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AL Amyloidosis and renal complications Alex Legg PhD Scientific Affairs Manager The Binding Site alex.legg@bindingsite.com Distributor in Poland BIOKOM beata.olsz@biokom.com.pl
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Why are FLCs associated with kidney disease? In plasma cell dyscrasias toxic monoclonal FLCs are produced: Light chain physico-chemical properties organisation of light chain aggregates Characteristic organ/tissue injury Location of deposits
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Acute tubular necrosis Fanconi’s syndrome AL amyloid LCDD 868 AL Amyloidosis patients Kidney involvement72% Nephrotic syndrome52% Renal failure (creat >2mg/dL)18% Merlini, G. et al. 2008. 2(1): p. 287 - 293. AL Cast nephropathy CN
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AL Amyloidosis Diagnosis Monoclonal Protein Investigations Serum electrophoresis: SPE + sIFE + Urine electrophoresis: UPE + uIFE and/or? Serum FLC assay
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AL Amyloidosis Lachmann H. et al. BJH 2003; 122 :78-84 IFE sensitivity - - SPE sensitivity
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Diagnostic Performance in AL Amyloidosis (n = 110) Assay% Positive FLC κ/λ ratio91 Serum IFE69 Urine IFE83 Serum IFE + urine IFE95 FLC κ/λ ratio + serum IFE99 FLC κ/λ ratio + serum IFE + urine IFE99 Katzmann et al. Clin Chem 2005; 51: 878-881 ‘Urine IFE did not add any additional information.’
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Diagnostic Performance in AL Amyloidosis (n = 115) Assay% Positive FLC κ/λ ratio76 Serum IFE80 Urine IFE67 Serum IFE + urine IFE96 FLC κ/λ ratio + serum IFE96 FLC κ/λ ratio + serum IFE + urine IFE100 Palladini et al. Clin Chem 2009; 55: 499-503 All three assays are complementary
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PublicationScreening IMWG for sFLC analysis Dispenzieri, A., et al. Leukemia, 2009. 23(2): p. 215-24. sIFE + sFLC + uIFE BCSH AL Amyloidosis guidelines Bird, J.M., et al. Br J Haematol, 2004. 125(6): p. 681-700. sIFE + sFLC + uIFE AL Amyloidosis Guidelines Summary Screening
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Polyclonal sFLC increase as GFR decreases Hutchison Clin J Am Soc Nephrol 3: 1684–1690, 2008 Kappa FLC Lambda FLC
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/ ratio increases as GFR decreases Hutchison Clin J Am Soc Nephrol 3: 1684–1690, 2008 New renal reference range for ratio: 0.37 – 3.1
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Can sFLC assays be used to diagnose multiple myeloma in patients with renal failure? Audit of 142 patients with new dialysis dependent acute renal failure 41 / 142 patients with multiple myeloma Hutchison et al. BMC Nephrology 2008, 9:11
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New reference range for / ratio for renal impairment Serum kappa FLC (mg/L) Serum lambda FLC (mg/L) 1,000 10 0.1 1,000 10 Normal / ratio 0.26 – 1.65 Proposed renal range / = 0.37 – 3.1 ARF - Myeloma ( ) ARF - Myeloma ( ) ARF - No MG Normal sera Hutchison et al. BMC Nephrology 2008, 9:11 0.1
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1.Interpret sFLC results in the context of clinical findings and other laboratory tests… including renal function 2.If patient has renal impairment, then renal reference range ( / = 0.37 – 3.1) may be applicable 3.Renal reference range improves diagnostic specificity without changing diagnostic sensitivity New reference range for / ratio for renal impairment
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Serum amyloid P scans: Reduction of AL deposits in the liver and spleen after one year of chemotherapy AL Amyloidosis Treatment
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AL amyloidosis: BD response Kastritis Haematologica 2007; 92: 1351 - 1358 Progressive disease “..at least a 50% reduction occurred in all [responding] patients within two courses of treatment.”
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Haematological Response Criteria Complete response Serum and urine negative immunofixation Free light chain ratio normal Marrow <5% plasma cells Partial response If serum M component > 5g/L, a 50% reduction If light chain in urine with visible peak and >100 mg/day and 50% reduction If serum iFLC >100 mg/L and 50% reduction Gertz et al., Am J Hematol, 2005: 79, 319-328 Definition of treatment Response
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Gertz et al., Curr Opin Oncol 2007. 19; 136-141 AL amyloidosis: Outcome
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PublicationMonitoring IMWG for sFLC analysis Dispenzieri, A., et al. Leukemia, 2009. 23(2): p. 215-24. sFLC essential (Recommended for LCDD) BCSH AL Amyloidosis guidelines Bird, J.M., et al. Br J Haematol, 2004. 125(6): p. 681-700. sFLC recommended International Consensus Opinion Gertz, M.A., et al., Am J Hematol, 2005. 79(4): p. 319-28. sFLC recommended AL Amyloidosis Guidelines Summary Monitoring
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Light chain deposition disease 2 large published studies: 1)Mayo Clinic n = 19 abnormal sFLC ratio 89% 2)NAC n = 17abnormal sFLC ratio 88% Katzmann J. et al. Clin Chem 2002; 48: 1437 - 1444 Wechalekar A. et al. Haematologica 2005; 90: 1414 Utility in monitoring: Brockhurst I. et al. Nephrol Dial Transplant 2005; 20: 1251 - 1253
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Gregorini, et al. 2008. Haematologica. 2(2): E41 Serum FLC Number of AL amyloidosis/ LCDD diagnoses
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Myeloma and renal insufficiency 10 – 20% myeloma patients present with acute renal failure 10% remain dialysis dependent long term –There is a high mortality rate –Chemotherapy and transplantation are hazardous Cast Nephropathy:
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Light chain removal strategies for cast nephropathy 1.Plasma exchange Used since 1980s 2.Haemodialysis New treatment strategy
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Challenges: 1.>80% of FLCs are extravascular. 2.PE procedures are of limited frequency & duration (typically 6 x 1.5 hour sessions over 2 weeks) Plasma exchange to remove sFLCs Typical recovery rates: 10 - 20%.
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Randomised control trial of plasma exchange Cumulative survival 100 % 0 % 80 % 60 % 40 % 20 % Control Plasma exchange 0123456 Time to death (months) Clark et al. Ann Intern Med 2005 143:777 – 84
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7 dialysers evaluated in vitro for filtration efficiency The Gambro HCO 1100* was the most efficient at removing FLC * Available in Poland Haemodialysis to remove sFLCs Hutchison, CA. et al. JASN 2007; 18: 886-895
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High Cut-Off High Flux Plasma Filter Size of albumin Pore size [ m] Distribution of filter pore sizes
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0 500 1000 1500 2000 2500 3000 051015202530 Days Serum lambda FLC (mg/L) Dexamethasone Pre-dialysis FLC Post-dialysis FLC Velcade Patient 3: Hutchison, CA. et al. JASN 2007; 18: 886-895
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Resolution of Cast Nephropathy Basnayake et al. 2008. J Med Case Reports; 2, ePub Renal biopsies: Haematoxylin and eosin stain A: Presentation B: After chemotherapy/ HCO1100 treatment
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Pilot study: Renal recovery rates Hutchison, CA. et al. 2009. Clin JASN 4, 745-54 28 days
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European Trial of Free Light Chain Removal by Extended Haemodialysis in Cast Nephropathy Contact: Dr Colin Hutchison cah692@bham.ac.uk AL amyloidosis? Publication in press
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IMWG 1 BCSH 2 International Consensus Opinion 3 Screening Prognosis Monitoring + sIFE & uIFE 1. Dispenzieri, A., et al. Leukemia, 2009. 23(2): p. 215-24 2. Bird, J.M., et al. Br J Haematol, 2004. 125(6): p. 681-700 3. Gertz, M.A., et al., Am J Hematol, 2005. 79(4): p. 319-28 N/A - Guidelines Summary
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Conclusions alex.legg@bindingsite.com FLCs in AL amyloidosis: “The introduction of FLC assay has greatly improved the management of patients with AL amyloidosis and is now an essential tool in the care of this disease.” Prof. G. Merlini 5 th International Symposium, Bath Assembly Rooms Biennial Meeting, 2008
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New reference range for / ratio for renal impairment Serum kappa FLC (mg/L) Serum lambda FLC (mg/L) 0.1 1,000 10 0.1 1,000 10 Normal / ratio ARF - Myeloma ( ) ARF - Myeloma ( ) ARF - No MG Normal sera Hutchison et al. BMC Nephrology 2008, 9:11
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Patient inclusion criteria Dialysis dependent renal failure, renal biopsy proven cast nephropathy Fulfils diagnostic criteria for the diagnosis of symptomatic de novo MM Abnormal sFLC ratio and sFLC > 500 mg/L Informed consent Commencement of study within 10 days of presentation
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Serum negative Urine positive n = 16 Serum Positive Urine negative n = 52 Frequency sFLC concentrations (mg/L Frequency Monoclonal urine FLC (g/day) Total: 219 patients Mead, G.P., et al., Clin Lymphoma Myeloma, 2009. February: p. 153a.
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AL amyloidosis: Serum FLC negative and urine positive? Patient X: Serum FLCs before developing AL amyloidosis: Kappa: 10 mg/ L Lambda: 10 mg/ L k/l ratio: 1 Patient X then develops a very subtle AL amyloidosis tumour Kappa: 12 mg/ L Lambda: 8 mg/ L k/l ratio: 1.5 This patient would normally be urine negative due to normal kidney function...... Normal
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Glomerulus damaged by amyloids Weakly positive urine Renal Metabolism of FLC Albumin saturates proximal tubule sIF + sFLC:98% sIF + sFLC + uIF:100%
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90 Patients recruited Randomisation Control Arm HD 45 Patients Standard high-flux HD ‘Modified PAD regimen’ Chemotherapy (P) VELCADE™ (bortezomib) iv1.0 mg/m 2 (A) Adriamycin (Doxorubicin)iv9.0 mg/m 2 (D) Dexamethasoneoral40 mg Assess outcome Research Arm HD 45 Patients Extended HD on HCO 1100 Randomised and controlled
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Trial time course Day012345678910111213141516171819202122 onwards Research arm HD (Hours) √ (6) √ (8) √ (8) √ (8) √ (8) √ (8) √ (8) √ (8) √ (8) √ (8) √ (8) √ (8) √ (8) Accord. to clin need (6) ChemoVADVAD ADAD ADAD VADVAD V D* V D* As per PAD protocol sFLC measured√√√√√√√√√√√√√√√√√√√√√√√ sFLC measured at assessment Run within 24 hours pre dialysis post dialysis non-dialysis Run once /week
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Kumar, S., et al., Haematologica, 2008. 2(2): p. C19 Four variables that had maximum impact on the outcome: FLCdifference troponin-T BNP B2M
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0 2000 4000 6000 8000 10000 12000 0124567891112131415171819202122242526272830 Time (days) Serum kappa (mg/L) 1 0 5 10 15 20 25 30 2 3 Model of sFLC Removal - PE Hutchison et al (2007) JASN 18, 886-895 1.100% tumour kill on day 1, RES clearance only 2.10% tumour kill/day, RES clearance only 3.10% tumour kill/day with PE
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2 3 4 5 1.100% tumour kill on day 1, RES clearance only 2.10% tumour kill /day, RES clearance only 3.10% tumour kill /day with PE 4.10% tumour kill /day with HD (3 x 4h /week) 5.10% tumour kill /day with HD (12h /day) Model of sFLC Removal – HCO1100
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Urine IFE + only Serum IFE + and Urine IFE + Serum IFE - and Urine IFE - Abnormal sFLC ratio 40/ 4034/ 3714/18 Abraham, R.S., et al., Am J Clin Pathol, 2003. 119(2): p. 274-8
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All urine IFE+ AL amyloidosis patients identified by sIFE + sFLC Katzmann, J.A., et al., Mayo Clin Proc, 2006. 81(12): p. 1575-8.
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Absolute FLC levels are prognostic in AL amyloidosis patients undergoing peripheral blood stem cell transplantation Higher FLC concentration correlated with: Bone marrow plasmacytosis Number of organs involved Beta-2-microglobulin Serum cardiac troponin T Dispenzieri et al. Blood, 2006; 3378-3383
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Higher FLC concentration correlated with: Bone marrow plasmacytosis Number of organs involved Beta-2-microglobulin Serum cardiac troponin T
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AL amyloidosis: MP response A.R. Bradwell: Serum Free Light Chain Analysis 5 th Edition
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Monoclonal Protein Investigations AL Amyloidosis Diagnosis Serum electrophoresis: SPE + sIFE Number of patients SPE+SPE-/ IFE+SPE-/ IFE-FLCTotal 100% 53% 26% 21% SPE quantifiable FLC 3% 98% Lachmann H. et al. BJH 2003; 122 :78-84
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Absolute FLC levels are prognostic in AL amyloidosis patients undergoing peripheral blood stem cell transplantation Dispenzieri et al. Blood, 2006; 3378-3383
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Comparison SAP scans and serum FLCs in 127 AL amyloidosis patients before and 12 months after chemotherapy. Lachmann, H.J., et al., Br J Haematol, 2003. 122(1): p. 78-84
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Monitoring plasma exchange with sFLC Chemotherapy: B c Bortezomib Dexamethasone Cyclophosphamide Thalidomide Serum FLC (mg/L) Creatinine (mg/dL) Plasma exchanges Cserti Transfusion 2007 47: 511 - 514
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Normal plasma cell FLC production Intravascular FLC pool Removal by kidneys A model of light chain production and metabolism Removal by Reticuloendothelial system Extravascular FLC pool
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Tumour Intravascular FLC pool Removal by kidneys A model of light chain production and metabolism Removal by PE or HD Removal by Reticuloendothelial system Extravascular FLC pool
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