Correlation of IgVH somatic mutation and disease course in chronic lymphocytic leukemia

Abstract

7068 Background: IgVH mutation status is a well accepted prognostic marker in chronic lymphocytic leukemia (CLL). Typically >98% of the germline sequence homology is considered unmutated, and =98% is considered mutated. The 98% cutoff was originally chosen to account for undefined IgVH polymorphisms that could be responsible for DNA sequence disparity. Prior data showed that mutated patients have a more benign course of disease vs unmutated patients . However an unanswered question is whether IgVH somatic mutations correlate to disease course in a linear, continuous fashion. Methods: Using a Cox proportional hazards model, we evaluated 146 patients and examined the relationship between time to first treatment (TTT) and percentage of mutation as a continuum. Results: Patients with higher mutation percentages were less likely to start treatment (p<0.0002). See table below. For each unit increase in mutation percent, the patient was 0.829 times less likely to start treatment. So, for example, a patient with a mutation percent of 3% is 0.829 times as likely to start treatment as a patient with a mutation percentage of 2%, and a patient with a mutation percent of 8% is 0.829 times as likely to start treatment as a patient with a mutation percentage of 7%, (i.e. any 1 unit increase in mutation percent). Similarly, a patient with mutation rate 3 percentage points higher than another patient is 0.570 times as likely to need treatment, and a patient with a mutation rate 5 percentage points higher than another patient is 0.392 times as likely to need treatment. Conclusion: These data suggest that as the percentage of mutation in IgVH increases, the time to first treatment increases. This has implications as to the role of the CLL B-cell receptor (BCR) and its specificity in clinical outcome. Assuming that in vivo BCR stimulation causes CLL cell proliferation, increased IgVH mutations may result in narrowed specificity of the BCR, thereby limiting the diversity of antigens capable of delivering a stimulatory signal. % Mutation and corresponding hazard ratios for requiring treatment Mutation % Hazard ratio 1 0.829 2 0.687 3 0.570 4 0.472 5 0.392 10 0.153 15 0.060 No significant financial relationships to disclose.