Jh Pinney

Solid organ transplantation in AL amyloidosis.

Vital organ failure remains common in AL amyloidosis. Solid organ transplantation is contentious because of the multisystem nature of this disease and risk of recurrence in the graft. We report outcome among all AL patients evaluated at the UK National Amyloidosis Centre who received solid organ transplants between 1984 and 2009. Renal, cardiac and liver transplants were performed in 22, 14 and 9 patients respectively, representing <2% of all AL patients assessed during the period. One and 5‐year patient survival was 95% and 67% among kidney recipients, 86% and 45% among heart recipients and 33% and 22% among liver recipients. No renal graft failed due to recurrent amyloid during median (range) follow up of 4.8 (0.2–13.3) years. Median patient survival was 9.7 years among 8/14 cardiac transplant recipients who underwent subsequent stem cell transplantation (SCT) and 3.4 years in six patients who did not undergo SCT (p = 0.01). Amyloid was widespread in all liver transplant recipients. Solid organ transplantation has rarely been performed in AL amyloidosis, but these findings demonstrate feasibility and support a role in selected patients.

A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis

Despite improvements in therapy amyloid light-chain (AL) amyloidosis, there are few studies comparing different regimens. Here we present a matched comparison with 69 patients in each cohort examining upfront therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) vs cyclophosphamide, thalidomide and dexamethasone (CTD). On an intention-to-treat basis, the overall response rates were 71.0% vs 79.7% in the CVD and CTD arms, respectively, (P=0.32). A higher complete response (CR) rate was observed in the CVD arm (40.5%) vs CTD (24.6%), P=0.046. One-year overall survival (OS) was 65.2% and 66.7% for CVD and CTD, respectively (P=0.87). The median progression-free survival (PFS) was 28.0 and 14.0 m for CVD and CTD, respectively (P=0.039). In a landmark analysis assessing outcomes performed at 6 months, the CR rate with CVD was 59.6% vs 34.0% for CTD (P=0.03). The 1-year OS was 96% with CVD and 92% with CTD (P=0.40). The median PFS with CVD was not reached and was 19.2 m with CTD, P=0.028). In summary, both regimens are unable to overcome the high rate of early deaths in AL amyloidosis. However, CVD correlates with improved depth of response and superior PFS supporting its use in the frontline setting. Further optimisation and better supportive-care strategies are required to increase the proportion of patients fully benefiting from therapy.

Renal Transplantation in Systemic Amyloidosis—Importance of Amyloid Fibril Type and Precursor Protein Abundance

Renal transplantation remains contentious in patients with systemic amyloidosis due to the risk of graft loss from recurrent amyloid and progressive disease. Outcomes were sought among all patients attending the UK National Amyloidosis Centre who received a renal transplant (RTx) between January 1978 and May 2011. A total of 111 RTx were performed in 104 patients. Eighty‐nine percent of patients with end‐stage renal disease (ESRD) due to hereditary lysozyme and apolipoprotein A‐I amyloidosis received a RTx. Outcomes following RTx were generally excellent in these diseases, reflecting their slow natural history; median graft survival was 13.1 years. Only 20% of patients with ESRD due to AA, AL and fibrinogen amyloidosis received a RTx. Median graft survival was 10.3, 5.8 and 7.3 years in these diseases respectively, and outcomes were influenced by fibril precursor protein supply. Patient survival in AL amyloidosis was 8.9 years among those who had achieved at least a partial clonal response compared to 5.2 years among those who had no response (p = 0.02). Post‐RTx chemotherapy was administered successfully to four AL patients. RTx outcome is influenced by amyloid type. Suppression of the fibril precursor protein is desirable in the amyloidoses that have a rapid natural history.

Hereditary lysozyme amyloidosis – phenotypic heterogeneity and the role of solid organ transplantation

Abstract.  Sattianayagam PT, Gibbs SDJ, Rowczenio D, Pinney JH, Wechalekar AD, Gilbertson JA, Hawkins PN, Lachmann HJ, Gillmore JD (University College London Medical School, London, UK). Hereditary lysozyme amyloidosis – phenotypic heterogeneity and the role of solid organ transplantation. J Intern Med 2012; 272: 36–44.

Lenalidomide and dexamethasone for systemic AL amyloidosis following prior treatment with thalidomide or bortezomib regimens.

The outcomes and responses to treatment remain poorly studied among patients with systemic AL amyloidosis who require further treatment following prior novel agent‐based therapy. We report here treatment with lenalidomide‐dexamethasone in 84 AL amyloidosis patients with relapsed/refractory clonal disease following prior treatment with thalidomide (76%) and/or bortezomib (68%). On an intention‐to‐treat (ITT) basis, the overall haematological response rate was 61%, including 20% complete responses. The median overall survival (OS) has not been reached; 2‐year OS and progression‐free survival (PFS) was 84% and 73%, respectively. Achieving a free light chain (FLC) response was an independent good prognostic factor for OS in multivariate analysis. There was no impact of prior thalidomide or bortezomib therapy on response rate, OS or PFS. 16% achieved an organ response at 6 months, with a marked improvement in organ responses in patients on long term therapy (median duration 11 months) and 55% achieving renal responses by 18 months. Lenalidomide/dexamethasone therapy achieves good haematological responses in patients with AL amyloidosis with relapsed/refractory clonal disease. The rate of renal responses among patients who received prolonged treatment was unexpectedly high, raising the possibility that immunomodulatory effects of lenalidomide therapy might enhance the otherwise slow natural regression of amyloid deposits.

OR14-001 – Tocilizumab in autoinflammation and AA amyloidosis

The value of IL-6 blockade has been established in rheumatoid arthritis (RA) and systemic onset juvenile idiopathic arthritis (SOJIA), but its wider utility in patients with AA amyloidosis and autoinflammatory diseases has been little studied.

THU0379 A 20 year single centre experience of aa amyloidosis demonstrating changes in its epidemiology

Background AA amyloidosis is the most serious potential complication of chronic inflammation and can result in renal failure and death. It is seen much less often in the USA than in Europe and is thought to have become less common in the developed world in general but there are few systematic data on its incidence and epidemiology. Objectives To analyze a single national centre experience of AA amyloidosis in the United Kingdom over the past 20 years. Methods Analysis of the UK National Amyloidosis Centres database and case records. Results 493 patients with confirmed AA amyloidosis were assessed at the UK National Amyloidosis Centre between 1992 and 2011. The referral rate has been stable at ∼30 new cases/yr over the past 12 yrs, in contrast with a three-fold increase among other types of amyloidosis. Median age at referral was 55 years, 54% were male and 81% of cases were ethnically white. The commonest underlying diseases are: rheumatoid arthritis (RA) 28%, chronic sepsis 19% and seronegative arthritis 10%, but in 18% the underlying inflammatory disease was uncharacterized at diagnosis. Comparing the cohort referred 1992-96 with the most recent 5 years, there has been a reduction in patients with RA from 33% to 19% (p 0.038), and juvenile idiopathic arthritis from 18% to 2% (p<0.001), but a rise in AA amyloidosis of unknown aetiology from 8% to 28% (p<0.001). Age at referral has risen from a median of 48 to 61 years (p<0.001), and the proportion referred with established end-stage renal failure (ESRF) has remained stable at 26%. Median time to ESRF in cases presenting with an eGFR>20 ml/min is unchanged at 157 months. Median survival is 118 months with no significant difference between cohorts, but age at death has increased from a median of 60.6 yrs in the earliest cohort to 79 in the most recent (p<0.001). Conclusions In contrast to a threefold increase in referrals of other types of amyloidosis during the past decade, referral rates for AA have not changed. Age at both diagnosis and death have increased significantly over the last 20 years. The incidence of AA amyloidosis among patients with inflammatory arthritis has decreased, perhaps reflecting greater use of biologic agents and a greater proportion of recent AA patients have uncharacterized underlying inflammatory disorders, posing challenges for clinical management. Disclosure of Interest None Declared

INCREMENTAL VALUE OF CMR FOR THE DIAGNOSIS OF CARDIAC INVOLVEMENT IN PATIENTS WITH END STAGE RENAL FAILURE AND SYSTEMIC AMYLOIDOSIS

Background: Cardiac involvement may occur in up to 50% of patients with amyloidosis and portends an adverse prognosis. Non-invasive diagnosis, particularly in the setting of chronic renal failure (CRF), remains imprecise due echocardiographic changes from concomitant pathology. CMR with typical late gadolinium enhancement (LGE) is a highly speciic method for diagnosis of cardiac amyloidosis in patients without CRF. Although nephrogenic systemic ibrosis (NSF) has been reported in patients with CRF after gadolinium, the incidence is rare. We sought to determine the incremental diagnostic value of LGE CMR in patients with systemic amyloidosis/light chain deposition disease (LCDD) and CRF in whom echocardiography and clinical signs were equivocal.