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NEOPLASIA
From the Department of Haematology, Royal Bournemouth
Hospital, United Kingdom; the Dorset Research and Development Support
Unit, Poole Hospital, United Kingdom; the Institute of Health and
Community Studies, Bournemouth University, United Kingdom; and the
Molecular Immunology Department, Tenovus Research Laboratory,
Southampton General Hospital, United Kingdom.
Although the presence or absence of somatic mutations in the
immunoglobulin variable region (IgVH)
genes in chronic lymphocytic leukemia (B-CLL) identifies subtypes with
very different prognoses, the assay is technically complex and
unavailable to most laboratories. CD38 expression has been suggested as
a surrogate marker for the 2 subtypes. IgVH
mutations and CD38 expression in 145 patients with B-CLL with a long
follow-up were compared. The 2 assays gave discordant results in 41 patients (28.3%). Multivariate analysis demonstrated that Binet stage,
IgVH mutations and CD38 were independent prognostic indicators. Median survival time in patients whose cells had
unmutated IgVH genes and expressed CD38 was 8 years; in those with mutated IgVH genes not
expressing CD38, it was 26 years. For those with discordant results,
median survival time was 15 years. Thus, although CD38 expression does
not identify the same 2 subsets as IgVH
mutations in CLL, it is an independent risk factor that can be used
with IgVH mutations and clinical stage to
select patients with B-CLL with the worst prognoses. Using
cryopreserved cells taken at intervals during the course of the
disease, however, changes of CD38 expression over time were
demonstrated in 10 of 41 patients. Causes of the variation of CD38
expression require further study. Additional prospective studies are
required for comparing CD38 expression with other prognostic factors
and for taking sequential measurements during the course of the disease.
(Blood. 2002;99:1023-1029) In 1999 our group1 and Damle et
al2 documented and mutually corroborated the finding that
the mutational status of immunoglobulin (Ig) heavy chain variable
region (VH) genes identified 2 subsets of
patients with chronic lymphocytic leukemia (CLL). One, with unmutated
IgVH genes, has a median survival of
approximately 8 years, whereas the other, with mutated
IgVH genes, has a median survival of
approximately 25 years. Others have since confirmed these
findings.3,4 Damle et al2 suggested that the
expression of surface CD38 on the tumor cells gave the same information
and might be a surrogate assay. Initial analysis of 50 of our patients, however, failed to show a significant correlation between
IgVH gene mutation status and CD38
expression.5
CD38 is a type 2 trans-membrane glycoprotein that acts as a complex
ecto-enzyme with adenosine diphosphate-ribosyl cyclase and cyclic
adenosine diphosphate-ribose hydrolase activities.6 In
the B-cell compartment CD38 is not a lineage marker, but it is
expressed at times during B-cell development when cell-to-cell interactions are crucial to development.7 Examples include an early bone marrow precursor cell, cells in the germinal center, and
plasma cells.8 All the factors that signal its
up-regulation are as yet unknown, but they include Standard management for stage A B-CLL is to delay therapy until there
is evidence of progression.10 Meta-analysis of 6 trials involving 2048 patients showed no benefit of immediate treatment over
delayed treatment with alkylating agents.11 Nevertheless, approximately half the patients allocated to the watch-and-wait option
eventually require treatment, and one fourth die of a cause related to
B-CLL.12 If those whose disease is destined to progress are identifiable at diagnosis, either by knowledge of the degree of
CD38 expression or the status of IgVH mutations,
it might be feasible to treat the disease more effectively with newer
agents while the tumor burden is low.
We have detailed clinical information on more than 600 patients with
B-CLL who have been treated and followed up by this department for the
past 28 years. This long follow-up has enabled us to appreciate fully
the natural history of B-CLL and has allowed us to take death, rather
than simply time to progression, as the end-point for our studies. For
the past 10 years we have been cryopreserving sequential blood samples
from many of these patients. This has given us a rare opportunity to
examine IgVH mutations and CD38 expression as
prognostic indicators for B-CLL. Moreover, we have the opportunity to
establish whether CD38 expression is a reproducible and stable marker
in the disease.
One hundred forty-five patients were chosen from more than 600 patients with B-CLL who have attended the hematology clinics of the
Royal Bournemouth Hospital in the past 28 years. An attempt was made to
include a representative selection of karyotypic disorders, but most
patients were chosen simply because they happened to be attending the
outpatient clinic for routine follow-up or because we had cryopreserved
previous samples. Details of IgVH mutational status have been reported for 61 patients,1 and details of IgVH mutational status and CD38 expression have
been reported for 50.5 All patients came from the local
area and included many whose diagnoses were made incidentally from a
blood count ordered for another purpose and whose B-CLL has remained
entirely asymptomatic. It has been our practice, nevertheless, to
continue to observe such asymptomatic patients once or twice a year.
They were staged at diagnosis according to the Binet
classification.13 Immunophenotyping was performed afresh
during the course of the current investigation. All patients scored 4 or 5 according to the Royal Marsden scoring system for
CLL.14
Patients have been followed up for at least a year since diagnosis;
those who died within that year have been included. The longest length
of follow-up was 28 years 4 months. Median follow-up was 98 months.
Patients were designated as having progressive disease on the basis of
the following criteria: lymphocyte count doubling time of less than 1 year; progression to a more advanced Binet stage; development of
systemic symptoms; development of Richter syndrome; downward trend of
hemoglobin or platelet count because of bone marrow suppression to
below the normal range (Hb less than 13.5 g/dL for males and less than
11.5 g/dL for females. platelet count less than
150 × 109/L) even when not meeting the criteria for
stage C disease (Hb less than 10 g/dL, platelet count less than
100 × 109/L). The presence of one of these
characteristics was sufficient to signify progressive disease. Patients
without these features were designated as having stable disease.
Generally, patients with progressive disease have been treated
conventionally with chlorambucil as first-line therapy and with
fludarabine for resistant disease. Patients with stable disease were
not offered chemotherapy. Because they had all been followed up
locally, it was possible to assess whether patients died because of
their leukemia or of an unrelated cause. Causes of death that were
regarded as unrelated to CLL included myocardial infarction, stroke in
the absence of thrombocytopenia, accident, and cancer. Two
investigators (T.J.H. and D.G.O.) made this assessment independently, and they resolved any discrepancy by discussion and careful examination of the case notes.
Blood samples
VH gene analysis
Analysis of CD38 expression Whole blood or 106 cells from cryopreserved specimens were incubated for 15 minutes with 5µL each of the following antibodies: fluorescein isothiocyanate (FITC)-labeled anti-CD5 (clone DK23; DAKO, Glostrup, Denmark), phycoerythrin (PE)-labeled anti-CD38 (clone HB7; Becton Dickinson, San Jose, CA); and RPE-Cy5 labeled anti-CD19 (clone HD37; DAKO). Red cells were lysed with Facslyse (Becton Dickinson), and at least 10 000 cells were acquired in the Cellquest program on a FACSCalibur flow cytometer (Becton Dickinson). Each sample was run with an appropriate isotype control (FITC-labeled mouse IgG1 and PE-labeled mouse IgG1, both from DAKO), and this was used to define the negatively stained cells. In each case the dot-plot was gated on the lymphoid gate on the side scatter-forward scatter (SCC-FSC) plot. Within this gate the markers were set on the isotype control to define the negative population. A single cell was regarded as CD38+ if its position lay outside this marker. The tumor population was defined by gating of the lymphoid population on the SCC-FSC plot, followed by gating of the CD5+CD19+ population. The percentage of CD38+ cells in this gate was then determined.To use CD38 positivity to screen for patients likely to die of B-CLL
within 10 years, we chose a cut-off point for CD38 that give the
highest possible Youden index.16 Cut-off points of 20%
and 30% gave the highest, but similar, Youden values Statistical analysis The significance of associations between characteristics was determined using the Fisher exact test. Survival curves from date of diagnosis and date of the sample used to determine CD38 expression were plotted using GraphPad Prism software (version 2; GraphPad Software, San Diego, CA). This program calculates survival fractions using the Kaplan-Meier method and compares survival curves using the log-rank test. Multivariate analysis to determine the interdependence of prognostic factors was carried out by Cox proportional hazards regression using SPSS for Windows, version 8. The type 1 error rate was set at 5%.Youden index We examined the validity of the 30% cut-off level for CD38 expression by calculating a Youden index on our own data. A larger group of 184 of our own patients, all of whom had CD38 estimations but 39 of whose IgVH genes had not been analyzed, was studied. Sensitivity and specificity were calculated for a number of different cut-off points. Sensitivity is the probability of having a CD38 level above the cut-off point among those dying, and specificity is the probability of having a CD38 level below the cut-off point among survivors. Specificity and sensitivity were calculated using 10-year survival rates (Kaplan-Meier method) separately for patients below and above the cut-off point, together with the percentage of patients above the cut-off point. The Youden index combines information on sensitivity and specificity (giving equal weight to each) to give an overall measure of the percentage gain in certainty of predicting death. If CD38 at a particular cut-off has a Youden index of 0, there is no predictive ability; if it has a score of 100, death is perfectly predicted.
We studied 145 patients with B-cell CLL. There were 88 men and 57 women. Age at diagnosis ranged from 35 to 93 years. One hundred twenty-two patients had stage A, 12 had stage B, and 11 had stage C disease; 91 had stable disease and 54 had progressive disease. At the time of analysis 46 patients had died, 24 of causes related to B-CLL and 22 of unrelated causes. Tumor cells with mutated IgVH genes were found
in 95 (66%) patients, whereas 50 (34%) patients had cells with
unmutated IgVH genes. The cells were
CD38
Although contingency tables show a highly significant association
between CD38 expression and unmutated IgVH genes
(Fisher exact test, P < .0001) and between CD38
expression and IgVH mutations and clinical stage
(P = .025 and .0002, respectively), for individual patients there are important discordances. Figure
1 shows the concordance for CD38
positivity and unmutated IgVH genes. In 15 patients with unmutated IgVH genes,
less than 30% of cells expressed CD38, and in 26 patients with mutated
IgVH genes, more than 30% of cells expressed
CD38. Forty-one of 145 (28.3%) patients had discordant results for the
2 assays. Discordant markers occurred as frequently in patients with
stable disease as in those with progressive disease.
Figure 2A shows a Kaplan-Meier survival
curve from diagnosis comparing patients with mutated and unmutated
IgVH genes and those with CD38+ and
CD38
Using Cox proportional hazards regression analysis, we compared
IgVH status and CD38 positivity with other prognostic
factors available to us
Diagnosis was made in the overwhelming proportion of patients (84%) in
this series at stage A disease. What is required of a prognostic factor
in stage A disease is the ability to predict those patients who will
die early of CLL. Although CD38 expression and the absence of
IgVH mutations were effective in this task, the
IgVH assay was more reliable. Comparison of survival curves plotted from the date of diagnosis for patients with stage A disease, censoring for patients dying of causes unrelated to B-CLL (Figure 3A) are as follows: median survival for
CD38
Figure 4 is a survival curve for all
patients in whom IgVH mutations and CD38 status
are discordant. There is no significant difference between the
curve for CD38+/IgVH mutated
patients and the curve for
CD38
Given that the survival curves for patients with both types of
discordant results are not significantly different, we decided to
analyze the whole group in comparison with patients who were concordant
for both assays. Figure 5 is a survival
curve comparing patients whose cells were CD38+ with
unmutated IgVH genes with those whose cells were
CD38
Reproducibility of CD38 expression after cell storage For 4 patients, cells were harvested from 9 separate tubes cryopreserved at the same time and containing separate aliquots taken from the same blood sample. They were labeled with antibodies against CD5, CD19, and CD38, as described earlier, and 6 replicates were counted from each tube. Reproducibility was very high. Mean percentages of CD38+ cells for the 4 patients were, respectively, 60.1 (SD, 1.007), 84.6 (SD, 1.475), 40.4 (SD, 0.979), and 10.7 (SD, 1.065).To assess the effect of cryopreservation, 10 samples were tested for CD38 expression fresh and after freezing-thawing. Spearman correlation showed close agreement between the 2 measurements (r = 0.9515; P = .0001). Mean and SD for the fresh samples were 27.98 and 39.22, and they were 28.44 and 39.07 for the frozen samples. CD38 expression during disease In 6 patients, CD38 expression on samples taken on the same day from blood and bone marrow did not differ. For one, a lymph node sample taken on the same day gave the same result.Sequential samples cryopreserved over periods ranging from 6 months to
9 years were harvested from 41 patients. Percentages of
CD38+ cells were assayed and compared. Following Damle et
al,2 differences smaller than 10% were ignored. For 8 patients there were increases in CD38 positivity over time; 2 showed
decreases, and 31 were stable. Details of the 10 patients with changes
in CD38 expression are given in Table 3.
In 2 patients (patients 20 and 143), increasing CD38 expression was
associated with increasing white blood cell count (37
Of the 2 remaining patients, patient 157 had stable CLL but became increasingly hypogammaglobulinemic. The increased expression of CD38 was associated with a series of chest infections. Patient 125 had concurrent chronic myelomonocytic leukemia. As the monocyte count rose, CD38 expression by lymphocytes decreased.
Although there are a number of valuable prognostic factors for B-CLL, clinical stage, according to the Binet13 or the Rai17 scoring system, is the one most commonly used. The common belief, supported by a meta-analysis,11 is that advanced-stage B-CLL requires treatment but that early-stage disease is best left until progression occurs. However, this analysis applies to treatment with alkylating agents and may not hold good for newer agents such as fludarabine. Moreover, approximately half the early-stage cases eventually progress and require treatment.11 French18 and Spanish19 CLL study groups
identified good risk factors IgVH gene analysis distinguishes between subtypes with different prognoses that arise from cells at different stages of maturation. We have previously shown that the presence of unmutated IgVH genes correlates with progressive disease, advanced stage, atypical morphology, and trisomy 12.1 Expression of high levels of CD38 is also an adverse prognostic factor. It has been shown to correlate with advanced stage, atypical morphology, higher lymphocyte count, and diffuse bone marrow infiltration.20 In this study we have confirmed the observation of Damle et al2 that there is a statistically significant correlation between CD38 expression and the presence of unmutated IgVH genes. However, though there is some overlap, the 2 tests do not identify the same patients. In this study CD38 expression and IgVH mutations give discordant results in 28.3% of patients; by multivariate analysis, they were independent prognostic indicators. Our results differ from those of Damle et al,2 but the reason for this is not obvious. Our earlier study5 used anti-CD5-anti-CD20 mAbs, which was criticized because some B-CLL cells express low levels of CD20. In this study we have eliminated this source of discrepancy by using the same anti-CD5-anti-CD19-anti-CD38 antibodies and the same fluorochromes as Damle et al.2 It is possible that the larger number of patients in this study has better revealed the discordance between CD38 expression and IgVH mutational status. Perhaps of more importance, CD38 expression did not remain constant
throughout the course of the disease. Several patterns of CD38
positivity may be seen. Although in some patients all the cells are
CD38+ or CD38p A decrease in CD38 expression in a single patient responding to treatment with chlorambucil has been reported,21 though the same group found no change in CD38 expression in another 16 patients.2 Recently, an additional study has shown an increase in the proportion of CD38+ cells in 1 of 10 patients investigated.22 This patient had clearly progressive disease but received no treatment. In 2 of our patients, changes in the proportion of cells expressing CD38 were not associated with progression. One had stable disease but contracted recurrent chest infections; the other had concurrent chronic myelomonocytic leukemia. As the monocyte count increased, the expression of CD38 by the lymphocytes decreased. CD38 is involved in interactions between cells of the immune
system.7 Expression of CD38 on B-CLL cells is up-regulated by exposure to The variability of CD38 expression calls into question its value as a prognostic factor at diagnosis. Given this, we have plotted survival curves from the date of diagnosis and from the date of the CD38 sample. Although the latter gave shorter median survival times in some patients because they had already survived for a long time before the test was performed, both sets of curves demonstrate that IgVH mutation and CD38 expression are excellent prognostic indicators in CLL. In this series, the prognostic information given by CD38 expression and the presence of IgVH mutations is complementary. If both adverse factors are present, a short survival may be predicted even in stage A patients. Such patients then become candidates for controlled trials examining the value of early intensive treatment. If neither adverse factor is present, a median survival of 25 years may be predicted. For most patients with B-CLL such a prediction implies that no treatment will ever be required. Patients who have discordant results with these assays have a median survival of 15 years. There is still a need to evaluate other prognostic indicators in the
context of CD38 expression and IgVH mutations. In
particular serum levels of soluble CD23,30,31 soluble
CD44,32 serum thymidine kinase,33,34 and
The prognostic effect of the 2 most common abnormalities, trisomy 12 and abnormalities at chromosome 13q14, are encompassed within the effect of IgVH mutations.36 However, more information on the effect of 11q23 and p53 abnormalities in relation to CD38 and IgVH is required.4,35 Clearly, further studies are also required to confirm the lability of CD38 expression in B-CLL. Prognostic factors are important in CLL. A sizable proportion of patients are managed by watchful waiting because meta-analysis has shown that stage A patients do not benefit from early treatment with chlorambucil.11 Nevertheless, roughly half of such patients will eventually require treatment and might be better served by early treatment with one of the newer agents, such as fludarabine. Some prognostic factors, such as stage or marrow histology, depend on progression already having taken place for their value. At present only IgVH mutations have been shown to be intrinsic to the nature of the disease and not to change during its course. Unfortunately, their detection is technically difficult and available in only a few laboratories. Other prognostic variables, including CD38 expression, must be evaluated prospectively.
We thank Dr Bob Chapman for help with the statistical data and Stuart Lanham and Gavin Babbage for technical help.
Submitted April 18, 2001; accepted September 26, 2001.
Supported by grants from Tenovus, the Leukaemia Research Fund, and the Bournemouth Leukaemia Fund.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Terry Hamblin, Department of Haematology, Royal Bournemouth Hospital, Castle Lane East, Bournemouth, BH7 7DW, United Kingdom; e-mail: terjoha{at}aol.com.
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© 2002 by The American Society of Hematology.
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N. Ishibe, M. Albitar, I. B. Jilani, L. R. Goldin, G. E. Marti, and N. E. Caporaso CXCR4 expression is associated with survival in familial chronic lymphocytic leukemia, but CD38 expression is not Blood, July 18, 2002; 100(3): 1100 - 1101. [Full Text] [PDF]
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N. E. Kay, T. J. Hamblin, D. F. Jelinek, G. W. Dewald, J. C. Byrd, S. Farag, M. Lucas, and T. Lin Chronic Lymphocytic Leukemia Hematology, January 1, 2002; 2002(1): 193 - 213. [Abstract] [Full Text]
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Top
Abstract
Introduction
- and
-interferon.
58% and 60%, respectively. To allow comparison with Damle et
al,
in 84 (58%) patients and CD38+ in 61 (42%) patients. Numbers of patients in each category in each Binet
stage at diagnosis is shown in Table 
) or unmutated (
)
IgVH genes.
2 = 28.9; P < .0001). For CD38, median
survival times are also 109 months (95% CI, 73-145) for
positive cases and 293 months (95% CI, 158-428) for negative cases.
Again the curves are significantly different
(
, n = 85) and have mutated (
,
n = 95) or unmutated (
145 and
8.3
-, or