours in a standard manner.
Chromosome preparations were made using standard
G-banding technique. A minimum of 20–30 metaphases (depending
on the sample quality) were analyzed and the
karyotype was described according to ISCN [17]. The chromosome
aberration was considered as clonally, if there were
found two and more cells with the same rearrangement or
three and more cells with the same aneuploidity.
Fluorescence in situ hybridization (FISH) analysis. In
fluorescence in situ hybridization study were used probes
directly labeled with SpectrumOrangeTM
respectively
SpectrumGreenTM
fluorochromes. LSI bcr/abl dual color ES
probe was used to identify t(9;22)(q34;q11.2), SO LSI p53
probe to identify rearrangements of chromosome 17 and
CEP®8
SpectrumOrangeTM
probe to identify numerical
changes of chromosome 8. The probes were provided by
VYSIS, Inc. Blue DAPI was used as a counterstaining. The
FISH procedure was performed according to manufacturer’s
instructions.
Reverse transcriptase-polymerase chain reaction (RT-PCR)
analysis. Total RNA was extracted from PB and/or BM samples
by the TRIzol Reagent (Gibco BRL, USA). PCR amplification
was performed with two sets of primers. The first –
external – primer set included primers
5’GAAGTGTTTCAAGCTTCTCC 3’ and
5’GTTTGGGCTTCACACCATTCC 3’.
The second – internal primer step included primers:
5’CAGATGCTGACCAACTCGTGT3’ and
5’TTCCCCATTGTGATTATAGCCTA3’ [7].
The PCR product was analyzed on 2% agarose gel.
Survival analysis. Survival analysis was performed considering
patients’ karyotype determined prior to transplantation.
The influence of another variables on post transplantation
outcome was also evaluated: the age of patient in the
time of transplantation, phase of CML, sex of donor and recipient,
time from diagnosis to transplantation, transplantation
from HLA-identical sibling or unrelated donor.
We evaluated the mean survival (months), defined as a survival
from performance of SCT to the end of study or to the
patient’s death; and the standard error, range and median of
survival. Patients’ mortality is defined as a share of death patients
to all patients in the group in the time of study (%). The
data were statistically evaluated by log-rank test to compare
survival curves (Mantel-Haenszel test, α=0.05) [22].
Results
Patients. Total amount of 589 patients with CML diagnosis
examined at Department of Genetic of National Cancer
Institute in Bratislava comprised 332 men and 257 women
(ratio 1.29 for men).
From these were chosen 78 patients that underwent allogeneic
stem cell transplantation (SCT). The mean survival
was 93.00 (±7.20) months (range: 1–138 months) and probability
of death 26/78. Mortality of patients reached 33.3%
(26/78). The main cause of death were posttransplantation
complications. Characteristics of patients are provided in Table
1.
Determination of karyotype of each patient. Using classical
cytogenetics, the karyotype of each patient was determined
and patients were divided into two main groups:
1. patients without additional chromosomal aberrations,
2. patients with additional chromosomal aberrations.
FISH and RT-PCR were used as additional methods to
classical cytogenetics.
382 VRANOVÁ, KATINA, KIRSCHNEROVÁ, MISTRÍK, LAKOTA et al.
Before allogeneic transplantation, PB and/or BM samples
of 78 patients were examined. In two cases we were not able
to perform examination. These two patients were excluded
from study of karyotype determination. The karyotypes of all
examinated patients are provided in Table 2.
Survival analysis considering the additional chromosomal
aberrations. The brief characteristics of post transplantation
outcome and statistic evaluation of two groups of allogeneic
transplanted patients is shown in Table 3 and survival curves
in Figure 1.
Survival analysis with regard to another variables influencing
post transplantation outcome. The influence of five
variables – the age of patient in the time of transplantation,
phase of CML, sex of donor and recipient, time from diagnosis
to transplantation, transplantation from HLA-identical
sibling or unrelated donor – established by GRATWOHL et al
[13] – was investigated in all 78 patients treated by allogeneic
transplantation.
The brief characteristics of post transplantation outcome
and statistic evaluation in each group of five variables is provided
in Table 3 and survival curves in Figures 2–5.
Discussion
Chronic myeloic leukemia is the best-characterized leukemia
at a molecular level. The studies in recent years have
helped to define further the molecular events involved in its
initiation and progression and relating to clinical manifestations,
the course of the disease, and therapeutic interventions.
In our study, six patients (7.7%) showed additional chromosomal
changes in karyotype. We documented their negative
influence to the post transplant outcome together with
negative influence of unrelated donor
compared to sibling donor.
Additional chromosomal changes
were detected only with simple
t(9,22)(q34;q11). Half of all detected
additional changes belonged to the
group of common additional chromosomal
aberrations [5, 15, 18]. Although
chromosome 19 was changed
in one case, we did not detect any
+19, which is described as one of the
frequent changes. Similar, additional
chromosomal aberrations belonging
to the minor group changes associated
with CML progression [4, 15]
were not detected. On the other hand,
we detected +6 in two cases (Tab. 2).
This aberration was not mentioned in
any available literature as the main
aberration associated with CML.
Post transplantation prognosis was
better for the patients without additional
changes compared to patients
AN ADDITIONAL CHROMOSOMAL ABERRATIONS IN TRANSPLANTED CML 383
Table 1. Patients’ characteristics
Number 78
Age (yrs)
Average 36
Range (8 – 59)
Sex of donor and recipient
M / M 27
F / F 14
F / M 14
M / F 23
Phase of CML
1st
CP 67
AP 3
BP 5
2nd
CP 3
Time from diagnosis to transplantation
< 1 yr. 49
> 1 yr. 29
Type of transplantation
MSD 72
MUD 6
Source of stem cells
BM 68
PBCS 10
Survival in time of study
Alive 52
Dead 26
M – male, F – female, yr – year, CP – chronic phase, AP – accelerated phase,
BP – blast phase, BM – bone marrow, PBSC – peripheral blood stem cells.
Table 2. The karyotypes of the patients determined before allogeneic transplantation
Group
Number of
patients
Description Karyotype
1. without additional aberrations 63 Simple translocation 46,XY/XX,t(9;22)(q34;q11.2)
2 Translocation bcr/abl
determined only at
molecular level 46,XY,t(9;22)(q34;q11.2)
5 Variant form of
translocation
46,XY/XX,t(9;V;22)
2. with additional aberrations 3 Common additional
changes
46,XX,t(9;22)(q34;q11.2), i(17q)
46,XY,t(9;22)(q34;q11.2), i(17q)
47,XY, t(9;22)(q34;q11.2),+Ph
3 Other additional
changes
46,XY,t(9;22)(q34;q11.2)/
46,XY,t(6;17)(q21;q22)
46,XY,t(9;22)(q34;q11.2)/
46,XY,t(9;22)(q34;q11.2),del (10p)
46,XX,t(9;21)(q34;q11.2)/
47,XY,t(9;22)(q34;q11.2) +6
with these changes (p-value = 0.001) (Tab. 3). Our results
support a theory of the prognostic significance of specific
cytogenetic aberrations for both types of transplantation and
also for any single diagnosis [38].
We did not detect any statistical difference between subgroups
(simple translocation, translocation at molecular level
and variant translocation) in the group of patients without additional
changes (data not shown). This supports the contention,
that patients with variant form of t(9;22)(q34;q11.2) [18,
36], and patients with translocation detected only at molecular
level [26, 36] have not worse post transplantation prognosis
compared to patients with simple t(9;22)(q34;q11.2).
We also did not detect statistically significant difference in
post transplantation outcome among patients with common
additional changes and other changes (data not shown), although
by KONSTANTINIDOU et al [21] have patients with
other than common additional changes worse prognosis.
The result of allogeneic CML transplantations depends on
many other variables [13]. One of them is the age of patient in
the time of transplantation. Some authors [13, 23, 36, 41]
state, that allogeneic transplantation should be performed before
the 40th year of age, the risk of failure increases with
higher age. We did not register statistically significant difference
(p-value = 0.466 ns) (Tab. 3) between patients underwent
transplantation before 20th year of age, between 20th
and 40th and after 40th year of age.
The second risk variable is the phase of CML. The recipient
should be in the CF [13, 23], with advanced AF or BF
successful performance of transplantation drops. We detected
higher mortality of patients that underwent
transplantation in higher than CF, but statistical comparison
of these two groups was not significant (p-value = 0.272 ns)
(Tab. 3). However, we want to bring your attention to the
very different rate of these groups.
The questionable risk variable that influences post transplantation
outcome is the time interval from diagnosis to the
transplantation. Some authors [1] consider the risk time 6
months after diagnosis, others [20] 3 years and more.
GRATWOHL et al [13] in 1998 stated as the risk time for transplantation
performance more than 1 year after diagnosis and
we also chose this time to compare post transplantation outcome.
Although, we detected higher mortality in patients
transplanted after 1 year from diagnosis, considering the statistical
comparision (p-value = 0.256 ns) (Tab. 3) we can say,
that allogeneic transplantation performed more than 1 year
after diagnosis has no negative influence on post transplantation
outcome.
GRATWOHL et al [13] also considered as a risk group the
men transplanted by women donors. The probable reason is
minor alloantigens, which also affect the growth of a marrow
transplant in a nonsyngeneic host and its tolerance of the
transplant recipient. The human Y chromosome encodes a
minor alloantigen, termed H-Y, which is expressed on the human
male hematopoietic cells and can be targeted by
cytotoxic T cells. The decreased risk of rejection and increased
likelihood of GvHD associated with marrow allo-
384 VRANOVÁ, KATINA, KIRSCHNEROVÁ, MISTRÍK, LAKOTA et al.
Table 3. Survival analysis of allogeneic transplanted CML patient with regard to additional changes and other five variables
Variables
Range Survival (months)
Probability of Death Patient’s Mortality Test-Statistics
Mean ± Standard error Median
Additional Changes
Without Additional Changes 70 58,08 ± 6,70 38,00 49/72 31,4 % (22/70) χ2
= 13, df = 1
With Additional Changes 6 5,17 ± 0,98 5,50 6/6 66,7 % (4/6) p-value = 0,001***
Patient´s Age
<20 yrs 6 28,2 ± 7,89 29,50 6/6 17 % (1/6) χ2
= 1,50, df = 2
> 20 < 40 47 60,0 ± 9,0 38,00 28/43 34 % (16/47) p-value = 0,466 ns
> 40 yrs 25 57,5 ± 10,56 39,00 15/23 36 % (9/25)
Phase of CML
1st
CP 67 60,4 ± 7,13 39,00 43/65 27 % (20/67) χ2
= 1,20, df = 1
Higher phase 11 33,9 ± 15,02 8,00 6/7 55 % (6/11) p-value = 0,277 ns
Time from Diagnosis. to SCT
< 1 yr 49 62,8 ± 8,18 45,00 31/47 22 % (11/49) χ2
= 1,30, df = 1
> 1 yr 29 43,9 ± 9,81 13,00 18/25 52 % (15/29) p-value = 0,256 ns
Sex of Recipient and Donor
M/M 27 56,2 ± 10,12 42,50 17/26 34 % (10/27)
M/F 23 26,3 ± 7,11 8,50 17/20 52 % (12/23) χ2
= 7,30, df = 3
F/M 14 67,9 ± 15,98 50,00 8/13 21 % (3/14) p-value = 0,062 ns
F/F 14 67,7 ± 11,11 51,00 7/13 7 % (1/14)
Type of SCT
MSD 72 56,6 ± 7,2 50,00 10/16 31 % (22/72) χ2
= 7,50, df = 1
MUD 6 13,0 ± 0,0 13,00 1/1 67 % (4/6) p-value = 0,006***
yrs – years, CP – chronic phase, M – male, F – female.
grafts from female donors administered to male recipients
may reflect in vivo responses to this minor alloantigen [31].
In our study, mortality of male recipients transplanted by female
donors reached 52%. Relaps of CML was deathly only
in one case. However, statistical comparison did not detect
any significant difference (p-value = 0.062 ns) (Tab. 3). We
can note, that sex of donor and recipient has no significant influence
on post transplantation outcome in our study.
Very important risk variable is a relationship between donor
and recipient of hematopoietic stem cells [13, 23]. Only
30–40% candidates to allogeneic transplantation have suitable
sibling donor [30]. Another possibility is a performance
of HLA-identical unrelated transplantation. The EBMT (The
European Group for Blood and Marrow Transplantation)
documented the 19% rate of unrelated allogeneic transplantation
in 1998. The low rate of the unrelated transplantation in
our sets of patients (8%) can be caused by expensiveness of
AN ADDITIONAL CHROMOSOMAL ABERRATIONS IN TRANSPLANTED CML 385
time of surviving in months
proportionsurviving
0 20 40 60 80 100 120 140
0.00.20.40.60.81.0
<20yrs
>=40yrs
>=20 & <40yrs
time of surviving in months
proportionsurviving
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
CF. 1
higher
time of surviving in months
proportionsurviving
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
Without AC
With AC
time of surviving in months
proportionsurviving
0 20 40 60 80 100 120 140
0.00.20.40.60.81.0
<1yr
>=1yr
Figure 2. Survival curves of allogeneic transplanted CML patients –
comparison with regard to the age of patient at the time of transplanta-
tion.
Figure 1. Survival curves of allogeneic transplanted CML patients –
comparison of patients without additional changes (without AC) to patients
with additional changes (with AC).
Figure 3. Survival curves of allogeneic transplanted CML patients –
comparison with regard to the phase of CML.
Figure 4. Survival curves of allogeneic transplanted CML patients –
comparison with regard to the time from diagnosis to transplantation.
Figure 5. Survival curves of allogeneic transplanted CML patients –
comparison with regard to the sex of recipient and donor (M – male, F –
female).
time of surviving in months
proportionsurviving
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
M-M
M-F
F-M
F-F
thus intervention, search for suitable donor in international
registers and more detailed and pretentious HLA-typing [25].
CML is the most common diagnosis in case of unrelated
allogeneic transplantation and comprise 35% of all performed
unrelated allogeneic transplantations [24]. Depending on our
results of statistical analysis of patients underwent transplantation
from sibling vs. unrelated donor (p-value=0.006) (Tab. 3)
we can decide, together with other authors [2, 14, 39, 42],
that patients with suitable sibling donor (MSD) have better
post transplantation prognosis compared to patients transplanted
from unrelated donors (MUD). The reason is higher
risk of post transplantation complications by unrelated transplantation,
which can cause death of patient [28].
Allogeneic transplantation is connected with many post
transplantation complications. It’s successful performance
depends not only on the presence of additional changes, but
also on many risk variables. However, together with many
other authors [2, 8, 11, 12, 33, 36] we can mention that it is
the only means of curing CML.
We would like to thank to MUDr. B. CZAKO and MUDR. M. HRUBIŠKO,
CSc. from Clinic of Hematology and Transfusiology in
Bratislava for their readiness with problems solving and also to all
co-workers from department of genetics of National Cancer Institute
namely RNDr. K. MARKOVÁ, MGR. M. ŠUJANOVÁ, MGR. A.
ŽÁKOVIČOVÁ and MUDr. D. ILENČÍKOVÁ, PhD.
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