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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1110-1111
B-CLL: is the enigma of disease heterogeneity about
to be revealed?
B-chronic lymphocytic leukemia (B-CLL) can be a
relatively easy management problem since a majority of these patients
initially come to the hematologist with minimal-to-low tumor burden.
But there is a compelling need for accurate prognostic parameters because at least 20%-30% of these patients will ultimately progress and require therapy. We are now in an era where exciting therapeutic options exist for the B-CLL patient. Thus, there is a therapeutic advantage to more accurately predict patients who are high risk and
which early stage patients will progress quickly. Current accepted
prognostic features include classification in the Rai or Binet staging
system, lymphocyte-doubling time, marrow infiltration patterns, and
select cytogenetic abnormalities. While these have proved
useful, they remain imperfect for use in an individual patient.
Two recent pivotal papers by the Hamblin and Chiorazzi groups have
defined immunoglobulin (Ig) mutational status and CD38 expression level
as 2 new important prognostic markers. In this issue, 3 papers studying
relatively large cohorts of B-CLL patients further study the
association of these 2 novel biologic parameters with other biologic
features to further our understanding of critical prognostic elements
in B-CLL. In summary, these articles (1) affirm the value of Ig
mutation status as an independent prognostic factor for B-CLL, (2)
demonstrate that the incidence of high-risk genetic aberrations is
significantly higher in patient tumor cells that express unmutated Ig
VH region genes than in those that express mutated
Ig genes, and (3) identify 17p and/or mutant p53 as a new
independent prognostic factor in multivariate analysis. Oscier and colleagues (page 1177) have added important new information
regarding survivorship of B-CLL patients in relationship to the
mutational status of the leukemic B-cell clone. Specifically, they have
determined that unmutated IgVH genes are associated with
trisomy 12 and deletion 11q23, two previously known unfavorable genetic
alterations. Conversely, they showed that clones with mutated
IgVH genes were associated with the more favorable genetic defect 13q14. Kröber and colleagues (page 1410) present from a large cohort
convincing data, which demonstrate that the high-risk 17p and 11q
genomic aberrations were seen almost exclusively in patients with unmutated IgVH genes. Conversely and consistent with
work by Oscier and colleagues, the clinically favorable 13q
abnormality was over represented in the patients with mutated Ig genes.
These data continue to affirm the growing body of information that
IgVH mutational status of the CLL B-cell clone is linked to
disease outcome. In addition, the finding of more frequent deleterious genetic defects in the unmutated IgVH-type clones suggests
that these clones are more likely to undergo critical genetic
transformation events. Future analysis of gene methylation patterns and
chromosomal stability parameters in sequential fashion in these clones
will be of interest. This latter study may lend insight into CLL B cell
clones that are prone to undergo clonal evolution. All 3 papers, using different approaches, affirm the unfavorable
clinical outcome for patients with 17p/p53 mutation and/or loss. Using an alternative assay of p53 function, that is,
responsiveness to ionizing radiation, Lin and colleagues (page 1404)
demonstrated that all of the patients studied with dysfunctional
p53 belonged to the unmutated IgVH subgroup.
Moreover, dysfunctional p53 was a highly significant
predictor of poor outcome. Of interest, when patients with functional
p53 were studied, the prognostic power of Ig mutation status
was lost. If the clinical use of this test is indeed feasible, there
may be a powerful prognostic test now available. The association of CD38 expression levels with genetic aberrations and
Ig mutation status and its utility as a prognostic factor was also
evaluated in the 3 papers. All 3 groups confirm the association between
CD38 expression and relative lack of IgVH region mutations.
Lin and colleagues were able to demonstrate that patients with more
than 20% CD38+ leukemic cells exhibited significant
shorter survival times than those with fewer than 20%
CD38+ cells. But Oscier et al using a cutoff of 30% CD38
and Kröber et al using a cutoff of 7% failed to demonstrate that
CD38 had independent prognostic significance. Since we know that CD38
levels on leukemic B cell clones may change with time and that mixed levels of CD38 expression are commonly observed in leukemic cells (Kröber et al), understanding the precise role that this molecule plays in this disease is problematic. Nevertheless, the association with Ig mutation status and prior reports in the literature
demonstrating prognostic value for CD38 in B-CLL validates further
functional studies (ie, adhesion, signaling capacity) of this molecule. We are now blessed with a surfeit of laboratory tools to more
accurately dissect the transformed programs in B-CLL clones. This
collection of papers substantiates that, by further understanding critical features of CLL B cell clones, we can further discern disease
outcome in B-CLL. This of course is not the final answer to the puzzle
of disease heterogeneity but encourages us to keep trying.
 Neil E. Kay and Diane F. Jelinek
Mayo
Clinic
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