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 Previous Article | Table of Contents
Blood, 15 March 2001, Vol. 97, No. 6, pp. 1902-1902
CORRESPONDENCE
To the editor:
CD38 expression and Ig VH gene mutation in B-cell
chronic lymphocytic leukemia
Ig VH somatic hypermutation has recently emerged as
a novel prognostic factor in chronic lymphocytic leukemia (CLL),
unmutated Ig VH genes predicting adverse
prognosis.1-4 However, the clinical usefulness of Ig
VH gene mutation analysis in predicting survival early in
the course of the disease is offset by the high cost and level of
expertise required for this technique. The report of Damle et
al2 that CD38 expression can predict the Ig VH gene mutational status of CLL cells (positivity indicating unmutated and negativity, mutated, Ig VH genes) offered the
possibility of a simple and inexpensive substitute for Ig
VH gene analysis. However, the association between CD38
expression and Ig VH gene mutation could not be confirmed
by Hamblin et al.5 This discrepancy prompted us to
undertake a survey of our own CLL patients to examine further the
relationship between CD38 expression, Ig VH gene mutation, and survival, and thereby determine to what extent measurement of CD38
can indeed be used as surrogate for Ig VH gene sequencing. We included 40 CLL patients (27 men, 13 women) with known clinical
history in the study. Of these, 6 were selected on the basis of their
tumor cells expressing CD38. The mean age was 65 (men 61.5, women 72.3)
years, and the mean follow-up time 5.4 (1-23) years. Ig VH
gene sequence analysis was performed using a protocol based on that of
Fais et al.6 Unmutated cases were defined as those with
less than 2% mismatch to the most similar germline Ig VH
gene in the V BASE directory.7 Immunophenotyping was
performed on a Becton Dickinson FACS scan analyzer (San Jose, CA)
using thawed samples of previously cryopreserved cells that had been double stained with CD38 PE and CD19 FITC (both from Becton
Dickinson). The proportion of CD19+ cells coexpressing CD38
was determined; values more than 30% were considered positive.
Survival analyses were performed by the method of Kaplan and Meier, and
significance was analyzed using the log-rank test. Twenty-four cases were unmutated and 16 mutated, with a male-female
ratio of 1.6 in the mutated and 2.4 in the unmutated groups. These
findings therefore support the observation made by Damle et al that
there is an unequal sex distribution between the mutated and unmutated
groups. CD38 was expressed in 2 (12.5%) of the 16 mutated cases and in
11 (46%) of the 24 unmutated cases. Among the 13 CD38+
cases, 2 (15%) were mutated and 11 (85%) unmutated. Twenty-seven cases were CD38 , of which 13 (48%) were unmutated and 14 (52%) mutated. These results are summarized in Figure
1.
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| Figure 1.
Relationship between CD38 expression and Ig
VH mutation.
The proportion of CD19+ cells coexpressing CD38 is shown on
the y-axis. Values greater than 30% were considered positive. The
percent mismatch with the closest Ig VH germline gene is
shown on the x-axis. Cases with more than 2% mismatch were defined as
being mutated.
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Survival analysis of mutated versus unmutated patients (Figure
2A) showed that the absence of Ig
VH gene somatic mutation was associated with a worse
outcome (median survival 9 years, versus not reached;
P = .05). Similarly, CD38+ patients had a
shorter median survival than the CD38 group (5 years
versus 13 years; P = .001) (Figure 2B).
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| Figure 2.
CD38 expression and Ig VH gene mutational
status as independent prognostic factors in B-CLL.
The figure shows Kaplan-Meier survival curves comparing cases with
mutated versus unmutated Ig VH genes (A) and
CD38+ versus CD38 cases (B). Deaths not
attributable to CLL were censored.
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Our results regarding the adverse prognostic significance of unmutated
Ig VH genes and CD38 expression are entirely in keeping with Damle et al's and Hamblin et al's. Furthermore, in agreement with Damle et al, we also found that CD38 expression is, indeed, able
to identify unmutated cases. Our confirmation that CD38 positivity is
informative, both as an independent prognostic parameter and as a
predictor of unmutated Ig VH status, therefore supports the idea that measurement of CD38 should form part of the routine diagnostic work-up of CLL. Importantly, in our series only half of the CLL patients with unmutated
Ig VH genes expressed CD38. This novel observation raises
the interesting possibility that unmutated CLL tumors may be clonal
expansions of 2 different types of pre-germinal center B cells: one
being CD38+ and the other, CD38.
Zoltan Matrai, Ke Lin, Michael Dennis, Paul Sherrington, Mirko Zuzel, Andrew R Pettitt, and John C. Cawley
Department of Haematology University of Liverpool
Liverpool, United Kingdom
Acknowledgments
Supported by grants from the Leukaemia Research Fund (UK) and
North West Cancer Research Fund
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