B CLL Subtypes--Correlation with Clinical Outcome

Project: Research project

Project Details


DESCRIPTION (provided by applicant): B-cell chronic lymphocytic leukemia
(B-CLL) is a common leukemia with significant patient variability to therapy
and without a definitive curative approach. However, B-CLL likely represents
distinct disease subtypes defined by a variety of cellular and molecular
features including apoptosis resistance, chromosomal abnormalities, and status
of immunoglobulin (Ig) genes in the CLL B cell clones. Specifically, there are
recent findings that a strong relationship exists between clinical outcome and
the presence or absence of somatic mutations in the Ig heavy chain variable
region genes in the B-CLL clone. The exact biologic features that determine why
the two B-CLL patient subgroups fare so differently are unknown. More
importantly, no correlation to date has been made between Ig mutation status
and specific therapeutic strategies, response rates, and key biologic and
molecular features such as apoptosis, drug sensitivities, and chromosomal
abnormalities. In this proposal, therefore, we will characterize apoptosis,
cytogenetic abnormalities, and gene expression profiles of germline versus
somatic mutation type B-CLL clones and more importantly, we will directly
correlate these molecular parameters with clinical outcome to therapy. Our
specific hypothesis is that one or more of these key discriminating features of
B-CLL clones will allow us to predict disease progression and therapeutic
response in CLL subsets. To test this hypothesis, we will conduct laboratory
studies in two North Central Cancer Treatment Group clinical trials for B-CLL:
one trial designed to test the efficacy of Fludarabine given on an alternating
basis with cyclophosphamide to previously untreated CLL patients; and the other
which uses Gemcitabine for previously treated CLL patients. Specifically, we
propose to 1) determine the relationship between B-CLL Ig VH gene region status
and key biological, genetic, and molecular features exhibited by the leukemic
clone; and 2) examine the association between clinical response parameters for
patients treated with fludarabine and cyclophosphamide or Gemcitabine and
clonal biologic and molecular features.
Effective start/end date4/1/013/31/05


  • Medicine(all)