Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Asymptomatic patients with an elevation in the serum viscosity ...do not require plasma exchange, and the majority will have other indications for therapeutic intervention. For patients with hemorrhagic or central nervous system manifestations, plasma exchange is the therapy of choice and is relatively safe. Viscosity measurements are not required to initiate therapy if the index of suspicion is high and the clinical presentation is typical. However, patients should have a sample sent for confirmation of the diagnosis. Whole-blood hyperviscosity is seen in patients with extreme elevation of the red cell and white cell count. Phlebotomy of patients with primary and secondary elevation of the red cell count is a well-established therapy.
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 of undetermined significance (MGUS).”
Diagnosis
Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple‐green birefringence is required for the diagnosis of AL amyloidosis. 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 or BNP), serum troponin T (or I), and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 73, 35, 15, and 5 months.
Therapy
All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Current first‐line therapy with the best outcome is daratumumab, bortezomib, cyclophosphamide, and dexamethasone. The goal of therapy is a complete response (CR). In patients failing to achieve this depth of response options for consolidation include pomalidomide, stem cell transplantation, venetoclax, and bendamustine.
Future challenges
Delayed diagnosis remains a major obstacle to initiating effective therapy prior to the development of end‐stage organ failure. Trials of antibodies to catabolize deposited fibrils are underway.
Pathophysiology of AL amyloidosis.
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.
Disease Overview
Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, ...hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity.
Diagnosis
Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in the majority of IgM MGUS patients.
Risk Stratification
Age, hemoglobin level, platelet count, β2 microglobulin, LDH and monoclonal IgM concentrations are characteristics that are predictive of outcomes.
Risk‐Adapted Therapy
Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab‐monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogues are active but usage is declining in favor of less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine.
Management of Refractory Disease
Bortezomib, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.
Disease Overview
Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, ...hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity.
Diagnosis
Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in >90% of patients and is found in the majority of IgM monoclonal gammopathy of undetermined significance patients.
Risk Stratification
Age, hemoglobin level, platelet count, β2 microglobulin, and monoclonal IgM concentrations are characteristics that are predictive of outcomes.
Risk‐Adapted Therapy
Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab‐monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogs are active but usage is declining for less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. Potential for stem cell transplantation should be considered in selected younger patients.
Management of Refractory Disease
Bortezomib, fludarabine, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.
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 restrictive cardiomyopathy, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and “atypical multiple myeloma.”
Diagnosis
Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple‐green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow, salivary gland, or subcutaneous fat aspirate 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 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 mm Hg, troponin T < 0.06 ng/mL, age < 70 years, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan‐dexamethasone or cyclophosphamide‐bortezomib‐dexamethasone. Daratumumab appears to be highly active in AL amyloidosis. Antibodies designed to dissolve existing amyloid deposits are under study.
Future Challenges
Delayed diagnosis remains a major obstacle to initiating effective therapy.
Educational Objectives
Upon completion of this educational activity, participants will be better able to:
Master recognition of clinical presentations that should raise suspicion of amyloidosis.
Understand simple techniques for confirming the diagnosis and providing material to classify the protein subunit.
Recognize that a tissue diagnosis of amyloidosis does not indicate whether the amyloid is systemic or of immunoglobulin light chain origin.
Understand the roles of the newly introduced chemotherapeutic and investigational antibody regimens for the therapy of light chain amyloidosis.
Amyloid light chain (AL) amyloidosis is a systemic disease characterised by the aggregation of misfolded immunoglobulin light chain (LC), predominantly in the heart and kidneys, causing organ ...failure. If untreated, the median survival of patients with cardiac AL amyloidosis is 6 months from the onset of heart failure. Protracted time to establish a diagnosis, often lasting >1 year, is a frequent factor in poor treatment outcomes. Cardiologists, to whom patients are often referred, frequently miss the opportunity to diagnose cardiac AL amyloidosis. Nearly all typical cardiac support measures, with the exception of diuretics, are ineffective and may even worsen clinical symptoms, emphasising the need for accurate diagnosis. Patients with severe cardiac involvement face poor outcomes; heart transplantation is rarely an option because of multiorgan involvement, rapid clinical decline and challenges in predicting which patients will respond to treatment of the underlying plasma cell disorder. Early diagnosis and prompt treatment with ââ'¬Ëœsource therapiesââ'¬â"¢ that limit the production of amyloidogenic LC are associated with better survival and improvement in organ function after a median of 2.4 months following haematological complete response. However, organ recovery is often incomplete because these source therapies do not directly target deposited amyloid. Emerging amyloid-directed therapies may attenuate, and potentially reverse, organ dysfunction by clearing existing amyloid and inhibiting fibril formation of circulating aggregates. Improved recognition of AL amyloidosis by cardiologists allows for earlier treatment and improved outcomes.
Disease Overview
Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, ...hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity.
Diagnosis
Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS patients. MYD88 is not required for the diagnosis.
Risk Stratification
Age, hemoglobin level, platelet count, β2 microglobulin, LDH, and monoclonal IgM concentrations are characteristics that are predictive of outcomes.
Risk‐Adapted Therapy
Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab‐monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or a BTK inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib.
Management of Refractory Disease
Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM's natural history, the reduction of therapy toxicity is an important part of treatment selection.
Key clinical features of macroglobulinemia.
How I treat cryoglobulinemia Muchtar, Eli; Magen, Hila; Gertz, Morie A.
Blood,
01/2017, Letnik:
129, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the ...underlying disease that triggers cryoglobulin formation. Cryoglobulinemia is categorized into two main subgroups: type I, which is seen exclusively in clonal hematologic diseases, and type II/III, which is called mixed cryoglobulinemia and is seen in hepatitis C virus infection and systemic diseases such as B-cell lineage hematologic malignancies and connective tissue disorders. Clinical presentation is broad and varies between types but includes arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. Life-threatening manifestations can develop in a small proportion of patients. A full evaluation for the underlying cause is required, because each type requires a different kind of treatment, which should be tailored on the basis of disease severity, underlying disease, and prior therapies. Relapses can be frequent and can result in significant morbidity and cumulative organ impairment. We explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients.
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