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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1732-1737
Elevated Serum Thymidine Kinase Levels Identify a Subgroup at High
Risk of Disease Progression in Early, Nonsmoldering Chronic
Lymphocytic Leukemia
By
Michael Hallek,
Irmgard Langenmayer,
Christoph Nerl,
Wolfgang Knauf,
Hermann Dietzfelbinger,
Dagmar Adorf,
Marianne Ostwald,
Raymonde Busch,
Ingrid Kuhn-Hallek,
Eckhard Thiel, and
Bertold Emmerich
From the Medizinische Klinik, Abteilung für Hämatologie
und Onkologie, Klinikum Innenstadt,
Ludwig-Maximilians-Universität München; Städtisches
Krankenhaus München Schwabing; I. Medizinische Klinik und
Poliklinik, Abteilung für Hämatologie und Onkologie,
Institut für Medizinische Statistik und Epidemiologie, Technische
Universität München; Medizinische Klinik III mit
Schwerpunkt Hämatologie, Onkologie und Transfusionsmedizin,
Universitätsklinikum Benjamin Franklin der Freien
Universität Berlin, Germany.
 |
ABSTRACT |
Chronic lymphocytic leukemia (CLL) shows a remarkably heterogeneous
clinical outcome; survival ranges from several months in advanced
stages to more than 10 years in early stages. The Binet and Rai staging
systems distinguish three major prognostic subgroups, but do not
accurately predict the individual risk of disease progression in early
CLL (Binet stage A or Rai stage 0 to II). Because most newly diagnosed
CLL patients present with early disease, it seems desirable to search
for additional prognostic factors to identify early CLL patients at
high risk of rapid progression. It has been shown that elevated serum
thymidine kinase (s-TK) levels predict disease progression in CLL.
Therefore, this study aimed to assess the prognostic value of s-TK in
122 previously untreated patients with Binet stage A CLL (mean age ± SD, 58.7 ± 8.5 years). In univariate analyses, 18 of the 22 parameters investigated predicted progression-free survival (PFS). In a
stepwise multiple regression analysis, only three parameters provided
independent prognostic information on PFS: s-TK greater than 7.1 U/L;
presence of lymphadenopathy; and white blood cell (WBC) count greater
than 75,000/µL. When added to the classification of smoldering versus nonsmoldering CLL, s-TK levels separated two groups within the group of
nonsmoldering stage A patients: patients with s-TK values greater than
7.1 U/L had a median PFS of 8 months, whereas patients with s-TK values  7.1 U/L expected a much longer PFS (49 months; P < .001),
similar to smoldering CLL (42 months). The results demonstrate that
s-TK is a prognostic parameter that adds independent prognostic
information to the definitions of smoldering and nonsmoldering CLL in
Binet stage A.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) is a
markedly heterogeneous disease with regard to its prognosis and
clinical course. Several staging systems have been
proposed1-3 that identify three major prognostic subgroups
and guide the treatment decision. There is general agreement that only
patients with advanced Binet or Rai stages require
chemotherapy.4-6 Patients with early CLL, ie, Binet stage A
or Rai stages 0 to II, do not usually receive treatment until
progression. However, approximately 30% to 40% of patients with early
CLL show a short progression-free survival (PFS)5 and might
benefit from early and/or intensified treatment. Unfortunately,
the current staging systems for CLL are not able to identify these
early CLL cases at high risk for progression.7 Therefore,
this study aimed to investigate whether novel prognostic factors might
assist in the identification of a high-risk category of early CLL.
It has been shown that elevated levels of serum thymidine kinase (s-TK)
predict a high risk of disease progression in low-grade non-Hodgkin's
lymphoma and CLL.8-14 In CLL and immunocytoma, s-TK seems
to provide prognostic information that is independent of the Binet
staging system.15 The present prospective clinical study
investigated the prognostic value of s-TK in 122 patients with
previously untreated early CLL (Binet stage A, Rai stage 0 to II). The
results demonstrate that s-TK is a parameter that adds independent
prognostic information to the definitions of smoldering and
nonsmoldering CLL in Binet stage A.
| |
MATERIALS AND METHODS |
Patients.
Between January 1987 and October 1992, 122 previously untreated
patients with CLL Binet stage A who presented to one of the four
participating study centers (Medizinische Klinik, Universität München, and I. Medizinische Klinik, Technische Universität München; Städtisches Krankenhaus München-Schwabing;
Klinikum Benjamin Franklin, Freie Universität Berlin, Germany)
were included. Informed consent was obtained from all patients.
Histopathologic diagnosis of CLL was established from bone marrow or
lymph node biopsies according to the Kiel
classification.16-18 Bone marrow histology was obtained
from 106 patients at diagnosis. Several patients were included in the
study some time after the diagnosis was established. The mean interval ± SD from diagnosis to inclusion in the study was 30.8 ± 5.75 months. There was a male preponderance of 71:51 (Table
1). Mean age ± SD was 58.7 ± 8.5 years (Table 1). Staging was performed according to the Binet
staging system, and only patients with Binet stage A were included in
the study.1 Eighteen patients (15%) were treated with
interferon- after inclusion in the study on a randomized multicenter
trial.19 The median observation time of all patients
evaluable by October 1996 was 36 months. Further characteristics of the
patients are listed in Table 1.
Staging and other tests.
Routine laboratory studies of these patients were performed at
inclusion in the study and consisted of complete blood cell count with
differential, platelet count, and blood chemistry, including serum
lactate dehydrogenase (s-LDH). Peripheral blood mononuclear cells were
analyzed by immunophenotyping to establish the diagnosis of typical
CD5+ CLL. At inclusion in the study, a complete physical
examination, chest x-ray, and abdominal ultrasound were performed. A
bone marrow biopsy was performed at study entry in 106 patients (Table
1). Computed tomographic scans of the abdomen and pelvis were performed if clinical symptoms required a more thorough investigation of thoracic
or abdominal organs. The physical performance status was determined
according to the Eastern Cooperative Oncology Group (ECOG) score. Sera
from patients obtained at inclusion in the study were stored at
 20°C until further analysis for s-TK and serum
 2-microglobulin (s-2M). The TK assay was
performed with a commercially available radioenzyme assay (Prolifigen;
Sangtec Medical, Bromma, Sweden).20 The TK activity is
expressed in units per liter. Control values of s-TK as determined in
22 healthy young adults were 3.8 ± 0.9 U/L (mean ± SD; range,
2.2 to 6.0). For TK values, the intraassay variability was between
5.4% and 7.5%, and the interassay variability between 5.7% and
8.3%. S-2m levels were determined with a
radioimmunoassay (Isotopen Diagnostik CIS GmbH, Dreieich, Germany).
Prognostic parameters.
The following prognostic parameters were evaluated at inclusion in the
study: age, sex, performance status (ECOG score), white blood cell
(WBC) count, peripheral blood lymphocyte count, peripheral blood
neutrophil count, platelet count, blood hemoglobin, s-LDH, s-2M, s-TK, serum creatinine, presence of
lymphadenopathy, time from diagnosis to inclusion in the study, serum
immunoglobulin levels (IgA, IgM, and IgG), presence of hepatomegaly,
presence of splenomegaly, bone marrow histology (nodular v
nonnodular infiltration), Rai stage, and lymphocyte doubling time
according to the method of Montserrat et al.21 Because some
patients were treated with interferon- 2b in a randomized
trial,19 interferon- treatment was also analyzed as a
prognostic variable.
Evaluation of disease progression.
It has been shown that the time to disease progression has an important
impact on survival of early-stage CLL patients.22 Therefore, this parameter can be used to shorten the duration of
clinical studies in early CLL (Binet stage A or Rai stages 0 to II),
because it is a valuable surrogate end point for overall survival.
Disease progression was assessed as described.19
Progressive disease was defined by an increase of the size of lymph
nodes or liver or spleen by greater than 50%, the appearance of new enlarged nodes or new hepatomegaly/splenomegaly, the increase of
peripheral lymphocyte counts to greater than 100,000/µL, transition from stage A to B or C, or transformation to prolymphocytic leukemia or
high-grade lymphoma (Richter's syndrome). Follow-up examinations were
scheduled every 3 months in the first year after inclusion in the study
or more often if the clinical situation indicated a rapid disease
progression. After the first year, the follow-up interval was 6 months.
Statistics.
Statistical analysis was performed with the SPSS program version 7.5 (SPSS Inc, Chicago, IL). PFS was estimated by the method of Kaplan and
Meier.23 Continuous variables were dichotomized with
optimal cut-off values using the classification and regression trees
(CART) method.24 Cox multiple regression analysis was performed to determine the independent contribution of the
variables.25 Correlations were assessed by the Spearman
rank test.
| |
RESULTS |
s-TK levels, presence of lymphadenopathy, and WBC counts independently
predict time to disease progression.
The cut-off values of 22 prognostic parameters investigated were
determined by the CART analysis (Table 2).
All parameters except age, sex, ECOG score, and presence of
hepatomegaly showed a statistically significant relationship with PFS
(P < .05). Using the cut-off values determined by the CART
analysis, a stepwise multiple regression analysis was performed. Only
three parameters provided independent prognostic information: (1) s-TK
greater than 7.1 U/L, (2) presence of lymphadenopathy, and (3) WBC
count greater than 75,000/µL (Table 2). s-TK values showed a weak
correlation with lymphocyte counts or WBC counts ( = .28; P < .05; Spearman rank test). Figure 1
demonstrates that each of the three independent prognostic variables
was able to separate two subgroups within Binet stage A that had a
different time to disease progression. For patients with high versus
low s-TK values, the median PFS duration was 9 (range, 5 to 13) versus
49 (range, 24 to 74) months (P < .001; Fig 1A). For patients
with high versus low leukocyte counts, PFS was 3 (range, 2 to 4) versus
34 (range, 9 to 49) months (P < .001; Fig 1B). For patients
with versus without lymphadenopathy, PFS was 5 (range, 1 to 9) versus
37 (range, 26 to 48) months (P < .001; Fig 1C).
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| Fig 1.
PFS of CLL Binet stage A patients in relation to
different prognostic parameters: (A) s-TK, with a cut-off level of 7.1 U/L; (B) peripheral blood leukocyte count with a cut-off level of
75,000/µL; (C) presence or absence of lymphadenopathy. Differences
were statistically significant (P < .001) for all three
parameters.
|
|
Elevated s-TK and presence of lymphadenopathy define a subgroup at
high risk of disease progression within nonsmoldering Binet stage A
CLL.
The current risk-assessment strategies in CLL are relatively potent in
identifying patients with a relatively poor prognosis (Binet stage C or
Rai stage III and IV patients), as well as patients with a very good
prognosis that is identical to the age-matched healthy population. The
latter group of patients is considered to have smoldering CLL. It is a
subgroup of Binet stage A patients identified by normal blood
hemoglobin greater than 13.0 g/dL, a low absolute lymphocyte count (< 30,000/µL), a lymphocyte doubling time greater than 12 months, and a
nondiffuse pattern of lymphoid bone marrow infiltration.26
Similar criteria were developed by the French CLL Study
Group27 and by the Rai staging system (Rai stage 0). While
there is clear evidence of a very good prognosis for smoldering CLL,
predicting the prognosis of the larger group of nonsmoldering CLL
patients in Binet stage A is more difficult.
Since our analyses found two parameters, s-TK and presence of
lymphadenopathy, that were not part of the above definition of
smoldering CLL,26 we tested whether their inclusion was
able to identify new prognostic subgroups. Figure
2A shows the PFS of CLL stage A patients
separated into those with smoldering and nonsmoldering disease. The 25 patients with smoldering CLL had a significantly longer PFS than the 81 patients with nonsmoldering CLL (P < .001; 42 v 18 months). In addition to the criteria defining smoldering CLL, elevated
s-TK levels were able to identify 31 patients within the group of
nonsmoldering Binet stage A patients who had a significantly shorter
PFS than patients with low s-TK levels (P < .001; 8 v
49 months; Fig 2B). Interestingly, only two of the patients with
smoldering CLL had an elevated s-TK value greater than 7.1 U/L. A
similar phenomenon was observed for the prognostic parameter
"lymphadenopathy." The PFS of nonsmoldering patients who
presented with lymphadenopathy was significantly shorter than that of
patients without lymphadenopathy (P < .001; 10 v 38 months; Fig 2C).
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| Fig 2.
PFS of 106 CLL Binet stage A patients assigned to
different prognostic subgroups (Kaplan-Meier plots). (A) 25 patients
with smoldering CLL versus 81 with nonsmoldering CLL: median PFS, 42 versus 18 months (P < .001). (B) 79 patients with
nonsmoldering CLL are further divided according to s-TK levels: 31 with
high s-TK values (>7.0 U/L) versus 48 with low s-TK values (7.0
U/L) had a PFS of 8 versus 49 months (P < .001). (C) 81 patients with nonsmoldering CLL are further divided according to the
presence or absence of lymphadenopathy: 42 with lymphadenopathy versus
39 without lymphadenopathy had a median PFS of 10 versus 38 months
(P < .001). (D) 106 Binet stage A patients, now classified in
52 patients with Rai stage 0, 42 patients with Rai stage I to II and
low s-TK values (7.0 U/L), and 25 patients with Rai stage I to II
and high s-TK values (>7.0 U/L). Median PFS was 75 months for Rai
stage 0 patients, 31 months for Rai stage I/II with low s-TK, and 9 months for Rai stage I/II with high s-TK (P < .001).
|
|
Binet stage A consists of Rai stage 0, I, and II. The major prognostic
parameter distinguishing Rai 0 patients from Rai I and II patients is
the presence of lymphadenopathy. Again, we asked whether elevated s-TK
levels would add prognostic information to the Rai staging system at
early stages (Rai 0 to II). When the subgroup of Rai stage I/II
patients was further split by s-TK levels greater than 7.1 U/L, a group
of patients with a very short PFS of 9 months was identified (Fig 2D).
Rai stage I/II patients with s-TK levels 7.1 U/L had a longer PFS
(31 months; P < .001). Rai stage 0 patients had the longest
PFS (75 months). Finally, the addition of s-2m values
seemed to further enhance the distinction between nonsmoldering
patients at high and low risk (data not shown).
| |
DISCUSSION |
This study shows that s-TK level provides independent prognostic
information on PFS in Binet stage A CLL, in addition to the criteria
defining smoldering CLL. Since the time to disease progression seems to
predict the survival time of CLL patients,22 it was used as
a surrogate end point in this study; it can be expected but needs to be
proven that s-TK levels will also be relevant for predicting survival
of Binet stage A CLL patients.
Thymidine kinase, adenosine triphosphate (ATP):thymidine
5'-phosphotransferase (EC 2.7.1.21), is a cellular enzyme known to be involved in a "salvage pathway" for DNA
synthesis.28 Mammalian cells contain at least two TK
isoenzymes, which differ in their biochemical properties and their
cellular distribution.29 The cytosolic isozyme, TK1 (also
known as fetal TK), is found in the G1/S phase of dividing cells, but
is absent in resting cells.30 In contrast, the levels of
the mitochondrial isozyme, TK2, remain stable throughout the cell
cycle. TK1 accounts for 95% of the s-TK activity found in most normal
and pathologic situations.29,31 The s-TK activity in CLL
patients is probably related to the number of dividing tumor cells as a
result of tumor mass and rate of tumor cell proliferation, since s-TK
levels correlate with the proliferative activity of CLL
cells.32 Moreover, the proportion of S-phase cells
detectable in tumor biopsies was found to correlate with s-TK, but not
with s-2M levels.33 Finally, s-TK levels, but not the TK activity of normal peripheral blood mononuclear cells,
correlate with the tumor stage of breast cancer patients.34 Taken together, s-TK levels in cancer patients seem to reflect the
proliferative activity of the tumor.
Since the commercial introduction of a reliable and technically easy
assay (see Materials and Methods), s-TK levels have been investigated
in a variety of malignancies. Elevated s-TK levels were found in
Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, acute
lymphatic and myeloid leukemia, breast cancer, prostate cancer, and
non-small-cell lung cancer.35 In low-grade non-Hodgkin's
lymphoma, s-TK levels correlate with the disease stage and provide
prognostic information on overall survival and PFS.8-15
Serum CD23 (s-CD23) is another serum parameter that has been shown to
identify patients at risk in early CLL.36,37 In a series of
untreated, newly diagnosed patients with Binet stage A, high levels of
s-CD23 were found to correlate with elevated s-TK levels, a lymphocyte
doubling time less than 12 months, and a nonnodular pattern of bone
marrow infiltration. Moreover, elevated s-CD23 levels predicted early
disease progression.36 Sarfati et al have shown that s-CD23
levels greater than 574 U/mL are associated with a rapid disease
progression in Binet stage A CLL patients.37 However, at
present, it is unknown which of the two parameters, s-TK or s-CD23, is
more potent in predicting progression of early CLL and whether they
provide prognostic information independently from one another. Both
parameters may be used for a risk-adapted management of early CLL. In a
recent trial testing the value of interferon- treatment in Binet
stage A patients, s-TK was used in combination with the type of bone
marrow infiltration and the lymphocyte doubling time to stratify
patients according to the risk of progression. This strategy allowed
prospective identification of a patient group with a significantly
shorter time to disease progression.19
Considerable progress has been made over the past 20 years in
identifying new prognostic parameters in CLL. In addition to advanced
Binet or Rai stages, at least four factors seem generally accepted to
predict a poor prognosis in CLL: diffuse bone marrow infiltration,
blood lymphocyte counts greater than 50,000/µL, a lymphocyte doubling
time 12 months, and multiple or complex abnormalities of the
karyotype.6,38 However, it should be emphasized that some
of these four prognostic factors were tested in a limited number of
studies or showed independent prognostic value in a small subgroup of
studies only. Moreover, a major disadvantage of bone marrow
histopathology as a prognostic marker may be its relatively low
reproducibility when different histopathologists review the biopsy slides.
In comparison with the above "established" parameters, the value
of serum parameters as prognostic factors for CLL may have been
underestimated in the past. Recent studies indicate that at least three
serum parameters s-TK, s-2m, and s-CD23may add prognostic information to the current staging
systems.15,19,36,37,39,40 The versatility and ease of serum
tests, which yield quantitative rather than qualitative results, are
important advantages, eg, in comparison to the laborious classic
cytogenetics or the investigator-biased evaluation of bone marrow
histology. The results of this study suggest that the use of s-TK
levels might improve the assessment of the individual prognosis in
patients with early CLL. It seems highly desirable to further define
its value by large prospective studies.
| |
FOOTNOTES |
Submitted May 26, 1998; accepted October 26, 1998.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Michael Hallek, MD,
Medizinische Klinik III, Klinikum Grohadern,
Ludwig-Maximilians-Universität München, Marchioninistr. 15, D-81377 München, Germany.
| |
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Abstract
Introduction