Abstract Introduction: Prognosis in CLL is heterogeneous with the elderly, males and those with multiple co-morbidities having the highest risk of poorer outcomes. Whether this reflects differences in the biology of CLL or the result of altered immunosuppression is unknown. In normal individuals, the telomeres in somatic cells shorten with age, predisposing those with shorter telomeres to death from infections, cancer and cardiovascular disease. In chronic lymphocytic leukemia (CLL), short telomere length in the leukemia cells predicts poor prognosis. The contribution of un-modifiable factors of age, sex or comorbidities to telomere shortening in CLL has not been elucidated. In the present study, we evaluated buccal cell (BC) telomere length in patients with CLL, to determine if this is predictive of survival, and can enhance the predictive value of leukemia cell telomere length. Methods: The Manitoba CLL tumor bank contains 168 samples from newly diagnosed CLL patients between 2007-2011; with a median follow-up of 4 years. Half of these patients required chemotherapy and one-tenth have died. Genomic DNA was extracted from purified CLL cells and buccal cells (BC) collected at diagnosis. Telomere length was established by multiplex quantitative real-time PCR. Telomere/standard (t/s) ratio was calculated using the beta-globulin gene as the standard. Statistical analysis was performed using Statistical Analysis Software (SAS) and Prism software. Results: The median adjusted telomere length was shorter in CLL cells than in BCs being 0.53 and 2.01, respectively. In BCs, telomere length significantly shortened with increasing age (p = 0.01) but was not reflective of the number of comorbidities or survival. In contrast, telomere length in CLL cells was independent of age (p = 0.44) and sex (p = 0.75). Short CLL telomere length correlated with other biological and clinical markers of poorer prognosis including un-mutated IGHV status (p<0.0001), Zap70 positivity (p = 0.05), CD38 positivity (p = 0.003), short lymphocyte doubling time (p = 0.004), higher Rai stage (p = 0.02) and an earlier time to treatment (p<0.0001). Patients with short CLL telomeres had also decreased survival at four years (p = 0.05); living 22 months less than those with normal telomeres. Adjusting for BC telomere length improved the prognostic value of CLL telomere length as an independent predictor of survival. Conclusions: These results demonstrate that BC telomere length in CLL patients shorten with age independent of co-morbidities, secondary malignancies and the respective CLL telomere length. CLL telomere shortening is strongly associated with biochemical and clinical markers of disease progression and survival. The predictive value for overall survival is enhanced by correcting for changes in buccal cell telomere length. Note: This abstract was not presented at the meeting. Citation Format: Lin Yang, Sara Beiggi, Yunli Zhang, Robert Schmidt, Spencer B. Gibson, James B. Johnston. Clinical impact of telomere shortening in normal and leukemia cells in chronic lymphocytic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4624. doi:10.1158/1538-7445.AM2015-4624
Single-Agent Lenalidomide in the Treatment of Previously Untreated Chronic Lymphocytic Leukemia
PurposeLenalidomide is an oral immunomodulatory drug with multiple effects on the immune system and tumor cell microenvironment leading to inhibition of malignant cell growth. Based on encouraging reports of lenalidomide in relapsed and refractory chronic lymphocytic leukemia (CLL), we investigated the first-line use of single-agent lenalidomide in CLL.Patients and MethodsUsing a starting dose of lenalidomide 10 mg/d for 21 days of a 28-day cycle and weekly 5-mg dose escalations to a target of 25 mg, we encountered severe toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and the protocol amended to a more conservative regimen: starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg, and extended tumor lysis prophylaxis and monitoring. Gene expression profiles from patient samples before and after 7 days of lenalidomide were performed.ResultsTwenty-five patients were enrolled on the amended protocol. No further tumor lysis events were reported. Tumor flare was common (88%) but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of febrile neutropenia. The overall response rate was 56% (no complete responses). Although rapid peripheral lymphocyte reductions were observed, rebound lymphocytoses during the week off-therapy were common. Lenalidomide-induced molecular changes enriched for cytoskeletal and immune-related genes were identified.ConclusionLenalidomide is clinically active as first-line CLL therapy and is well-tolerated if a conservative approach with slow dose escalation is used. A lenalidomide-induced molecular signature provides insights into its immunomodulatory mechanisms of action in CLL.