ALBERT

Description: Localised AL (light chain) amyloidosis arises due to local formation and deposition of AL amyloid fibrils within a tissue. Little data exists as to the underlying aetiology, biological significance and natural progression of this disease. The primary objective of this study was to evaluate the incidence, clinical course, treatment outcomes and risk of progression to systemic disease. Methods This study included all patients with localised amyloidosis assessed at the UK National Amyloidosis centre between 1980 and 2011. Localised amyloidosis was defined as biopsy proven amyloid deposition confined to a single site without any evidence of vital organ involvement (including cardiac, renal, liver, peripheral or autonomic neuropathy) on detailed baseline assessment organ function and no visceral organ uptake on 123I serum amyloid P component (SAP) scintigraphy. Progression to systemic AL was defined as development of new vital organ involvement or dysfunction as by tests of organ function or SAP scintigraphy. Kaplan Meier curves were used to estimate the overall survival (OS); calculated from the start of diagnosis until death or last follow-up. Results Six hundred and six patients were diagnosed with localised amyloidosis, accounting for 12% of all newly diagnosed amyloidosis patients during this period at our Centre. The baseline characteristics are given in table 1. The median age was 59.5 years (range 48.8-68.6), 51% were male and median symptom duration was 7 months (range 4-24). All patients had biopsy proven amyloid deposition. Definitive light chain immunostaining for AL kappa or lambda was positive in only 15% while 52% had no immunostaining with antibodies to kappa, lambda, transthyretin or SAA. Three patients had ATTR on bladder biopsy (none with ATTR at other sites) and one with ApoA1 on laryngeal amyloidosis (with ApoA1 Ala164Ser mutation). The sites of localised amyloidosis included: bladder 94 (15%), lung 47 (7.7%), trachea-bronchial 35 (5.7%), larynx/vocal cords - 70 (11.6%), tonsil 4 (0.7%), conjunctiva 12 (2%), orbit 10 (1.7%), lymph nodes 31 (5.1%), GI tract 36 (6%), skin 54 (13.8%) and others. Presenting symptoms depended upon the tissue involved. A serum monoclonal protein was present in 12.5%, with an abnormal kappa/lambda ratio in 13.8%. Therapeutic options for localised disease include surgical procedures (36%), laser therapy (7%), steroids (2%), radiotherapy (2.8% predominantly for amyloidomas/symptom control) and chemotherapy (2.3%; treating amyloid symptoms/disease in 1%, treating co-existing multiple myeloma, lymphoplasmacytic lymphoma and MALT lymphoma in 1.3%). Some patients undergoing surgical procedures had recurrent local amyloid deposition needing repeated procedures. Only one patient out of 606 progressed to systemic AL amyloidosis. This patient presented with mediastinal LN involvement, progressed 5 years following diagnosis, with evidence of new uptake by 123I SAP scintigraphy localised within the spleen and bone marrow infiltration of 10% clonal plasma cells but no abnormal free light chain ratio or presence of a paraprotein. The majority of patients had other co-morbidities with the median age of death 74 years (range 66.5-80). There were no deaths due to progressive amyloidosis. The median follow up was 64 months. The median overall survival (OS) was 69.7 months (range 37.1-130.7) with 2 and 5 year OS 96% and 92% respectively figure 1. Conclusion The overall survival of localised AL amyloidosis is excellent and strikingly different from systemic AL amyloidosis. Treatment options are primarily directed locally to the amyloid deposit which is adequate in the majority, with less than satisfactory control and numerous procedures required in some patients, especially those with tracheobronchial amyloidosis, leading to a poor quality of life. Progression to systemic disease is an exceptionally rare occurrence even in presence of a detectable M-protein or abnormal light chain ratio. Disclosures: Bridoux: Janssen Cilag: Honoraria; Celgene: Honoraria; Celgene: Research Funding, Research support, Research support Other.

Description: Bortezomib based chemotherapy (especially cyclophosphamide-bortezomib-dexamethasone – CVD) has been increasingly adopted as front line therapy for treatment of patients with systemic AL amyloidosis. The phase II prospective study of single agent Bortezomib in relapsed setting, suggested both once weekly or biweekly Bortezomib are equally effective. Based on a risk adapted model, in the UK, weekly Bortezomib (usually as part of CVD) is often used to reduce toxicity and improve tolerability. We report the outcomes of 115 patients diagnosed with systemic AL amyloidosis at the National Amyloidosis centre between 2010-2012 followed up prospectively as a part of the ALChemy observational study and received Bortezomib based first line therapy either on biweekly or weekly regimens. 75% of these patients had cardiac involvement and 73% renal involvement. Haematological response and survival were analysed in the context of Bortezomib regimen used. Further analysis was also performed in patients matched for cardiac staging. 79% patients received CVD regime and 82% had Dexamethasone with their Bortezomib. Response and survival data was available on all 115 patients; 3 patients lacking dosing details were excluded from the dosing analysis. 89% had measurable disease for response assessment analysis. 63% patients had once and 37% had twice weekly Bortezomib. 74% of patient received their Bortezomib intravenously and 26% subcutaneously. 17% of patients had only received a maximum of 1 cycle of which 58% (10% of total cohort) had died within 4 weeks of commencing chemotherapy. On an intention to treat analysis, haematological response was achieved in 59% of weekly and 72% receiving biweekly regimes - 45% achieved a VGPR or better (38% of weekly and 58% of biweekly patients, fisher’s exact p=0.061). 94% responses were achieved within the first three cycles (57% of the weekly and 64% of the biweekly) - 25% responders (14% of weekly and 19% of biweekly) had achieved their best response by end of cycle 1 and 67% ( 44% of weekly and 39% of biweekly) by cycle 2 and 94% (57% weekly and 64% biweekly) by cycle 3 (Figure1). Median OS for patients treated with Bortezomib was 73.5months. The 2 year survival rate for patients achieving a VRPR or better, PR or NR are 87%, 64% and 31% respectively. Median OS for the group treated on a weekly regimen was 27.2 months and those treated biweekly was not reached (p=0.020), (figure 2). The 2 and 4 year survival is 59%, 47% for weekly treated and 77% (both), for biweekly treated groups respectively. For patients who were matched for mayo cardiac stage (n=38 in each group), the median OS was not reached in either group. The overall survival was superior in the group receiving the biweekly regimen with survival at 2 and 4 years of 78% (both) compared to 72% and 55% in the weekly group. In the matched group, patients with Mayo stage 3 disease (n=15 in each group) had not reached their median OS when receiving biweekly regimen but those who received weekly regimen had a median OS of 27.2 months (p=0.574). On a multivariate analysis, NT-proBNP 〉8500ng/L remained the only statistically significant prognostic factor. In summary, patients treated with biweekly Bortezomib regimen appear to have a 20% higher rate of achieving a VGPR or better and have a superior overall survival compared to those treated on the less intensive weekly regimen. Better criteria for patient selection are needed to allow more patients to receive Bortezomib on the more potent biweekly regimen at least for the first three cycles to achieve a rapid deep clonal response. Disclosures: Wechalekar: Jansen Cilag: Honoraria.

Description: Abstract 3958 Schnitzler syndrome is a rare acquired autoinflammatory disease characterized by relapsing urticarial rashes, periodic fevers, arthralgias, lymphadenopathy and IgM paraproteinaemia, which can be very low level. Fewer than 100 patients have been reported and in general chemotherapy directed at the B cell clone has not been effective in controlling the inflammatory symptoms. We describe our series of six patients, their phenotype and response to treatment. The median age at symptom onset was 55.6 years (range 52.8–78.9 years) and 4 of the patients were male. All patients presented with rash, recurrent fever, constitutional upset with appetite loss, fatigue and myalgia. The rash was urticarial in appearance but non itchy and on biopsy demonstrated a marked neutrophil infiltrate. Three patients had intermittent lymphadenopathy and one disabling bone pain. An IgM paraprotein was detected in all cases, median 7g/L (range: detected on immunofixation only – 8g/L). The IgM paraprotein was kappa in 5 cases and only one patient had abnormal serum free light chains. The Hevylite™ assay was abnormal in all 4 cases in whom the test was performed. Of note the patient with an IgM lambda paraprotein detected only on immunofixation has a clear IgM lambda excess on Hevylite™ assay. Baseline bone marrow demonstrated significant abnormalities in three patients: one has a 10% infiltrate of clonal cells consistent with lymphoplasmacytic lymphoma, one demonstrated a myeloproliferative picture with dysplastic features but no obvious plasma or lymphoid infiltrate and one was reported as reactive. Three patients had been treated with broad spectrum immunosupression without benefit and all had had corticosteroids with only partial benefit. In all cases treatment with anakinra (recombinant IL-1 receptor antagonist) as monotherapy produced a complete clinical response with normalisation of inflammatory markers. The median duration of treatment has been 9 months (range 0.1–2.7 years) and no patients have lost their response to daily ankinra injections. Median follow up from presentation has been 7.1 years with no evidence of evolution of overt lymphoproliferative disease nor change in the paraprotein concentration. In conclusion Schnitzler's syndrome is a rare acquired autoinflammatory disease which can be very effectively treated by anakinra suggesting that IL-1 is central to its pathogenesis. Treatment does not appear to have had any direct effect on clonal markers and the role of the IgM paraprotein in this disease remains unclear. Disclosures: Off Label Use: Anakinra - IL-1 receptor blockade, used off licence in Schniztlers syndrome.

Description: Abstract 2978 Background: Novel agents have emerged as important therapeutic options for plasma cell dyscrasias and consequently have been adopted into treatment strategies for Systemic AL amyloidosis. Several studies to date have shown the efficacy of immunomodulatory drugs (IMiD) in this disease. However, little data exists exploring the efficacy of these agents especially in the context of previous treatment lines. The primary objective of this study was to evaluate the response, OS and PFS in patients treated with lenalidomide regimens in the relapsed setting. Further analysis was carried out examining outcomes based on previous lines of therapy. The importance of continuous therapy for control of the clonal disease stable disease was also examined. Patients and Methods: Our primary cohort consisted of 66 AL amyloidosis patients who presented to our Centre between July 2007 and July 2012, identified from the database of the UK National Amyloidosis Centre, commencing a lenalidomide regimen in the relapsed setting. It was recommended that treatment continue until disease progression or unacceptable toxicity. Organ involvement and haematological and organ response were defined according to the 2010 consensus criteria. Overall survival (OS) was calculated from the start of lenalidomide treatment until death or last follow-up. Progression-free survival (PFS) was calculated from the start of lenalidomide treatment until relapse, death or last follow-up. Survival endpoints were examined based on previous lines of treatment. A subgroup analysis was carried out in those attaining at least stable disease to examine the impact of continuous therapy. In this cohort PFS was examined based on those remaining on continuous therapy versus those discontinuing treatment due to intolerance or patient preference. Results: The median age was 59.1 years (range 39.9–76.9) and 52% were male. A lambda clonal plasma cell dyscrasia was present in 62%. 44% had ≥ 3 organ involvement with 50% having cardiac involvement by echo criteria. Mayo cardiac staging (at diagnosis) was stage I, II and III in 30%, 62% and 8% respectively. The median number of previous treatment lines was 2 (range 1–5), with thalidomide and bortezomib pre-treatment in 80% and 68% respectively. Grade 3 toxicity was seen in 27% of patients and was mainly haematologic. A thrombotic complication was noted in 1 patient. On an intention-to-treat basis, 56% achieved a haematological response with a complete response in 11%. A dFLC response was observed in 57% and 26% achieved a dFLC-VGPR or better. The median follow-up of 12.4 months. The median OS was 46.3 months and the estimated 2-year PFS was 67% (figure 1). Compared to those who did not receive the drug, previous exposure to thalidomide did not confer a worse survival outcome (estimated 2-year OS 67% vs 67%, p = 0.59). Similarly, previous exposure to Bortezomib did not confer a worse survival (estimated 2-year OS OS 88% vs 79%, p=0.09). 58 patients (88%) achieved stable disease or better. In this subgroup, the median duration on lenalidomide was 17.2 months. The 2-year OS and PFS were 84% and 78% respectively. Compared to those who halted therapy, continuous treatment with lenalidomide correlated with an improved PFS (estimated 2-year PFS 62% vs 80% respectively, p = 0.02). Conclusion: This data further supports the effectiveness of lenalidomide containing regimens in the treatment of relapsed AL amyloidosis. Previous lines of therapy did not negatively impact survival outcomes. Continuous therapy is important in maximizing the duration of the clonal response. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Systemic light chain amyloidosis (AL) is characterized by the deposition of immunoglobulin light chains as amyloid fibrils in different organs, where they form toxic protein aggregates. The underlying disease is a plasma cell disorder, likely a monoclonal gammopathy, but limited data are available on the biology of the plasma cell clone underlying AL and existing studies have concentrated on chromosomal abnormalities. We report the final findings of the first exome sequencing to define the plasma cell signature in AL and compared this to other mature lymphoid malignancies. Methods: Whole exome sequencing was performed on 27 newly diagnosed, histologically proven amyloidosis patients. DNA was extracted from peripheral blood and CD138+ plasma cells and whole exome sequencing was performed using SureSelect (Agilent). In addition to capturing the exome, extra baits were added covering the IGH, IGK, IGL and MYC loci in order to determine the breakpoints associated with translocations in these genes. Tumour and germline DNA were sequenced and data processed to generate copy number, acquired variants and translocation breakpoints in the tumour. Patient demographics: The median age at diagnosis was 69 (range: 41-81) years old. All cases were histologically proven, newly diagnosed AL amyloid. 74% were lambda restricted and 26% kappa with median respective median involved sFLC were 180 mg/L (range: 58.9-986 mg/L) and 730 mg/L (609-3190 mg/L) respectively. The median plasmocytosis was 17.5% (range: 2-90%). 78% of them had evidence of heart involvement, 70% had renal involvement and 33% had liver involvement. Mutation load: The median number of acquired non-synonymous variants per sample was 65 (range 7-285) with 40 (4-251) potentially disease causing variants per sample. Mutational landscape: Although no genes were significantly mutated, the genes closest to significance were NRAS, PIM1, and HIST1H3F. We identified 2 cases with NRAS mutations in the codon 61 (Q61R and Q61H) but no KRAS mutations were seen. Interestingly, there were mutations in some of the significantly mutated genes in myeloma such as EGR1 (Q95R), DIS3 (M505L and D317E) and TRAF3 (splice site). One patient bore a CARD11 (R1077W) mutation, more commonly seen in non-Hodgkin’s lymphoma. Although 22% of our samples had a t(11;14) translocations we did not observe any mutations in CCND1. We identified a t(1;14) (p36;q32) previously described in non-hodgkin lymphoma in one patient. We also identified a Myc translocation in a patient who met the criteria for smouldering myeloma. As previously described in myeloma, both DIS3 mutants occurred in patients with a del(13q). Finally, there was no APOBEC signature in our small samples cohort butwe identified an unspecific mutational signature that was related to age. When comparing the spectrum of mutated genes in both amyloidosis (n=27) and previously sequenced myeloma samples (n=463), we identified 948 genes in common between myeloma and amyloidosis. Four hundred and forty two genes were only mutated in amyloidosis most of them being in housekeeping genes. The clustering of the most frequent and significantly mutated genes in each B-cell malignancy, suggests amyloidosis resembles myeloma and MGUS more than other B-cell malignancies. Discussion: The mutational landscape of amyloidosis resembles myeloma with no disease defining mutations but a variety of mutations occurring in different pathways such as RAS and NF-kB. Two samples had an NRAS mutation, which is a known driver mutation also found in MM. We identified a non-canonical IgH translocation that is a rare event in myeloma. There was little overlap in mutated genes indicating a diverse spectrum of mutations, which is in common with MM. Given the diverse mutational spectrum it will be necessary to study a large cohort to fully understand the genetic complexity of the disease. Conclusion: We conclude that exome sequencing identifies a genetic signature of AL amyloidosis which is similar to other plasma cell disorders in terms of translocations and non-synonymous mutations. Disclosures Walker: Onyx Pharmaceuticals: Consultancy, Honoraria.

Description: Background: Light chain deposition disease (LCDD) is a systemic disorder characterized by monoclonal light chain deposition in organs, most often the kidney but also in the liver, heart and nervous system. Treatment aims to suppress the monoclonal plasma cell population producing the light chains to allow for improvement in or delay deterioration of organ function. Treatments are generally modeled on those for myeloma and light chain amyloidosis. The options are cyclical chemotherapy lately using a novel agent based conditioning regime and, in selected patients, high dose melphalan followed by autologous stem cell transplantation. Due to LCDD being an immunoglobulin disease, based on experience with systemic AL amyloidosis, there is a reluctance to consider ASCT due perceived risks of morbidity and transplant related mortality. There is limited data on the safety and outcomes after ASCT in LCDD. We report here the role of autologous stem cell transplantation to treat LCDD in the largest cohort of patients to date. Methods: This study included all patients between 2003 and 2013 with LCDD who had undergone ASCT from the database of the UK National Amyloidosis Centre (NAC). Data on disease status (clonal markers and organ involvement) at diagnosis, pre and post ASCT was collected from the respective transplant centres for patient progress during and immediately after ASCT. Organ function and clonal response data were serially collected for all patients including clinical course, renal, cardiac and neurological function. Results: A total of ten patients with LCDD were identified who underwent ASCT. This accounted for 23% of all LCDD patients seen at the NAC over this time period. The baseline characteristics were: median age 48 (range 36-60), eGFR 17 ml/min (10% (median 15; range 12-50%) and 5/10 ,

Description: Background: Systemic AL amyloidosis is a rare complication of plasma cell dyscrasias. Much progress has occurred in treatment of AL amyloidosis but long term survival remains limited with advanced organ involvement, in particular, cardiac dysfunction determining outcomes. However, controlling the underlying plasma cell clone with chemotherapy or ASCT is the key to improving outcomes. Yet the role of plasma cell clones in determining prognosis remains to be fully explored and understood. The plasma cell burden in patient with AL amyloidosis is generally lower than that of multiple myeloma but reported degree of plasma cell infiltration has varied. A large study from the Mayo group reported markedly poor outcomes for patients with AL amyloidosis who have 〉10% BMPCs, even in the absence of symptomatic myeloma (Kourelis et al, JCO 2013). However, apart from just the number of BMPC, the composition appears to be of importance. Multiparameter flow cytometry (MFC) can identify proportion of normal and clonal plasma cells. Patients with 〉5% normal BMPC (defined as cells expressing CD38+CD138+CD19+) at diagnosis had a better prognosis (Paiva et al. Blood 2011). MFC underestimates the total proportion of BMPCs due to sample dilution effect. We report the impact of normal' plasma cells, as determined by MFC, on the outcome of AL patients in context of the total plasma cell burden as determined by standard morphological techniques in 104 patients with biopsy proven systemic AL amyloidosis, who had both bone marrow trephine and MFC performed at presentation between 2005-2013 assessed at UK National amyloidosis centre and St James's University Hospital. Methods: The bone marrow trephine biopsy (BMTB) plasma cell burden was estimated by morphology supplemented by CD138 immunohistochemistry as required. Patients with 〉10% CD138+ cells were classified as having AL-multiple myeloma (AL-MM) and those with 10% CD138+ PCs on trephine (classed as AL-MM) and 42 (40%) had

Description: Key PointsDeep clonal responses improve outcomes and can change the natural history of advanced (cardiac stage III) AL amyloidosis. NT-proBNP 〉8500 ng/L and SBP