Advances in Treatment of Cardiac Amyloid
Systemic amyloidosis represents a complex group of diseases with a common feature characterized by misfolded autologous proteins depositing into tissues or organs throughout the body. Light chain amyloidosis (AL) and transthyretin (TTR) amyloid are the two most prevalent forms of this disease that commonly results in cardiac amyloidosis. In both of these conditions, the myocardium is a frequent site of infiltration and end-organ involvement often with devastating consequences. With cardiac amyloidosis becoming an increasingly identified disease that has previously been under-recognized, the purpose of this comprehensive review is to focus on the diagnosis and treatment of these two types of cardiac amyloidosis including a contemporary update on currently available therapies being investigated in clinical trials. Subsequently, we will detail potential therapeutic efficacy and limitations of these regimens, and then complete the review by highlighting newer treatment modalities. A high-level overview of modern therapeutic approaches for AL amyloid includes targeted therapies directed at reducing the production of precursor proteins and inhibitors intended to limit the deposition of fibrils in tissues. In the case of TTR amyloid, current therapy is focused on stabilization of TTR proteins, suppression of protein formation, and blocking the deposition of amyloid fibrils in tissue. Novel therapies are focused on removing amyloid fibril deposition from affected tissues. In summary, cardiac amyloidosis is a progressively devastating disease requiring swift recognition and treatment now with groundbreaking therapies on the horizon.
KeywordsSystemic amyloidosis Cardio-oncology Light chain amyloidosis Transthyretin
Compliance with Ethical Standards
Conflict of Interest
Cherie N. Dahm and R. Frank Cornell each declare no potential conflicts of interest.
Daniel J. Lenihan reports research support from Takeda and is a consultant for Roche, BMS, Prothera, Amgen, Takeda, and Janssen.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 10.Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22 April 2004. Am J Hematol. 2005;79(4):319–28.CrossRefPubMedGoogle Scholar
- 30.Maurer MS, Elliott P, Merlini G, et al. Design and rationale of the phase 3 ATTR-ACT clinical trial (tafamidis in transthyretin cardiomyopathy clinical trial). Circ Heart Fail. 2017;10(6)Google Scholar
- 43.Cohen AD, Scott EC, Liedtke M, et al. A phase I dose-escalation study of carfilzomib in patients with previously-treated systemic light-chain (AL) amyloidosis. Blood. 2014;124:4741.Google Scholar
- 44.Merlini G, Sanchorawala V, Jeffrey ZA, et al. Long-term outcome of a phase 1 study of the investigational oral proteasome inhibitor (PI) ixazomib at the recommended phase 3 dose (RP3D) in patients (Pts) with relapsed or refractory systemic light-chain (AL) amyloidosis (RRAL). Blood. 2014;124:3450.CrossRefGoogle Scholar
- 45.Langer AL, Miao S, Mapara M, et al. Results of a phase 1 study of chimeric fibril-reactive monoclonal antibody 11-1F4 in patients with AL amyloidosis. Blood. 2015;126:188.Google Scholar
- 47.Edwards CV, Gould J, Langer AL, et al. Final analysis of the phase 1a/b study of chimeric fibril-reactive monoclonaL ANTIBODY 11-1F4 in patients with relapsed or refractory AL amyloidosis. Am Soc Hematol. 2017;1(30):509.Google Scholar
- 52.• Adams D, Gonzalez-Duarte A, O’Riordan W, et al. Patisiran, an investigational RNAi therapeutic for the treatment of hereditary ATTR amyloidosis with polyneuropathy: results from the phase 3 APOLLO study. EU ATTR Meeting- Paris. 2017. Includes the most up to date findings on treatment of TTR amyloidosis with both showing an improvement in quality of life. Both drugs showed significant stabilization/improvement in cardiac structure/function.Google Scholar
- 54.•• https://seekingalpha.com/article/4120357-ionis-pharmaceuticals-ions-inotersen-attr-webcast slideshow. Includes the most up to date findings on treatment of TTR amyloidosis with both showing an improvement in quality of life. Both drugs showed significant stabilization/improvement in cardiac structure/function.
- 61.Kaufmann G, Witteles R, Wheeler M, et al. Hematologic responses and cardiac organ improvement in patients with heavily pretreated cardiac immunoglobulin light chain (AL) amyloidosis receiving daratumumab. Blood. 2016;128:abstr 4525.Google Scholar