Molecular Profiling of Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a cancer of the blood that originates in the hematopoietic cells in bone marrow. In the West, CLL is the most common type of adult leukemia (Zenz et al. 2010). In the United States, 18,960 cases of CLL and 4,660 deaths due to CLL were estimated for 2016 (ACS 2016). In the U.S. there is an estimated incidence rate for CLL of 4.5 per 100,000 people, with a median age at diagnosis of 72 years, making CLL a disease of the elderly (ten Hacken and Burger 2016). Men are nearly twice as susceptible to CLL as women and the disease is more common in white populations (Dores et al. 2007). Five-year survival rates for patients with CLL is nearly 90% (Wall and Woyach 2016); however, CLL is quite heterogeneous in its presentaion, ranging from an indolent disease with little to no therapeutic intervention to a more aggressive clinical course (Guièze and Wu 2015; Wall and Woyach 2016; Zhang and Kipps 2014).
The pathological hallmark of CLL is clonal expansion of B cells in blood (Figure 1), marrow, and secondary lymphoid tissues (Chiorazzi, Ria, and Ferrarini 2005; Zhang and Kipps 2014); these B cells typically express the B cell antigens CD23, CD19, and CD20 (weak), with co-expression of CD5 (Wall and Woyach 2016; Zenz et al. 2010). These B cells are characterized by weak surface membrane immunoglobulin (Ig) levels, most often IgM or IgM and IgD (Zenz et al. 2010). In about half of cases of CLL, the leukemia cells express Ig encoded by mutated Ig heavy-chain variable region genes (IGHVs) that differ by more than 2% from the germline gene (M-CLL); M-CLL correlates with an indolent disease phenotype (Zenz et al. 2010; Zhang and Kipps 2014). On the other hand, leukemia cells that express unmutated IGHVs (U-CLL) are associated with a more aggressive phenotype (Zenz et al. 2010; Zhang and Kipps 2014).
Figure 1. The hallmark of CLL is lymphocytosis.
The probability that two clonally independent B-cell groups carry the same B-cell receptor (BCR) is less than 1 x 10-12, but CLL cells often express identical BCRs, termed “stereotyped” BCRs (Zenz et al. 2010; Zhang and Kipps 2014). U-CLL cells are more likely than M-CLL cells to express stereotyped BCRs; these stereotyped BCRs are structurally restricted and typically reactive to autoantigens (Zenz et al. 2010; Zhang and Kipps 2014). It is thus thought that common environmental- or self-antigens may play a role in the development of CLL (Zenz et al. 2010; Zhang and Kipps 2014). This hypothesis is supported by evidence of low cell surface IgM expression on CLL cells that recovers after incubation in vitro, suggestive of a cell that is undergoing endocytosis of antigen-associated IgM (Stevenson, Forconi, and Packham 2014). Significant debate has surrounded the question of the origination of the CLL B-cell population from its healthy B-cell counterpart (Zenz et al. 2010; Zhang and Kipps 2014). Recent evidence suggests that U-CLL B cells derive from mature CD5+CD27- B cells with unmutated IGHVs, while IGHV-mutated CLL B cells derive from a subpopulation of CD5+CD27+ post-germinal center B cells with mutated IGHVs (Seifert et al. 2012; ten Hacken and Burger 2016; Zhang and Kipps 2014).
The two CLL subgroups (U-CLL and M-CLL) also have other biological differences, such as differential expression of protein tyrosine kinase zeta-associated protein 70 (ZAP70) and CD38, differential pathway activation, different telomere lengths, and differential rates of acquisition of other genetic lesions (Zenz et al. 2010). Higher ZAP70 and higher CD38 expression are both associated with a more aggressive disease phenotype (ten Hacken and Burger 2016). Genetic lesions typically observed in CLL include 13q deletions (55%; associated with favorable clinical outcome), trisomy 12 (15%; associated with intermediate prognosis), 11q deletions (12%; associated with poor clinical outcome), 17p deletions (8%; associated with poor clinical outcome), and recurrent mutations (2–11%) in NOTCH1, SF3B1, BIRC3, TP53, and MYD88 (Baliakas et al. 2015; ten Hacken and Burger 2016; Puiggros, Blanco, Espinet 2014). Other important prognostic factors are clinical staging systems, serum markers (e.g., β2 microglobulin levels), thymidine kinase levels, and soluble CD23 levels (ten Hacken and Burger 2016).
Because of the elderly age of many patients with CLL and the high morbidity and mortality associated with allogeneic stem cell transplantation (Allo-SCT), Allo-SCT is rarely a treatment option for patients with CLL, though its effects may be curative in a few (Wall and Woyach 2016). In non-symptomatic disease, monitoring has been the standard clinical course, while immune-chemotherapy was the conventional choice for symptomatic disease (Guièze and Wu 2015). However, the recent FDA approval of new targeted therapies, some of which act on the BCR-initiated signaling pathway, promises to change the therapeutic landscape for CLL (Guièze and Wu 2015). Idelalisib is a phosphatidylinositol 3 kinase (PI3K) delta inhibitor FDA-approved for treatment of relapsed/refractory CLL (Wall and Woyach 2016). Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved for treatment of relapsed/refractory CLL or upfront treatment of patients with 17p deletions (Wall and Woyach 2016). Other drugs approved for CLL include monoclonal antibodies to CD20 (ofatumumab, obinutuzumab, and rituximab) and CD52 (alemtuzumab) (NCI; Wall and Woyach 2016). Drugs under investigation in clinical trials include GDC-0199/ABT-199, a BCL2 inhibitor, additional BTK inhibitors (ONO-4059 and ACP-196), PI3K inhibitors (duvelisib, pilaralisib, TGR-1202, GS-9820, and ACP-319), and spleen tyrosine kinase (SYK) inhibitors (fostamatibinib, GS-9973, and PRT-2020) (Guièze and Wu 2015; ten Hacken and Burger 2016), which focus on the BCR-initiated cell signaling pathways.
Suggested Citation: Reddy, N. 2016. Molecular Profiling of Chronic Lymphocytic Leukemia. My Cancer Genome https://www.mycancergenome.org/content/disease/chronic-lymphocytic-leukemia/ (Updated February 12).
Last Updated: February 12, 2016