AL Amyloidosis and renal complications

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AL Amyloidosis and renal complications
Alex Legg PhD Scientific Affairs Manager The
Binding Site alex.legg_at_bindingsite.com
Distributor in Poland BIOKOM beata.olsz_at_biokom.com
.pl
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Why are FLCs associated with kidney disease?

• In plasma cell dyscrasias toxic monoclonal FLCs
  are produced

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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

• SPE
• sensitivity

IFE sensitivity -
Lachmann H. et al. BJH 2003 122 78-84
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Diagnostic Performance in AL Amyloidosis (n 110) Diagnostic Performance in AL Amyloidosis (n 110)
Assay Positive
FLC ?/? ratio 91
Serum IFE 69
Urine IFE 83
Serum IFE urine IFE 95
FLC ?/? ratio serum IFE 99
FLC ?/? ratio serum IFE urine IFE 99
Urine IFE did not add any additional
information.
Katzmann et al. Clin Chem 2005 51 878-881
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Diagnostic Performance in AL Amyloidosis (n 115) Diagnostic Performance in AL Amyloidosis (n 115)
Assay Positive
FLC ?/? ratio 76
Serum IFE 80
Urine IFE 67
Serum IFE urine IFE 96
FLC ?/? ratio serum IFE 96
FLC ?/? ratio serum IFE urine IFE 100
All three assays are complementary
Palladini et al. Clin Chem 2009 55 499-503
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AL Amyloidosis Guidelines Summary Screening
Publication Screening
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
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Polyclonal sFLC increase as GFR decreases
Hutchison Clin J Am Soc Nephrol 3 16841690, 2008
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?/? ratio increases as GFR decreases
New renal reference range for ratio 0.37 3.1
Hutchison Clin J Am Soc Nephrol 3 16841690, 2008
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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, 911
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New reference range for ?/? ratio for renal
impairment
ARF - Myeloma (?)
ARF - Myeloma (?)
ARF - No MG
1,000
Normal sera
Normal ?/? ratio 0.26 1.65
Serum lambda FLC (mg/L)
10
0.1
10
0.1
1,000
Serum kappa FLC (mg/L)
Hutchison et al. BMC Nephrology 2008, 911
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New reference range for ?/? ratio for renal
impairment

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

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AL Amyloidosis Treatment
Serum amyloid P scans Reduction of AL deposits
in the liver and spleen after one year of
chemotherapy
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AL amyloidosis BD response
..at least a 50 reduction occurred in all
responding patients within two courses of
treatment.
Progressive disease
Kastritis Haematologica 2007 92 1351 - 1358
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Definition of treatment Response
Haematological Response Criteria Haematological Response Criteria
Complete response Serum and urine negative immunofixation Free light chain ratio normal Marrow lt5 plasma cells
Partial response If serum M component gt 5g/L, a 50 reduction If light chain in urine with visible peak and gt100 mg/day and 50 reduction If serum iFLC gt100 mg/L and 50 reduction
Gertz et al., Am J Hematol, 2005 79, 319-328
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AL amyloidosis Outcome
Gertz et al., Curr Opin Oncol 2007. 19 136-141
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AL Amyloidosis Guidelines Summary Monitoring
Publication Monitoring
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
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Light chain deposition disease

• 2 large published studies
• Mayo Clinic n 19 abnormal sFLC ratio 89
• NAC n 17 abnormal sFLC ratio 88

Katzmann J. et al. Clin Chem 2002 48 1437 -
1444 Wechalekar A. et al. Haematologica 2005 90
1414
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Number of AL amyloidosis/ LCDD diagnoses
Serum FLC
Gregorini, et al. 2008. Haematologica. 2(2) E41
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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

• Plasma exchange
• Used since 1980s
• Haemodialysis
• New treatment strategy

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Plasma exchange to remove sFLCs

• Challenges
• gt80 of FLCs are extravascular.
• PE procedures are of limited frequency duration
  (typically 6 x 1.5 hour sessions over 2 weeks)

Typical recovery rates 10 - 20.
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Randomised control trial of plasma exchange
100
80
60
Cumulative survival
40
20
0
0
1
2
3
4
5
6
Time to death (months)
Clark et al. Ann Intern Med 2005 143777 84
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Haemodialysis to remove sFLCs

• 7 dialysers evaluated in vitro for filtration
  efficiency
• The Gambro HCO 1100 was the most efficient at
  removing FLC
• Available in Poland

Hutchison, CA. et al. JASN 2007 18 886-895
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Distribution of filter pore sizes
Pore size ?m
Size of albumin
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Patient 3
Hutchison, CA. et al. JASN 2007 18 886-895
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Resolution of Cast Nephropathy
Renal biopsies Haematoxylin and eosin stain A
Presentation B After chemotherapy/ HCO1100
treatment
Basnayake et al. 2008. J Med Case Reports 2, ePub
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Pilot study Renal recovery rates
28 days
Hutchison, CA. et al. 2009. Clin JASN 4, 745-54
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European Trial of Free Light Chain Removal by
Extended Haemodialysis in Cast Nephropathy
Contact Dr Colin Hutchison cah692_at_bham.ac.uk
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Guidelines Summary
IMWG 1 BCSH 2 International Consensus Opinion 3
Screening
Prognosis
Monitoring
N/A
sIFE uIFE
N/A
-
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
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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

• alex.legg_at_bindingsite.com

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New reference range for ?/? ratio for renal
impairment
ARF - Myeloma (?)
ARF - Myeloma (?)
ARF - No MG
1,000
Normal sera
Normal ?/? ratio
Serum lambda FLC (mg/L)
10
0.1
0.1
10
1,000
Serum kappa FLC (mg/L)
Hutchison et al. BMC Nephrology 2008, 911
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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 gt 500 mg/L
• Informed consent
• Commencement of study within 10 days of
  presentation

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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
Normal
Normal
This patient would normally be urine negative due
to normal kidney function......
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Renal Metabolism of FLC
Glomerulus damaged by amyloids
sIF sFLC 98 sIF sFLC uIF 100
Albumin saturates proximal tubule
Weakly positive urine
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Randomised and controlled
90 Patients recruited
Randomisation
Control Arm HD 45 Patients Standard high-flux HD
Research Arm HD 45 Patients
Extended HD on HCO 1100
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
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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) v (6) v (8) v (8) v (8) v (8) v (8) v (8) v (8) v (8) v (8) v (8) v (8) v (8) Accord. to clin need (6)
Chemo V A D A D A D V A D V D D D V D D D D D As per PAD protocol
sFLC measured v v v v v v v v v v v v v v v v v v v v v v v

• sFLC measured
• at assessment Run within 24 hours
• pre dialysis
• post dialysis
• non-dialysis

Run once /week
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Four variables that had maximum impact on the
outcome FLCdifference troponin-T BNP B2M
Kumar, S., et al., Haematologica, 2008. 2(2) p.
C19
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Model of sFLC Removal - PE

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

Serum kappa (mg/L)
1
0



5 10 15

20

25 30
Time (days)
Hutchison et al (2007) JASN 18, 886-895
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Model of sFLC Removal HCO1100

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)

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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 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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AL amyloidosis MP response
A.R. Bradwell Serum Free Light Chain Analysis
5th Edition
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Monoclonal Protein Investigations AL Amyloidosis
Diagnosis
Serum electrophoresis SPE sIFE
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
Plasma exchanges
Serum FLC (mg/L)
Creatinine (mg/dL)
Chemotherapy
Bortezomib Dexamethasone Cyclophosphamide Thalidom
ide
B
c
Cserti Transfusion 2007 47 511 - 514
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A model of light chain production and metabolism
Normal plasma cell FLC production
Extravascular FLC pool
Intravascular FLC pool
Removal by kidneys
Removal by Reticuloendothelial system
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A model of light chain production and metabolism
Tumour
Extravascular FLC pool
Intravascular FLC pool
Removal by kidneys
Removal by PE or HD
Removal by Reticuloendothelial system