Patients with chronic lymphocytic leukemia with mutated VH genes presenting with Binet stage B or C form a subgroup with a poor outcome.
OBJECTIVE
The immunoglobulin VH gene mutation status is a strong prognostic indicator in B-cell chronic lymphocytic leukemia (CLL), since unmutated VH genes are correlated with short survival. However, the traditional cut-off level dividing mutated and unmutated cases, i.e. more or less than 2% mutations, has been questioned and other cut-offs have been suggested. We investigated whether an alternative cut-off should be applied and the relation of mutational status to another prognostic marker, Binet staging.


METHODS
VH gene mutation status was assessed in 332 CLL cases by polymerase chain reaction amplification and nucleotide sequencing and was further correlated with overall survival using different VH mutation cut-offs (1-7%) and Binet stage.


RESULTS
After testing different mutation borders, the 2% cut-off remained the best discriminative level for determining prognosis. Interestingly, prognostic stratification was improved by combining the information on VH gene mutation status with that of Binet stage: unmutated cases (all stages, n=151, mutated cases with stage A (n=77), and mutated cases with stage B or C (n=37) had a median survival of 82, 179 and 74 months, respectively.


CONCLUSIONS
CLL cases displaying mutated VH genes with Binet stage B or C had a survival similar to that of unmutated cases and significantly shorter than that of mutated stage A CLL. Our result reveals clinical heterogeneity within the VH mutated CLL group by inclusion of Binet stage data, a finding which is of importance when considering surrogate marker(s) for VH mutation status.
Tobin
Gerard
G
Dept. of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Thunberg
Ulf
U
Laurell
Anna
A
Karlsson
Karin
K
Aleskog
Anna
A
Willander
Kerstin
K
Söderberg
Ola
O
Merup
Mats
M
Vilpo
Juhani
J
Hultdin
Magnus
M
Sundström
Christer
C
Roos
Göran
G
Rosenquist
Richard
R
D000328:Adult; D018572:Disease-Free Survival; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin / Q000502:physiology*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D009367:Neoplasm Staging; D027041:Somatic Hypermutation, Immunoglobulin; D016896:Treatment Outcome
D007135:Immunoglobulin Variable Region