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AL Amyloidosis and renal complications
Alex Legg PhDScientific Affairs Manager
The Binding [email protected]
Distributor in Poland [email protected]
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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 oflight chain aggregates Characteristic
organ/tissue injury
Location of deposits
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Acute tubular necrosisFanconi’s syndromeAL amyloid
LCDD
868 AL Amyloidosis patients
Kidney involvement 72%Nephrotic syndrome 52%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 DiagnosisMonoclonal Protein Investigations
Serum electrophoresis: SPE + sIFE
+
Urine electrophoresis: UPE + uIFE
and/or?
Serum FLC assay
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AL AmyloidosisAL 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 ratio 91
Serum IFE 69
Urine IFE 83
Serum IFE + urine IFE 95
FLC κ/λ ratio + serum IFE 99
FLC κ/λ ratio + serum IFE + urine IFE 99
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 ratio 76
Serum IFE 80
Urine IFE 67
Serum IFE + urine IFE 96
FLC κ/λ ratio + serum IFE 96
FLC κ/λ ratio + serum IFE + urine IFE 100
Palladini et al. Clin Chem 2009; 55: 499-503
All three assays are complementary
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Publication Screening
IMWG for sFLC analysisDispenzieri, A., et al. Leukemia, 2009. 23(2): p. 215-24.
sIFE + sFLC + uIFE
BCSH AL Amyloidosis guidelinesBird, J.M., et al. Br J Haematol, 2004. 125(6): p. 681-700.
sIFE + sFLC + uIFE
AL Amyloidosis Guidelines SummaryScreening
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Polyclonal sFLC increase as GFR decreases
Hutchison Clin J Am Soc Nephrol 3: 1684–1690, 2008
Kappa FLCLambda 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
0.1
1
10
100
1000
10000
100000
0.1 1 10 100 1000 10000 100000
Serum kappa FLC (mg/L)
Ser
um
lam
bd
a F
LC
(m
g/L
)
1,000100.1
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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Publication Monitoring
IMWG for sFLC analysisDispenzieri, A., et al. Leukemia, 2009. 23(2): p. 215-24.
sFLC essential(Recommended for LCDD)
BCSH AL Amyloidosis guidelinesBird, J.M., et al. Br J Haematol, 2004. 125(6): p. 681-700.
sFLC recommended
International Consensus OpinionGertz, M.A., et al., Am J Hematol, 2005. 79(4): p. 319-28.
sFLC recommended
AL Amyloidosis Guidelines SummaryMonitoring
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Light chain deposition disease2 large published studies:1) Mayo Clinic n = 19 abnormal sFLC ratio 89%
2) NAC n = 17 abnormal sFLC ratio 88%Katzmann J. et al. Clin Chem 2002; 48: 1437 - 1444Wechalekar 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
Cum
ulat
ive
surv
ival
100 %
0 %
80 %
60 %
40 %
20 % ControlPlasma exchange
0 1 2 3 4 5 6
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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pore size [µm]
0,001 0,01 0,1 1
n/no
[-]
0,0
0,2
0,4
0,6
0,8
1,0
pore size [µm]
0,001 0,01 0,1 1
n/n o
[-]
0,0
0,2
0,4
0,6
0,8
1,0HighFlux Plasmafilter
High Cut-Off
High Flux
PlasmaFilter
Size of albumin
Pore size [m]
Distribution of filter pore sizes
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0
500
1000
1500
2000
2500
3000
0 5 10 15 20 25 30
Days
Ser
um
lam
bd
a F
LC
(m
g/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 stainA: 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 [email protected]
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. 215-242. Bird, J.M., et al. Br J Haematol, 2004. 125(6): p. 681-7003. Gertz, M.A., et al., Am J Hematol, 2005. 79(4): p. 319-28
N/A
N/A-
Guidelines Summary
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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 5th International Symposium, Bath Assembly Rooms
Biennial Meeting, 2008
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New reference range for / ratio for renal impairment
0.1
1
10
100
1000
10000
100000
0.1 1 10 100 1000 10000 100000
Serum kappa FLC (mg/L)
Ser
um
lam
bd
a F
LC
(m
g/L
)
0.1 1,000100.1
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 negativeUrine positive
n = 16
Serum PositiveUrine negative
n = 52
Fre
qu
ency
sFLC concentrations (mg/L
Fre
qu
ency
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/ LLambda: 10 mg/ Lk/l ratio: 1
Patient X then develops a very subtle AL amyloidosis tumour
Kappa: 12 mg/ LLambda: 8 mg/ Lk/l ratio: 1.5
This patient would normally be urine negative due to normal kidney function......
Normal
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 HD45 PatientsStandard high-flux HD
‘Modified PAD regimen’ Chemotherapy (P) VELCADE™ (bortezomib) iv 1.0 mg/m2
(A) Adriamycin (Doxorubicin) iv 9.0 mg/m2
(D) Dexamethasone oral 40 mg
Assess outcome
Research Arm HD 45 Patients Extended HD on HCO 1100
Randomised and controlled
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Trial time course
Day 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 onwards
Research arm HD(Hours)
√(6)
√(8)
√(8)
√(8)
√(8)
√(8)
√(8)
√(8)
√(8)
√(8)
√(8)
√(8)
√(8)
Accord. to clin need (6)
Chemo VAD
AD
AD
VAD
V
D* D* D*
V
D* D* D* D* D*
As per PAD protocol
sFLCmeasured √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
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: FLCdifferencetroponin-TBNPB2M
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0
2000
4000
6000
8000
10000
12000
0 1 2 4 5 6 7 8 9 11 12 13 14 15 17 18 19 20 21 22 24 25 26 27 28 30
Time (days)
Ser
um
kap
pa
(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 only2. 10% tumour kill/day, RES clearance only3. 10% tumour kill/day with PE
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0
2000
4000
6000
8000
10000
12000
0 1 2 4 5 6 7 8 9 11 12 13 14 15 17 18 19 2 0 2 1 2 2 2 4 2 5 2 6 2 7 2 8 3 0
Time (days)
Seru
m k
app
a (m
g/L
)
1
0 5 10 15 20 25 30
2
3
4
5
1. 100% tumour kill on day 1, RES clearance only2. 10% tumour kill /day, RES clearance only3. 10% tumour kill /day with PE4. 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/ 40 34/ 37 14/18
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 concentrationcorrelated with:
Bone marrow plasmacytosisNumber of organs involvedBeta-2-microglobulinSerum cardiac troponin T
Dispenzieri et al. Blood, 2006; 3378-3383
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Higher FLC concentrationcorrelated with:
Bone marrow plasmacytosisNumber of organs involved
Beta-2-microglobulinSerum cardiac troponin T
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AL amyloidosis: MP response
A.R. Bradwell: Serum Free Light Chain Analysis 5th Edition
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Monoclonal Protein InvestigationsAL Amyloidosis DiagnosisSerum electrophoresis: SPE + sIFEN
um
ber
of
pat
ien
ts
SPE+ SPE-/ IFE+ SPE-/ IFE- FLCTotal
100%
53%
26%21%
SPEquantifiable
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
BortezomibDexamethasoneCyclophosphamideThalidomide
Ser
um
FL
C (
mg
/L)
Cre
atin
ine
(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