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AL Amyloidosis

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David C Seldin – One of the best experts on this subject based on the ideXlab platform.

  • ClinicAL presentation and treatment responses in IgM-related AL Amyloidosis
    Amyloid, 2015
    Co-Authors: Moussa Sissoko, David C Seldin, Vaishali Sanchorawala, John L. Berk, Brian Sworder, Kenneth Angelino, Mike Broce, J. Mark Sloan

    Abstract:

    Amyloid light-chain (AL) Amyloidosis is a multi-organ disease due to deposition of misfolded monoclonAL immunoglobulin light chains. IgM AL Amyloidosis is a rare variant, about 6% of AL Amyloidosis cases, and more data are needed for treatment guidance. In IgM AL Amyloidosis, the clonAL cell of origin may be a plasma or lymphoplasmacytic cell, and treatments targeting each are employed. We describe presenting clinicAL and laboratory features of 95 patients with IgM AL Amyloidosis treated at Boston University Amyloidosis Center from 1996 to 2012. The median diagnosis age was 66 years (range: 38-89) with 56% mALes. Organ involvement rates were: kidney (51%); heart (40%); lymph nodes (25%) and gastrointestinAL tract (17%). Treatment responses were anALyzed for 46 patients seen after 2003. Five treatment regimens were assigned by bone marrow pathology and patient-specific factors. OverALl hematologic response rates and very good partiAL or complete hematologic response rates, respectively, were: high-dose melphALan/stem cell transplant (HDM/SCT) 100%;80%, Bortezomib 82%;27%, Rituximab 80%;27%, immunomodulatory agents (IMids) 75%;0%, and standard dose ALkylating agents (MelphALan or cyclophosphamide) 63%;19%. OverALl, 5-year survivAL rates were significantly higher in patients with a hematologicAL response: 79.2 ± 8.5% versus 41 ± 14.9% in non-responders, which is more favorable than typicALly expected in AL Amyloidosis.

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  • ClinicAL Presentation and Treatment Responses In IgM-Related AL Amyloidosis
    Blood, 2013
    Co-Authors: Vaishali Sanchorawala, David C Seldin, John L. Berk, Brian Sworder, John Mark Sloan

    Abstract:

    AL Amyloidosis is a multiorgan disease due to deposition of misfolded monoclonAL immunoglobulin light chains. AL Amyloidosis associated with IgM paraproteinemia is a rare variant of this disease, constituting approximately 6% of AL Amyloidosis cases in the literature. The clonAL cell of origin may be a plasma cell or a lymphoplasmacytic cell, and treatments targeting each of these populations have been employed. This study defines the clinicAL and laboratory characteristics of IgM-related AL Amyloidosis patients as well as their response to different therapeutic regimens. We identified 94 patients with IgM-related AL Amyloidosis evALuated at the BUMC Amyloidosis Center from 2003 through 2012 for which data was available on 50 who completed treatment. The median age at diagnosis was 65 years (range: 42-79 years) with 31 (62 %) mALes. The most commonly involved organ was the kidney (59%) followed by heart (37%) and GI tract (22%). The mean IgM was 1049 g/dL (range: 29-9130). The clonAL population had lambda light chain restriction in 34 (68%) of patients. Patients were categorized into 5 treatment groups: high-dose melphALan/stem cell transplant (HDM/SCT), bortezomib-based, non-transplant ALkylating agents based (melphALan or cyclophosphamide), immunomodulatory agents (IMiDs), and rituximab-based. This grouping was not mutuALly exclusive. The highest hematologic response rate was observed with HDM/SCT (10/10: 100%), followed by non-transplant ALkylating agents (16/22: 73%), bortezomib (7/10: 70%) rituximab (9/13: 69%) then by IMiDs (2/4: 50%). We did not observe an association between positive response to treatment and organ involvement, sex or age at diagnosis. In conclusion, IgM-related ALAmyloidosis is an unusuAL variant of AL Amyloidosis. Multiple active therapies with different mechanisms of action exist; treatment should be tailored based upon clinicopathologic and patient-specific factors. Disclosures: Sloan: Millenium: Consultancy.

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  • cancer testis antigen expression and immunogenicity in AL Amyloidosis
    Blood Cancer Journal, 2012
    Co-Authors: Michael Rosenzweig, Heather Landau, David C Seldin, Carl Ohara, Saulius Girnius, Nicole Hanson, Denise Frosina, Christine Sedrak, Maria E Arcila, Raymond L Comenzo

    Abstract:

    Light-chain Amyloidosis (AL) is a plasma cell dyscrasia closely related to multiple myeloma. In multiple myeloma, the cancer-testis antigens (CTAs) CT7 (MAGE-C1), CT10 (MAGE-C2) and MAGE-A CTAs are expressed in up to 80% of cases. In this study, we investigated the expression and immunogenicity of severAL CTAs in patients with AL Amyloidosis in a totAL of 38 bone marrow specimens by employing standard immunohistochemistry techniques on paraffin-embedded archivAL tissues. Plasma samples from 35 patients (27 with matched bone marrow samples) were ALso anALyzed by ELISA for sero reactivity to a group of full-length CTA proteins. CT7 was present in 25/38 (66%) while CT10 was demonstrated in 3/38 and GAGE in 1/38 AL amyloid cases. The expression pattern was mostly focAL. There were no significant differences with regard to organ involvement, response to treatment, or prognosis in CTA positive compared to negative cases. None of the specimens showed spontaneous humorAL immunity to CT7, but sero reactivity was observed in individuAL patients to other CTAs. This study identifies CT7 as the prevALent CTA in plasma cells of patients with AL Amyloidosis. Further anALyses determining the biology of CTAs in AL Amyloidosis and their vALue as potentiAL targets for immunotherapy are warranted.

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Vaishali Sanchorawala – One of the best experts on this subject based on the ideXlab platform.

  • Long-term outcome of kidney transplantation in AL Amyloidosis
    Kidney International, 2019
    Co-Authors: Avital Angel-korman, Vaishali Sanchorawala, J. Mark Sloan, Gheorghe Doros, Lauren Stern, Shayna Sarosiek, Andrea Havasi

    Abstract:

    Therapies for AL Amyloidosis have dramaticALly improved, leading to longer patient survivAL; however, more AL Amyloidosis patients are reaching end-stage renAL disease (ESRD). There are no clear guidelines regarding eligibility for kidney transplantation in patients with AL Amyloidosis, and data on outcomes are limited. We evALuated the clinicAL and laboratory data of 49 patients who were followed in the Amyloidosis Center at Boston University and underwent kidney transplantation at a center in the United States between 1987-2017. During a median follow-up of 7.2 years (range 0-19), the median patient survivAL from diagnosis was 15.4 years, and from kidney transplantation was 10.5 years. One, three, and five-year graft survivAL were 94%, 89%, and 81%, respectively. Patients with hematologic complete response or very good partiAL response prior to kidney transplantation had significantly better patient survivAL than patients with partiAL response or no response, and the median time to graft loss was 10.4 years versus 5.5 years, respectively. This is the largest published series of kidney transplantation in patients with AL Amyloidosis, suggesting that kidney transplantation can have a good outcome in carefully selected patients, particularly in those who have achieved a complete response or very good partiAL response at the time of kidney transplantation.

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  • Bendamustine-Induced Nephrogenic Diabetes Insipidus in a Patient With AL Amyloidosis
    American Journal of Kidney Diseases, 2017
    Co-Authors: Nsabimana A. Uwumugambi, Vaishali Sanchorawala, Lauren Stern, Anthony C Shelton, Craig E. Gordon

    Abstract:

    Nephrogenic diabetes insipidus is a condition characterized by polyuria with dilute urine due to the inability of the principAL cells of the renAL collecting ducts to respond to antidiuretic hormone and concentrate urine. Nephrogenic diabetes insipidus can be drug induced, and severAL chemotherapeutic agents have been reported to cause it. Bendamustine is a traditionAL chemotherapeutic agent being studied for treatment for relapsed systemic AL Amyloidosis. We report a case of a 59-year-old man with AL Amyloidosis who developed partiAL nephrogenic diabetes insipidus after receiving bendamustine for treatment of AL Amyloidosis. The nephrogenic diabetes insipidus responded well to sodium restriction, hydrochlorothiazide, and desmopressin treatment, ALlowing the patient to receive subsequent bendamustine cycles without polyuria. Nephrogenic diabetes insipidus resolved shortly after completion of bendamustine therapy.

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  • ClinicAL presentation and treatment responses in IgM-related AL Amyloidosis
    Amyloid, 2015
    Co-Authors: Moussa Sissoko, David C Seldin, Vaishali Sanchorawala, John L. Berk, Brian Sworder, Kenneth Angelino, Mike Broce, J. Mark Sloan

    Abstract:

    Amyloid light-chain (AL) Amyloidosis is a multi-organ disease due to deposition of misfolded monoclonAL immunoglobulin light chains. IgM AL Amyloidosis is a rare variant, about 6% of AL Amyloidosis cases, and more data are needed for treatment guidance. In IgM AL Amyloidosis, the clonAL cell of origin may be a plasma or lymphoplasmacytic cell, and treatments targeting each are employed. We describe presenting clinicAL and laboratory features of 95 patients with IgM AL Amyloidosis treated at Boston University Amyloidosis Center from 1996 to 2012. The median diagnosis age was 66 years (range: 38-89) with 56% mALes. Organ involvement rates were: kidney (51%); heart (40%); lymph nodes (25%) and gastrointestinAL tract (17%). Treatment responses were anALyzed for 46 patients seen after 2003. Five treatment regimens were assigned by bone marrow pathology and patient-specific factors. OverALl hematologic response rates and very good partiAL or complete hematologic response rates, respectively, were: high-dose melphALan/stem cell transplant (HDM/SCT) 100%;80%, Bortezomib 82%;27%, Rituximab 80%;27%, immunomodulatory agents (IMids) 75%;0%, and standard dose ALkylating agents (MelphALan or cyclophosphamide) 63%;19%. OverALl, 5-year survivAL rates were significantly higher in patients with a hematologicAL response: 79.2 ± 8.5% versus 41 ± 14.9% in non-responders, which is more favorable than typicALly expected in AL Amyloidosis.

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Giampaolo Merlini – One of the best experts on this subject based on the ideXlab platform.

  • Improved outcomes for kidney transplantation in AL Amyloidosis: impact on practice.
    Kidney International, 2019
    Co-Authors: Mario Nuvolone, Giampaolo Merlini

    Abstract:

    Effective therapies for Ig light chain (AL) Amyloidosis has led to an increasing proportion of patients with end-stage renAL disease requiring renAL replacement therapy, yet kidney transplantation is seldom performed in this setting due to concerns of renAL and extrarenAL disease progression. Angel-Korman et AL. report unprecedented positive long-term outcomes in the largest series of kidney transplantation in AL Amyloidosis providing the basis for a more proactive approach to this procedure.

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  • Management of the elderly patient with AL Amyloidosis.
    European Journal of Internal Medicine, 2018
    Co-Authors: Mario Nuvolone, Paolo Milani, Giovanni Palladini, Giampaolo Merlini

    Abstract:

    Abstract Systemic immunoglobulin light chain (AL) Amyloidosis is an aging-associated protein misfolding and deposition disease. This condition is caused by a smALl and otherwise indolent plasma cell (or B cell) clone secreting an unstable circulating light chain, which misfolds and deposits as amyloid fibrils possibly leading to progressive dysfunction of affected organs. AL Amyloidosis can occur in the typicAL setting of other, rarer forms of systemic Amyloidosis and can mimic other more prevALent conditions of the elderly. Therefore, its diagnosis requires a high degree of clinicAL suspicion and reliable diagnostic tools for accurate amyloid typing, available at speciALized referrAL centers. In AL Amyloidosis, frailty is dictated by the type and severity of organ involvement, with heart involvement being the main determinant of morbidity and mortALity. Still, given a similar disease stage, elderly patients with AL Amyloidosis are often an even frailer group, due to significant comorbidities, associated disability and polypharmacotherapy, socioeconomic restrictions, and limited access to clinicAL triALs. Recent improvements in the use of biomarkers for early diagnosis, risk stratification and response monitoring, the flourishing of novel, effective anti-plasma cell therapies developed against multiple myeloma and adapted to treat AL Amyloidosis, and possibly the introduction of anti-amyloid therapies are rapidly changing the clinicAL management of this disease and are reflected by improved outcomes. Of note, hematologic and organ responses in elderly patients with AL Amyloidosis do translate in better outcome, advocating the importance of treating these patients and striving for a rapid response to therapy ALso in this chALlenging clinicAL setting.

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  • AL Amyloidosis from molecular mechanisms to targeted therapies
    Hematology, 2017
    Co-Authors: Giampaolo Merlini

    Abstract:

    Systemic Amyloidosis is caused by misfolding and extracellular deposition of circulating proteins as amyloid fibrils, resulting in the dysfunction of vitAL organs. The most common systemic Amyloidosis, light-chain (AL) Amyloidosis, is caused by misfolded light chains produced by a smALl, dangerous B-cell clone. The process of amyloid formation, organ targeting, and damage is multifaceted and, after disease initiation, the complexity of the downstream pathogenic cascade increases, rendering its control a chALlenge. Because of the progressive nature of the disease, early diagnosis to prevent end-stage organ damage is vitAL. Improving awareness and systematic use of biomarkers of organ damage in screening populations at risk may improve the still unsatisfactory diagnostic process. Amyloid imaging is now emerging as an important companion of biomarkers in formulating the diagnosis and prognosis and monitoring the effects of therapy. An accurate diagnosis is the basis for appropriate therapy that is risk-adapted and response-tailored. Effective treatments targeting the clone and rapidly and profoundly reducing the amyloid light chains have produced marked improvements in overALl survivAL, making AL Amyloidosis the most successful model of ALl amyloidoses. New therapies targeting the amyloid deposits are now under development, together with novel agents modulating light chain aggregation and proteotoxicity. The future of AL Amyloidosis treatment is combination therapy and will require an innovative collaborative model for a rapid translation from bench to bedside with the ultimate aim of achieving a cure for this complex disease.

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