RESUMO
Age-related cardiac amyloidosis results from deposits of wild-type tranthyretin amyloid (ATTRwt) in cardiac tissue. ATTR may play a role in carpal tunnel syndrome (CTS) and in spinal stenosis (SS), indicating or presaging systemic amyloidosis. We investigated consecutive patients undergoing surgery for SS for ATTR deposition in the resected ligamentum flavum (LF) and concomitant risk of cardiac amyloidosis. Each surgical specimen (LF) was stained with Congo red, and if positive, the amyloid deposits were typed by mass spectrometry. Patients with positive specimens underwent standard of care evaluation with fat pad aspirates, serum and urine protein electrophoresis with immunofixation, free light-chain assay, TTR gene sequencing and technetium 99 m-pyrophosphate-scintigraphy. In 2018-2019, 324 patients underwent surgery for SS and 43 patients (13%) had ATTR in the LF with wild-type TTR gene sequences. Two cases of ATTRwt cardiac amyloidosis were diagnosed and received treatment. In this large series, ATTRwt was identified in 13% of the patients undergoing laminectomy for SS. Patients with amyloid in the ligamentum flavum were older and had a higher prevalence of CTS, suggesting a systemic form of ATTR amyloidosis involving connective tissue. Further prospective study of patients with SS at risk for systemic amyloidosis is warranted.
Assuntos
Neuropatias Amiloides Familiares , Amiloidose , Ligamento Amarelo , Estenose Espinal , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/cirurgia , Humanos , Pré-Albumina/genética , Estudos Prospectivos , Estenose Espinal/diagnóstico por imagem , Estenose Espinal/genética , Estenose Espinal/cirurgiaAssuntos
Cadeias Leves de Imunoglobulina/sangue , Amiloidose de Cadeia Leve de Imunoglobulina , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Cadeias Leves de Imunoglobulina/urina , Amiloidose de Cadeia Leve de Imunoglobulina/sangue , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Amiloidose de Cadeia Leve de Imunoglobulina/urina , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
BACKGROUND: Systemic AL amyloidosis (AL) is a rare disease in which clonal immunoglobulin light chains produced by monoclonal plasma cells circulate and misfold, resulting in direct toxicity and fibrillar deposition of amyloid in numerous tissues. Early mortality from cardiac damage remains high. As depth of organ response carries a prognostic significance, combining anti-plasma cell and anti-amyloid therapies might hold the key to achieving long lasting responses. We report a series of patients who received 2 monoclonal antibodies, anti-CD38 and anti-amyloid, simultaneously. MATERIALS AND METHODS: We describe the characteristics and outcomes of 19 patients who received daratumumab (anti-CD38) on progression with front-line therapy for AL, 9 of whom were on concurrent dual monoclonal antibody treatment with daratumumab and NEOD001 (anti-amyloid), and also provide data on the schedule, safety, and tolerability of intravenous infusions of these monoclonal antibodies. RESULTS: The 9 patients who received treatment with dual monoclonal antibodies achieved a high rate (100%) of hematologic response in a median of 33 days. There was no significant toxicity to dual monoclonal antibody therapy. Seven of the 8 met criteria for cardiac response, achieved in less than 3 months of combined therapy. Ten patients who received daratumumab alone also had high rates of hematologic and organ responses. CONCLUSIONS: Monoclonal antibodies with distinctly different targets can be safely combined in patients with AL and cardiac involvement. Patients experienced high rates of hematologic and cardiac response with combined anti-CD38 and anti-amyloid monoclonal antibody therapies. Further study of this combined approach is warranted.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Doenças Cardiovasculares/etiologia , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Idoso , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Doenças Cardiovasculares/patologia , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Immunoglobulin light-chain (AL) amyloidosis is a rare life-threatening disease caused by light chains that are toxic to vital organs such as the heart, kidneys, liver and peripheral nervous system, and that misfold and assemble as amyloid fibrils and deposit both in affected organs and systemically in the vasculature and other tissues. Patients afflicted by this disease have B-cell disorders, almost always related to clonal plasma cells in the bone marrow, the burden of which can range from small clones involving 5% or less of marrow cells to frank multiple myeloma. The goal of therapy is to eliminate the clonal plasma cells producing these toxic light chains to halt and possibly reverse symptomatic organ damage. While autologous stem cell transplantation can be a very effective treatment modality in AL, it has a limited role due to the frailty of this particular population. Conservative treatment in the form of chemotherapy has become the backbone of therapy. Bortezomib combined with alkylators has proven quite successful in inducing hematologic responses. However, despite these advances, tolerability and resistance continue to be an ongoing issue. Novel anti-plasma cell therapies such as ixazomib, carfilzomib, lenalidomide and pomalidomide are actively being combined and evaluated in clinical trials for efficacy and toxicity in this challenging patient population. Other approaches, such as monoclonal antibodies targeting surface proteins and amyloid deposits, are being tested and combined with novel agents. In this review, we will provide an overview of the clinical trials that have led to current treatment algorithms and will also discuss monoclonal antibodies currently under investigation and in various stages of clinical development.
Assuntos
Amiloidose/terapia , Cadeias Leves de Imunoglobulina/metabolismo , Amiloidose/patologia , HumanosAssuntos
Anticorpos Monoclonais/uso terapêutico , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/genética , Lactente , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Patients with immunoglobulin (Ig) light-chain (LC) diseases such as LC light-chain amyloidosis die with organ failure and need new therapies. We sought a model to test anti-LC siRNA delivery to human plasma cells, requiring circulating LC, in vivo indicators of tumor presence, and capacity for multiple injections of delivery vehicle. The JJN-3 human myeloma reporter cell line expressing firefly luciferase (FFL) implanted intraperitoneally (IP) in the NOD scid γ (NSG) mouse has a 90% prompt tumor-take, rapid LC production, and in vivo indicators of tumor measurable on day 5 post-implant (κ LC, bioluminescent signal, and soluble B-cell maturation antigen [sBCMA]) with median day 5 serum levels of κ LC of 1482 ng/mL (range, 255-4831) and robust correlations with all in vivo indicators. In preliminary attempts to deliver siRNA against κ LC constant region mRNA, we identified the 306-O18B3 lipidoid nanoparticle (LNP) as promising, safe and efficient in vitro. In vivo in the JJN-3 NSG IP model, after daily IP 306-O18B3:siRNA injections on days 5-10, a reduction in κ LC was observed on day 8 between control and test groups that continued through day 12 at sacrifice. This model is potentially useful as a platform for refining anti-LC therapies.
Assuntos
Técnicas de Transferência de Genes , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Cadeias kappa de Imunoglobulina/genética , Terapêutica com RNAi/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Humanos , Cadeias kappa de Imunoglobulina/metabolismo , Luciferases de Vaga-Lume/genética , Luciferases de Vaga-Lume/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Nanopartículas/efeitos adversos , Nanopartículas/químicaRESUMO
BACKGROUND: The monoclonal antibody daratumumab, approved for treating myeloma, targets CD38, a protein on myeloma and also on CD34+ hematopoietic progenitor cells. Because mobilized CD34+ cells are critical for stem cell transplant, we investigated the in vitro activity of daratumumab on mobilized CD34+ cells from myeloma patients with no prior exposure to daratumumab. METHODS: We determined the number of CD38 molecules per CD34+ cell, and whether daratumumab bound to CD34+ cells, whether C1q bound to daratumumab-coated CD34+ cells and whether daratumumab-related complement-dependent cytotoxicity (CDC) occurred. We also examined CD34+ cell progenitor cell colony capacity in assays with pre-plating incubation of CD34+ cells with daratumumab alone or with daratumumab and the CD59 inhibitory antibody BRIC229, and also assessed CD34+ cell responses to increasing doses of daratumumab in caspase 3/7 activity assays. RESULTS: Although 75% of mobilized CD34+ cells co-express CD38, CD38 was minimally present on CD34+ cells compared to Daudi and KG-1 controls, C1q did not bind to daratumumab-coated CD34+ cells, and CDC did not occur. CD34+ cells incubated in complement-rich human serum with daratumumab alone or with daratumumab and BRIC229, and then plated in progenitor cell assays, produced similar numbers of colonies as controls. In progenitor cell assays with cryopreserved or fresh unselected or CD34-selected cells, daratumumab did not affect progenitor cell capacity, and in caspase 3/7 activity assays CD34+ cells were not affected by increasing doses of daratumumab. CONCLUSION: In vitro, daratumumab is not toxic to mobilized CD34+ progenitor cells from myeloma patients.
RESUMO
INTRODUCTION: Deletion 17p (del 17p) portends a poor prognosis in myeloma, but its significance in light-chain amyloidosis is unknown. PATIENTS AND METHODS: We identified patients with light-chain amyloidosis and del 17p at diagnosis, and analyzed presenting characteristics, treatments, and clinical outcomes. All had baseline biopsy results showing amyloid and serologic and marrow studies, including standard fluorescence in-situ hybridization determinations of del 17p using commercial probes. Consensus criteria for hematologic and organ involvement, progression, and response were used. Kaplan-Meier (log rank) analyses and Cox regression analysis of baseline variables were used to identify predictors of overall and progression-free survival (PFS). Six-month landmark analyses were performed to assess the impact of treatment-related variables. RESULTS: We identified 44 patients from 7 countries with median marrow and del 17p plasma cells of 22% (range, 3%-100%) and 30% (2%-93%). Ninety-five percent had cardiac involvement, including 44% stage III. Two-thirds of the patients initially received bortezomib-based therapy. Forty-nine percent of patients experienced complete response or very good partial response, with median time to best response of 4 months (range, 1-28 months). Median overall survival and PFS were 49 and 32 months. Cardiac stage and hematologic response were the key predictors of outcomes. Patients with > 50% and ≤ 50% del 17p in clonal plasma cells had median survivals of 28 and 52 months, respectively (P = .08). In landmark analyses, only hematologic response predicted both overall survival and PFS. CONCLUSION: Cardiac stage, hematologic response, and del 17p percentage impact outcomes in these cases. Emphasis should be placed on optimizing supportive care and achieving a deep hematologic response.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Transplante de Células-Tronco/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Seguimentos , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/genética , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Outcomes in primary amyloid renal patients are of interest as the era of monoclonal antibody therapies begins. PATIENTS AND METHODS: We studied 77 consecutive primary amyloid renal patients (58% men) for renal progression (end stage renal disease [ESRD]), renal response (RR), and overall survival (OS). RESULTS: At diagnosis median age was 63 (range, 35-81) years, estimated glomerular filtration rate 70 mL/min (range, 5-114), difference between involved and uninvolved free light chains 127 mg/L (range, 1-9957), ESRD 4%, renal stage 2 and 3 78%, and cardiac stage 2 and 3 56%. Ninety-six percent received bortezomib and 44% stem cell transplantation as well as bortezomib, 68% achieved complete or very good partial hematologic response (CR/VGPR), 34% had ESRD, and 39% RR. Median times to ESRD and RR were 18 (range, 3-81) and 12 (range, 2-30) months, respectively. Median OS was not reached in this cohort and was not reached from onset of ESRD. More than two-thirds of patients with ESRD also achieved CR/VGPR. In those without ESRD at diagnosis, baseline creatinine and absent RR predicted progression to ESRD in multivariate Cox regression analysis, whereas CR/VGPR predicted RR. In multivariate Cox regression analysis, cardiac stage and achievement of CR/VGPR predicted OS, enabling construction of a prognostic model. CONCLUSION: Anti-plasma cell therapies provide a definite albeit limited benefit and new approaches to amyloid-related organ dysfunction are needed.