AL Amyloidosis and renal complications Alex Legg PhD Scientific Affairs Manager The Binding Site Distributor in Poland BIOKOM
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
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 (1): p AL Cast nephropathy CN
AL Amyloidosis Diagnosis Monoclonal Protein Investigations Serum electrophoresis: SPE + sIFE + Urine electrophoresis: UPE + uIFE and/or? Serum FLC assay
AL Amyloidosis Lachmann H. et al. BJH 2003; 122 :78-84 IFE sensitivity - - SPE sensitivity
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: ‘Urine IFE did not add any additional information.’
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: All three assays are complementary
PublicationScreening IMWG for sFLC analysis Dispenzieri, A., et al. Leukemia, (2): p sIFE + sFLC + uIFE BCSH AL Amyloidosis guidelines Bird, J.M., et al. Br J Haematol, (6): p sIFE + sFLC + uIFE AL Amyloidosis Guidelines Summary Screening
Polyclonal sFLC increase as GFR decreases Hutchison Clin J Am Soc Nephrol 3: 1684–1690, 2008 Kappa FLC Lambda FLC
/ 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
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
New reference range for / ratio for renal impairment Serum kappa FLC (mg/L) Serum lambda FLC (mg/L) 1, , 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
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
Serum amyloid P scans: Reduction of AL deposits in the liver and spleen after one year of chemotherapy AL Amyloidosis Treatment
AL amyloidosis: BD response Kastritis Haematologica 2007; 92: Progressive disease “..at least a 50% reduction occurred in all [responding] patients within two courses of treatment.”
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, Definition of treatment Response
Gertz et al., Curr Opin Oncol ; AL amyloidosis: Outcome
PublicationMonitoring IMWG for sFLC analysis Dispenzieri, A., et al. Leukemia, (2): p sFLC essential (Recommended for LCDD) BCSH AL Amyloidosis guidelines Bird, J.M., et al. Br J Haematol, (6): p sFLC recommended International Consensus Opinion Gertz, M.A., et al., Am J Hematol, (4): p sFLC recommended AL Amyloidosis Guidelines Summary Monitoring
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: Wechalekar A. et al. Haematologica 2005; 90: 1414 Utility in monitoring: Brockhurst I. et al. Nephrol Dial Transplant 2005; 20:
Gregorini, et al Haematologica. 2(2): E41 Serum FLC Number of AL amyloidosis/ LCDD diagnoses
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:
Light chain removal strategies for cast nephropathy 1.Plasma exchange Used since 1980s 2.Haemodialysis New treatment strategy
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: %.
Randomised control trial of plasma exchange Cumulative survival 100 % 0 % 80 % 60 % 40 % 20 % Control Plasma exchange Time to death (months) Clark et al. Ann Intern Med :777 – 84
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:
High Cut-Off High Flux Plasma Filter Size of albumin Pore size [ m] Distribution of filter pore sizes
Days Serum lambda FLC (mg/L) Dexamethasone Pre-dialysis FLC Post-dialysis FLC Velcade Patient 3: Hutchison, CA. et al. JASN 2007; 18:
Resolution of Cast Nephropathy Basnayake et al J Med Case Reports; 2, ePub Renal biopsies: Haematoxylin and eosin stain A: Presentation B: After chemotherapy/ HCO1100 treatment
Pilot study: Renal recovery rates Hutchison, CA. et al Clin JASN 4, days
European Trial of Free Light Chain Removal by Extended Haemodialysis in Cast Nephropathy Contact: Dr Colin Hutchison AL amyloidosis? Publication in press
IMWG 1 BCSH 2 International Consensus Opinion 3 Screening Prognosis Monitoring + sIFE & uIFE 1. Dispenzieri, A., et al. Leukemia, (2): p Bird, J.M., et al. Br J Haematol, (6): p Gertz, M.A., et al., Am J Hematol, (4): p N/A - Guidelines Summary
Conclusions 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
New reference range for / ratio for renal impairment Serum kappa FLC (mg/L) Serum lambda FLC (mg/L) 0.1 1, , Normal / ratio ARF - Myeloma ( ) ARF - Myeloma ( ) ARF - No MG Normal sera Hutchison et al. BMC Nephrology 2008, 9:11
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
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, February: p. 153a.
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
Glomerulus damaged by amyloids Weakly positive urine Renal Metabolism of FLC Albumin saturates proximal tubule sIF + sFLC:98% sIF + sFLC + uIF:100%
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
Trial time course Day 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
Kumar, S., et al., Haematologica, (2): p. C19 Four variables that had maximum impact on the outcome: FLCdifference troponin-T BNP B2M
Time (days) Serum kappa (mg/L) Model of sFLC Removal - PE Hutchison et al (2007) JASN 18, % tumour kill on day 1, RES clearance only 2.10% tumour kill/day, RES clearance only 3.10% tumour kill/day with PE
% 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
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, (2): p
All urine IFE+ AL amyloidosis patients identified by sIFE + sFLC Katzmann, J.A., et al., Mayo Clin Proc, (12): p
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;
Higher FLC concentration correlated with: Bone marrow plasmacytosis Number of organs involved Beta-2-microglobulin Serum cardiac troponin T
AL amyloidosis: MP response A.R. Bradwell: Serum Free Light Chain Analysis 5 th Edition
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
Absolute FLC levels are prognostic in AL amyloidosis patients undergoing peripheral blood stem cell transplantation Dispenzieri et al. Blood, 2006;
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, (1): p
Monitoring plasma exchange with sFLC Chemotherapy: B c Bortezomib Dexamethasone Cyclophosphamide Thalidomide Serum FLC (mg/L) Creatinine (mg/dL) Plasma exchanges Cserti Transfusion :
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
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