The median age at diagnosis of patients (pts) with chronic lymphocytic leukemia (CLL) is 72 years (yrs). According to the Surveillance and Epidemiology End Results (SEER) database, approximately 11% of all pts diagnosed with CLL in 2009 were <55 yrs. All previously reported series on the natural history of younger CLL pts are more than a decade old, and did not include information on contemporary prognostic parameters (such as immunoglobulin heavy chain gene mutation status [IGHV], genetic abnormalities by fluorescence in-situ hybridization [FISH], ZAP-70, etc). These reports also occurred prior to the introduction of modern treatment strategies (e.g. chemoimmunotherapy (CIT); reduced intensity allogenic stem cell transplant [SCT]), making their data on important clinical outcomes such as time to first treatment (TTT) and overall survival (OS) of uncertain relevance to younger pts in the modern era.
We explored the natural history of younger pts with CLL using the Mayo Clinic Database. All pts ≤ 55 with pathologic diagnosis of CLL who were seen at the Mayo Clinic between January 1995 and April 2012 were included in this study. Baseline demographic and clinical characteristics, prognostic variables and administered treatments were abstracted from the medical records. Outcomes of pts in this cohort was compared to CLL pts >55 seen during the same time period. OS of pts ≤55 was also compared to the age- and sex- matched normal population of the state of Minnesota. The Mayo Clinic Institutional Review Board approved this study.
Collectively, 844 pts ≤ 55 yrs (median age, 48.7 yrs) with newly diagnosed CLL and seen within 1 year of diagnosis were included in this analysis. The characteristics of these pts were compared to 2324 newly diagnosed pts>55 yrs (median age, 68.4 yrs) seen during the same interval. When compared to pts>55, younger pts were more likely to present as intermediate Rai stage disease (p<0.0001), IGHV unmutated (p=0.001), and ZAP-70 positive (p=0.009). Younger pts were also more likely to have 1 or more first degree relatives with CLL (familial CLL) than older pts (10.9% vs. 8.5%; p=0.04). No significant differences were seen in the gender distribution, CD38 status, or FISH risk category.
When pts ≤ 55 were further stratified by age, 204 (24%) were ≤45 yrs, 272 (32%) were 46–50 yrs, and 368 (44%) age 51–55 yrs at diagnosis. Similar to the comparison with the >55 year old group, pts ≤45 were more likely to present with intermediate Rai stage disease (61.7%) than those 46–50 yrs (52.5%), or 51–55 yrs (48.8%; p<0.01). Pts ≤45 were also more likely to be IGHV unmutated (p=0.034) and ZAP-70 positive; however, the ZAP-70 status was not significantly different (p=0.095). No difference in the prevalence of familial CLL was observed by the age stratifications of the ≤55 group.
After a median follow-up of 5.5 yrs (range, 0–17 yrs), 426 (50%) pts ≤55 had received treatment for CLL and 192 (23%) pts had died. Pts ≤55 had a shorter TTT (4.0 yrs vs. 5.2 yrs; p=0.001) but longer OS (12.5 yrs vs. 9.5 yrs; p<0.0001) compared to pts >55 yrs. In contrast, no differences in TTT or OS were observed when the age ≤55 pts were sub-stratified into the ≤45, 46–50, and 51–55 age groups. A significantly higher proportion of pts≤55 received SCT than those >55 (7% vs. 1%; p<0.0001), with even further stratification of the ≤55 group (SCT age≤45: 13.7%; age 46–50: 5.1%; age 51–55: 3.5%; p<0.0001).
As a group, CLL pts ≤55 have significantly shorter OS than the age- and sex-matched population (median CLL=12.5 yrs; median population=not reached; p<0.0001, Figure). However, pts≤55 who were Rai Stage 0 and had mutated IGHV had comparable survival to the general population (p=0.97). Similarly, pts≤55 who were Rai Stage 0 and had favorable FISH results (13q- or normal) had comparable survival to the general population (p=0.27).
Our study is the first comprehensive analysis of younger CLL pts in the modern era. We found that younger pts are more likely to present with intermediate Rai stage disease, and have IGHV unmutated and ZAP-70 positive status. Consistent with these characteristics, younger pts experience shorter TTT. Although the OS of younger CLL pts is longer than those >55, their survival relative to the age- and sex-matched normal population is profoundly shortened even with the advent of CIT and SCT.
Shanafelt:Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.
Asterisk with author names denotes non-ASH members.