[Show abstract][Hide abstract] ABSTRACT: Abstract We report on a 58-year-old man who presented with simultaneous kappa-restricted chronic lymphocytic leukemia (CLL) and a lambda-restricted plasma cell dyscrasia causing AL amyloidosis involving the kidney and GI tract. While monoclonal immunoglobulins occasionally produced by CLL has previously been implicated in AL amyloidosis, this is the first case of AL amyloidosis resulting from a distinct plasma cell dyscrasia that is not clonally related to the concurrent CLL. Appropriate treatment depended on detailed pathologic diagnosis of both disease processes.
No preview · Article · Jan 2014 · Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE: Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro.
OBJECTIVE: To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy.
DESIGN, SETTING, AND PARTICIPANTS: International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012.
INTERVENTION: Participants were randomly assigned to receive diflunisal, 250mg (n=64), or placebo (n=66) twice daily for 2 years.
MAIN OUTCOMES AND MEASURES: The primary endpoint, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data.
RESULTS: By multiple imputation, the NIS+7scoreincreasedby25.0(95%CI,18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, −7.6 to −2.2) points in the placebo group and increased by 1.5 (95% CI, −0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, −4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group
(P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007).
CONCLUSIONS AND RELEVANCE : Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.
TRIAL REGISTRATION: clinicaltrials.govIdentifier:NCT00294671
Full-text · Article · Dec 2013 · JAMA The Journal of the American Medical Association
[Show abstract][Hide abstract] ABSTRACT: Primary light chain amyloidosis is the most common form of systemic amyloidosis and is caused by misfolded light chains that cause proteotoxicity and rapid decline of vital organ function. Early diagnosis is essential in order to deliver effective therapy and prevent irreversible organ damage. Accurate diagnosis requires clinical skills and advanced technologies. The disease can be halted and the function of target organs preserved by the prompt reduction and elimination of the plasma cell clone producing the toxic light chains in the bone marrow. Heart damage is the major determinant of survival, and staging with cardiac biomarkers guides treatment. Two-thirds of patients can benefit from treatment with improved quality of life and extended survival. Future efforts should be directed at early diagnosis, improving the tolerability and efficacy of anti-plasma cell therapy, accelerating recovery of organ function via promoting resorption of amyloid deposits, and developing novel approaches to counter light chain proteotoxicity.
No preview · Article · Dec 2013 · Expert Review of Hematology
[Show abstract][Hide abstract] ABSTRACT: In Ig light chain (AL) amyloidosis, cardiac involvement is associated with worse prognosis and increased treatment-related complications. In this retrospective cohort study, we assessed survival, hematologic and cardiac responses to high-dose melphalan and auto-SCT (HDM/SCT) in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarkers brain natriuretic peptide and Troponin I, analogous to the Mayo cardiac staging. Forty-seven patients underwent HDM/SCT based upon functional measures; six patients had modified cardiac stage I disease, seventeen had modified cardiac stage II disease and twenty-four had modified cardiac stage III disease. Treatment-related mortality was 4% for all patients and 8% for patients with stage III disease. Three-year survival was 88% and EFS was 47%; these did not differ by stage. By intention-to-treat analysis, 27% of patients achieved a hematologic complete response and 32% a very good partial response, of whom 70 and 45%, respectively, have not required additional therapy at 36 months. Cardiac response was achieved in 53% of patients. We conclude that with appropriate patient selection and a risk-adapted treatment approach, HDM/SCT is safe and effective in patients with AL amyloidosis and cardiac involvement.Bone Marrow Transplantation advance online publication, 9 December 2013; doi:10.1038/bmt.2013.192.
Preview · Article · Dec 2013 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: Familial transthyretin amyloidosis (ATTR) is an autosomal-dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR, protein secreted from the liver aggregates and forms fibrils in target organs, chiefly the heart and peripheral nervous system, highlighting the need for a model capable of recapitulating the multisystem complexity of this clinically variable disease. Here, we describe the directed differentiation of ATTR patient-specific iPSCs into hepatocytes that produce mutant TTR, and the cardiomyocytes and neurons normally targeted in the disease. We demonstrate that iPSC-derived neuronal and cardiac cells display oxidative stress and an increased level of cell death when exposed to mutant TTR produced by the patient-matched iPSC-derived hepatocytes, recapitulating essential aspects of the disease in vitro. Furthermore, small molecule stabilizers of TTR show efficacy in this model, validating this iPSC-based, patient-specific in vitro system as a platform for testing therapeutic strategies.
Full-text · Article · Nov 2013 · Stem Cell Reports
[Show abstract][Hide abstract] ABSTRACT: Orthotopic heart transplant (OHT), followed by myeloablative chemotherapy and autologous stem cell transplant (ASCT), has been successful in the treatment of amyloid light-chain (AL) cardiac amyloidosis. The purpose of this study was to identify predictors of survival to OHT in patients with end-stage heart failure due to AL amyloidosis and compare post-OHT survival of cardiac amyloid patients with survival of other cardiomyopathy patients undergoing OHT.
From January 2000 to June 2011, 31 patients with end-stage heart failure secondary to AL amyloidosis were listed for OHT at Massachusetts General Hospital. Univariate and multivariate regression analyses identified predictors of survival to OHT. Kaplan-Meier analysis compared survival between the Massachusetts General Hospital amyloidosis patients and non-amyloid cardiomyopathy patients from the Scientific Registry of Transplant Recipients (SRTR).
Low body mass index was the only predictor of survival to OHT in patients with end-stage heart failure caused by cardiac amyloidosis. Survival of cardiac amyloid patients who died before receiving a donor heart was only 63 ± 45 days after listing. Patients who survived to OHT received a donor organ at 53 ± 48 days after listing. Survival of AL amyloidosis patients on the waiting list was less than patients on the waiting list for all other non-amyloid diagnoses. The long-term survival of amyloid patients who underwent OHT was no different than the survival of non-amyloid, restrictive (p = 0.34), non-amyloid dilated (p = 0.34), or all non-amyloid cardiomyopathy patients (p = 0.22) in the SRTR database.
Amyloid patients who survive to OHT, followed by ASCT, have a survival rate similar to other cardiomyopathy patients undergoing OHT; however, 35% of the patients died awaiting OHT. The only predictor of survival to OHT in AL amyloidosis patients was a low body mass index, which correlated with a shorter time on the waiting list. To optimize the survival of these patients, access to donor organs must be improved.
No preview · Article · Nov 2013 · The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation
[Show abstract][Hide abstract] ABSTRACT: Immunoglobulin light chain (LC) amyloidosis (AL) results from overproduction of circulating amyloidogenic LC proteins and subsequent amyloid fibril deposition in organs. Mortality in AL amyloidosis patients is highly associated with a rapidly progressive AL cardiomyopathy, marked by profound impairment of diastolic and systolic cardiac function and significant early mortality. While myocardial fibril deposition contributes to the severe diastolic dysfunction seen in AL cardiomyopathy patients, the degree of fibril deposition has not been found to correlate with prognosis. Previously, we and others showed a direct cardiotoxic effect of amyloidogenic LC proteins (AL-LC), which may contribute to the pathophysiology and mortality observed in AL cardiomyopathy patients. However, the mechanisms underlying AL-LC related cardiotoxicity remain unknown. Mammalian stanniocalcin1 (STC1) is associated with a number of cellular processes including oxidative stress and cell death. Herein, we find that STC1 expression is elevated in cardiac tissue from AL cardiomyopathy patients, and is induced in isolated cardiomyocytes in response to AL-LC, but not non-amyloidogenic LC. STC1 overexpression in vitro recapitulates the pathophysiology of AL-LC mediated cardiotoxicity, with increased ROS production, contractile dysfunction and cell death. Overexpression of STC1 in vivo results in significant cardiac dysfunction and cell death. Genetic silencing of STC1 prevents AL-LC induced cardiotoxicity in cardiomyocytes and protects against AL-LC induced cell death and early mortality in zebrafish. The cardiotoxic effects of STC1 appears to be mediated via mitochondrial dysfunction as indicated by loss of mitochondrial membrane potential, ROS production and increased mitochondrial calcium levels. Collectively, this work identifies STC1 as a critical determinant of AL-LC cardiotoxicity.
No preview · Article · Sep 2013 · Archiv für Kreislaufforschung
[Show abstract][Hide abstract] ABSTRACT: We designed a trial using two sequential cycles of modified high-dose melphalan at 100 mg/m(2) and autologous SCT (mHDM/SCT) in AL amyloidosis (light-chain amyloidosis, AL), AL with myeloma (ALM) and host-based high-risk myeloma (hM) patients through SWOG-0115. The primary objective was to evaluate OS. From 2004 to 2010, 93 eligible patients were enrolled at 17 centers in the United States (59 with AL, 9 with ALM and 25 with hM). The median OS for patients with AL and ALM was 68 months and 47 months, respectively, and has not been reached for patients with hM. The median PFS for patients with AL and ALM was 38 months and 16 months, respectively, and has not been reached for patients with hM. The treatment-related mortality (TRM) was 12% (11/93) and was observed only in patients with AL after SCT. Grade 3 and higher non-hematologic adverse events were experienced by 81%, 67% and 57% of patients with AL, ALM and hM, respectively, during the first and second HDM/SCT. This experience demonstrates that with careful selection of patients and use of mHDM for SCT in patients with AL, ALM and hM, even in the setting of a multicenter study, OS can be improved with acceptable TRM and morbidity.Bone Marrow Transplantation advance online publication, 15 July 2013; doi:10.1038/bmt.2013.98.
Full-text · Article · Jul 2013 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: Systemic amyloid light-chain (AL) amyloidosis is associated with a rapidly progressive and fatal cardiomyopathy resulting from the direct cardiotoxic effects of circulating AL-light-chain (AL-LC) proteins and the indirect effects of amyloid fibril tissue infiltration. Cardiac amyloidosis is resistant to standard heart failure therapies, and to date there are limited treatment options for these patients. The mechanisms underlying the development of cardiac amyloidosis and AL-LC cardiotoxicity are largely unknown, and their study has been limited by the lack of a suitable in vivo model system. Herein we establish an in vivo zebrafish model of human AL-LC induced cardiotoxicity. AL-LC, isolated from AL cardiomyopathy patients, or control non-amyloidogenic LC protein isolated from multiple myeloma patients (Con-LC), were directly injected into the circulation of zebrafish at 48 hours post fertilization. AL-LC injection resulted in impaired cardiac function, pericardial edema and increased cell death relative to Con-LC, culminating in compromised survival with 100% mortality within 2 weeks, independent of amyloid fibril deposition. Prior work has implicated non-canonical p38MAPK activation in the pathogenesis of AL-LC induced cardiotoxicity and p38MAPK inhibition via SB203580 rescued AL-LC induced cardiac dysfunction and cell death, and attenuated mortality in zebrafish. This in vivo zebrafish model of AL-LC cardiotoxicity demonstrates that antagonism of p38MAPK within the AL-LC cardiotoxic signaling response may serve to improve cardiac function and mortality in AL amyloid cardiomyopathy. Furthermore, this in vivo model system will allow for further study of the molecular underpinnings of amyloid cardiotoxicity and identification of novel therapeutic strategies.
[Show abstract][Hide abstract] ABSTRACT: Abstract AL amyloidosis presenting as a solitary mediastinal mass is a rare occurrence, with only a few cases reported in the literature. We describe a case of a man presenting with a mediastinal mass diagnosed as amyloidosis, confirmed by mass spectrometry to consist of lambda light chains. Here we review the literature and discuss treatment options for this rare entity.
No preview · Article · Mar 2013 · Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis
[Show abstract][Hide abstract] ABSTRACT: CK2 Overexpression in Human Cancer CK2 Is Overexpressed in Animal Models of Cancer CK2 Overexpression in Transgenic Mice Leads to Cancer Possible Targets of CK2 in Cancer: Wnt, NF-κB, and PI3-Kinase Pathways
[Show abstract][Hide abstract] ABSTRACT: Cardiac amyloidosis due to amyloid fibril deposition in the heart results in cardiomyopathy (CMP) with heart failure (HF) and/or conduction disturbances. Immunoglobulin light chain-related CMP (AL-CMP) features rapidly progressive HF with an extremely poor prognosis compared with a CMP due to the deposition of mutant (ATTR) amyloidosis or wild-type (senile systemic amyloidosis, SSA) transthyretin (TTR) proteins. Amyloid fibril deposition disrupts the myocardial extracellular matrix (ECM) homeostasis, which is partly regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). We therefore tested the hypothesis that circulating levels of MMPs and TIMPs in patients with AL-CMP and TTR-related CMP (TTR-CMP) are dissimilar and indicative of cardiac amyloid disease type.
Fifty AL-CMP patients were compared with 50 TTR-CMP patients (composed of 38 SSA and 12 ATTR patients). Clinical and laboratory evaluations including echocardiography were performed at the initial visit to our center and analyzed. Serum MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were determined by ELISA. Compared with TTR-CMP patients, AL-CMP patients had higher levels of brain natriuretic peptide (BNP), troponin I (TnI), MMP-2, TIMP-1, and MMP-2/TIMP-2 ratio, despite less left ventricular (LV) hypertrophy and better preserved LV ejection fraction. Mortality was worse in AL-CMP patients than in TTR-CMP patients (log-rank P<0.01). MMP-2/TIMP-2 plus BNP and TnI showed the highest discriminative ability for distinguishing AL-CMP from TTR-CMP. Female sex (HR, 2.343; P=0.049) and BNP (HR, 1.041; P<0.01) were predictors for mortality for all patients with cardiac amyloidoses. Only BNP was a predictor of death in AL-CMP patients (HR, 1.090; P<0.01). There were no prognostic factors for all-cause death in TTR-CMP patients.
Circulating concentrations of MMPs and TIMPs may be useful in differentiating patients with AL-CMP from those with TTR-CMP, resulting in earlier diagnostic vigilance, and may add prognostic information. In addition to an elevated BNP level, female sex increased the risk of death in patients with cardiac amyloidoses.
Full-text · Article · Feb 2013 · Journal of the American Heart Association
[Show abstract][Hide abstract] ABSTRACT: Background:
Immunoglobulin light chain (AL) amyloidosis can be treated with high-dose melphalan and autologous stem cell transplantation (HDM/SCT). Risk factors for infections may include hyposplenism, hypogammaglobulinemia, treatment-related neutropenia, melphalan-induced mucositis, and nosocomial exposures.
Methods and design:
A review of 493 patients with AL amyloidosis undergoing treatment with HDM/SCT from August 1994 to August 2009 was performed. The objectives were to determine the rate and types of infections following HDM/SCT, to identify factors associated with microbiologically documented infections, and to assess the contribution of infections to all-cause treatment-related mortality (TRM; defined as deaths within 100 days of SCT).
Microbiologically documented infections after HDM/SCT occurred in 24% (n = 119) of patients. TRM was 10% (n = 48) overall, and 21% (n = 25) in patients who had a documented infection. Thus, the relative risk of TRM in a patient with a documented infection was 3.42 (95% confidence interval [CI] 2.02-5.79). Infections were caused by gram-positive bacteria in 51%, anaerobic bacteria in 16%, gram-negative bacteria in 13%, and fungi in 9% of cases. Serum creatinine >2 mg/dL was associated with increased risk of post-SCT infection (38% vs. 21%, P = 0.0007) with an odds ratio of 2.27 (95% CI 1.40-3.68). No significant association for infection was found for age, gender, cardiac involvement, prior steroid therapy, dose of melphalan, multiorgan involvement, days to neutrophil engraftment, or dose of CD34 + cells infused.
Serum creatinine >2 mg/dL is a risk factor for infections in patients with AL amyloidosis undergoing HDM/SCT. The relative risk of TRM in a patient with a documented infection was increased >3-fold. A broad spectrum of infections, similar to that in other SCT patients, is seen in this population in the early post-SCT period.
No preview · Article · Dec 2012 · Transplant Infectious Disease