Free Light Chain Levels Offer Predictive Value for Both Myelofibrosis and Myelodysplasia
June 1, 2012 4 minutes read
Free Light Chain Levels Offer Predictive Value for Both Myelofibrosis and Myelodysplasia
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Host-related immunoproliferation may contribute to the pathogenesis of certain clonal myeloid disorders such as myelofibrosis and myelodysplasia. In cohorts of such patients, the demonstration of elevated free immunoglobulin light chains (considered a surrogate of polyclonal immunoproliferation) is shown to be associated with poor overall survival in patients with these disorders.
Source: Pardanani A, et al. Polyclonal immunoglobulin free light chain levels predict survival in myeloid neoplasms. J Clin Oncol 2012;30:1087-1094.
Both primary myelofibrosis (PMF) and myelodysplasia (MDS) are clonal hematopoietic stem cell disorders associated with aberrant host responses including immunoproliferation and inflammation. Whereas therapies directed at the involved stem cells have proven only marginally effective, treatments directed at these dysregulated host responses occasionally produce gratifying responses in terms of quality of life. It has been speculated that dysregulated host responses contribute to the pathogenesis of these disorders and to the extent that these host responses can be quantified, it is possible that they would predict meaningful clinical outcomes. In this regard, investigators from the Mayo Clinic had previously demonstrated the prognostic significance of certain pro-inflammatory cytokines for patients with both PMF and MDS.1,2 In the current report, these same investigators sought to elaborate further the concept of prognostically relevant host-specific biomarkers in PMF and MDS by using a readily accessible B-cell activation marker, plasma immunoglobulin free light chain (FLC) concentration.
They proposed that FLC, as a surrogate marker of host immune response, would predict survival for these non-plasma cell myeloid malignancies (PMF and MDS). Because the FLC assay is readily available (as opposed to the more complex cytokine assays), the findings might have immediate practical applicability.
The study was conducted on two different cohorts of referred patients those with PMF (n = 240) and those with MDS (n = 74). Kappa (k) and lambda (l) FLCs were measured by a quantitative nephelometric assay. For patients with an abnormal k/l ratio, monoclonal production was ruled out by immunofixation, but if present, such patients were excluded from analysis.
Values that were above the upper limit of normal for k or l FLC were documented in 33% of 240 patients with PMF and 46% of 74 patients with MDS. Increased FLC was significantly associated with increased creatinine, and advanced age in PMF (P < 0.001) and hemoglobin < 10 g/dL in MDS (P < 0.005). In multivariable analysis, increased FLC predicted shortened survival in both PMF and MDS, independent of age, creatinine, and other conventional risk factors. Cutoff levels based on receiver operating characteristic analysis for k plus l total FLCs delineated risk groups with highly significant differences in overall survival. For PMF, this cutoff value was 3.78 mg/dL and for MDS it was somewhat lower at 3.24 mg/dL.
For patients with PMF, the International Prognostic Scoring System-adjusted hazard ratio was 1.9 (95% confidence interval [CI], 1.3 to 2.7), and for MDS it was 6.3 (95% CI, 2.7 to 16.6). No correlations were seen with leukemia-free survival, karyotype, or JAK2, MPL, or IDH mutations. In patients with PMF who had previously been studied by cytokine profiling, the prognostic value of an increased FLC level was independent of that from circulating interleukin-2 receptor (IL-2R) or IL-8 levels and when the data were taken together, a more precise predictive value was determined. For example, a composite risk model based on total FLC greater than 3.78 mg/dL and two selected cytokines (IL-2R or IL-8; values greater than three SDs): both normal (n = 39; median survival not reached), either abnormal (n = 98; median survival, 70 months), and both abnormal (n = 61; median survival, 32 months; P < 0.001).
Commentary
Conventional prognostic variables for inferior survival in PMF and MDS are based on cell-intrinsic properties of the malignant clone, such as unfavorable karyotype, increased tumor burden or proliferative capacity, and ineffective hematopoiesis. A number of reports for both PMF and MDS have indicated various mutations, many of which confer some prognostic information.3-5 However, these mutations are limited by low mutation frequency and, of course, varying laboratory expertise and technical capabilities, let alone expense. Yet, various host-related factors including age, performance status, dysregulated cytokines,2,6,7 and now FLC are also relevant to outcomes in patients with these disorders.
The findings from this report indicating the predictive value of plasma FLCs are of interest at a variety of levels. From a biological perspective, the lack of correlation with leukemia-free survival and tumor-specific genetic markers suggests that the increase relates primarily to host response, and the correlation suggests dysregulated immunoproliferation may be causally related to disease progression. Furthermore, for the clinician, this readily available laboratory parameter (FLC) may prove very useful in refining prognosis and determining appropriate interventions. The report capitalized on two relatively large and carefully evaluated cohorts, yet the overall added value remains to be determined in prospective studies.
References
1. Pardanani A, et al. IPSS-independent prognostic value of plasma CXCL10, IL-7 and IL-6 levels in myelodysplastic syndromes. Leukemia 2012;26:693-699.
2. Tefferi A, et al. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: A comprehensive cytokine profiling study. J Clin Oncol 2011;29:1356-1363.
3. Bejar R, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011;364:2496-2506.
4. Lasho T, et al. Inhibition of JAK-STAT signaling by TG101348: A novel mechanism for inhibition of KITD816V-dependent growth in mast cell leukemia cells. Leukemia 2010;24:1378-1380.
5. Pardanani A, et al. Primary myelofibrosis with or without mutant MPL: Comparison of survival and clinical features involving 603 patients. Leukemia 2011;25:1834-1839.
6. Gangat N, et al. DIPSS plus: A refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011;29:392-397.
7. Garcia-Manero G, et al. A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia 2008;22:538-543.
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