Serum Free Light Chain in Lymphoproliferative Disorders
Persons infected with human immunodeficiency virus (HIV) have an elevated risk of developing NHL particularly DLBCL, primary central nervous system (CNS) lymphoma, and to a lesser extent, Burkitt lymphoma; this risk remains increased in the era of effective HIV therapy and is directly associated with CD4 T-lymphocyte counts and the presence of B-cell dysfunction. Moreover, serum Ig level, mainly IgG, is high, reflecting nonspecific polyclonal B-cell activation. To evaluate whether acquired immunodeficiency syndrome (AIDS) lymphomas are typically preceded by a precursor state manifested in elevated markers of B-cell activation, Landgren et al evaluated the usefulness of FLC assays in 66 individuals who developed NHL and 225 matched HIV-infected, lymphoma-free controls in a case-control study. The 66 patients with NHL included 27 with DLBCL, 10 with primary CNS lymphoma, 3 with Burkitt lymphoma, and 26 with other/unknown NHL subtypes. They found that increased sFLC was a strong predictor of NHL up to 2 to 5 years before diagnosis in a dose-response manner. This strong association between sFLC level and development of NHL is mostly noted in patients not receiving highly active antiretroviral therapy (HAART). In addition, Landgren et al speculated that, in addition to CD4 cell counts, elevated sFLC levels can help identify patients who might most benefit from starting early HAART therapy.
DLBCL is the most common NHL in the United States. The International Prognostic Index (IPI) is currently considered a prognostic score for the aggressive type of DLBCL. However, risk-adaptive treatment approaches related to other biomarkers are needed. Therefore, there is a need for additional prognostic markers to better identify patients who experience a relapse after immunochemotherapy or fail to achieve remission. The 8% frequency of abnormal κ/λ ratio in DLBCL was previously described by Martin et al as one of the lowest compared with other NHL types based on a study of 25 patients (Table 1). A larger study was published recently by Maurer et al including 2 independent cohorts (N0489 and MER with 76 and 219 patients, respectively) of 295 patients with DLBCL. They investigated the association of pretreatment sFLC with event-free and overall survival. Elevated sFLC concentrations and abnormal κ/λ sFLCr were seen in 34% and 12% of the N0489 group and in 31% and 15% of the MER group, respectively. Patients with elevated sFLC had inferior overall and event-free survival in both cohorts compared with patients with normal FLC (N0489: event-free survival HR, 3.06; overall survival HR, 3.16; P < .02 for both; MER: event-free survival HR, 2.57; overall survival HR, 3.74; P < .001 for both). All associations remained significant for event-free and overall survival after adjusting for the IPI. Abnormal sFLCr, however, was modestly associated with event-free and overall survival in combined groups (event-free survival HR, 1.61; overall survival HR, 1.67, P = .07 for both), with the association only related to a concomitantly elevated sFLC regardless of its being monoclonal or polyclonal in nature. Therefore, patients with abnormal sFLCr without an elevation of either chain should be considered to be at normal risk. In a multivariate analysis, sFLC turned out to have stronger association with event-free survival (HR, 2.26; P < .001) and overall survival (HR, 2.5; P < .001) compared with the 5 IPI components. The association between outcome and sFLC was maintained in patients with normal creatinine level, suggesting that renal failure is not an interfering factor. The authors also found an association between elevated sFLC and stage, and probably with a more aggressive tumor. In conclusion, this study demonstrates increased sFLC to be an independent, adverse prognostic factor for event-free and overall survival rather than for sFLCr, and further evaluation of sFLC assays as a biomarker in DLBCL is required.
AIDS-Related Lymphoma and sFLC
Persons infected with human immunodeficiency virus (HIV) have an elevated risk of developing NHL particularly DLBCL, primary central nervous system (CNS) lymphoma, and to a lesser extent, Burkitt lymphoma; this risk remains increased in the era of effective HIV therapy and is directly associated with CD4 T-lymphocyte counts and the presence of B-cell dysfunction. Moreover, serum Ig level, mainly IgG, is high, reflecting nonspecific polyclonal B-cell activation. To evaluate whether acquired immunodeficiency syndrome (AIDS) lymphomas are typically preceded by a precursor state manifested in elevated markers of B-cell activation, Landgren et al evaluated the usefulness of FLC assays in 66 individuals who developed NHL and 225 matched HIV-infected, lymphoma-free controls in a case-control study. The 66 patients with NHL included 27 with DLBCL, 10 with primary CNS lymphoma, 3 with Burkitt lymphoma, and 26 with other/unknown NHL subtypes. They found that increased sFLC was a strong predictor of NHL up to 2 to 5 years before diagnosis in a dose-response manner. This strong association between sFLC level and development of NHL is mostly noted in patients not receiving highly active antiretroviral therapy (HAART). In addition, Landgren et al speculated that, in addition to CD4 cell counts, elevated sFLC levels can help identify patients who might most benefit from starting early HAART therapy.
DLBCL and sFLC
DLBCL is the most common NHL in the United States. The International Prognostic Index (IPI) is currently considered a prognostic score for the aggressive type of DLBCL. However, risk-adaptive treatment approaches related to other biomarkers are needed. Therefore, there is a need for additional prognostic markers to better identify patients who experience a relapse after immunochemotherapy or fail to achieve remission. The 8% frequency of abnormal κ/λ ratio in DLBCL was previously described by Martin et al as one of the lowest compared with other NHL types based on a study of 25 patients (Table 1). A larger study was published recently by Maurer et al including 2 independent cohorts (N0489 and MER with 76 and 219 patients, respectively) of 295 patients with DLBCL. They investigated the association of pretreatment sFLC with event-free and overall survival. Elevated sFLC concentrations and abnormal κ/λ sFLCr were seen in 34% and 12% of the N0489 group and in 31% and 15% of the MER group, respectively. Patients with elevated sFLC had inferior overall and event-free survival in both cohorts compared with patients with normal FLC (N0489: event-free survival HR, 3.06; overall survival HR, 3.16; P < .02 for both; MER: event-free survival HR, 2.57; overall survival HR, 3.74; P < .001 for both). All associations remained significant for event-free and overall survival after adjusting for the IPI. Abnormal sFLCr, however, was modestly associated with event-free and overall survival in combined groups (event-free survival HR, 1.61; overall survival HR, 1.67, P = .07 for both), with the association only related to a concomitantly elevated sFLC regardless of its being monoclonal or polyclonal in nature. Therefore, patients with abnormal sFLCr without an elevation of either chain should be considered to be at normal risk. In a multivariate analysis, sFLC turned out to have stronger association with event-free survival (HR, 2.26; P < .001) and overall survival (HR, 2.5; P < .001) compared with the 5 IPI components. The association between outcome and sFLC was maintained in patients with normal creatinine level, suggesting that renal failure is not an interfering factor. The authors also found an association between elevated sFLC and stage, and probably with a more aggressive tumor. In conclusion, this study demonstrates increased sFLC to be an independent, adverse prognostic factor for event-free and overall survival rather than for sFLCr, and further evaluation of sFLC assays as a biomarker in DLBCL is required.
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