Hematologic relapse in AL amyloidosis after high-dose melphalan and stem cell transplantation

Browning, Sabrina L.; Quillen, Karen; Sloan, J. Mark; Doros, Gheorghe; Sarosiek, Shayna; Sanchorawala, Vaishali

doi:10.1182/blood-2017-06-788729

Cited by 31 publications

(31 citation statements)

References 8 publications

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“…Hematologic relapse occurs at a median of 4 years. The median survival in patients with hematologic relapse after an initial CR is 8.5 years after relapse 94 . Renal and cardiac organ responses and high complete hematologic response rates have been reported after SCT 95 .…”

Section: Therapymentioning

confidence: 99%

Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment

Gertz

2020

American J Hematol

114

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Disease Overview Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include heart failure with preserved ejection fraction, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and “atypical smoldering multiple myeloma or monoclonal gammopathy undetermined significance (MGUS).” Diagnosis Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple‐green birefringence is required for diagnosis. Invasive organ biopsy is not required in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy. Prognosis N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain (FLC) values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. Therapy All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include systolic blood pressure >90 mmHg, troponin T < 0.06 ng/mL and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered cyclophosphamide‐bortezomib‐dexamethasone or daratumumab‐containing regimens as it appears to be highly active in AL amyloidosis. Future Challenges Delayed diagnosis remains a major obstacle to initiating effective therapy prior to the development of end‐stage organ failure.

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Section: Therapymentioning

confidence: 99%

Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment

Gertz

2020

American J Hematol

114

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“…[18] Novel approaches targeting the plasma cell While upfront LC suppressive therapy yields high hematologic overall response rates, the majority of patients do not achieve a complete hematologic response to therapy allowing ongoing toxic amyloid deposition. [43] Improvement in involved organ function is even less common, and almost all patients eventually experience a relapse requiring additional LC suppressive therapy. [43] These considerations justify the ongoing search for novel therapeutic strategies.…”

Section: Therapies Targeting the Plasma Cells: At The Root Of The Promentioning

confidence: 99%

“…[43] Improvement in involved organ function is even less common, and almost all patients eventually experience a relapse requiring additional LC suppressive therapy. [43] These considerations justify the ongoing search for novel therapeutic strategies.…”

Section: Therapies Targeting the Plasma Cells: At The Root Of The Promentioning

confidence: 99%

Therapies for cardiac light chain amyloidosis: An update

Aimo

Buda

Fontana

et al. 2018

International Journal of Cardiology

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Light-chain (AL) amyloidosis is the most common type of systemic amyloidosis, affecting around 10 people per million per year. This serious disorder is characterized by the presence of a clone of bone marrow plasma cells that produces monoclonal light chains (LCs) of the κ or predominantly λ type. These amyloidogenic LCs undergo extracellular misfolding and aggregation into proteotoxic soluble oligomers and amyloid fibrils that deposit within tissues. The lethal consequences of AL amyloidosis are due to the toxic products (the LCs) and not to the malignant behaviour of the plasma cell clone. Almost 80% of patients with AL amyloidosis have some degree of cardiac involvement, manifesting as heart failure (HF), and carrying a particularly poor prognosis. The past decade has seen major advances in the treatment of AL amyloidosis, and a rapidly fatal disease has become a treatable and possibly curable condition. The number of therapeutic options is rapidly expanding, offering hope to address currently unmet needs (most notably, the treatment of frail patients). The treatment of AL amyloidosis consists in a combination of agents targeting multiple steps of the amyloid cascade, associated with effective HF management, and there is ground for hope for dramatically improving the outcome in the near future. In the present review we will summarize our current knowledge on therapy for cardiac AL amyloidosis, targeting clinical cardiologists involved in the care of this serious disorder.

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“…Therapy for AL amyloidosis is largely focused on elimination of the clonal plasma cell population that produces the amyloidogenic light chains via risk-adapted treatment approaches based on the severity of organ involvement and the performance status of each individual. For low-risk patients (approximately 25% of those diagnosed) treatment with highdose melphalan followed by autologous stem cell transplantation (HDM/SCT) is recommended and can achieve hematologic complete responses in 25-67% of patients, organ responses in 27-83% of patients, and a median OS of 7.6 years, with some patients achieving a complete hematologic response and a median overall survival of more than 10 years 1, 8,17 . The remainder of patients have intermediate or high-risk disease that is treated with a combination of therapies including the proteasome inhibitors bortezomib and ixazomib, the alkylating agents melphalan or cyclophosphamide, and glucocorticosteroids 1, 2,18,19 .…”

Section: Introductionmentioning

confidence: 99%

Clonal plasma cells in AL amyloidosis are dependent on pro survival BCL-2 family proteins and sensitive to BH3 mimetics

Fraser¹,

Presser²,

Sanchorawala

et al. 2019

Preprint

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Immunoglobulin light chain (AL) amyloidosis is a protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains misfold and accumulate as amyloid fibrils in healthy tissues causing devastating multi-organ dysfunction that is rapidly fatal. Current treatment regimens, which include proteasome inhibitors, alkylating agents, and immunomodulatory agents, were developed for the treatment of the more common plasma cell disease, multiple myeloma, and have limited efficacy in AL amyloidosis as demonstrated by the median survival of 2-3 years. The recent development of novel small-molecule inhibitors of the major pro-survival proteins from the apoptosis-regulating BCL-2 family has created an opportunity to therapeutically target abnormal cell populations, yet identifying the extent of these dependencies and how to target them clinically has thus far been challenging. Using bone marrow-derived plasma cells from 45 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins. Specifically, we find that clonal plasma cells in a majority of patients are highly dependent on the pro-survival protein MCL-1 and undergo apoptosis when treated with an MCL-1 inhibitor as a single agent. In addition, BCL-2 inhibition sensitizes clonal plasma cells to several current standard of care therapies. Our results suggest that BH3 mimetics, when deployed rationally, may be highly effective therapies for AL amyloidosis.

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Hematologic relapse in AL amyloidosis after high-dose melphalan and stem cell transplantation

Abstract: An association between decreased cardiopulmonary complications (transfusion-related acute lung injury and transfusion-associated circulatory overload) and implementation of universal leukoreduction of blood transfusions.

Cited by 31 publications

References 8 publications

Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment

Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment

Therapies for cardiac light chain amyloidosis: An update

Clonal plasma cells in AL amyloidosis are dependent on pro survival BCL-2 family proteins and sensitive to BH3 mimetics

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