IgVH Mutations

CLL has long been considered a homogeneous disease of CD5+B-cells, which are pregerminal cells that have not been exposed to antigenic stimulation. In 1999, two different groups reported an important breakthrough in CLL (29,88). These groups clearly showed that the mutational status of the somatic mutations of the variable region of the immunoglobulin genes (IgVH) correlates with different disease subsets. Thus, those patients with unmutated IgVH genes have a poorer prognosis than those displaying mutated IgVH genes. Hamblin et al. (29) analyzed the IgVH gene sequences of 84 patients with CLL and demonstrated two patterns: 38 (45%) showed 98% sequence homology with the germline IgVH gene, whereas 46 (55%) showed evidence of somatic mutation. Since somatic mutation takes place in the germinal center, CLL can be either a tumor of pregerminal center B-cells (unmutated) or a tumor of postgerminal center B-cells (mutated).

According to different studies, CLL cases present distinctive clinical features, treatment requirements, and outcome, depending on the mutational status of the IgVH gene (Table 2). Thus, patients with an unmutated IgVH gene (mostly men) are more likely to have an advanced stage, progressive disease, atypical morphology, unfavorable cytogenetic findings [i.e., del(11q), del(17p)], need for therapy, and shorter survival irrespective of stage than those presenting with a mutated IgVH gene. It is of great interest that the prognostic value of the IgVH mutational status is independent of clinical stage. Thus, patients with stage A CLL have a median survival of 8 yr if they have unmutated B-cells, compared with 25 yr if B-cells are mutated (29). Lin et al. (87) have recently shown that the poor outcome of unmutated cases may be related to p53 dysfunction.

Fig. 3. Prognostic implications of ZAP-70 expression in Binet A patients with CLL. (A) Actuarial risk of disease progression in Binet A patients according to the category of ZAP-70 expression. (B) Survival curves of Binet A stage patients according to ZAP-70 expression.

Unfortunately, most laboratories are currently unable to isolate and characterize IgVH gene sequences, and, even if the technique is available, it is quite costly and time-consuming. Damle et al. (88) first suggested a correlation between CD38 expression on the surface of neoplastic lymphocytes and IgVH mutational status: CD38+ > 30%, unmutated IgVH genes; CD38+ < 30%, mutated IgVH genes. Nevertheless, the value of CD38 as a surrogate for the IgVH mutation is controversial (89,90). It is worth emphasizing, however, that CD38 expression has prognostic importance by itself. Recently, Hamblin et al. (28) have reported that CD38 expression and IgVH mutational status are independent prognostic variables and that CD38 expression may vary during the course of the disease. In this study based on 145 patients it was found that the two assays (IgVH mutations, CD38 expression) gave discordant results in 42 patients (28.3%) and that in 10 of 41 patients CD38 expression varied over time (28).

Table 3

Parameters With Prognostic Significance in CLL


Table 3

Parameters With Prognostic Significance in CLL






Clinical stage



B, C




Bone marrow infiltration


Nondiffuse pattern

Diffuse pattern

Aspirate WBC count (x 109/L)a

<80% lymphocytes

>80% lymphocytes



Prolymphocytes in peripheral blood (%)a



Lymphocyte doubling timea

<12 mo

>12 mo


Serum markers b






del(13q) isolated


CD38 expression



IgVn genes



ZAP-70 expression



a Continuous variables.

Lactate dehydrogenase, P2 microglobulin, thymidine kinase, CD23, and others.

a Continuous variables.

Lactate dehydrogenase, P2 microglobulin, thymidine kinase, CD23, and others.

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