Systemic AL amyloidosis in 2014 – The challenges and promises

Wechalekar, A.D.

doi:10.1016/j.rce.2014.10.001

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Wechalekar" "autores" => array:1 [ 0 => array:3 [ "nombre" => "A.D." "apellidos" => "Wechalekar" "email" => array:1 [ 0 => "a.wechalekar@ucl.ac.uk" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "National Amyloidosis Centre, University College London (Royal Free Campus), London, UK" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Amiloidosis systemic AL en 2014 – desafios y promesas" ] ] "textoCompleto" => "Systemic AL amyloidosis is an increasingly recognised complication of plasma cell dyscrasias; with deposition of amyloid fibrils derived from monoclonal immunoglobulin light chains (FLC) in tissues or organs leading to progressive organ failure. In this issue of Rev Clin Esp, Krsnik et al.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> report the outcomes of patients presenting with systemic AL amyloidosis to a tertiary referral centre. The paper captures the spectrum of AL amyloidosis from most challenging cases with advanced cardiac amyloidosis needing cardiac transplantation as a life saving procedure, to those with more limited disease treated with alkylator based regimes.Amyloidosis is a silent killer. Disease is rare but symptoms mimic those seen in common diseases. Patients with amyloidosis present only when organ damage is advanced and often irreversible.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> All patients with AL amyloidosis have an underlying plasma cell dyscrasias ranging from MGUS to myeloma but usually low grade. In any patient with suspected amyloidosis, diagnosis needs confirmation by a tissue biopsy. Fat aspirates are good but targeted organ biopsy, as shown in the current study, offers the highest chance of a positive result. Fibril typing is the next essential step in the diagnostic pathway since treatment is entirely dependent of the primary fibril type – clinical phenotype is an inaccurate guide with risk of misdiagnosis in ∼12% cases. <a class="elsevierStyleCrossRef" href="#bib0015">3</a> Methods using combination of immunohistochemistry with specific anti-fibril protein antibodies and laser capture of the amyloid deposits followed by mass spectrometry achieves accurate typing in majority of cases.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> AL amyloidosis is commonest and, in our experience, followed by hereditary or AA amyloidosis in 15% cases respectively. Cardiac amyloidosis caused by wild type transthyretin deposition (senile cardiac amyloidosis – SSA) is being increasingly diagnosed with routine use of cardiac MRI scanning in elderly patients with heart failure. SSA is an important differential diagnosis in an older patient with isolated cardiac amyloidosis and cardiac biopsy is often the only method to accurately determine the amyloid type in the heart.Assessment of end organ damage allows appropriate risk stratification of the patients. Majority of deaths in AL amyloidosis are due cardiac arrhythmias or heart failure as indeed was the case in the current series by Krsnik et al.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> where 40% of all patients and 68% of all deaths were cardiac. Cardiac biomarkers (NT-proBNP and Troponin-T) with addition of the precursor protein, FLC, form the basis of the staging systems in AL amyloidosis – patients with stage III disease still have poor prognosi.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Additionally, the absolute value of NT-proBNP (>8500ng/L) and presenting low systolic BP (<100mm of Hg) define a particularly poor prognostic subgroup (advanced stage III) with a median survival of ∼3 months.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Patients with stage I and II disease can expect excellent long term outcomes with modern treatment regimes, with over 80% survival at 5 years.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>Outcome for patients with AL amyloidosis has improved with use of novel agents for treatment of plasma cell dyscrasias as well as judicious use of high dose melphalan followed by autologous stem cell transplantation (HDM-ASCT). Bortezomib based chemotherapy has emerged as the treatment of choice for majority of patients with AL amyloidosis with high rates of complete response (CR) and very good partial (VGPR) haematological responses.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> As noted in the current paper, 13/14 patients treated with bortezomib +/− HDM-ASCT achieved a haematological CR which translated into an organ response in two thirds of those patients. Cyclophosphamide-bortezomib-dexamethasone is generally considered as the regime of first choice for treatment of most patients AL amyloidosis. It offers a rapidly effective stem cell sparing regime. Dose reduction of bortezomib and/or steroids is needed in most patients with AL amyloidosis. Use of this regime in a risk adapted manner based on the severity of organ involvement allows safe use in most patients. Full dose twice weekly bortezomib is reserved for younger fitter patients with limited heart involvement while once weekly bortezomib is preferred in those with more advanced cardiac involvement. Alkylator based regimes like oral melphalan-dexamethasone have significantly inferior outcomes in good risk patients and time has come to move beyond these combinations.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> Patients with excellent performance status, limited organ involvement (≤2 organs involved), good renal function, no significant amyloid related bleeding and low cardiac biomarkers (NT-proBNP <5000ng/L and Troponin-T <0.06ng/ml) appear to have low risk of treatment related mortality with HDM-ASCT.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Patients achieving haematological CR with HDM-ASCT appear to have median survival over 10 years and excellent improvement in organ function – superior to any chemotherapy regime. HDM-ASCT is the treatment of choice in suitable patients.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Patients with 10% or more plasma cells in the bone marrow have poorer outcomes and more intensive treatment strategies including maintenance treatments will need to be explored.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Heart transplantation followed by highly effective chemotherapy or HDM-ASCT for clonal control after the heart transplant, as also reported in the current paper, achieves remarkable improvement in outcomes for highly selected patients with single organ cardiac involvement. Patients with advanced stage III disease account for about 15% of all cases and unfortunately, most patients with advanced stage III disease are not suited for such an approach. Novel agent base chemotherapy does not appear offer any survival advantages over and above standard therapy in majority of these patients.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> The remains a major unmet need in AL amyloidosis.Treatment directed at accelerating removal of the amyloid fibrils has been an area in intense research in many specialist laboratories and lately immunotherapy for amyloidosis is reaching the bedside. Our group has developed an approach of depleting the plasma of serum amyloid P component (SAP) – a universal plasma protein which is a component of all amyloid deposits – using a drug called CPHPC and then giving a monoclonal antibody to SAP targeting the SAP remaining the amyloid fibrils.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> It is remarkable effective in clearing AA amyloid deposits in a mouse model and is currently undergoing human phase I clinical trials. Two other phase I trials using antibodies that directly target amyloid fibrils are also ongoing in Unites States and Europe.Early diagnosis remains an important key in improving outcomes in AL. Screening of individuals at risk (such as those with a monoclonal gammopathy and raised FLC) using simple tests like urine dip stick for proteinuria and NT-proBNP every year may make a substantial difference. Progress in novel agents used for treating the plasma cell dyscrasias achieving a very deep haematological responses as well as approaches directed as direct removal of the amyloid fibrils promise to transform the treatment and outcomes in systemic AL amyloidosis." 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Revista Clínica Española

ISSN: 0014-2565

Revista Clínica Española, publicó su primer número en 1940 y es órgano de expresión de la Sociedad Española de Medicina Interna (SEMI).
La Revista hace suyos los objetivos de actualizar los conocimientos y facilitar la adquisición de los avances claves de la medicina interna aplicados a la clínica. Revista Clínica Española somete a una rigurosa revisión doble ciega los artículos que recibe en español o inglés. Publica 10 números al año fundamentalmente con originales, revisiones y documentos de consenso.

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Current Contents / Clinical Medicine , JCR / SCI-Expanded, Index Medicus / Medline y Excerpta Medica / EMBASE

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