Prognostic Importance of Serum Light Chains in Patients with CLL

Abstract & Commentary

By William B. Ershler, MD

Synopsis: A full panel of prognostic indicators was examined in 449 treatment-naïve CLL patients and it was found that serum light chain ratio was useful in confirming clonality. However, the sum of both k and l serum light chains proved of greater prognositc value in determining an early need to offer CLL treatment. A total (k + l) level of > 60.6 mg/mL was an independent predictor of limited treatment-free survival.

Source: Morabito F, et al. The cumulative amount of serum-free light chain is a strong prognosticator in chronic lymphocytic leukemia. Blood 2011;118:6353-6361.

Clinicians are well aware that chronic lymphocytic leukemia (CLL) is a heterogeneous disorder, with some patients experiencing rapid progression and others surviving for years or even decades without ever requiring therapy. Clinical staging, such as by the Rai or Binet classification systems, are useful, as are the incorporation of various biomarkers including ZAP-70, CD38, immunoglobulin heavy chain variable gene (IGHV) mutation status, and cytogenetic abnormalities, which have proven useful in predicting progressive disease and survival.1 However, these assays are cumbersome, expensive, and not always reproducible or even available outside of the clinical research environment.

In contrast, the measurement of serum free light chain (sFLC) can be reproducibly and inexpensively assayed by straightforward nephelometry.2 Antibody production by B lymphocytes involves the assembly of an immunoglobulin molecule combining heavy and light chains. Under physiological conditions, light chains, either k or l, are produced in excess, pass through the serum transiently, and are excreted renally. In clonal B cell malignancies (such as CLL), certain lymphomas, and most notably multiple myeloma, clonality can be demonstrable by the appearance of an abnormal k/l ratio in the serum. In addition to confirming clonality, there has been recent interest in examining the utility of the serum free light chain ratio (sFLC k/l) as a prognostic marker for CLL.3,4

Identification of patients at risk for early disease progression facilitates the likelihood of tailored management in CLL. Abnormality of k and l serum-free light chain ratio [sFLC (k/l)] has been proposed as a straightforward prognostic factor in CLL. To determine if assessment of this ratio [sFLC (k/l)] is of added value to our existing prognositic factors, Morabito and colleagues analyzed clinical data and blood samples from 449 therapy-naïve patients evaluated throughout Italy. They found that an abnormal sFLC (k/l), along with CD38, ZAP-70, IGHV mutations, cytogenetics, and clinical stage, independently predict treatment-free survival (TFS). The investigators also introduced a new measure, the cumulative amount of clonal and nonclonal FLCs [sFLC (k+l)], and found that when in excess of 60.6 mg/mL, this measure is associated with cytogenetic risk and significantly predicts short TFS.

Commentary

Approximately 50% of CLL patients display an abnormal sFLC (k/l) and/or elevated levels of clonally unrestricted k or l sFLC. In their analysis of a large cohort (n = 449) of untreated CLL patients for the panel of established CLL biomarkers, the investigators document that sFLC(k/l) and sFLC absolute (summed k+l) levels are distinct prognostic variables in CLL. Although abnormal sFLC(k/l) was associated with parameters reflecting disease aggressiveness (i.e., stage, CD38/ZAP-70, IGHV mutations) and independently predicted TFS, it did not correlate with cytogenetic risk. In contrast, unfavorable cytogenetics were associated with the quantitative sum of k and l serum levels. Accordingly, they demonstrate the prognostic value of an abnormal sFLC(k/l) becomes irrelevant if the sFLC(k+l) value is above the threshold value of (60.6 mg/mL). In contrast, by multivariate analysis, sFLC(k+l) more than 60.6 mg/mL was demonstrated as a strong predictor of TFS together with ZAP-70, staging, and cytogenetics, whereas CD38, IGHV mutations, and sFLC(k/l) abnormalities lost their prognostic power. A straightforward model, including sFLC(k+l) more than 60.6 mg/mL, Binet staging, ZAP-70, and cytogenetics, was validated to accurately predict time to treatment requirement in untreated CLL patients.

Thus, determination of serum light chains is a useful and inexpensive adjunct to the initial evaluation of CLL patients. An abnormal k/l ratio indicates clonality and offers prognostic information. Of note, if the total quantitative serum light chain (k+l) exceeds the 60.6 mg/mL threshold, there is likely to be a threshold that is highly predictive of a short interval before treatment will be required.

References

1. Zenz T, et al. Moving from prognostic to predictive factors in chronic lymphocytic leukaemia (CLL). Best practice & research. Clinical Haematol 2010;23:71-84.

2. Bradwell AR, et al. Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine. Clin Chem 2001;47:673-680.

3. Pratt G, et al. Abnormal serum free light chain ratios are associated with poor survival and may reflect biological subgroups in patients with chronic lymphocytic leukaemia. Br J Haematol 2009;144:217-222.

4. Yegin ZA, et al. Free light chain: A novel predictor of adverse outcome in chronic lymphocytic leukemia. Eur J Haematol 2010;84:406-411.