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Prognostic indicators

• Categorizing a patient based on a set of prognostic factors provides complementary information on predictors of disease outcome and survival^9,19-25 (Table 3 and Figure 3). A patient may present with 1 or multiple prognostic markers. Indicators that suggest a poor prognosis may include:
  • High beta₂-microglobulin (B2M) expression²⁴
  • Presence of an unmutated immunoglobulin variable region (IgV_H)¹⁹
  • High ZAP-70 expression^9,25
  • High CD38 expression^9,25
  • Certain cytogenetics (chromosomal abnomalities by FISH)⁹
• B2M serum level expression is a reliable prognostic marker in CLL patients²⁴; high serum level expression of >2×ULN is a poor prognostic indicator¹⁰
• Because IgV_H mutation status is difficult to assess, several studies have investigated surrogate markers. The most promising are the expression levels of ZAP-70 and CD38^9,25
  • It is important to note that assays to detect the expression of these biomarkers are not widely used outside of clinical trials. Thus far, these prognostic factors have not been used routinely because their impact on clinical decision-making is still an active area of research^9,25
  • ZAP-70 is an intracellular kinase and its high expression (>20%) correlates with a more aggressive clinical course^13,26
  • CD38 is a surface marker that may suggest a poor prognosis when expressed (≥30%) on leukemic B lymphocytes^27,28
    • Both ZAP-70 and CD38 modify B-cell receptor (BCR) signaling. Aberrant BCR signaling has been associated with increased survival of malignant cells in CLL²⁹ (read more about targeting the BCR signaling in CLL in Emerging therapeutic options)

Figure 3. Schematic of selected biological differences between lgV_H unmutated and mutated CLL B-cell clones.^19-21

• Additionally, CLL is characterized by a variety of chromosomal abnormalities³⁰. These genetic aberrations include chromosomal deletions del 17p, del 11q, del 13q, del 6q, and trisomy 12²⁷ (Table 4)
  • Current National Comprehensive Cancer Network (NCCN) recommendations are generally based on the presence or absence of a chromosome 17p deletion³¹
    • Patients with chromosomal deletion 17p have a poor prognosis³⁰ (Figure 4); treatment approaches for this patient population continue to be a topic of active investigation²⁷

Figure 4. Prognostic implication of chromosomal abnormalities.³⁰ Adapted from Döhner H et al. N Engl J Med. 2000;343:1910-1916.

Table 4. Chromosomal aberrations in CLL involve the rearrangement of specific genes that may play a role in the patient prognosis.^27,32-35

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