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B-cell chronic lymphocytic leukemia (B-CLL) has a very variable prognosis and no single clinical or laboratory feature accurately predicts prognosis in individual patients at this time. Thus, a group of prognostic features are used. One of the best prognostic indicators is the presence or absence of somatic hypermutation within the immunoglobulin heavy chain gene (IGH) variable (V) region of the neoplastic clone.
Each mature B cell contains 2 IGH alleles, and 1 or both may have undergone rearrangement from the germ line state during the antigen-independent stage of normal B-cell development. It is generally believed that only a single functional rearrangement (ie, able to make a functional immunoglobulin heavy chain protein) is transcribed, although the other allele may contain a nonfunctional rearrangement. The rearranged gene contains, as contiguous components, a leader sequence, a variable (V) segment, and a diversity (D) segment. A noncontiguous constant (C) segment is also present.
Some B cells also undergo the antigen-dependent mutation process termed somatic hypermutation, which introduces point mutations into the V region. Patients with clones carrying unmutated IGH V region rearrangements are associated with a significantly worse prognosis than patients with clones carrying mutated IGH V region rearrangements. This finding is based on survival curve data in which 2% or greater mutation frequency in the complete V region of a functional IGH rearrangement was used as the criteria for mutated status. In 2 large studies, patients with unmutated status had a median survival of approximately 9 years, while those with mutated status had a median survival of at least 20 years.
Prognostic information in patients with newly diagnosed B-cell chronic lymphocytic leukemia
The presence or absence of somatic hypermutation in the immunoglobulin heavy chain gene (IGH) variable (V) region DNA will be reported. A mutation frequency of 2% or greater will be reported as mutated. Both the percent mutation and the V region allele identified in the rearrangement will be included in the report.
B-cell chronic lymphocytic leukemia (B-CLL) lacking somatic hypermutation of the IGH V region (unmutated) is associated with a significantly worse prognosis than B-CLL containing somatic hypermutation of the IGH V region (mutated).
The prognostic significance of somatic hypermutation status is only known when a single functional IGH rearrangement is identified. However, a variety of situations can occur, for which the clinical significance is unknown at this time. These can broadly be grouped into the following:
1. Greater than 1 functional rearrangement is identified, with discordant mutation status
2. Only nonfunctional rearrangements are identified
Rearrangements with mutation status at or near the 2% cutoff should be interpreted with caution for the purposes of prognosis, particularly if the entire IGH V sequence could not be sequenced due to the use of V region primers. Neoplasms with this type of result will be identified by a comment in the report.
An interpretive report will be provided.
1. Hamblin TJ, Davis Z, Gardiner A, et al: Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999 September 15;94(6):1848-1854
2. Damle RN, Wasil T, Fais F, et al: Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999 September 15;94(6):1840-1847