Sheena Surindran Grand Rounds 2/15/11
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1 Sheena Surindran Grand Rounds 2/15/11
2 Affects 5 12 person per million / year 5 10% associated with myeloma Median survival without treatment is months Most commonly affected organs are kidney, heart and liver
3 Pathology Abnormality in protein folding leading to deposition in organs (except central nervous system) Clonal B cell proliferation with production of Ig light chains lambda more common than kappa Thermodynamically unstable LC are prone to self aggregation Clin J Am Soc Nephrol 1: , 2006
4 Aggregates form protofilaments that associate in amyloid fibrils Glycosaminoglycan moieties of proteoglycan and serum amyloid protein (SAP) interact with the fibrils and promote formation and stability in tissue. Ig light chain variable region (VL) genes are expressed by AL clones (somatic mutation occurring during B cell maturation) Clin J Am Soc Nephrol 1: , 2006
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6
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8 EM amyloid fibrils
9 Organ dysfunction as a disruption of tissue architecture and direct cytotoxic effects of amyloid precursor proteins. Peripheral neuropathy, renal and cardiac function improve dramatically after chemotherapy prior to resolution of amyloid deposits.
10 Amyloid fibril formation 2 patient derived protein sequence AL 09 and A 103 Share 90% sequence identity but clinical different phenotypes AL 09 died of cardiac amyloid 3mths while AL 103 survived 3yrs with cardiac and liver involvement. Analysed fibril fromation across a wide range of solution conditions. Amyloid, September December 2010; 17(3 4):
11 Amyloid, September December 2010; 17(3 4):
12
13 Transmission EM Amyloid, September December 2010; 17(3 4):
14 Conclusions VL protein from AL 09 patient formed fibrils more rapidly than AL 103 Divergent behavior in 2 proteins that share >90% sequence identity and thermodynamic stability Nucleation may be step that plays a critical role Proteins that readily and rapidly form fibrils have a more aggressive disease phenotype.
15 Diagnosis Fat pad biopsy 100% specific, 57% sensitive, ppv 100% Demonstration of amyloid in the tissue Demonstration of plasma cell dyscrasia Serum free light chain assay (FLC) is prefered to Immunofixation Ratio of kappa to lambda is more important that absolute levels in pt with renal impairment.
16 Prognosis Poor prognostic markers FLC burden Cardiac involvement Elevated NT ProBNP Elevated troponin
17 Prognosis BLOOD, 9 DECEMBER 2010 VOLUME 116, NUMBER 24
18 Treatment
19 Treatment response Complete response (CR) Absence of monoclonal protein by IF in urine and serum Normal serum free light chain ratio Bone marrow biopsy with <5% plasma cells with no clonal predominance
20 Melphalan and Stem cell transplant
21 Melphalan and SCT in ESRD 15 patients between in Boston University Received high dose melphalan (HDM) mg/m 2 Stem cells infused 24 72hrs later Kidney International, Vol. 63 (2003), pp
22 Kidney International, Vol. 63 (2003), pp
23 Kidney International, Vol. 63 (2003), pp
24 Conclusions 8 out of 15pts had CR at end of 12mths of treatment. 6 out of the 8 patients were alive 4.5yrs post treatment. Correlation of survival with hematological response No significant difference in toxicities in ESRD and non ESRD group except mucositis. Kidney International, Vol. 63 (2003), pp
25 Proteinuria after stem cell transplant Am J Kidney Dis 46:
26 Survival based on renal response Am J Kidney Dis 46: , 2005
27 Bortezomib and dexamethasone 18 patients AL biopsy proven amyloid Treated with velcade 1.3mg/m2 day 1,4,8,11 and dex days 1 4days every 21days for 6 cycles 6 patients had creatinine > 2 The hematology journal 2007;92(10)1355
28
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30 Conclusion Hematological response in 94% with CR in 44% Median time to response was 0.9months compared to 3.5 6mth with conventional treatment. FLC kinetics afetr BD treatment showed at least 50% reduction after 2 cycles suggest BD may be d/c if no response after 2 cycles The hematology journal 2007;92(10)1355
31 Phase 1 dose escalation study Velcade Canada 2007 group In relapsed patients with AL amyloidosis 31 patients enrolled Hematological response achieved in 50% patients with CR in 20% BLOOD, 20 AUGUST 2009 VOLUME 114, NUMBER 8
32 Dialysis and Amyloidosis Retrospective analysis of patients patients with AL and 20 pts with AA AL amyloid patients had shorten time from diagnosis to dialysis compared to AA amyloid (25mths vs 63mths) Mean survival was shorter in AL amyloidosis (26mths) Cardiac involvement, symptoms of heart failure and shorter time from diagnosis to dialysis were independent risk factors for death. Clin J Am Soc Nephrol 3: , 2008
33 Renal transplantation in amyloidosis All organ transplants in AL patients between UK national amyloid center database 45 out of 2272 patients 22 patients received renal transplant Mean time to transplant from start of dialysis 26mths Mean age 54 yrs No renal allografts failed secondary to recurrance Mean survival post transplant was 6.5 years 2 graft failures 1 at 9mths and 1 at 13.3yrs One death <1yr post transplant American Journal of Transplantation 2010; 10:
34
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