updates in al amyloidosis and light chain deposition disease...objectives •review basic...
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Updates in AL Amyloidosis and Light Chain Deposition Disease
Andrew J. Cowan, M.D.University of Washington / Fred Hutch / Seattle Cancer Care Alliance
Disclosures• Advisory Board: Sanofi; Cellectar• Consulting: Bristol Myers Squibb; Janssen• Research support: Bristol Myers Squibb; Janssen; Abbvie; Sanofi
Objectives• Review basic pathophysiology, diagnosis of AL amyloidosis and light
chain deposition disease
• Distinguish between different treatment options for newly diagnosed patients with AL amyloidosis and LCDD
• Understand new/emerging treatment options for patients with relapsed or refractory AL amyloidosis
• Definition: a group of diseases characterized by:– Normally soluble proteins deposit, leading to formation of
insoluble extracellular amyloid fibrils• Classification:
– Systemic: amyloidogenic protein produced at site distant from site of deposition
– Localized: amyloid deposition at same site as production of amyloidogenic protein
What is Amyloidosis?
Clinical presentations that should raise concern for amyloidosis
• Heart failure with preserved ejection fraction (HFPEF)
• Nephrotic range proteinuria
• Gastroparesis, isolated hepatomegaly
• Peripheral neuropathy with autonomic features, carpal tunnel syndrome
• Any patient with MGUS (esp λ clonality), or Multiple Myeloma (12-20% of patients)
How does a pathologist find amyloidosis?• Congo Red: stain used in histology for documenting the presence of
amyloidosis in tissue• Congo red initially began as a textile dye; in 1922, was found to bind avidly
to amyloid protein1
• “Amyloid” initially termed by German botanist Matthias Schleiden to describe starch material in plants that stained blue with iodine1
Specimen from abdominal fat aspirate; note intense congophilicstaining
Characteristic “apple green birefringence” under polarized light microscopy
1David P. Steensma (2001) “Congo” Red. Archives of Pathology & Laboratory Medicine: February 2001, Vol. 125, No. 2, pp. 250-252.
What is light chain deposition disease (LCDD)?• Monoclonal immunoglobulin light chains are deposited (not as
amyloid fibrils)• Most common site of involvement – kidney à nephrotic range
proteinuria• Hepatic, cardiac, neural deposits also possible
Sayed RH et al. Blood. 2015 Dec 24;126(26):2805-10
Classic Physical Examination Findings in AL Amyloidosis
Diagnostic Algorithm for Amyloidosis
Suspicion for Amyloidosis
Biopsy of surrogate site:• Fat pad aspirate• Minor labial salivary gland biopsy
Typing:• Gold standard: Laser capture / Mass
spectrometry• Also: IHC; Immunogold electron microscopy
Plasma cell dyscrasia work-up:• Serum free light chain
assay• Bone marrow aspirate and
biopsy with flow cytometry, FISH, and conventional cytogenetics
• SPEP with immunofixation• 24 hour urine protein with
UPEP
Other testing for assessment of vital organ involvement:• Orthostatic vital
signs• nt-pro BNP,
troponin T (or BNP, Tn-I)
• LFTs• Transthoracic
echocardiogram• Cardiac MRI
PYP/DPD scan (for ATTR-CM) *
If negative:• Biopsy of involved organ
Concern for ATTR?
Revised Prognostic Staging System for AL Amyloidosis
Factors
dFLC ≥ 18 mg/dL
Cardiac troponin-T ≥ 0.025 ng/ml
NT-ProBNP ≥ 1,800 pg/mL
Each gets 1 point; score from 0, 1, 2, and 3 points denoting stages I, II, III and IV
Kumar S et al. J Clin Oncol. 2012 Mar 20;30(9):989-95
Treatment of Newly Diagnosed AL Amyloidosis and LCDD
Newly Diagnosed Patient with AL Amyloidosis
Autologous Stem Cell Transplantation
Conditioning:Melphalan 200 mg/m2
Bortezomib-based regimens (e.g., CyBorD, Vd, VMP)
ORClinical Trial
Transplant Eligible Not Transplant Eligible
Clinical Pearls for Treating Patients with AL Amyloidosis
• Watch the dexamethasone dose… 10-20 mg is usually enough
• Manage fluid retention carefully
• Bortezomib can unmask neuropathy (peripheral and autonomic)
• Spironolactone can be helpful for amyloid cardiomyopathy
• Midodrine very useful for orthostatic hypotension
• Key Point: Treating this like Multiple Myeloma (same doses, regimens, etc) is often too much for these frail patients
Eligibility Criteria for ASCT – Key Concerns• Due to risks of transplant-related mortality (TRM), eligibility
criteria have evolved over time to select optimal patients• Typical Criteria:
• Cardiac ejection fraction > 40%• DLCO > 50% predicted• Supine systolic blood pressure > 90 mmHg• NT pro BNP < 5,000 / Troponin T < 0.06
• Common challenges:• Cardiac involvement – increased TRM (16%) seen in cardiac
involvement with ASCT• Determining extent of organ involvement
Autologous Stem Cell Transplantation (ASCT) for AL Amyloidosis
Sanchorawala V, et al. Blood (2015) 126 (20): 2345-2347
Upfront Bortezomib-based therapy for AL Amyloidosis
Manwani R et al. Blood 2019 Dec 19;134(25):2271-2280
Daratumumab and CyBorD for Newly Diagnosed AL: The ANDROMEDA Trial• Phase 3 study of daratumumab SC
plus CyBorD vs CyBorD alone
• Newly diagnosed AL Amyloidosis
• Primary endpoint: Overall complete hematologic response rate
• Eligibility:• AL with ≥ 1 organ involved• Cardiac Stage I-IIIA
Comenzo RL et al. EHA Annual Meeting, 2019
NEOD001 + CyBorD: The Phase 3 VITAL Study
• NEOD001: Investigational humanized IgG1 monoclonal antibody
• Preclinical evidence of promotion of phagocytic clearance of amyloid deposits
• Phase 3 study of CyBorD +/- NEOD001 in newly diagnosed, untreated AL was conducted
• No significance difference between study arm and control for the PE
• Post hoc analysis suggest potential survival benefit for Stage IV AL patients
ITT and mITT (Initial 12-Month Study Period) Results:
Mayo Stage(N) Endpoint
ITT analysesHR (95%CI)
p-value
mITT analyses
HR (95%CI)p-value
All(N=260)
Composite primary
endpoint
0.835 (0.5799, 1.2011)
p=0.3300
0.784 (0.5341, 1.1507)
p=0.2129
Stage I-III(n=183)
All-cause mortality
1.334 (0.7386, 2.4107)
p=0.3375
1.244 (0.6435, 2.4035)
p=0.5159
Stage IV(n=77)
All-cause mortality
0.544 (0.2738, 1.0826)
p=0.0787
0.498 (0.2404, 1.0304)
p=0.0556
Gertz MA et al. Blood (2019) 134 (Supplement_1): 3166.
Sanchorawala V, et al. Blood. 2020 Jan 24
Daratumumab for Relapsed AL Amyloidosis
Immunomodulatory agents for Relapsed AL Amyloidosis • Lenalidomide and
dexamethasone:• Overall Response Rates: 41-67%,
median time to response ~6 months1,2
• Tox profile: Myelosuppression, dermatologic, fatigue
• Pomalidomide:• Overall Response Rates: 48-50 %,
median time to response, 1.9 months3,4
• Tox: Myelosuppression, fatigue1Dispenzieri A et al. Blood 2007 Jan 15;109(2):465-70; 2Sanchorawala V et al. Blood. Blood. 2007 Jan 15;109(2):492-63Sanchorawala V et al. Blood. 2016 Aug 25;128(8):1059-62; 4Dispenzieri A et al Blood 2012 Jun 7;119(23):5397-404 5Warsame R et al. Blood Cancer j. 2020 Jan 8;10(1):4
• Venetoclax – an oral, small molecule BCL2 inhibitor; most promising development in plasma cell neoplasms in patients harboring t(11;14)
• AL Amyloidosis – 50% prevalence of t(11;14)1
• Small case reports have suggested benefit in AL amyloidosis2-3; Clinical trials are enrolling
Venetoclax in AL Amyloidosis
1Hayman SR et al, Blood. 2001; 98(7):2266-2268; 2Premkumar V et al. Clin Lymphoma Myeloma Leuk. 2019; Oct;19(10):686-688; 3Leung N et al. Haematologica 2018; Mar;103(3):e135-e137
Conclusions• Think about the diagnosis in appropriate scenarios! Remember that
typing of the amyloid protein is critical
• Differentiate between LCDD and AL amyloidosis – different diseases, similar treatment modalities
• Upfront treatment – prefer autologous HSCT for eligible patients, bortezomib-based therapies for all others
• No FDA approved options for relapsed AL amyloidosis/LCDD – but MM therapies like daratumumab, IMiDs, all effective