Novel monoclonal antibodies: A really specific therapy for light chain amyloidosis.

Light chain amyloidosis is a rare disease caused by clonal plasma cells in the bone marrow generating an excessive amount of immunoglobulin light chains. These chains misfold and produce insoluble fibrils that deposit in various organs, including the heart, kidneys, liver, nervous system, and digestive tract. Life expectancy and symptoms during the course of the disease vary depending on which and how many organs are affected. Targeted plasma cell therapy has significantly advanced the clinical management of amyloidosis, with ongoing progress. However, current clinical studies are investigating innovative targets, drug combinations and treatment strategies to improve therapeutic outcomes by minimizing adverse effects and refining patient prognosis in these challenging hematological conditions. In this paper, we review the state of the art regarding the use of anti-amyloid antibodies, as a revolutionary and innovative approach in the current scenario of amyloid treatment.

Re-Engineering Therapeutic Anti-Aß Monoclonal Antibody to Target Amyloid Light Chain.

Amyloidosis involves the deposition of misfolded proteins. Even though it is caused by different pathogenic mechanisms, in aggregate, it shares similar features. Here, we tested and confirmed a hypothesis that an amyloid antibody can be engineered by a few mutations to target a different species. Amyloid light chain (AL) and ß-amyloid peptide (Aß) are two therapeutic targets that are implicated in amyloid light chain amyloidosis and Alzheimer's disease, respectively. Though crenezumab, an anti-Aß antibody, is currently unsuccessful, we chose it as a model to computationally design and prepare crenezumab variants, aiming to discover a novel antibody with high affinity to AL fibrils and to establish a technology platform for repurposing amyloid monoclonal antibodies. We successfully re-engineered crenezumab to bind both Aß42 oligomers and AL fibrils with high binding affinities. It is capable of reversing Aß42-oligomers-induced cytotoxicity, decreasing the formation of AL fibrils, and alleviating AL-fibrils-induced cytotoxicity in vitro. Our research demonstrated that an amyloid antibody could be engineered by a few mutations to bind new amyloid sequences, providing an efficient way to reposition a therapeutic antibody to target different amyloid diseases.

Feasibility and safety of left bundle branch area pacing in cardiac amyloidosis. A single center experience.

BACKGROUND: Conventional right ventricle (RV) pacemaker stimulation has been associated with worse clinical outcomes in patients with cardiac amyloidosis (CA). Left bundle branch area pacing (LABPP) has been suggested as a promising alternative. We sought to assess the safety, feasibility, and outcomes of LABPP in patients with CA. METHODS: We retrospectively analyzed echocardiography and pacing parameters and clinical outcomes in 23 consecutive patients with CA and LBBAP implanted from June 2020 to October 2022. RESULTS: LBBAP was successfully performed in 22 over 23 patients (19 male, 78.6 ± 11.7 years, 20 ATTR, mean LVEF 45.5 ± 16.2%). After the procedure, 9 patients showed Qr pattern and 11 a qR pattern in V1 on ECG. Average procedure time was 67 ± 28 min. After 7.7 ± 5.2 months follow-up, no procedure-related complications had occurred. Although, a significant reduction in QRS width (p = .001) was achieved, we did not observe significant changes in LVEF and Nt ProBNP at 6 months of follow-up. Pacing parameters were stable during follow-up: LBB capture threshold and R wave amplitude were 1.0 ±  0.5 V and 10.6 ± 6.0 mV versus 0.8 ±  0.1 V, p = .21 and 10.6 ± 5.1 mV (p = .985) at follow up. CONCLUSION: LBBAP is safe and feasible pacing technique for patients with CA. LBBAP is associated with significant narrowing of QRSd without worsening in LVEF and Nt-proBNP.

Transgenic amyloid precursor protein mouse models of amyloidosis. Incomplete models for Alzheimer's disease but effective predictors of anti-amyloid therapies.

INTRODUCTION: Amyloid precursor protein (APP) transgenic mice are models of Alzheimer's disease (AD) amyloidosis, not all of AD. Diffuse, compacted, and vascular deposits in APP mice mimic those found in AD cases. METHODS: Most interventional studies in APP mice start treatment early in the process of amyloid deposition, consistent with a prevention treatment regimen. Most clinical trials treat patients with established amyloid deposits in a therapeutic treatment regimen. RESULTS: The first treatment to reduce amyloid and cognitive impairment in mice was immunotherapy. The APP mouse models not only predicted efficacy, but presaged the vascular leakage called ARIA. The recent immunotherapy clinical trials that removed amyloid and slowed cognitive decline confirms the utility of these early APP models when used in therapeutic designs. DISCUSSION: New mouse models of AD pathologies will add to the research armamentarium, but the early models have accurately predicted responses to amyloid therapies in humans.

Immunoglobulin light chain amyloidosis: 2024 update on diagnosis, prognosis, and treatment.

DISEASE OVERVIEW: Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include heart failure with preserved ejection fraction, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and "atypical smoldering multiple myeloma or MGUS." DIAGNOSIS: Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for the diagnosis of AL amyloidosis. Organ biopsy is not required in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy. PROGNOSIS: N-terminal pro-brain natriuretic peptide (NT-proBNP or BNP), serum troponin T(or I), and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four stages; 5-year survivals are 82%, 62%, 34%, and 20%, respectively. THERAPY: All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Current first-line therapy with the best outcome is daratumumab, bortezomib, cyclophosphamide, and dexamethasone. The goal of therapy is a ≥VGPR. In patients failing to achieve this depth of response options for consolidation include pomalidomide, stem cell transplantation, venetoclax, and bendamustine. FUTURE CHALLENGES: Delayed diagnosis remains a major obstacle to initiating effective therapy prior to the development of end-stage organ failure. Trials of antibodies to deplete deposited fibrils are underway.

Cardiac Amyloidosis: Clinical Features, Pathogenesis, Diagnosis, and Treatment.

Cardiac amyloidosis is a type of amyloidosis that deserves special attention as organ involvement significantly worsens the prognosis. Cardiac amyloidosis can be grouped under three main headings: immunoglobulin light chain (AL) amyloidosis that is dependent on amyloidogenic monoclonal light chain production; hereditary Transthyretin (TTR) amyloidosis that results from accumulation of mutated TTR; and wild-type (non-hereditary) TTR amyloidosis formerly known as senile amyloidosis. Although all three types cause morbidity and mortality due to severe heart failure when untreated, they contain differences in their pathogenesis, clinical findings, and treatment. In this article, the clinical features, pathogenesis, diagnosis, and treatment methods of cardiac amyloidosis will be explained with an overview, and an awareness will be raised in the diagnosis of this disease.

Renal AA amyloidosis revealing extramedullary plasmocytoma / Amylose rénale AA révélant un plasmocytome extra-médullaire : étude de cas

Introduction: Solitary plasmacytoma is a rare, localized malignancy. Bone localizations are the most common. Extramedullary plasmacytomas are much rarer. They are most often in the upper respiratory tract and can be complicated by amyloidosis. Here is an original report of a mediastinal extramedullary plasmacytoma revealed by type AA renal amyloidosis. Case presentation: We present the case of a 52-year-old patient with mediastinal extramedullary plasmocytoma diagnosed by renal failure due to type AA renal amyloidosis. Treatment was based on surgery with chemotherapy based on prednisone and melphalan. The patient presented end-stage renal failure that required hemodialysis at discharge. Conclusion: Extramedullary plasmacytoma is a rare tumour that may be associated with amyloidosis, usually type AL. To our knowledge, its association with AA amyloidosis has not been reported in the literature. Treatment is based on surgery combined with radiotherapy or chemotherapy.

Introduction: Le plasmocytome solitaire est une tumeur maligne rare localisée. Les localisations osseuses sont les plus fréquentes. Les plasmocytomes extra­médullaires (PEM) sont beaucoup plus rares, localisés le plus souvent au niveau des voies respiratoires supérieures. Présentation du cas: Nous rapportons une observation de PEM médiastinal révélé par une insuffisance rénale en rapport avec amylose rénale de type AA chez un patient âgé de 52 ans. Le traitement a comporté une tumorectomie de la masse associée à une chimiothérapie. Sur le plan rénal, le patient était au stade d'insuffisance rénale terminale nécessitant le recours à l'hémodialyse chronique. Conclusion: Le PEM est une tumeur rare pouvant se compliquer d'une amylose le plus souvent de type AL. Son association à une amylose AA n'a pas été rapportée auparavant à notre connaissance. Le traitement est basé surtout sur la chirurgie associée à une radiothérapie ou chimiothérapie.

The importance of pathways to facilitate early diagnosis and treatment of patients with cardiac amyloidosis.

Cardiac amyloidosis (CA) is a condition caused by extracellular deposition of amyloid fibrils in the heart. It is an underdiagnosed disease entity which can present with a variety of cardiac and non-cardiac manifestations. Diagnosis usually follows an initial suspicion based on clinical evaluation or imaging findings before confirmation with subsequent imaging (echocardiography, cardiac magnetic resonance imaging, 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy) in combination with biochemical screening for monoclonal dyscrasia (serum free light chains and serum and urine electrophoresis) and/or histology (bone marrow trephine, fat or endomyocardial biopsy). More than 95% of CA can be classified as either amyloid light-chain (AL) CA or amyloid transthyretin (ATTR) CA; these two conditions have very different management strategies. AL-CA, which may be associated with multiple myeloma, can be managed with chemotherapy agents, autologous stem cell transplantation, cardiac transplant and supportive therapies. For ATTR-CA, there is increasing importance in making an early diagnosis because of novel treatments in development, which have transformed this once incurable disease to a potentially treatable disease. Timely diagnosis is crucial as there may only be a small window of opportunity where patients can benefit from treatment beyond which therapies may be less effective. Reviewing the existing patient pathway provides a basis to better understand the complexities of real-world activities which may be important to help reduce missed opportunities related to diagnosis and treatment for patients with CA. With healthcare provider interest in improving the care of patients with CA, the development of an optimal care pathway for the condition may help reduce delays in diagnosis and treatment and thus enhance patient outcomes.

Cardiac and autologous stem cell transplantation hematopoietic in patients with AL amyloidosis.

OBJECTIVE: To describe the evolution of serum free light chains (FLC) in the period between orthotopic heart transplantation (OHT) and autologous stem cell transplantation (ASCT), the hematological response one year after ASCT and chemotherapy and immunosuppressive treatment in patients with AL amyloidosis. METHOD: Case series of consecutive patients diagnosed with AL amyloidosis who received OHT followed by ASCT from the Institutional Registry of Amyloidosis of the Italian Hospital of Buenos Aires, between January 2010 and November 2021. FLC values between transplants and at year post ASCT. Quantitative variables were described with their median and interquartile range. Categorical variables as absolute and relative frequencies. RESULTS: Of 106 patients with AL amyloidosis, 6 had an OHT followed by ASCT. The median age was 55 years. Most were men (n = 5). In the period between transplants, the involved CLL decreased in two patients and remained stable in three. All achieved complete hematologic remission 1 year after ASCT. A single patient presented relapse in the transplanted solid organ. Tacrolimus, mycophenolate mofetil, and corticosteroids were the immunosuppressive regimen used after OHT. CONCLUSIONS: OHT represents a treatment option in patients with severe heart failure due to amyloidosis, allowing later intensive treatment with induction chemotherapy and ASCT. Although studies are lacking, immunosuppressive therapy after OHT might have some effect on clonal plasma cells.

OBJETIVO: Describir la evolución de las cadenas livianas libres séricas (CLL) en el período comprendido entre el trasplante cardíaco ortotópico (TCO) y el trasplante de células progenitoras hematopoyéticas (TCPH), la respuesta hematológica al año tras el TCPH y el tratamiento quimioterápico e inmunosupresor en pacientes con amiloidosis AL. MÉTODO: Serie de casos de pacientes consecutivos con diagnóstico de amiloidosis AL que recibieron TCO seguido de TCPH del Registro Institucional de Amiloidosis del Hospital Italiano de Buenos Aires, entre enero de 2010 y noviembre de 2021. Se reportaron los valores de CLL entre trasplantes y al año del TCPH. Las variables cuantitativas se describieron como mediana e intervalo intercuartil, y las variables categóricas como frecuencias absolutas y relativas. RESULTADOS: De 106 pacientes con amiloidosis AL, seis tuvieron TCO seguido de TCPH. La mediana de edad fue de 55 años. La mayoría eran hombres (n = 5). En el período entre trasplantes, la CLL involucrada disminuyó en dos pacientes y se mantuvo estable en tres. Todos lograron la remisión hematológica completa al año del TCPH. Un solo paciente presentó recaída en el órgano sólido trasplantado. Tacrolimus, micofenolato de mofetilo y corticoides fue el esquema inmunosupresor utilizado después del TCO. CONCLUSIONES: El TCO representa una opción de tratamiento en pacientes con falla cardíaca grave por amiloidosis, permitiendo luego un tratamiento intensivo con quimioterapia de inducción y TCPH. Si bien faltan estudios, la terapia inmunosupresora después del TCO podría tener algún efecto sobre las células plasmáticas clonales.

Standardising Care and Treatment of Transthyretin Amyloid Cardiomyopathy.

Transthyretin cardiac amyloidosis (ATTR-CA) has been traditionally considered a rare and inexorably fatal condition. ATTR-CA now is an increasingly recognised cause of heart failure and mortality worldwide with effective pharmacological treatments. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have transformed the diagnosis of ATTR-CA, which is now possible without recourse to endomyocardial biopsy in around 70% of cases. Many patients are now diagnosed at an earlier stage. Echocardiography and cardiac magnetic resonance have enabled identification of patients with possible ATTR-CA and more accurate prognostic stratification. Therapies able to slow or halt ATTR-CA progression and increase survival are now available and there is also evidence that patients may benefit from specific conventional heart failure medications. A wide horizon of possibilities is unfolding and awaits discovery.

How I Approach Light Chain Amyloidosis.

Immunoglobulin Light Chain Amyloidosis (AL) is a progressive disease which leads to organ dysfunction and death. Tremendous progress has been made in staging, response, and treatment. The key to better survival though is early diagnosis which can be difficult since the symptoms are often nonspecific and can be seen in more common conditions. Once the diagnosis is confirmed, staging systems are available to provide prognosis on overall and renal survival. There are a number of treatments now available that are effective and well-tolerated. Response criteria have also been developed for hematologic and renal response in order to maximize response and minimize adverse effects. Newer therapies are being developed in particular anti-fibril therapies that are in clinical trials. For those patients who had a very good partial response or better, kidney transplantation may be an option if the kidney failure is not reversed.

A Rare Case of Subcutaneous Amyloidoma Associated with Localized Lymphoplasmacytic Lymphoma: Diagnostic Challenges and Treatment Considerations.

BACKGROUND AL amyloidomas are solitary, localized, tumor-like deposits of immunoglobulin light-chain-derived amyloid fibrils in the absence of systemic amyloidosis. A rare entity, they have been described in various anatomical sites, typically in spatial association with a sparse lymphoplasmacytic infiltrate, ultimately corresponding to a clonal, malignant, lymphomatous disorder accounting for the amyloidogenic activity. Most frequently, the amyloidoma-associated hematological disorder corresponds to either a solitary plasmacytoma or an extranodal marginal zone lymphoma of MALT. Much rarer is the association with lymphoplasmacytic lymphoma, which by itself is usually a bone marrow-bound disorder with systemic burden. The almost anecdotic combination of an amyloidoma and a localized lymphoplasmacytic lymphoma deserves attention, as it entails a thorough diagnostic workup to exclude systemic involvement and a proportionate therapeutic approach to avoid overtreatment. A review of the literature provides an insight on pathogenesis and prognosis, and can assist both pathologists and clinicians in establishing optimal patient management strategies. CASE REPORT We herein report the incidental finding of a subcutaneous amyloidoma caused by a spatially related, similarly localized lymphoplasmacytic lymphoma diagnosed in a 54-year-old female patient with no other disease localizations and a complete remission following 2 subsequent surgical excisions. CONCLUSIONS Whatever the specific combination of an amyloidoma and the related hematological neoplasm, a multidisciplinary collaboration and a comprehensive clinical-pathological staging are warranted to exclude systemic involvement and identify patients with localized diseases who would benefit from local active treatment and close follow-up.

Recent successes in heart failure treatment.

Remarkable recent advances have revolutionized the field of heart failure. Survival has improved among individuals with heart failure and a reduced ejection fraction and for the first time, new therapies have been shown to improve outcomes across the entire ejection fraction spectrum of heart failure. Great strides have been taken in the treatment of specific cardiomyopathies such as cardiac amyloidosis and hypertrophic cardiomyopathy, whereby conditions once considered incurable can now be effectively managed with novel genetic and molecular approaches. Yet there remain substantial residual unmet needs in heart failure. The translation of successful clinical trials to improved patient outcomes is limited by large gaps in implementation of care, widespread lack of disease awareness and poor understanding of the socioeconomic determinants of outcomes and how to address disparities. Ongoing clinical trials, advances in phenotype segmentation for precision medicine and the rise in technology solutions all offer hope for the future.

Recent Progress in the Development and Clinical Application of New Drugs for Transthyretin Cardiac Amyloidosis.

ABSTRACT: Transthyretincardiac amyloidosis is a rare disease that has gained significant attention in recent years because of misfolding of transthyretin fibrils produced by the liver, leading to their deposition in the myocardium. The disease has an insidious onset, nonspecific clinical manifestations, and historically lacked effective drugs, making early diagnosis and treatment challenging. The survival time of patients largely depends on the extent of heart involvement at the time of diagnosis, and conventional treatments for cardiovascular disease do not provide significant benefits. Effective management of the disease requires treatment of its underlying cause. Orthotopic liver transplantation and combined hepato-heart transplantation have been clinically effective means of treating transthyretin cardiac amyloidosis mutants for many years. However, transplantation has many limitations in clinical practice. In recent years, the development of new drugs has brought new hope to patients. This review presents the latest advances in drug development and clinical application to provide a reference for clinicians managing transthyretin cardiac amyloidosis.

The spectrum of pulmonary amyloidosis.

Amyloidosis is a disease caused by misfolded proteins that deposit in the extracellular matrix as fibrils, resulting in the dysfunction of the involved organ. The lung is a common target of Amyloidosis, but pulmonary amyloidosis is uncommonly diagnosed since it is rarely symptomatic. Diagnosis of pulmonary amyloidosis is usually made in the setting of systemic amyloidosis, however in cases of localized pulmonary disease, surgical or transbronchial tissue biopsy might be indicated. Pulmonary amyloidosis can be present in a variety of discrete entities. Diffuse Alveolar septal amyloidosis is the most common type and is usually associated with systemic AL amyloidosis. Depending on the degree of the interstitial involvement, it may affect alveolar gas exchange and cause respiratory symptoms. Localized pulmonary Amyloidosis can present as Nodular, Cystic or Tracheobronchial Amyloidosis which may cause symptoms of airway obstruction and large airway stenosis. Pleural effusions, mediastinal lymphadenopathy and pulmonary hypertension has also been reported. Treatment of all types of pulmonary amyloidosis depends on the type of precursor protein, organ involvement and distribution of the disease. Most of the cases are asymptomatic and require only close monitoring. Diffuse alveolar septal amyloidosis treatment follows the treatment of underlying systemic amyloidosis. Tracheobronchial amyloidosis is usually treated with bronchoscopic interventions including debulking and stenting or with external beam radiation. Long-term prognosis of pulmonary amyloidosis usually depends on the type of lung involvement and other organ function.

Peripheral Nervous, Hepatic, and Gastrointestinal Endpoints for AL Amyloidosis Clinical Trials: Report from the Amyloidosis Forum Multi-organ System Working Group.

Systemic immunoglobulin light chain (AL) amyloidosis is a heterogeneous rare disease driven by a destructive monoclonal gammopathy and typified by misfolded immunoglobulin light and/or heavy chains which aggregate and deposit in organs as insoluble amyloid fibrils. Disease heterogeneity is driven by the degree of multi-systemic involvement; cardiac, renal, neurological, and gastrointestinal (GI) systems are affected to varying degrees in different patients. While prognosis is primarily driven by hematologic response to treatment and outcomes associated with cardiac events and overall survival, the involvement of the peripheral nervous, hepatic, and GI systems can also have a significant impact on patients. The Amyloidosis Forum ( https://amyloidosisforum.org ) is a public-private partnership between the nonprofit Amyloidosis Research Consortium ( www.arci.org ) and the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research formed to advance drug development for the treatment of systemic amyloid disorders. A series of virtual workshops focused on the development of novel, patient-relevant endpoint components and analytical strategies for clinical trials in AL amyloidosis. This review summarizes the proceedings and recommendations of the Multi-Systemic Working Group which identified, reviewed, and prioritized endpoints relevant to the impacts of AL amyloidosis on the peripheral nervous, hepatic, and GI systems. The Working Group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the FDA, Medicines and Healthcare products Regulatory Agency (MHRA), and pharmaceutical companies. Prioritized neuropathy/autonomic endpoints included a modified form of the Neuropathy Impairment Score (NIS + 7) and the Composite Autonomic Symptom Score (COMPASS-31), respectively. Alkaline phosphatase was identified as the most relevant indicator of liver involvement and disease progression. Following extensive review of potential GI endpoints, the Working Group identified multiple exploratory endpoints. These recommended components will be further explored through evaluation of clinical trial datasets and possible integration into composite endpoint analysis.