Serum Free Light Chain Difference and β 2 Microglobulin Levels Are Risk Factors for Thromboembolic Events in Patients With AL Amyloidosis

AbstractThe disease causing agent in systemic AL amyloidosis is a monoclonal immunoglobulin free light chain, or fragments thereof, circulating in the blood. It is not surprising, therefore, that measurement of serum free light chains plays a central role in the management of this disorder. In this paper, we review the utility of the serum free light chain assay in the investigation, prognostication and monitoring of AL amyloidosis. Data on the two currently available commercial assays is compared and some practical applications of the assay’s use are presented. While there are limitations, it is clear that the availability of the free light chain assay in the laboratory is a major advance and plays an essential role in the management of patients with AL amyloidosis.

Download Full-text

Heavy/Light Chain Quantification Identifies Clonal Plasma Cell Disease in Patients with AL Amyloidosis and Normal Serum Free Light Chain Ratio

Blood ◽

10.1182/blood.v126.23.2956.2956 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2956-2956

Author(s):

Tatiana Prokaeva ◽

Brian Spencer ◽

Fangui Sun ◽

Nathaniel McConnell ◽

Richard M O'hara ◽

...

Keyword(s):

Overall Survival ◽

Binding Site ◽

Plasma Cell ◽

Light Chain ◽

Free Light Chain ◽

Al Amyloidosis ◽

Cell Disease ◽

Serum Free ◽

Serum Free Light Chain ◽

Combined Use

Abstract Background: Serum and urine immunofixation electrophoreses (SIFE/UIFE) are routinely used for detection of clonal immunoglobulins (Ig) in AL amyloidosis. Serum free light chain (FLC) assays (Freelite®, The Binding Site Ltd., Birmingham, UK) have significantly improved the management of patients with AL amyloidosis by providing quantitative measure for the detection and monitoring of clonal plasma cell disease. However, up to 20% of patients with AL amyloidosis may have uninformative serum free light chain values. Objective: To assess the quantitative potential of serum Heavy/Light Chain (HLC) pairs (Hevylite®, The Binding Site Ltd., Birmingham, UK) assay in identification of clonal plasma cell disease in AL amyloidosis. Methods: One hundred and ninety-nine untreated patients with AL amyloidosis were included in this study. Patients with multiple myeloma or B cell lymphoproliferative diseases associated AL amyloidosis were excluded. Serum sampleswere obtained at initial evaluation and stored at -20°C. SIFE/UIFE were performed at the time of sample collection. HLC pairs were assessed by the Hevylite® assay. HLC κ/λ normal ratios (HLCR) were: 1.12-3.21 for IgG κ/λ; 0.78-1.94 for IgA κ/λ; and 1.18-2.74 for IgM κ/λ. FLCs were assessed by the Freelite® assay; FLC κ/λ normal ratio (FLCR) was 0.26-1.65. In 103 cases, FLC testing was performed at the time of sample collection; 96 cases were tested at The Binding Site. Vital status of patients was obtained from either medical records or Social Security Death Index. Follow-up ended in June 2014. Results: An abnormal HLCR was found in 74 (37.2%), an abnormal FLCR in 163 (81.9%), and SIFE/UIFE positivity in 187 (94%) of 199 patients with AL amyloidosis. Of 36 patients with a normal FLCR, 23 (63.9%) were noted with an abnormal HLCR compared to 51 (31.3%) patients in an abnormal FLCR group (P = 0.001). In total 186/199 (93.5%) patients with AL amyloidosis had abnormalities in either HLCR or FLCR, compared to 187/199 (94%) of patients who were SIFE/UIFE+ (Table 1). The combined use of both FLCR and HLCR yielded quantifiable information in 93.5% of cases; the use of both tests in combination with SIFE/UIFE identified plasma cell clonality in 100% of patients. Seventy-two cases presented with an abnormal HLCR for a single isotype and 2 in multiple Ig isotypes. In all cases, involved LC type of abnormal HLCR matched LC type identified by SIFE/UIFE. None of 12 cases that were negative on the SIFE/UIFE presented with an abnormal HLCR, however, all showed abnormalities in FLCR. Table 1. Comparative efficiency of FLCR, HLCR and Serum/Urine Immunofixation in AL Amyloidosis patients. SIFE/UIFE+ (n=187) SIFE/UIFE- (n=12) HLCR+/FLCR+ 51 (27.2%) - HLCR+/FLCR- 23 (12.3%) - HLCR-/FLCR+ 100 (53.5%) 12 (100%) HLCR-/FLCR- 13 (7%) - Overall survival was similar in patients with and without abnormal HLCR (Log rank p=0.092; Figure 1), whereas patients with an abnormal FLCR had a significantly inferior overall survival compared to those with a normal FLCR (Log rank p=0.027; Figure 2). Combined use of both HLCR and FLCR demonstrated a trend toward superior overall survival in a group of patients with an abnormal HLCR / normal FLCR (Wilcoxon p=0.037; Log rank p=0.107; Figure 3). Conclusions: The Hevylite® assay provided information in addition to other laboratory tests for clonal plasma cell disease in AL amyloidosis. The combined use of the HLCR and FLCR provided quantifiable information in 93.5% of patients. The use of both assays in combination with SIFE/UIFE detected clonal disease in all patients. HLCR has potential to quantify clonal disease in patients with uninformative FLCR results. An abnormal HLCR was not predictive of overall survival, while an abnormal FLCR was, in this series of patients. Combined use of HLCR and FLCR could be beneficial in prognostication of outcome in AL amyloidosis. Disclosures McConnell: The Binding SIte: Employment. O'hara:The Binding Site: Employment.

Download Full-text

Early Serum Free Light Chain Responses Following High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis Predict Treatment Outcomes.

Blood ◽

10.1182/blood.v106.11.1160.1160 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1160-1160

Author(s):

Vaishali Sanchorawala ◽

Daniel G. Wright ◽

Karen Quillen ◽

Catherine Fisher ◽

Martha Skinner ◽

...

Keyword(s):

Stem Cell ◽

Treatment Outcomes ◽

Light Chain ◽

Free Light Chain ◽

High Dose ◽

Al Amyloidosis ◽

Serum Free ◽

Serum Free Light Chain ◽

Treatment Responses ◽

High Dose Melphalan

Abstract AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by widespread, progressive deposition of amyloid fibrils derived from monoclonal Ig light chains, leading to multisystem organ failure and death. Aggressive treatment of AL amyloidosis with high-dose melphalan followed by autologous stem cell transplant (HDM/SCT) can induce hematologic and clinical remissions and extend survival. Several approaches have been used to define hematologic responses following HDM/SCT and other forms of treatment. The standard definition of a hematologic complete response (CR) that we have used requires that there be no evidence of a persistent monoclonal gammopathy by immunofixation electrophoresis (IFE) of serum and urine proteins, or of a persistent plasmacytosis or plasma cell clonality in a bone marrow biopsy by immunohistochemistry. Others have defined hematologic responses according to reductions in free light chain (FLC) measurements. Treatment responses as defined by both criteria correlate with survival and clinical improvement following HDM/SCT. We have carried out a prospective analysis of HDM/SCT treatment outcomes for patients with AL amyloidosis to determine the extent to which early FLC responses within weeks of treatment predict hematologic CR, as defined by our standard criteria. Serum free light chain concentrations (FLC) were measured by a sensitive nephelometric immunoassay in 31 patients with AL amyloidosis, between 2003–2005, 1–3 weeks after treatment with HDM/SCT. Hematologic responses, as defined by standard criteria, as well as FLC responses were subsequently determined at 3, 6 and 12 months. Serum FLC levels or κ/λ FLC ratios were abnormal and informative in 28 patients (90%) prior to HDM/SCT, and these patients were included in subsequent analyses. Twenty patients (71%) achieved normalization of abnormal serum FLC levels or ratios within 1–3 weeks of undergoing HDM/SCT. Of these 20 patients, 13 patients (65%) subsequently achieved a hematologic CR as defined by standard criteria, while 7 (35%) did not, within 3 months following HDM/SCT. In contrast, none of the 8 patients with no demonstrable FLC response within 1–3 weeks of HDM/SCT, were found to have achieved a hematologic CR subsequently. In conclusion, meaningful quantitative FLC responses (or lack of response) can be detected within weeks following HDM/SCT treatment that predict hematologic responses, as defined subsequently by standard criteria based on IFE and marrow studies (p=0.0018 by chi square analysis). Moreover, a lack of an early FLC response predicts for hematologic non-CR. We anticipate that prospective studies of FLC responses in HDM/SCT and other clinical trials for AL amyloidosis will eventually lead to more rapid assessment of treatment responses that will guide therapeutic decisions.

Download Full-text

Standard Oral Melphalan Chemotherapy for AL Amyloidosis Revisited Using the Serum Free Light Chain Assay.

Blood ◽

10.1182/blood.v106.11.3495.3495 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3495-3495 ◽

Cited By ~ 2

Author(s):

Mark Offer ◽

Ashutosh D. Wechalekar ◽

Hugh J.B. Goodman ◽

Julian D. Gillmore ◽

Helen J. Lachmann ◽

...

Keyword(s):

Partial Response ◽

Light Chain ◽

Nyha Class ◽

Single Agent ◽

Complete Response ◽

Free Light Chain ◽

Al Amyloidosis ◽

Serum Free ◽

Haematological Response ◽

Serum Free Light Chain

Abstract Treatment of systemic AL amyloidosis (AL) remains difficult, especially in older and sicker patients in whom dose intensive therapies are often associated with unacceptable morbidity and mortality. Many such patients continue to be treated with oral melphalan ± prednisone (MP) despite early trials having shown only very modest clinical efficacy, presumably encouraged by its perceived low toxicity. The recent advent of the sensitive nephelometric serum free light chain (sFLC) assay has for the first time enabled the typically subtle underlying clonal disease to be monitored in an effective quantitative manner in the majority of patients with AL. We report here sFLC responses and clinical outcome of patients with AL who received MP first-line and underwent serial evaluations at the UK National Amyloidosis Centre. The 90 patients comprised 46 males and 44 females with a median age of 68yrs (range 43–83). Median number of organs involved was 3 (1–4), including kidneys in 72%, heart in 56%, and liver in 29%. 16 (17%) had ≥ NYHA class III heart failure. Median ECOG performance status was 1. Median follow-up was 2.3 yrs (0.3–14). 60 patients received oral melphalan with prednisone, and 30 received single agent melphalan. Patients received a median of 6 cycles of treatment (range 1– 26), and the sFLC assay was scheduled following each cycle after availability of the assay and retrospectively on stored sera for earlier patients. Haematological response data using sFLC assay were evaluable in 54 (60%). Responses were defined as complete response (CR) - sustained normalisation of sFLC ratio, partial response (PR) - sustained ≥50% reduction in pre-treatment clonal isotype. There was a haematological response in 22 (40%) of evaluable patients. 4 (7%) had a complete response, 18 (33%) had a partial response and 32 (59%) did not respond. 42% of patients treated with single agent melphalan responded compared with 39% of those treated with melphalan and prednisone (p=0.8). Responders received a median 6 cycles of treatment, and complete responders received a median of 14 cycles. Non-responders received a median of 5 cycles of treatment. The median time to commencing further chemotherapy was 5 months. The median overall survival (OS) was 5.8yrs, but most patients received further salvage treatments and the influence of MP treatment on OS could not be ascertained. Toxicities during MP were seen in 13 (14%) cases, including myelodysplasia in 2 patients. There were no treatment related deaths. In conclusion, use of the sFLC assay confirms that response of the underlying clonal plasma cell disease to standard oral melphalan and prednisone is poor in AL amyloidosis, and that response is usually very delayed even among patients who respond completely. Encouragingly however, toxicity was low among this relatively old and sick cohort of patients. These findings support frequent sFLC measurements in AL patients receiving MP to enable rational treatment decisions to be made at the earliest opportunity.

Download Full-text