Hearts are NOT Made to Be Broken: Expert Opinion on Amyloid Light-Chain Cardiac Amyloidosis

Amyloid light-chain (AL) amyloidosis is a rare systemic disease caused by plasma cell dyscrasia. These plasma cells produce excess Ig light chains, which can misfold, aggregate, and deposit in tissues, resulting in toxicity and organ dysfunction. The heart is among the most commonly affected organs and cardiac involvement is associated with significantly worse outcomes. Despite advances in the treatment of the underlying plasma cell dyscrasia, the survival of patients with advanced heart involvement is extremely poor. The median survival of patients with cardiac AL can be as short as 6 months from diagnosis, depending on severity of cardiac involvement. It is a condition of high unmet medical need. Timely diagnosis is essential, yet detecting the disease is fraught with challenges, not least a lack of recognition among clinicians. In addition, the treatments that are currently available, which include anti-plasma cell dyscrasia chemotherapy and immunotherapy, are far from ideal, offering complete response rates of around 50% and organ response rates of between 40–50%. However, new antibodies with the potential to target the amyloid deposits have demonstrated encouraging results in early phase studies and are now moving into late-stage development. Giovanni Palladini, Amyloidosis Research and Treatment Centre Foundation, San Matteo, Italy, and Department of Molecular Medicine, University of Pavia, Italy, explained how these new agents have the potential to change the AL amyloidosis treatment landscape and calls on cardiologists everywhere to consider AL amyloidosis when assessing patients with heart failure (HF)

The lung in amyloidosis

Amyloidosis is a disorder caused by misfolding of autologous protein and its extracellular deposition as fibrils, resulting in vital organ dysfunction and eventually death. Pulmonary amyloidosis may be localised or part of systemic amyloidosis.Pulmonary interstitial amyloidosis is symptomatic only if the amyloid deposits severely affect gas exchange alveolar structure, thus resulting in serious respiratory impairment. Localised parenchymal involvement may be present as nodular amyloidosis or as amyloid deposits associated with localised lymphomas. Finally, tracheobronchial amyloidosis, which is usually not associated with evident clonal proliferation, may result in airway stenosis.Because the treatment options for amyloidosis are dependent on the fibril protein type, the workup of all new cases should include accurate determination of the amyloid protein. Most cases are asymptomatic and need only a careful follow-up. Diffuse alveolar-septal amyloidosis is treated according to the underlying systemic amyloidosis. Nodular pulmonary amyloidosis is usually localised, conservative excision is usually curative and the long-term prognosis is excellent. Tracheobronchial amyloidosis is usually treated with bronchoscopic interventions or external beam radiation therapy

Bioprofiling TS/A Murine Mammary Cancer for a Functional Precision Experimental Model

The TS/A cell line was established in 1983 from a spontaneous mammary tumor arisen in an inbred BALB/c female mouse. Its features (heterogeneity, low immunogenicity and metastatic ability) rendered the TS/A cell line suitable as a preclinical model for studies on tumor-host interactions and for gene therapy approaches. The integrated biological profile of TS/A resulting from the review of the literature could be a path towards the description of a precision experimental model of mammary cancer

Guidelines for high dose chemotherapy and stem cell transplantation for systemic AL amyloidosis: EHA-ISA working group guidelines

AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High dose intravenous melphalan and autologous stem cell transplantation was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in multiple myeloma. This application has evolved significantly over the past three decades. These guidelines provide a comprehensive assessment of eligibility criteria, stem cell collection and mobilisation strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies, specific supportive care management, long-term outcome with respect to survival, haematologic response and relapse and organ responses following stem cell transplantation. These guidelines are developed by the experts in the field on behalf of the stem cell transplant working group of the International Society of Amyloidosis (ISA) and European Haematology Association (EHA)

Diagnostyka i leczenie amyloidozy AL

Light chain amyloidosis (AL amyloidosis) is a disease in which monoclonal immunoglobulin light chains, produced by clonal plasma cells are deposited extracellularly in the form of misfolded, insoluble protein complexes known as amyloid. This disease is a heterogeneous condition, due to the organ tropism, which varies among patients. Heart involvement prevails (80% of patients), whereas kidneys, liver and nervous system may be also involved. To diagnose AL amyloidosis, amyloid should be detected by staining tissue samples with Congo red, and the amyloid typing should reveal the immunoglobulin light chain character of the amyloid fibrils. The therapy usually focuses on the elimination of clonal plasma cells. Assigning the patient to the proper risk group (low, intermediate, high) is crucial. For younger patients of the low-risk group, high-dose melphalan with autologous hematopoietic stem cell transplantation (auto-HSCT) with optional bortezomib-based consolidation treatment should be considered. For the most numerous (70% of patients), intermediate-risk group, MDex (melphalan, dexamethasone), as well as bortezomib-based therapies should be given. Patients in the high-risk group should undergo a chemotherapy with reduced intensity. Refractory disease can be treated with IMIDs (immunomodulatory drugs), as well as new-generation proteasome inhibitors, bendamustine and monoclonal antibodies.W przebiegu amyloidozy łańcuchów lekkich (amyloidozy AL) monoklonalne łańcuchy lekkie immunoglobulin, wytwarzane przez klonalne plazmocyty, odkładają się w tkankach i narządach w postaci nieprawidłowo sfałdowanych, nierozpuszczalnych kompleksów białkowych nazywanych amyloidem. Choroba ma heterogenny obraz kliniczny ze względu na tropizm narządowy prekursorów amyloidu różnorodny u poszczególnych pacjentów. Do najczęściej zajętych narządów należą serce (ok. 80% chorych), nerki, wątroba, a także układ nerwowy. Aby rozpoznać amyloidozę AL, należy przede wszystkim wykryć obecność amyloidu za pomocą barwienia próbki danej tkanki czerwienią Kongo oraz potwierdzić, że składa się on z łańcuchów lekkich immunoglobulin wytwarzanych przez monoklonalny rozrost plazmocytowy. Terapia amyloidozy AL przeważnie jest skierowana na eliminację klonalnych plazmocytów wytwarzających łańcuch lekki immunoglobulin. Kluczowa przed rozpoczęciem leczenia jest klasyfikacja chorych do odpowiedniej grupy ryzyka (niskiego, pośredniego lub wysokiego). W grupie niskiego ryzyka chorzy w młodszym wieku powinni być kierowani na terapię dużymi dawkami melfalanu wspartą przeszczepieniem autologicznych krwiotwórczych komórek macierzystych szpiku kostnego z ewentualnym leczeniem konsolidującym bortezomibem. W najliczniejszej (70% pacjentów) grupie średniego ryzyka standardem jest chemioterapia melfalanem i deksametazonem, a także schematy oparte na bortezomibie. W grupie wysokiego ryzyka zaleca się chemioterapię o zredukowanej intensywności. W leczeniu postaci nawrotowej oraz opornej amyloidozy AL podstawę schematów terapeutycznych stanowią leki immunomodulujące, a także inhibitory proteasomu nowej generacji, bendamustyna oraz przeciwciała monoklonalne

Changing paradigm in the treatment of amyloidosis: From disease-modifying drugs to anti-fibril therapy.

Cardiac amyloidosis is a rare, debilitating, and usually fatal disease increasingly recognized in clinical practice despite patients presenting with non-specific symptoms of cardiomyopathy. The current standard of care (SoC) focuses on preventing further amyloid formation and deposition, either with anti-plasma cell dyscrasia (anti-PCD) therapies in light-chain (AL) amyloidosis or stabilizers of transthyretin (TTR) in transthyretin amyloidosis (ATTR). The SoC is supplemented by therapies to treat the complications arising from organ dysfunction; for example, heart failure, arrhythmia, and proteinuria. Advancements in treatments have improved patient survival, especially for those whose disease is detected and for whom treatment is initiated at an early stage. However, there still are many unmet medical needs, particularly for patients with severe disease for whom morbidity and mortality remain high. There currently are no approved treatments to reverse amyloid infiltration and deplete the amyloid fibrils already deposited in organs, which can continue to cause progressive dysfunction. Anti-fibril therapies aimed at removing the deposited fibrils are being investigated for safety and efficacy in improving outcomes for patients with severe disease. However, there is no clinical evidence yet that removing deposited amyloid fibrils will improve organ function, thereby improving quality of life or extending life. Nevertheless, anti-fibril therapies are actively being investigated in clinical trials to evaluate their ability to complement and synergize with current SoC.This manuscript was funded by Alexion AstraZeneca Rare Disease. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.S

A novel approach for the purification and proteomic analysis of pathogenic immunglobulin free light chains from serum

An excess of circulating monoclonal free immunoglobulin light chains (FLC) is common in plasma cell disorders. A subset of FLC, as amyloidogenic ones, possess intrinsic pathogenicity. Because of their complex purification, little is known on the biochemical features of serum FLC, possibly related to their pathogenic spectrum. We developed an immunopurification approach to isolate serum FLC from patients with monoclonal gammopathies, followed by proteomic characterization. Serum monoclonal FLC were detected and quantified by immunofixation and immunonephelometry. Immunoprecipitation was performed by serum incubation with agarose beads covalently linked to polyclonal anti-κ or λ FLC antibodies. Isolated FLC were analyzed by SDS-PAGE, 2D-PAGE, immunoblotting, mass spectrometry (MS). Serum FLC were immunoprecipitated from 15 patients with ALλ amyloidosis (serum λ FLC range: 98-2350mg/L), 5 with ALκ amyloidosis and 1 with κ light chain (LC) myeloma (κ FLC range: 266-2660mg/L), and 3 controls. Monoclonal FLC were the prevalent eluted species in patients. On 2D-PAGE, both λ and κ FLC originated discrete spots with multiple pI isoforms. The nature of eluted FLC and coincidence with the LC sequence from the bone marrow clone was confirmed by MS, which also detected post-translational modifications, including truncation, tryptophan oxidation, cysteinylation, peptide dimerization. Serum FLC were purified in soluble form and adequate amounts for proteomics, which allowed studying primary sequence and detecting post-translational modifications. This method is a novel instrument for studying the molecular bases of FLC pathogenicity, allowing for the first time the punctual biochemical description of the circulating forms

Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group

Background: This guideline has been developed jointly by the European Society of Haematology and International Society of Amyloidosis recommending non-transplant chemotherapy treatment for patients with AL amyloidosis. / Methods: A review of literature and grading of evidence as well as expert recommendations by the ESH and ISA guideline committees. / Results and Conclusions: The recommendations of this committee suggest that treatment follows the clinical presentation which determines treatment tolerance tempered by potential side effects to select and modify use of drugs in AL amyloidosis. All patients with AL amyloidosis should be considered for clinical trials where available. Daratumumab-VCD is recommended from most untreated patients (VCD or VMDex if daratumumab is unavailable). At relapse, the two guiding principles are the depth and duration of initial response, use of a class of agents not previously exposed as well as the limitation imposed by patients’ fitness/frailty and end organ damage. Targeted agents like venetoclax need urgent prospective evaluation. Future prospective trials should include advanced stage patients to allow for evidence-based treatment decisions. Therapies targeting amyloid fibrils or those reducing the proteotoxicity of amyloidogenic light chains/oligomers are urgently needed

Interleukin-15 is required for immunosurveillance and immunoprevention of HER2/neu-driven mammary carcinogenesis

We previously demonstrated that HER2/neu-driven mammary carcinogenesis can be prevented by an interleukin-12 (IL-12)-adjuvanted allogeneic HER2/neu-expressing cell vaccine. Since IL-12 can induce the release of interleukin-15 (IL-15), in the present study we investigated the role played by IL-15 in HER2/neu driven mammary carcinogenesis and in its immunoprevention