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Advances in Systemic Amyloidosis: A Spotlight on New Disease-Modifying Therapies Across the Clinical Spectrum
  • CME
  • CE

Beth Faiman, PhD, MSN, APRN-BC, AOCN
Shaji K. Kumar, MD
Released: October 21, 2021

ATTR Amyloidosis

Distribution of New Cases of Amyloidosis at Mayo Clinic Rochester (2012-2017)

Shaji K. Kumar, MD:
There are 2 broad groups of ATTR amyloidosis: wild-type (ATTRwt), where there is no structural abnormality of the ATTR protein, and the genetic variants (ATTRmt), where point mutations can lead to the misfolding of the TTR protein and the development of ATTR amyloidosis.

ATTRwt: Underdiagnosis

Shaji K. Kumar, MD:
There is a serious problem with underdiagnosis of ATTRwt. Several autopsy series have shown that a high proportion of patients may have had underlying, undetected ATTR.70-74

Natural History of ATTRwt: Mayo Clinic Series

Shaji K. Kumar, MD:
The natural history of ATTRwt has been studied in large cohorts in different centers. One study included a retrospective review of patients (N = 414) diagnosed with ATTRwt from 1965-2013.75 Patients in this cohort were preponderantly male (91%). At the time of diagnosis, most (62%) of these patients had cardiac dysrhythmia (atrial fibrillation or flutter), and 39% had a history of carpal tunnel syndrome. In addition, the fat aspirate was positive for 13% of patients, and 28% of patients had a left ventricular ejection fraction of <40%. 

ATTR Amyloidosis: Clinical Presentation

Shaji K. Kumar, MD:
There are some distinctions in terms of clinical presentation. Patients with hereditary ATTRmt present more commonly with heart failure or peripheral or autonomic neuropathy, and only one half of them report a positive family history of ATTR amyloidosis.76-78 There also is considerable heterogeneity regarding the penetrance for this genomic variance.78

In ATTRwt, patients often present with heart failure or carpal tunnel syndrome. Cardiac arrythmias also may be seen in this group, particularly in the later stages.4,79 

ATTR Amyloidosis: Spectrum of Cardiac and Nerve Phenotypes Based on Amyloidogenic TTR Mutation

Shaji K. Kumar, MD:
Genotyping in the ATTR amyloidosis population is important because almost one half of patients with hereditary ATTR report no family history of the disease.78 Identification and early detection may be important for other family members, especially as new therapies are being developed.

There is some relationship between the TTR genetic variant and the clinical presentation. For example, the V30M mutation is strongly associated with neurological presentation, whereas several mutations, such as the V122I and I68L mutations, are more commonly associated with cardiac involvement.77

99mTc-Pyrophosphate Imaging for ATTR Cardiac Amyloidosis

Shaji K. Kumar, MD:
PYP imaging helps us diagnose ATTR cardiac amyloidosis. For example, in a person who has negative monoclonal proteins, a PYP scan for cardiac amyloid may show a grade 2 or grade 3 uptake.4 With grade 2 uptake, the opacity of the cardiac region, ribs, and sternum are equal, and with grade 3 uptake, the cardiac region will appear more opaque than the ribs and sternum with a PYP scan.

The absence of the M protein is often sufficient for ATTR diagnosis, but in other cases a biopsy will be required. It is also important to note that a negative scan does not rule out ATTR amyloidosis, but a positive scan in the current clinical context can be diagnostic.

ATTRwt: Risk Stratification and Mortality

Shaji K. Kumar, MD:
Grogan and colleagues75 have developed a novel staging system to stratify the risk of patients with ATTRwt cardiac amyloidosis. Factoring in various baseline characteristics and survival predictors from a retrospective review of a large institutional amyloidosis database, the investigators adopted optimal cut points in levels of the peptides troponin T and NT-proBNP.

The cut points are 0.05 ng/mL for troponin T (or 65 ng/L for the higher sensitivity test) and 3000 pg/mL for NT-proBNP. Patients with neither biomarker above the cut points are considered stage 1 and at lower risk of death. Those with only 1 biomarker above the cut point are stage 2, and those with both biomarkers above the cut points are stage 3 and at highest risk. Being able to predict the outcome of these patients can be a valuable tool in the clinical setting.

ATTR Amyloidosis: Treatment Options

Shaji K. Kumar, MD:
Three main classes of drugs are being used to treat ATTR amyloidosis.80 TTR silencers are the first class of agents; these work to stop/silence the production of the TTR protein in the liver. Drugs in this class include the oligonucleotide drugs inotersen and patisiran, which will be discussed in further detail later. TTR stabilizers are the second class, and they include tafamidis, diflunisal, and acoramidis (AG10). Tafamidis was the first approved treatment for ATTR cardiomyopathy, and diflunisal is often used off label for ATTR cardiomyopathy.81 Acoramidis (AG10) is being investigated for safety and efficacy in patients with cardiomyopathy and ATTRwt and ATTRmt in a randomized phase II study.82 Finally, a third approach focuses on disrupting amyloid fibrils. Fibril disruptors include doxycycline plus TUDCA and the mAb PRX0004, which is currently being tested in clinical trials.80

Oligonucleotide Drugs for ATTR Amyloidosis

Shaji K. Kumar, MD:
Inotersen and patisiran are FDA-approved oligonucleotide drugs that interfere with amyloid folding. Inotersen is a transthyretin-directed antisense oligonucleotide, and patisiran contains a transthyretin-directed small interfering RNA. Both of these TTR stabilizers bind untranslated TTR mRNA, leading to mRNA degradation and thereby reducing the amount of TTR mRNA available for translation and conversion into the amyloid fibril, as seen in the top middle and right panels of this figure.83,84

Decreasing the hepatic synthesis of transthyretin is a promising approach. The phase III NEURO-TTR and APOLLO trials showed improvements in TTR-associated neuropathy with inotersen and patisiran compared with placebos, respectively.85,86 These trials led to the approval of both agents for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.87,88

In the presence of TTR stabilizers such as tafamidis and diflunisal, mutant TTR protein is unable to dissociate from normal TTR protein and cannot be converted into amyloid fibrils. This is depicted in the bottom panel of this figure.83

Phase III ATTR-ACT: Tafamidis vs Placebo in Patients With Transthyretin Cardiomyopathy

Shaji K. Kumar, MD:
The ATTR-ACT phase III clinical trial examined the  efficacy of tafamidis in patients with transthyretin cardiomyopathy (wild-type or genetic variants).89,90 This was a large, multicenter, double-blind, placebo-controlled, randomized trial that enrolled 441 patients with transthyretin cardiomyopathy into 1 of 3 arms: tafamidis 80 mg, tafamidis 20 mg, or placebo. The placebo arm included 177 patients, and the 2 treatment arms were pooled (n = 264) for data analysis at 30 months.

The primary endpoint for the ATTR-ACT trial was the hierarchical assessment of all causes of mortality and the rate of cardiovascular-related hospitalizations. Key secondary endpoints were changes in distance covered on a 6-minute walk and scores on QoL surveys. 

Tafamidis vs Placebo in Patients With Transthyretin Cardiomyopathy (ATTR-ACT): Survival

Shaji K. Kumar, MD:
The ATTR-ACT study showed significantly better primary outcomes in the pooled treatment group vs the placebo group after 30 months (P <.001).91 There was a 30% reduction in all causes of mortality and a significant reduction in average cardiovascular-related hospitalizations during 30 months of the trial (0.30/year vs 0.46/year with placebo).

Results of the ATTR-ACT trial led to the FDA approval of tafamidis for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.92

ATTR Amyloidosis Supportive Care

Beth Faiman, PhD, MSN, APRN-BC, AOCN:
ATTR amyloidosis leads to peripheral neuropathy, which is often exhibited by pain, numbness, or tingling in the feet. We manage patients’ pain with appropriate medications such as gabapentin, if necessary.93

Patients with TTR amyloidosis tend to have poorer health than patients with AL amyloidosis and are more likely to have declining organ function. When ATTR amyloidosis affects the heart muscle, we can prescribe patisiran, which is administered by IV every 3 weeks.88 By the time patients get treated for ATTR cardiomyopathy, they usually need to receive aggressive supportive care with cardiology medications and heart failure–directed therapies. That is why it is so important to partner with a multidisciplinary team and work in tandem with cardiologists and heart failure specialists. At our institution, we have a shared clinic with cardiology and hematology to share cardiac amyloidosis patients and discuss best practices.


Shaji K. Kumar, MD:
In summary, the initial diagnostic approach for light-chain amyloidosis should screen for monoclonal protein and ascertain the type and source of the amyloid fibril.32 It is critical to ascertain the presence of a plasma cell clone and demonstrate that the light chain is indeed the source of amyloid fibrils. It also is important to assess the degree of involvement of the cardiac amyloidosis and determine the risk using any of the prognostic tools available. An ASCT is a reasonable treatment choice for patients who are eligible for this procedure. Patients who do not want a transplant or who cannot tolerate the associated risk should consider a daratumumab-based treatment combination. Once a treatment is started, it is important to quickly assess the hematologic response. This is especially critical for patients with advanced organ involvement for whom a quick hematologic response may mean the difference between life and death. Fortunately, there are well-validated tools and criteria to monitor hematologic and organ response that should be used in the clinic to carefully monitor toxicity of therapy. In addition, after therapy is discontinued, patients should be monitored for evidence of disease progression or recurrence of the light-chain or plasma cell clone, which invariably happens in most patients with AL amyloidosis.

Early and accurate diagnosis and proper treatment are critical for patients with ATTRwt and ATTRmt. Patients with ATTRwt, which is frequently underdiagnosed, may present with atrial fibrillation several years before heart failure and a history of carpal tunnel syndrome.4,79 Patients with hereditary ATTRmt more commonly present with heart failure or peripheral or autonomic neuropathy, but there is a significant range of genetic variants and penetrance, which can impact clinical presentation.77,78 Consequently, genotyping is critical for early intervention, especially as new targeted therapies are developed. In addition, 99mTc pyrophosphate imaging can aid in the identification of ATTR-associated cardiac involvement in the absence of a biopsy.4 Cardiac biomarkers also are being used to stage the disease and can help predict outcome and inform treatment.75

There are 3 common approaches to treating ATTR amyloidosis: stopping the production of the TTR protein in the liver (using drugs such as inotersen and patisiran), stabilizing the TTR proteins so they do not form amyloid fibrils (using drugs like tafamidis or diflunisal), or introducing fibril disruptors (such as doxycycline plus TUDCA and PRX0004, currently in clinical trials).80

We are hopeful that outcomes for patients with AL amyloidosis and ATTR amyloidosis will continue to improve as healthcare professionals are able to make accurate diagnoses more rapidly and new drug combinations and investigational agents are developed and tested in clinical trials.

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