Clinical and molecular predictors of disease severity and survival in chronic lymphocytic leukemia

Abstract

Several parameters may predict disease severity and overall survival in chronic lymphocytic leukemia (CLL). The purpose of our study of 190 CLL patients was to compare immunoglobulin heavy chain variable region (IgV H ) mutation status, cytogenetic abnormalities, and leukemia cell CD38 and Zap-70 to older, traditional parameters. We also wanted to construct a simple, inexpensive prognosis score that would significantly predict TTT and survival in patients at the time of diagnosis and help practicing clinicians. In univariate analyses, patients with higher clinical stage, higher leukocyte count at diagnosis, shorter leukocyte doubling time, elevated serum lactate dehydrogenase (LDH), unmutated immunoglobulin heavy chain variable region (IgV H ) genes, and higher CD38 had a shorter overall survival and time-to-treatment (TTT). CLL cell Zap-70 expression was higher in patients with unmutated IgV H , and those with higher Zap-70 tended to have shorter survival. IgV H 4-34 or IgV H 1-69 was the most common IgV H genes used (16 and 12%, respectively). Of those with IgV H 1-69, 86% had unmutated IgV H and had a significantly shorter TTT. A cytogenetic abnormality was noted in 71% of the patients tested. Patients with 11q22 del and 17p13 del or complex abnormalities were significantly more likely to have unmutated IgV H . We found that a prognostic score constructed using modified Rai stage, cellular CD38, and serum LDH (parameters easily obtained clinically) significantly predicted TTT and survival in patients at the time of diagnosis and performed as well or better than models using the newer markers. Am.

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

“…1,2,6,[16][17][18] Overall, women were of lower stage than men (P ¼ 0.02). Women with CLL and an APOE4 genotype compared with the non-APOE4 women patients were less likely to have Zap-70-positive cells (P ¼ 0.03), had a higher hematocrit at the time of diagnosis (P ¼ 0.009) and had fewer deaths (P ¼ 0.02) ( Table 1).…”

“…6 The 183 patients studied here (from the cohort of 190 patients we reported earlier 6 ) were those on whom we had sufficient DNA to genotype for APOE. Fifty-eight patients (32%) were from the Durham VA Medical Center, and 125 patients (68%) from Duke University Medical Center.…”

“…Diagnosis and staging of CLL, and decisions regarding initiation of treatment were determined according to NCI Working Group criteria. 6,7 The length of time from diagnosis to death from any cause was defined as overall survival, and the length of time to initiation of treatment from the date of diagnosis was defined as the time to treatment (TTT). All subjects had not received CLL therapy for at least 4 weeks before blood was sampled, and all patients gave informed consent according to protocols approved by the VA and Duke University Institutional Review Boards.…”

“…6,8 The enriched CLL cells contained 0.9±0.1% (mean±s.e.m.) T cells and 3.4±0.6% CD19 þ /CD5 À cells ('normal' B cells).…”

“…Doubling times, CLL cell phenotypes including CD38 and Zap-70 assessment, IgV H mutation status and FISH analyses were performed as we have done before. 6,8 APOE genotyping was performed as previously described. 9 We assayed lipoprotein lipase (LPL) mRNA by quantitative reverse transcriptase-PCR using TaqMan premade primers (Applied Biosystems, Foster City, CA, USA) for LPL and b-actin (ACAB) genes.…”