Papers by Julian Gillmore
Rheumatology, May 5, 2016
Objective. This study was undertaken to characterize the phenotype and response to treatment in p... more Objective. This study was undertaken to characterize the phenotype and response to treatment in patients with autosomal dominant FMF caused by MEFV p.M694del mutation and to use haplotype reconstruction to investigate the possibility of common ancestry. Methods. MEFV gene was analysed in 3500 subjects with suspected FMF referred to a single UK centre between 2002 and 2014. Patients with p.M694del underwent additional screening of the SAA1 gene as well as haplotype reconstruction of the MEFV locus. Results. The p.M694del variant was identified in 21 patients, sharing an identical disease haplotype that appears to have arisen about 550 years ago. The SAA1.1 allele was found in four patients, including two with AA amyloidosis. The clinical features comprised typical FMF symptoms with median age at onset of 18 years; three patients presented with AA amyloidosis, of whom two had had symptoms of FMF in retrospect. Fifteen patients had received colchicine treatment, all with excellent responses. Conclusion. The p.M694del variant is associated with autosomal dominantly inherited FMF in Northern European Caucasians. Symptoms may develop later in life than in classical recessive FMF but are otherwise similar, as is the response to colchicine treatment. The 14% incidence of AA amyloidosis may reflect delay in diagnosis associated with extreme rarity of FMF in this population. The common haplotype suggests a single founder living in about 1460.
Bortezomib has shown great promise in the treatment of amyloid light-chain (AL) amyloidosis. We p... more Bortezomib has shown great promise in the treatment of amyloid light-chain (AL) amyloidosis. We present our experience of 43 patients with AL amyloidosis who received cyclophosphamide, bortezomib, and dexamethasone (CVD) upfront or at relapse. Of these, 74% had cardiac involvement and 46% were Mayo Cardiac Stage III. The overall hematologic response rate was 81.4%, including com-plete response (CR) in 41.9% and very good partial response with > 90% decrease in difference between involved/ uninvolved light chain (VGPR-dFLC) in 51.4%. Patients treated upfront had higher rates of CR (65.0%) and VGPR-dFLC (66.7%). The estimated 2-year progressionfree survival was 66.5% for patients treated upfront and 41.4% for relapsed patients. Those attaining a CR or VGPR-dFLC had a significantly better progression-free survival (P ؍ .002 and P ؍ .026, respectively). The estimated 2-year overall survival was 97.7% (94.4% in Mayo Stage III patients). CVD is a highly effective regimen producing durable responses in AL amyloidosis; the deep clonal responses may overcome poor prognosis in advanced-stage disease. (Blood. 2012;119(19):4387-4390)
European Heart Journal, Jan 17, 2020
Pediatric Rheumatology, Sep 28, 2015
European Heart Journal, Oct 1, 2022
British Journal of Haematology
SummaryThis study reports health‐related quality of life (HRQL) among newly‐diagnosed immunoglobu... more SummaryThis study reports health‐related quality of life (HRQL) among newly‐diagnosed immunoglobulin light‐chain (AL) patients (n = 914) treated with a bortezomib‐based regimen and its association with response depth and survival. Haematologic response/HRQL were assessed over 24 months in an ongoing, prospective study. HRQL change was calculated across haematologic/cardiac response levels. The relationship between baseline HRQL and survival was evaluated by the Cox proportional‐hazard model (PH). Shared‐random‐effects models (SREMs) estimated time‐to‐death conditional on current HRQL/longitudinal HRQL trajectory. At 3 months, there was consistent decline in 5/8 HRQL domains across all haematologic response levels. By 12 months, 3/5 declining domains improved among complete response (CR) patients. In contrast, the mean change in less‐than‐CR patients did not indicate improvement. Under the Cox PH, having a baseline HRQL score five points higher than the sample mean was associated wit...
American Journal of Hematology
British Journal of Haematology
SummaryDepth of response is the critical determinant of prognosis in amyloid light‐chain (AL) amy... more SummaryDepth of response is the critical determinant of prognosis in amyloid light‐chain (AL) amyloidosis. Here, we aim to identify patients who are unlikely to improve response based on analysis of baseline characteristics and 1‐month response. In a multivariate model, difference in involved amyloidogenic and uninvolved serum free light chains (dFLC) at diagnosis (dFLC >400 mg/l, odds ratio [OR] 4.051, p < 0.005) and no response at 1 month (OR 4.787, p < 0.005) were significant predictors of no improvement in response. Only 5% of patients with a dFLC of >400 mg/l and no response at 1 month improved their response (p < 0.005). We suggest that these patients should switch treatment early, subject to their functional status.
Circulation, 2014
Introduction: Cardiac transthyretin (ATTR) amyloidosis is an increasingly diagnosed cause of hear... more Introduction: Cardiac transthyretin (ATTR) amyloidosis is an increasingly diagnosed cause of heart failure. Wild-type ATTR amyloidosis (ATTRwt) is a disease of older Caucasian men. Hereditary (mutant) cardiac ATTR amyloidosis (ATTRm) is most commonly associated with the V122I transthyretin (TTR) variant carried by 3-4% of African Americans or the T60A TTR variant in patients of Irish ancestry, the latter presenting with a mixed cardiac and neurologic phenotype. Most published data consider electrocardiographic (ECG) findings in ATTR amyloidosis as a single entity. Prognostic factors for survival in cardiac ATTR amyloidosis are poorly defined. Methods and Results: We analysed ECGs from 158 patients with cardiac ATTR amyloidosis (ATTRwt=75; V122I=49; T60A=34) in a longitudinal retrospective study. Results are shown in Table 1. 63 patients died; 29 ATTRwt, 24 V122I, 10 T60A, during follow-up of 22.7±14.6, 23.8±12.8, and 31.3±20.4 months respectively. Overall median survival: ATTRwt 3.1...
Circulation, 2014
Introduction: Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement technique ... more Introduction: Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement technique (LGE) is a candidate reference standard for non invasive diagnosis of light chain and transthyretin cardiac amyloidosis (AL, ATTR). However, conflicting results on morphology and LGE have been reported in small retrospective studies. Hypothesis: that morphology and LGE can guide differential diagnosis and predict survival in AL and ATTR amyloidosis. Methods: 242 patients were recruited: 116 with AL, 126 with ATTR (8 of which were mutations carriers). All subjects underwent CMR with standard cine imaging, LGE (with and without phase sensitive inversion recovery, PSIR) and T1 mapping with Extracellular Volume (ECV) measurement. Results: Compared to AL, ATTR had more LVH, more asymmetry, more LV impairment and more RVH. Using the ECV as truth standard, in 43% initial non-PSIR had incorrect initial regional or global nulling with the highest ECV myocardium displayed as nulled. PSIR always di...
Blood, 2020
Background: Cardiac involvement is the major determinant of prognosis in systemic AL amyloidosis.... more Background: Cardiac involvement is the major determinant of prognosis in systemic AL amyloidosis. The extent is assessed by cardiac biomarker-based staging system using N-terminal pro-brain natriuretic peptide (NT-proBNP) and Troponin T. Longitudinal strain evaluates the global and regional function of the left ventricle (LV) and may be preferable to both LV ejection fraction and NT-proBNP, which is limited by its sensitivity to changes in fluid balance, in determining prognosis. This is the first report of a large cohort of uniformly treated prospectively followed patients assessing the utility of changes in longitudinal function by 2-D strain (LS%), impairment of which is a hallmark of amyloidosis. Methods: 915 newly diagnosed patients seen at the UK National Amyloidosis Centre (February 2010 - August 2017) were studied. All patients underwent comprehensive assessments including echo-cardiogram at baseline and each follow up visit. Results: 628/915 (68.6%) patients had cardiac inv...
Blood, 2007
Cardiac involvement in AL amyloidosis is associated with a poor prognosis and greatly increased t... more Cardiac involvement in AL amyloidosis is associated with a poor prognosis and greatly increased treatment related morbidity and mortality, and regression of cardiac amyloid deposits is extraordinarily slow following chemotherapy that suppresses the underlying aberrant light chain production. Diagnosis of cardiac amyloidosis is normally made by echocardiography, by which time significant diastolic dysfunction has usually developed. Atrial natriuretic peptides (ANP, BNP and its N-terminal fragment NT-ProBNP) are useful in early diagnosis of myocardial dysfunction. Serum NT-ProBNP concentration has been reported to be a promising marker of cardiac dysfunction in AL amyloidosis, and patients with normal NT-ProBNP values at diagnosis have superior outcomes. We report here the outcome of patients attending the UK National Amyloidosis Centre (NAC) who had elevated NT-ProBNP at diagnosis of AL amyloidosis but who did not have accompanying evidence of cardiac involvement using conventional c...
Blood, 2005
Kidneys are the commonest site of amyloid deposition in AL amyloidosis (AL) and many patients pre... more Kidneys are the commonest site of amyloid deposition in AL amyloidosis (AL) and many patients present in advanced renal failure. Successful treatment of the underlying plasma cell dyscrasia may not prevent development of end stage renal failure and dialysis dependence. Even in the presence of good clonal response the prognosis of these patients on dialysis is poor with mortality being 3 times that for patients with diabetes (UK renal registry data 2003). Renal transplantation is controversial due to the systemic and progressive nature of AL amyloidosis. We report the experience with renal transplantation in 16 patients with AL seen at the National Amyloidosis Centre UK between 1986 and 2000. All patients had histologically proven amyloidosis with an underlying plasma cell dycrasia. None of the patients had extra-renal organ dysfunction. Median age at diagnosis of AL was 64 years (range 49–74) with 3 males and 13 females. 15 (93%) had monoclonal gammopathy as the underlying clonal di...
Blood, 2011
992 Background: There have been few prospective clinical trials in AL amyloidosis; existing prosp... more 992 Background: There have been few prospective clinical trials in AL amyloidosis; existing prospective studies in this heterogeneous disease have been hampered by small patient numbers due to rarity of the condition, a lack of validated endpoints and high cost. More importantly, they have been subject to considerable bias due to almost complete exclusion of poor prognosis patients. Aims: The aims of this prospective observational study, was to include all patients with systemic AL amyloidosis regardless of age or disease severity, in order to convey a ‘real-world' picture of the disease, its response to myeloma-type chemotherapy regimens, associated toxicity and outcomes in terms of amyloidotic organ function, quality of life (QoL) and survival. Methods: All patients referred to the UK National Amyloidosis Centre (NAC) from 1st September 2009 were screened for participation in the AL chemotherapy study (ALchemy). Patients were eligible if they were newly diagnosed with systemic...
Blood, 2015
A PROSPECTIVE STUDY OF TREATMENT OUTCOMES IN 179 PATIENTS WITH ADVANCED CARDIAC STAGE IIIB AMYLOI... more A PROSPECTIVE STUDY OF TREATMENT OUTCOMES IN 179 PATIENTS WITH ADVANCED CARDIAC STAGE IIIB AMYLOIDOSIS Authors: Belen Sevillano, Darren Foard, Carol Whelan, Mariana Fontana, Critina Quarta, Shameem Mahmood, Helen Lachmann, Julian Gillmore, Philip Hawkins and Ashutosh Wechalekar INTRODUCTION The prognosis of systemic light chain amyloidosis is determined by extent of cardiac involvement. The Mayo cardiac staging system (Dispenzieri et al JCO 2004) is widely used for prognosis and we defined a particularly poor prognostic subgroup within Mayo stage III patients (Wechalekar et al Blood, 121(17), 2013) characterized by NT-proBNP…
Blood, 2014
Introduction: Systemic light chain amyloidosis (AL) is characterized by the deposition of immunog... more 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 tran...
Blood, 2007
AL amyloidosis has a poor outcome. Survival of only about one year was frequently reported in stu... more AL amyloidosis has a poor outcome. Survival of only about one year was frequently reported in studies performed in the 1990s, and the diagnosis of AL amyloidosis continues to be widely regarded as incompatible with long term survival. We report here the features of patients with AL amyloidosis followed up at the UK Amyloidosis centre (NAC) for more than 10 years, who encouragingly represented more than 10% of all cases. All patients with AL amyloidosis who first attended the NAC between 1979–1997 and subsequently survived for more than 10 years were included in this study. AL type amyloidosis was confirmed in all patients histologically with genetic studies to robustly exclude hereditary amyloidosis as indicated. Organ involvement and responses were defined as per the international consensus criteria (Gertz et al 2005). I123 serum amyloid P (SAP) scintigraphy was used to identify additional organ involvement and monitor amyloid load. 361 patients with AL amyloidosis were assessed at...
Blood, 2014
Background: Systemic AL amyloidosis is a rare complication of plasma cell dyscrasias. Much progre... more 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 proportio...
Blood, 2012
4074 AL amyloidosis is caused deposition of monoclonal immunoglobulin light chain and is associat... more 4074 AL amyloidosis is caused deposition of monoclonal immunoglobulin light chain and is associated with IgM-paraproteinemia in 5% of cases – mostly due to underlying Waldenstrom's macroglobulinaemia. The standard treatments for AL amyloidosis are typically regimes derived from multiple myeloma and are inappropriate in this group of patients. Response to alkylating agents is poor and there is no agreed standard treatment. We describe here the treatment and outcome of 297 patients with IgM-related AL amyloidosis, with particular focus on the impact of outcomes when treated with regimes developed specifically for Waldenstrom's macroglobulinaemia. 267 consecutive IgM patients with AL amyloidosis were identified form the databases of amyloidosis groups based in London, UK, Pavia, Italy and Limonges/Tolouse/Paris, France- evaluated between 1988 and 2011. 64% of patients had underlying lymphoma mainly of lymphoplasmocytic subtype; lymph node amyloid was present in 18%. Commonest o...
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Papers by Julian Gillmore