AL AmyloidThe Other GuysMargot Davis, MD MSc FRCPCClinical Assistant ProfessorUniversity of British Columbia

AL AmyloidThe Other GuysMargot Davis, MD MSc FRCPCClinical Assistant ProfessorUniversity of British Columbia Disclosures›Consultancy/speaking fees: Janssen, Novartis, Boehringer-Ingelheim, Takeda, Pfizer, Akcea, Alnylam, Amgen, Ferring, TerSera›Grant funding: Pfizer, Takeda, Boehringer-Ingelheim, Servier, Akcea Objectives›Review the presentation of AL amyloid including the conditions associated with it›Differentiate the presentation & clinical course of AL amyloid from TTR-amyloid›Discuss treatment options for AL amyloid Haematologica2014;99:209-221 AL Amyloid:the Basics›Annual incidence ~10/1,000,000›Prevalence ~50/1,000,000 py›Mean age Dx63›55% men›Risk factors:›MGUS›Genetic predisposition? AL Amyloid:Clinical Presentation Death in >1/2 due to HF or arrhythmia NatRevDisPrimers4, 38 (2018). Clinical Clues Between Subtypes of Amyloid CardiomyopathyAmyloid TypeSystemic AmyloidosisTransthyretin (TTR) AmyloidosisSubtypeAL ATTRmATTRwtAge range, yrs50+40+ (V122I, 60-65 yrs)65+Sex 55% maleEither, slight male dominanceMarked male predominance >15:1Clinical cues•Multiorgan involvement•Periorbital bruising or macroglossia are almost pathognomonic •Severe hypotension with ACE inhibitors •African-American/Caribbean origin (for V122I variant)•Left ventricular hypertrophy without presence of prior history ofhypertension •History of carpal tunnel syndrome 5-10 yrs earlier, with no other organ involvement ACE, angiotensin-converting enzyme; AL, light-chain amyloidosis; ATTRm, mutated transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; ECHO, echocardiogram; MRI, magnetic resonance imaging.Adapted from Falk RH et al. J Am Coll Cardiol 2016;68(12):1323-1341. Amyloid TypeSystemic AmyloidosisTransthyretin (TTR) AmyloidosisSubtypeAL ATTRm ATTRwtProtein depositedLight chainMutated TTR proteinwtTTR monomersDisease etiologyPlasma cell dyscrasia with ↑ light chainsFamilial mutation of TTRAge-related TTR deposition-common in elderly aged >75 yearsSpecific featuresKidney, heart, nerves, GI tract, and liver affectedV122I common in African AmericansCarpal tunnel Male dominanceMedian survival1-3 years2 years4-6 yearsClinical courseHF can be fulminant, but may improve dramatically if rapid response to therapy Similar to wt, but may be more rapid; may be dominated by neuropathy Insidious, but easy decompensation Comparison of Cardiac Amyloid Types Free Light Chains in AL›Primary pathogenic mechanism›Tissue deposition›Direct myocardial toxicity›Biomarker useful for diagnosis and monitoring response to therapy›Treatment target Diagnostic Pitfalls in AL›Amyloidosis plus monoclonal protein does notnecessarily equal AL amyloidosis unless immunofluorescence or mass spec demonstrates light chains in amyloid deposits›Conversely, nuclear scintigraphy cannotdifferentiate between AL and ATTR in the presence of a monoclonal protein (FLC or SPEP/UPEP) Prognosis in AL Amyloidosis›Burden of amyloid deposition –cardiac biomarkers›Predicts early deaths (<1 year)›Size and biology of plasma cell clone –dFLC, %BMPC, t(11:14)›Predicts late deaths›Response to therapy Prognosis in AL: Revised Mayo Staging Mayo ClinProc. 2019;94(3):472-483 5 yrOS 82%62% 39%20% Median survival 94.1 mos40.3 mos 14 mos5.8 mos dFLC≥18 mg/dLTnT≥0.025NT-proBNP≥1800orBNP ≥400Stage 1: 0/3Stage 2: 1/3Stage 3: 2/3Stage 4: 3/3 Prognosis in AL: Hematologic & Organ Responses Mayo ClinProc. 2019;94(3):472-483Leukemia (2012) 26, 2317–2325 AL: Light chain-suppressive therapy NatRevDisPrimers4, 38 (2018). Doxycycline improves survival in patients receiving chemo for AL amyloidosis Blood Cancer Journal (2017) 7, e546 Symptom-Directed Management Cardiomyopathy Medications•Avoid β-blockers, ACEi, and ARB•Do not modify disease progression •Can result in worsening fatigue and hypotension Hypotension•α-1 blocker midodrine and compression stockings Atrial Arrhythmias•Amiodarone•Catheter ablation•Calcium channel blockers are contraindicated (bind to the amyloid fibrils)•Digoxin can cause cardiac toxicity (progressive accumulation in amyloid-rich heart despite normal serum levels)•Catheter ablation has high recurrence rate, necessitating AV ablation with permanent pacemaker placement in refractory cases Congestive Symptoms •Loop diuretics and thiazides in combination with mineralocorticoid receptor antagonist Importance of early diagnosis and therapy NatRevDisPrimers4, 38 (2018). Conclusions›AL is a rare disease associated with multiorgan dysfunction and a very poor prognosis if not promptly treated›Differentiation between AL, ATTR, and other causes of HFpEFis essential to ensure appropriate treatment›Free light chains are the pathologic basis of the disease, a valuable tool in its diagnosis, and the primary treatment target›Despite advances in therapy, advanced cardiac involvement is still associated with a poor prognosis›Novel and developing therapies will hopefully change this prognosis in the future Case Presentation 85 year old man referred for possible ATTR cardiac amyloidosis›Admitted with ADHF September 2018›Recently returned from trip, eating lots of salty food›Troponin 0.20 on presentation›MIBI normal›Echo in hospital:›Normal LV size, EF 39%›Dilated RV, normal function›Septum 15 mm, PW 11 mm, increased RV wall thickness›Biatrialenlargement›Mild-moderate MR and AR›Strain not reported ›PMHx: HTN, DM2, CKD (GFR 30), Atrial fibrillation –diagnosed 2017, rate controlled›Meds:›Ramipril 1.25 mg daily›Metoprolol 25 mg BID›Warfarin›Lasix 20 mg daily›Atorvastatin 20 mg daily›Trajenta Tc-PYP scan›Marked increased activity throughout the left ventricular myocardium, low grade activity within the right ventricle›Diffuse activity typical of TTR cardiac amyloidosis Clinic Evaluation›NYHA 2›No syncope›No history CTS›Numbness/paresthesiasin arms/hands at night›Intermittent foamy urine›No macroglossia, change in taste, GI symptoms, weight loss. Bleeds but on OAC. ›Exam›117/70; 81 bpm (irregular)›JVP 4 cm ASA, AJR+›No macroglossia›S1S2 irregular, no murmurs›Chest clear, trace edema›BNP 364, TnI0.07›Cr 179, GFR 25, K 4.6, Na 142, Hb139 Further Investigations›SPEP: Normal pattern›UPEP: Small band in gamma region›Immunofixation: small monoclonal free kappa light chain›Serum free light chain assay›Kappa: 205›Lambda: 17.1›Ratio: 11.99 Audience response: What is the most appropriate next step?›1. Prescribe tafamidis 61 mg daily›2. Refer for liver transplant›3. Tissue biopsy›4. Refer for stem cell transplant›5. Suggest patient enroll in clinical trial of novel TTR-directed therapy ›Abdominal fat pad biopsy:›Negative for amyloid›Bone marrow biopsy:›Mild increase (5-10%) in kappa restricted plasma cells. Histologic findings consistent with a diagnosis of a plasma cell neoplasm. No definite evidence of amyloid infiltrate by Congo red staining. ›Next? Case summary›Overall most consistent with ATTR with concomitant MGUS›Older age, male›AF for 2 years›Rapid recovery after ADHF episode›Cannot rule out AL, given abnormal FLC and marrow›History of unexplained renal disease and lack of CTS also concerning›Needs EMBxwith mass spec to differentiate, as management vastly different for 2 diseases