11/13/2014
1
The Role of Transplant and New Treatments in Amyloidosis:
A Focus on Minimizing Toxicity
Jonathan L. Kaufman, MD Associate ProfessorHematology & OncologyWinship Cancer Institute of Emory University
Amyloidosis• Protein Conformation/Deposition
Disorder
• AL Amyloidosis
• Hereditary Amyloidosis– Transthyretin
– Fibrinogen Aα
– Apolipoprotein AI and AII
– Lysozyme
• Secondary Amyloidosis
11/13/2014
2
The cascade of molecular events leading to amyloidosis.
Merlini G et al. JCO 2011;29:1924-1933
©2011 by American Society of Clinical Oncology
Clinical Manifestations of Amyloidosis
11/13/2014
3
AL Amyloidosis
• Monoclonal plasma cell disorder
• 3,000 cases annually in the USA
• 10% of patients are < 50 years old
• Presenting symptoms are varied
• Delays in diagnosis are common
Comenzo and Gertz, Blood, 15 June 2002, Vol. 99, No. 12, pp. 4276-4282
• Clonal plasma cell disorder
• λ to κ ratio ~ 3:1
• Plasma cells less than 30%
• Low proliferation
• Small portion of light chains are amyloidogenic
• Certain variable regions more likely
AL Amyloidosis
11/13/2014
4
Clinical Manifestations of AL Amyloidosis
Merlini and Bellotti N Engl J Med. 2003 Aug 7;349(6):583-96
Merlini and Stone, Blood 2006
11/13/2014
5
Establishing the Clinical Diagnosis
Assay% Positive
(CI)1
FLC / ratio 91 (84–96)
Serum IFE 69 (60–78)
Urine IFE 83 (74–89)
Serum IFE + urine IFE 95 (90–99)
FLC / ratio + urine IFE 91 (84–96)
FLC / ratio + serum IFE 99 (95–100)
All 3 assays 99 (95–100)
Clinical Chemistry 51: 878-881, 2005.
Establishing the Diagnosis by “non-invasive” testing
Fat+ Marrow+ 62%
Fat+ Marrow– 11%
Fat– Marrow+ 15%
Fat– Marrow– 13%
Gertz, M. A. et al. Hematology 2004;2004:257-282
11/13/2014
6
Diagnostic algorithm for systemic amyloidosis.
Merlini G et al. JCO 2011;29:1924-1933
©2011 by American Society of Clinical Oncology
11/13/2014
7
11/13/2014
8
Prognosis
• Cardiac involvement
• Age
• Number of organs involved
• Cardiac Biomarkers
• Serum Free Light Chain
• Fluid retention during mobilization
11/13/2014
9
Prognosis
• Cardiac involvement
• Age
• Number of organs involved
• Cardiac Biomarkers
• Serum Free Light Chain
• Fluid retention during mobilization
Dispenzieri, A. et al. J Clin Oncol; 22:3751-3757 2004
Cardiac Biomarkers are Prognostic
Copyright© American Society of Clinical Oncology
11/13/2014
10
Cardiac Biomarker Staging System
Dispenzieri A, J Clin Oncol. 2004 Sep 15;22(18):3751-7.
Stage INormal Troponin and NT-ProBNP
26 months
Stage IIEither Troponin-T >0.03ng/L or NT-ProBNP >36 pMol/L
10 months
Stage III Both abnormal3.5 months
Cardiac Biomarker are Prognostic Even in Patients without a Clinical Suspicion of Cardiac Involvement
Dispenzieri, A. et al. J Clin Oncol; 22:3751-3757 2004
11/13/2014
11
Troponin T as Predictor of TRM
Principles of Treatment:The Overflowing Sink Theory
• Unclog the drain (impair assembly, prevent filament formation, dissolve fibrils)
• Turn off the faucet (cytoreduction of plasma cells)
11/13/2014
12
Targeting the Plasma Cell Clone
Kyle et al. 336 (17): 1202, Figure 1 April 24, 1997
MP versus Colchicine
Median Survival for MP was 18 months
11/13/2014
13
11/13/2014
14
Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
Palladini, G. et al. Blood 2007;110:787-788
Melphalan and Dexamethasone is an effective therapy for patients with Amyloidosis
Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.
Dispenzieri, A. et al. Blood 2004;103:3960-3963
Patients treated with transplant fare better than case matched controls
11/13/2014
15
Skinner Ann Intern Med. 2004 Jan 20;140(2):85-93
But, High Mortality in Patients with Cardiac Involvement
Careful Patient Selection for High Dose Therapy
Gertz, M. A. et al. Hematology 2004;2004:257-282
11/13/2014
16
11/13/2014
17
Sanchorwala, IMW, 2009
New Therapies: Targeting the Clone
• Lenalidomide
• Bortezomib
• Mel/Dex/Bortezomib
• CyBorD
• Carfilzomib
11/13/2014
18
Lenalidomide
• Lenalidomide: Highly active derivative of thalidomide. Effective alone and with dexamethasone for patient with myeloma
• Two independent phase II studies. The combination of dex plus lenalidomide improved response rates
Sanchorwala et al; Blood. 2006 Sep 7 Dispenzieri et al; Blood. 2006 Sep 28;
Progression-free survival in patients with hematologic CR.
Sanchorawala V et al. Blood 2010;116:1990-1991
©2010 by American Society of Hematology
11/13/2014
19
Lenalidomide: Conclusions
• Toxicity significant at 25mg 21/28 days
• Starting dose should be at most 15mg 21/28 days
• Should be used in combination with dex if possible
Single Agent Bortezomib
Reece et al, Blood
11/13/2014
20
Reece et al; Blood 2011
Bortezomib: Evidence of Hematologic and Organ Response
Copyright ©2007 Ferrata Storti Foundation
Kastritis, E. et al. Haematologica 2007;92:1351-1358
Bortezomib and Dexamethasone is Associated with Rapid Response
11/13/2014
21
Survival of patients according to (A) hematologic and (B) proBNP response
Kastritis E et al. JCO 2010;28:1031-1037©2010 by American Society of Clinical Oncology
Bortezomib Mel Dex
• Patient Population: newly diagnosed and relpased
• Hematologic Response: ORR 83%; CR%
• Organ Response: 50%
11/13/2014
22
11/13/2014
23
Treatment algorithm for immunoglobin light chain amyloidosis.
Merlini G et al. JCO 2011;29:1924-1933
©2011 by American Society of Clinical Oncology