MON-469 Rapidly Expanding Thyroid Goiter as the First Manifestation of Systemic Amyloidosis

Abstract INTRODUCTION Amyloidosis is a condition manifesting with extracellular tissue deposition of fibrils of low molecular weight proteins. In Ig light chain amyloidosis (AL), the deposition of Ig light chains can cause organ dysfunction, and patients can have involvement of a range of organs including kidney (70%), liver (70%), heart (60%), peripheral nerves (20%), the tongue, skin, and the coagulation system (1). We describe a unique case of AL amyloidosis, which first presented with thyroid involvement. CLINICAL CASE A 78 year old female patient with hx of small lymphocytic lymphoma and normal thyroid function presented with an expanding symptomatic goiter and compressive symptoms (positive Pemberton sign) for which a total thyroidectomy was performed. Pathology showed Congo red-birefringent amyloid deposition. SPEP showed a small amount of M protein, with circulating monoclonal free lambda light chain on immunofixation. The free kappa lambda light chain ratio was low (0.04) with an elevated serum free lambda light chain (283.93). Mass spectrometry confirmed AL light chain amyloidosis - lambda type. A work up was initiated to assess other organ involvement. Echocardiogram showed mild thickening of left ventricle with a preserved EF and EKG showed low voltage in limb leads. Creatinine (1.05) was minimally elevated from baseline with minimal proteinuria (396 mg/24 hours). Alkaline phosphatase, APTT, and PT were normal. The patient described tongue enlargement and scalloping of the tongue from tooth impingement was seen. Biopsies of tongue and bone marrow also showed amyloidosis thereby securing the diagnosis of systemic amyloidosis, and chemotherapy was initiated. CONCLUSION This case illustrates the importance of considering amyloid goiter in the differential for a rapidly enlarging thyroid, even when there is no history of amyloidosis. Although extremely uncommon, a few case reports have described amyloid goiter. In our case, thyroid AL was the initial presentation of systemic amyloidosis. Because disease can be localized or systemic, work up should include an assessment for the presence of a monoclonal gammopathy and an assessment for amyloid mediated organ dysfunction. Tissue should be sent for amyloid typing – there are 35 different proteins known to form amyloid fibrils and prognosis and treatment depends on amyloid type (2). Typing using Liquid Chromatography-Tandem Mass Spectrometry, is the most sensitive and specific methodology, though, in experienced hands, typing by immune histochemistry is an option. REFERENCES 1. Rajkumar, S.V., Dispenzieri, A. Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis. Uptodate. 2019. 2. Winter, M., Tholey, A., Kristen, A., Röcken, C. MALDI Mass Spectrometry Imaging: A Novel Tool for the Identification and Classification of Amyloidosis. Proteomics 2017, 17, 1700236.

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AMYLOID GOITER AS THE FIRST RECOGNIZABLE MANIFESTATION OF IMMUNOGLOBULIN LIGHT CHAIN AMYLOIDOSIS

AACE Clinical Case Reports ◽

10.4158/accr-2019-0161 ◽

2019 ◽

Vol 5 (5) ◽

pp. e326-e329 ◽

Cited By ~ 1

Author(s):

John J. Orrego ◽

Joseph A. Chorny

Keyword(s):

Light Chain ◽

Congo Red ◽

Monoclonal Gammopathy ◽

Amyloid Deposition ◽

Systemic Amyloidosis ◽

Cardiac Conduction ◽

Light Chain Amyloidosis ◽

Amyloid Goiter ◽

Congo Red Staining ◽

Bethesda System

Objective: Clinically apparent thyroid enlargement due to massive amounts of amyloid deposition, known as amyloid goiter, is rare. Endocrinologists should become familiar with this manifestation of systemic amyloidosis, which may be diagnosed by Congo red staining of the specimen obtained by fine-needle aspiration. Methods: We describe a 70-year-old man who presented with a slowly enlarging goiter. It was asymptomatic, predominantly left-sided, nontoxic, and multinodular with atypia of undetermined significance (Bethesda System category III) by cytology. The goiter tested negative using the ThyraMIR miRNA Gene Expression Classifier kit (eviCore Healthcare, Bluffton, SC). Results: Left thyroid lobectomy produced a 220-g specimen with nodular hyperplasia and prominent amyloid deposition confirmed by Congo red staining. Liquid chromatography tandem mass spectrometry detected a peptide profile consistent with light chain amyloid deposition of the lambda type, formerly called primary amyloidosis. In retrospect, he had been diagnosed with restrictive cardiomyopathy, cardiac conduction system disease, coronary artery disease, non-nephrotic range proteinuria, and chronic kidney disease, which had been attributed to his longstanding type 2 diabetes mellitus. Extensive workup subsequently demonstrated cardiac amyloidosis and monoclonal gammopathy of unknown significance, consistent with light chain amyloidosis. Conclusion: Amyloid goiter should be included in the differential diagnosis of enlarging goiters with Bethesda System category III cytology in patients with monoclonal gammopathy of uncertain significance, clinical manifestations of systemic amyloidosis, or known diagnosis of monoclonal cell dyscrasia.

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Deposition of Lambda Chain Constant Region within AL-Amyloid Lesion

Blood ◽

10.1182/blood.v124.21.3348.3348 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3348-3348

Author(s):

Hiroyuki Hata ◽

Masayoshi Tasaki ◽

Konen Obayashi ◽

Taro Yamashita ◽

Yukio Ando ◽

...

Keyword(s):

Mass Spectrometry ◽

Light Chain ◽

Mass Spectrometry Analysis ◽

Light Chains ◽

High Dose ◽

Al Amyloidosis ◽

Constant Region ◽

Rt Pcr ◽

Immunoglobulin Light Chain ◽

Lambda Light Chain

Abstract [Introduction] Diagnosis of AL amyloidosis is dependent on the proof of light chains in amyloid lesions. However, immunostaining does not always successfully prove the presence of light chains in lesions in AL amylidosis patients. Here we report that the constant region of immunoglobulin lambda light chain (IGLC2) is seen in amyloid lesions where no positive signals are found with regular immunostaining. [Materials and Methods] Amyloid samples were stained with anti-human lambda light chain antibody (DAKO PO-0130) and analyzed with mass-spectrometry combining laser micro-dissection. Bone marrow samples were obtained from patients with amyloidosis, who gave written informed consent, and were subjected to plasma cell purification using CD138-immunomagnetic beads. Expression of immunoglobulin light chain mRNA was examined with RT-PCR. Anti-human IGLL5 antibody, capable of detecting immunoglobulin light chain constant region 2 (IGLC2) in paraffin embedded samples, was utilized. [Results and Discussion] We performed immunostaining for immunoglobulin light chains with 18 samples and found that six and eight cases were positive for kappa and lambda light chains, respectively, whereas light chains were not detected in remaining four cases (immunostaining-negative amyloidosis; INA). However, interestingly, mass spectrometry analysis revealed the presence of IGLC2 in all of the INA cases. RT-PCR analysis revealed the presence of IGLC2 mRNA in plasma cells from such INA cases. Surprisingly, amyloid lesions in all of the INA cases were positively stained with anti-IGLL5 antibody, whereas no staining was found in other samples positively stained with DAKO PO-0130. These observations suggest that the deposition of IGLC2 may cause AL amyloidosis, which otherwise could not be diagnosed with regular immunostaining. Although high dose chemotherapy produced hematological remission, half of such cases died within one year, suggesting irreversible and life-threatening amyloid fibril depositions in critical organs in IGLC2-related cases. We further examined additional twelve cases with AL amyloidosis to determine the incidence of IGLC2-related amyloidosis by immunostaining. With regular immunostaining, kappa and lambda chain were found in three and five cases, respectively. Interestingly, the remaining four cases were negative with regular immunostaining but positive with anti-IGLL5 antibody. Taken these observations together, eight IGLC2-related amyloidosis cases and thirteen lambda type amyloidosis were identified. Thus, the incidence of IGLC2-related amyloidosis should be approximately 38% (8/21) among lambda type AL amyloidosis. We conclude that diagnosis of IGLC2-related AL amyloidosis was possible only with the use of anti-IGLL5 antibody, but not with regular immunostaining. Given the relatively high incidence and often poor prognosis of IGLC2-related amyloidosis, it is important that this clinical entity is recognized to potentially improve outcomes of treatments. Analysis of mechanisms regulating amyloid formation with IGLC2 peptides is currently underway. Disclosures No relevant conflicts of interest to declare.

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Isolated cardiovascular involvement in light chain amyloidosis

BMJ Case Reports ◽

10.1136/bcr-2019-233227 ◽

2020 ◽

Vol 13 (4) ◽

pp. e233227

Author(s):

Ahamed Shaheer Ahmed ◽

Sampath Kumar ◽

Gautam Sharma ◽

Sudheer Arava

Keyword(s):

Light Chain ◽

Cardiac Amyloidosis ◽

Low Voltage ◽

Systolic Dysfunction ◽

Organ System ◽

Lambda Light Chain ◽

Text Book ◽

Light Chain Amyloidosis ◽

Amyloid Deposits ◽

Cardiovascular Involvement

A 50-year-old woman presented with complaints of palpitations and breathlessness of 6 months’ duration. She was being treated elsewhere as a case of dilated cardiomyopathy. On evaluation she had racoon eyes, poor progression of R wave on ECG and low-voltage complexes in the limb leads. Echocardiography revealed biventricular hypertrophy, diastolic dysfunction and moderate systolic dysfunction. Cardiac MRI showed features suggestive of amyloidosis. Bone marrow biopsy revealed raised plasma cell count, and endomyocardial biopsy showed amyloid deposits in the myocardium. Free lambda light chain levels were elevated, even though serum and urine electrophoresis did not show any monoclonal band. In this ‘text book case of cardiac amyloidosis’, apart from cardiovascular system no other organ system was affected, which is uncommon in primary light chain amyloidosis. The patient was started on CyBorD (cyclophosphamide, bortezomib and dexamethasone) regimen.

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Two Distinct Syndromes of Lymphoma-Associated Amyloidosis: Findings From a Case Series.

Blood ◽

10.1182/blood.v114.22.2938.2938 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2938-2938

Author(s):

David Telio ◽

Denis Bailey ◽

Christine Chen ◽

Michael Crump ◽

Donna E. Reece ◽

...

Keyword(s):

Light Chain ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Systemic Amyloidosis ◽

M Protein ◽

Al Amyloidosis ◽

Lambda Light Chain ◽

Light Chain Restriction ◽

Protein Levels

Abstract 2938 Poster Board II-914 Introduction: Light chain (AL) amyloidosis has a rare but recognized association with non-Hodgkin lymphoma; however, limited information regarding this association exists. We present the clinical features and outcomes of patients with lymphoma -associated AL amyloidosis identified at Princess Margaret Hospital (PMH). We describe two distinct syndromes of lymphoma-associated amyloidosis: 1) peritumoral amyloidosis in which amyloid deposition occurs in the immediate vicinity of the lymphoma and 2) systemic amyloidosis where deposition is in sites remote from the underlying lymphoma. Methods: Cases were identified retrospectively at PMH by survey of hematologists and a pathologist. The International Consensus Criteria (ICC) (Gertz et al., 2005) were used to determine organ involvement by amyloid. Results: We identified 10 patients with lymphoma -associated AL amyloidosis seen between 1997 and 2008. The median age was 69 (52-81) and 50% were female. Five patients had peritumoral amyloidosis. All had extranodal marginal zone lymphoma, MALT subtype (MALT lymphoma).A monoclonal immunoglobulin (M-protein), as determined by serum protein electrophoresis (SPEP) and free light chain (FLC) analysis, was undetectable in two patients, was present in trace amount in two patients and detected but not quantified in a fifth. Of the patients with detectable M-protein, the isotype was IgM in two and IgG in one. Four had lambda light chain restriction while biclonality was questioned in the fifth. All but one patient had single organ involvement by amyloid with lung and soft tissues being the only sites affected. Rectal biopsies and fat pad aspirates, when performed, were negative. Four patients received systemic therapy: two patients were treated with chlorambucil, one received melphalan and prednisone, and one received rituximab, cyclophosphamide, and prednisone followed by rituximab maintenance. Radiographic follow-up of pulmonary lesions in two patients did not identify significant change in lymphoma/amyloid related abnormality. No complete responses were seen. Despite therapy, three patients experienced continuing local symptoms at the site of lymphoma/amyloid involvement while one remained asymptomatic. A fifth patient, untreated at last follow up, was asymptomatic. No patients with peritumoral amyloidosis were found to develop systemic amyloidosis even after a median follow up of 11 months (3-60 mo). The other five patients had lymphoma with systemic amyloidosis. These patients had lymphoma restricted to the bone marrow with histology showing lymphoplasmacytic lymphoma (LPL) in three and small B cell lymphoma with plasmacytic differentiation in two (differential diagnosis LPL vs marginal zone lymphoma). An IgM M-protein was detectable in all five patients. Waldenstrom's macroglobulinemia was therefore present in at least three patients. High levels of M-protein were detected by SPEP in four patients (mean 31 g/L) and FLC analysis in one. Kappa was more common than lambda light chain restriction (3:2). Amyloid was detected in a median of three organs (1-5) including cardiac involvement in four patients. Four patients received multiple lines of therapy with first line being R-CVP in three and ASCT in a fourth. Organ responses, as defined by the ICC, in sites affected by amyloid were not observed. Three of the four treated patients had >50% reductions in M-protein levels, but none had complete haematological response. Response of the underlying lymphoma, which would have required repeat biopsy, was not assessed. Median follow up was 30 months (4-100) with one patient dying of sepsis, one developing therapy-related AML and three surviving with ongoing symptoms of congestive heart failure, dyspnea and/or neuropathy. Conclusions: Lymphoma-associated amyloidosis presents as two distinct syndromes which are associated with characteristic clinical, laboratory and pathologic features. Patients with peritumoural amyloidosis have low level M-protein expression with predominant lambda light chain restriction, symptoms confined to the site of their MALT lymphoma and poor radiological responses to systemic therapy. Patients with systemic amyloidosis have high M-protein levels with a uniform IgM isotype, lymphoma localized to the bone marrow, multiorgan involvement by amyloid and worse outcomes. Future studies aimed at better defining prognosis and optimal treatment in these patients are warranted. Disclosures: Kukreti: Celgene: Honoraria.

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Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis

Blood Cancer Journal ◽

10.1038/s41408-021-00428-0 ◽

2021 ◽

Vol 11 (2) ◽

Cited By ~ 2

Author(s):

Giovanni Palladini ◽

Bruno Paiva ◽

Ashutosh Wechalekar ◽

Margherita Massa ◽

Paolo Milani ◽

...

Keyword(s):

Minimal Residual Disease ◽

Organ Dysfunction ◽

Light Chain ◽

Residual Disease ◽

Cell Clone ◽

Cardiac Response ◽

Al Amyloidosis ◽

Next Generation ◽

Organ Response ◽

Minimal Residual

AbstractLight chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.

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Apolipoprotein C-II Deposition Amyloidosis: A Potential Misdiagnosis as Light Chain Amyloidosis

Case Reports in Nephrology ◽

10.1155/2016/8690642 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Sadichhya Lohani ◽

Emily Schuiteman ◽

Lohit Garg ◽

Dhiraj Yadav ◽

Sami Zarouk

Keyword(s):

Mass Spectrometry ◽

Light Chain ◽

Amyloid Fibrils ◽

Plasma Cells ◽

Laser Microdissection ◽

Density Lipoprotein ◽

Definitive Diagnosis ◽

Diagnostic Challenge ◽

Light Chain Amyloidosis ◽

Apolipoprotein C

Hereditary amyloidoses are rare and pose a diagnostic challenge. We report a case of hereditary amyloidosis associated with apolipoprotein C-II deposition in a 61-year-old female presenting with renal failure and nephrotic syndrome misdiagnosed as light chain amyloidosis. Renal biopsy was consistent with amyloidosis on microscopy; however, immunofluorescence was inconclusive for the type of amyloid protein. Monoclonal gammopathy evaluation revealed kappa light chain. Bone marrow biopsy revealed minimal involvement with amyloidosis with kappa monotypic plasma cells on flow cytometry. She was started on chemotherapy for light chain amyloidosis. She was referred to the Mayo clinic where laser microdissection and liquid chromatography mass spectrometry detected high levels of apolipoprotein C-II, making a definitive diagnosis. Apolipoprotein C-II is a component of very low-density lipoprotein and aggregates in lipid-free conditions to form amyloid fibrils. The identification of apolipoprotein C-II as the cause of amyloidosis cannot be solely made with routine microscopy or immunofluorescence. Further evaluation of biopsy specimens with laser microdissection and mass spectrometry and DNA sequencing of exons should be done routinely in patients with amyloidoses for definitive diagnosis. Our case highlights the importance of determining the subtype of amyloidosis that is critical for avoiding unnecessary therapy such as chemotherapy.

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Diagnostic approach to light-chain cardiac amyloidosis and its differential diagnosis

Acta Haematologica Polonica ◽

10.2478/ahp-2018-0002 ◽

2018 ◽

Vol 49 (1) ◽

pp. 9-14

Author(s):

Monika Adamska ◽

Anna Komosa ◽

Tatiana Mularek ◽

Joanna Rupa-Matysek ◽

Lidia Gil

Keyword(s):

Differential Diagnosis ◽

Light Chain ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Diagnosis And Treatment ◽

Diagnostic Approach ◽

Al Amyloidosis ◽

Delay In Diagnosis ◽

Light Chain Amyloidosis ◽

Novel Approaches

AbstractCardiac amyloidosis is a rare and often-misdiagnosed disorder. Among other forms of deposits affecting the heart, immunoglobulin-derived light-chain amyloidosis (AL amyloidosis) is the most serious form of the disease. Delay in diagnosis and treatment may have a major impact on the prognosis and outcomes of patients. This review focuses on the presentation of the disorder and current novel approaches to the diagnosis of cardiac involvement in AL amyloidosis.

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Quantitative Immunoprecipitation Free Light Chain Mass Spectrometry (QIP-FLC-MS) Simplifies Monoclonal Protein Assessment and Provides Added Clinical Value in Systemic AL Amyloidosis

Blood ◽

10.1182/blood-2019-128175 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4375-4375 ◽

Cited By ~ 1

Author(s):

Faye Amelia Sharpley ◽

Hannah Victoria Giles ◽

Richa Manwani ◽

Shameem Mahmood ◽

Sajitha Sachchithanantham ◽

...

Keyword(s):

Mass Spectrometry ◽

Light Chain ◽

Residual Disease ◽

Renal Involvement ◽

Light Chains ◽

Al Amyloidosis ◽

Free Light Chains ◽

Accurate Identification ◽

Monoclonal Protein ◽

Serum And Urine

Introduction Early diagnosis, effective therapy and precise monitoring are central for improving clinical outcomes in systemic light chain (AL) amyloidosis. Diagnosis and disease response assessment is primarily based on the presence of monoclonal immunoglobulins and free light chains (FLC). The ideal goal of therapy associated with best outcomes is a complete responses (CR), defined by the absence of serological clonal markers. In both instances, detection of the monoclonal component (M-component) is based on serum FLC assessment together with traditional serum and urine electrophoretic approaches, which present inherent limitations and lack sensitivity particularly in AL where the levels are typically low. Novel mass spectrometry methods provide sensitive, accurate identification of the M-component and may prove instrumental in the timely management of patients with low-level amyloidogenic light chain production. Here we assess the performance of quantitative immunoprecipitation FLC mass spectrometry (QIP-FLC-MS) at diagnosis and during monitoring of AL amyloidosis patients treated with bortezomib-based regimens. Methods We included 46 serial patients with systemic AL amyloidosis diagnosed and treated at the UK National Amyloidosis Centre (UK-NAC). All patients had detailed baseline assessments of organ function and serum FLC measurements. Baseline, +6- and +12-month serum samples were retrospectively analysed by QIP-FLC-MS. Briefly, magnetic microparticles were covalently coated with modified polyclonal sheep antibodies monospecific for free kappa light chains (anti-free κ) and free lambda light chains (anti-free λ). The microparticles were incubated with patient sera, washed and treated with acetic acid (5% v/v) containing TCEP (20 mM) in order to elute FLC in monomeric form. Mass spectra were acquired on a MALDI-TOF-MS system (Bruker, GmbH). Results were compared to serum FLC measurements (Freelite®, The Binding Site Group Ltd), as well as electrophoretic assessment of serum and urine proteins (SPE, sIFE, UPE and uIFE). Results Cardiac (37(80%) patients) and renal (31(67%) patients) involvement were most common; 25(54%) patients presented with both. Other organs involved included liver (n=12), soft tissue (n=4), gastrointestinal tract (n=3) and peripheral nervous system (n=2). Baseline Freelite, SPE, sIFE and uIFE measurements identified a monoclonal protein in 42(91%), 22(48%), 34(74%) and 21(46%) patients, respectively. A panel consisting of Freelite + sIFE identified the M-component in 100% of the samples. QIP-FLC-MS alone also identified an M-component in 100% of the samples and was 100% concordant with Freelite for typing the monoclonal FLC (8 kappa, 34 lambda). In 4 patients, QIP-FLC-MS identified an additional M-protein that was not detected by the other techniques. In addition, 4/8(50%) kappa and 4/38(11%) lambda patients showed a glycosylation pattern of monoclonal FLCs at baseline by mass spectrometry. Interestingly, the frequency of renal involvement was significantly lower for patients with non-glycosylated forms (25% vs 76%, p=0.01), while no similar relationship was found for any other organs. During the 1-year follow-up period, 17 patients achieved a CR; QIP-FLC-MS identified serum residual disease in 13(76%) of these patients. Conclusion In our series, QIP-FLC-MS was concordant with current serum methods for identifying the amyloidogenic light chain type and provided, against all other individual tests, improved sensitivity for the detection of the monoclonal protein at diagnosis and during monitoring. The ability to measure the unique molecular mass of each monoclonal protein offers clone-specific tracking over time. Glycosylation of free light chains is over-represented in AL patients which may allow earlier diagnosis and better risk-assessment of organ involvement. Persistence of QIP-FLC-MS positive M component in patients otherwise in CR may allow targeted therapy. Overall, QIP-FLC-MS demonstrates potential to be exploited as a single serum test for precise serial assessment of monoclonal proteins in patients with AL amyloidosis. Disclosures Wechalekar: GSK: Honoraria; Janssen-Cilag: Honoraria; Amgen: Research Funding; Takeda: Honoraria; Celgene: Honoraria.

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Patients with light-chain amyloidosis and low free light-chain burden have distinct clinical features and outcome

Blood ◽

10.1182/blood-2017-02-767467 ◽

2017 ◽

Vol 130 (5) ◽

pp. 625-631 ◽

Cited By ~ 51

Author(s):

Paolo Milani ◽

Marco Basset ◽

Francesca Russo ◽

Andrea Foli ◽

Giampaolo Merlini ◽

...

Keyword(s):

Clinical Features ◽

Light Chain ◽

Free Light Chain ◽

Al Amyloidosis ◽

Renal Survival ◽

Light Chain Amyloidosis ◽

Hematologic Response ◽

Heart Involvement ◽

Key Points

Key PointsPatients with AL amyloidosis and low dFLC burden (<50 mg/L) have less severe heart involvement and better survival. These patients are evaluable for hematologic response with adapted criteria predicting improvement of overall and renal survival.

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A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis

Blood ◽

10.1182/blood-2011-12-396903 ◽

2012 ◽

Vol 119 (23) ◽

pp. 5384-5390 ◽

Cited By ~ 46

Author(s):

Efstathios Kastritis ◽

Evangelos Terpos ◽

Maria Roussou ◽

Maria Gavriatopoulou ◽

Constantinos Pamboukas ◽

...

Keyword(s):

Light Chain ◽

Low Dose ◽

Phase 1 ◽

Al Amyloidosis ◽

Oral Cyclophosphamide ◽

Phase 2 ◽

Light Chain Amyloidosis ◽

Intention To Treat ◽

Oral Regimen ◽

Dose Oral

Abstract In this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespecified cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to-treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections, and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. This study is registered at www.clinicaltrials.gov as NCT00981708.

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