scholarly journals Primary Amyloidosis and Acute Leukemia Associated With Melphalan Therapy

Blood ◽  
1974 ◽  
Vol 44 (3) ◽  
pp. 333-337 ◽  
Author(s):  
Robert A. Kyle ◽  
Robert V. Pierre ◽  
Edwin D. Bayrd
Keyword(s):  
Acute Leukemia ◽  
Significant Role ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Light Chains ◽  
Primary Amyloidosis ◽  
Immunoglobulin Light Chains ◽  
Full Consideration

Abstract Amyloid fibrils consist in part of immunoglobulin light chains. Because light chains are synthesized by plasma cells, it seems reasonable to treat patients with amyloidosis with alkylating agents. Two patients who had primary amyloidosis and were treated with melphalan subsequently developed a rapidly fatal acute leukemia. Since melphalan may play a significant role in the development of acute leukemia, we suggest that alkylating agents not be used in the treatment of patients with amyloidosis without full consideration of risks involved, particularly until it has been proved that these drugs are beneficial.

scholarly journals Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo

Blood ◽  
1978 ◽  
Vol 52 (4) ◽  
pp. 818-827 ◽  
Author(s):  
RA Kyle ◽  
PR Greipp
Keyword(s):  
Nephrotic Syndrome ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Systemic Amyloidosis ◽  
Light Chains ◽  
Primary Amyloidosis ◽  
Double Blind ◽  
Progression Of Disease ◽  
To Receive

Abstract Satisfactory treatment for primary amyloidosis does not exist. Because the amyloid fibrils consist of a portion of a monoclonal light chain, it appears reasonable to treat amyloidosis with alkylating agents that are effective against the plasma cells that synthesize monoclonal light chains. Fifty-five patients with primary systemic amyloidosis were randomized (double blind) to melphalan-prednisone or placebo. In comparison with the placebo group, patients given melphalan-prednisone were able to continue on treatment for a longer time and to receive larger doses before the code was broken. Among this group, the nephrotic syndrome disappeared in two patients and urinary excretion of protein was reduced by more than 50% in eight others. Of 13 patients who received melphalan-prednisone for more than 12 mo, 6 improved, 3 were stable, and 4 had progression of disease. Survival did not differ significantly between the groups.

scholarly journals Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo

Blood ◽  
1978 ◽  
Vol 52 (4) ◽  
pp. 818-827 ◽  
Author(s):  
RA Kyle ◽  
PR Greipp
Keyword(s):  
Nephrotic Syndrome ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Systemic Amyloidosis ◽  
Light Chains ◽  
Primary Amyloidosis ◽  
Double Blind ◽  
Progression Of Disease ◽  
To Receive

Satisfactory treatment for primary amyloidosis does not exist. Because the amyloid fibrils consist of a portion of a monoclonal light chain, it appears reasonable to treat amyloidosis with alkylating agents that are effective against the plasma cells that synthesize monoclonal light chains. Fifty-five patients with primary systemic amyloidosis were randomized (double blind) to melphalan-prednisone or placebo. In comparison with the placebo group, patients given melphalan-prednisone were able to continue on treatment for a longer time and to receive larger doses before the code was broken. Among this group, the nephrotic syndrome disappeared in two patients and urinary excretion of protein was reduced by more than 50% in eight others. Of 13 patients who received melphalan-prednisone for more than 12 mo, 6 improved, 3 were stable, and 4 had progression of disease. Survival did not differ significantly between the groups.

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

2019 ◽  
Author(s):  
Cameron Fraser ◽  
Adam Presser ◽  
Vaishali Sanchorawala ◽  
Shayna Sarosiek ◽  
Kristopher Sarosiek
Keyword(s):  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Single Agent ◽  
Current Treatment ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Current Standard ◽  
Bh3 Mimetics

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.

scholarly journals Stabilization of amyloidogenic immunoglobulin light chains by small molecules

2019 ◽  
Vol 116 (17) ◽  
pp. 8360-8369 ◽  
Author(s):  
Gareth J. Morgan ◽  
Nicholas L. Yan ◽  
David E. Mortenson ◽  
Enrico Rennella ◽  
Joshua M. Blundon ◽  
...  
Keyword(s):  
Small Molecules ◽  
Light Chain ◽  
Cardiac Involvement ◽  
Plasma Cells ◽  
Full Length ◽  
Light Chains ◽  
Immunoglobulin Light Chains ◽  
X Ray ◽  
Tissue Degeneration ◽  
Dimerization Interface

In Ig light-chain (LC) amyloidosis (AL), the unique antibody LC protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. As a step toward developing treatments for AL patients with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, we introduce small-molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which can slow or stop the amyloidogenicity cascade at its origin. A protease-coupled fluorescence polarization-based high-throughput screen was employed to identify small molecules that kinetically stabilize LCs. NMR and X-ray crystallographic data demonstrate that at least one structural family of hits bind at the LC–LC dimerization interface within full-length LCs, utilizing variable-domain residues that are highly conserved in most AL patients. Stopping the amyloidogenesis cascade at the beginning is a proven strategy to ameliorate postmitotic tissue degeneration.

Analysis of Vλ-Jλ expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r(λIII) as a new amyloid-associated germline gene segment

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 948-953 ◽  
Author(s):  
Vittorio Perfetti ◽  
Simona Casarini ◽  
Giovanni Palladini ◽  
Maurizio Colli Vignarelli ◽  
Catherine Klersy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Light Chain ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Strong Association ◽  
Gene Segment ◽  
Variable Region ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Primary Amyloidosis

Abstract Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by extracellular deposition of monoclonal light-chain variable region (V) fragments in the form of amyloid fibrils. Light-chain amyloid is rare, and it is not fully understood why it occurs in only a fraction of patients with a circulating monoclonal component and why it typically associates with λ isotype and λVI family light-chain proteins. To provide insights into these issues, we obtained complete nucleotide sequences of monoclonal Vλ regions from 55 consecutive unselected cases of primary amyloidosis and the results were compared with the light-chain expression profile of polyclonal marrow plasma cells from 3 healthy donors (a total of 264 sequences). We demonstrated that: (1) the λIII family is the most frequently used both in amyloidosis (47%) and in polyclonality (43%); (2) both conditions are characterized by gene restriction; (3) a very skewed repertoire is a feature of amyloidosis, because just 2 germline genes belonging to the λIII and λVI families, namely 3r (22% of cases, λIII) and 6a (20%, λVI), contributed equally to encode 42% of amyloid Vλ regions; (4) these same 2 gene segments have a strong association with amyloidosis if their prevalences are compared with those in polyclonal conditions (3r, 8.3%,P = .024; 6a, 2.3%, P = .0008, χ2 test); (5) the Jλ2/3 segment, encoding the fourth framework region, appears to be slightly overrepresented in AL (83% versus 67%, P = .03), and this might be related to preferential Jλ2/3 rearrangement in amyloid (11 of 12 cases) versus polyclonal 3r light chains (13 of 22 cases). These findings demonstrate that Vλ-Jλ expression is more restricted in plasma cells from amyloidosis than from polyclonal bone marrow and identify 3r as a new disease-associated gene segment. Overusage of just 2 gene segments,3r and 6a, can thus account for the λ light-chain overrepresentation typical of this disorder.

A Molecular Model for Self-Assembly of Amyloid Fibrils: Immunoglobulin Light Chains

Biochemistry ◽  
1995 ◽  
Vol 34 (34) ◽  
pp. 10697-10702 ◽  
Author(s):  
Fred J. Stevens ◽  
Elizabeth A. Myatt ◽  
Chong-Hwan Chang ◽  
Florence A. Westholm ◽  
Manfred Eulitz ◽  
...  
Keyword(s):  
Self Assembly ◽  
Amyloid Fibrils ◽  
Molecular Model ◽  
Light Chains ◽  
Immunoglobulin Light Chains

Human Immunoglobulin Light Chains λ Form Amyloid Fibrils and Granular Aggregates in Solution

2005 ◽  
Vol 70 (4) ◽  
pp. 458-466 ◽  
Author(s):  
O. P. Bliznyukov ◽  
L. D. Kozmin ◽  
L. L. Vysotskaya ◽  
A. K. Golenkov ◽  
V. M. Tishchenko ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Human Immunoglobulin ◽  
Light Chains ◽  
Immunoglobulin Light Chains

scholarly journals Identification of two principal amyloid-driving segments in variable domains of Ig light chains in AL amyloidosis

2018 ◽  
Author(s):  
Boris Brumshtein ◽  
Shannon R. Esswein ◽  
Michael R. Sawaya ◽  
Alan T. Ly ◽  
Meytal Landau ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Experimental Approach ◽  
Amyloid Fibril ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chains ◽  
Monoclonal Immunoglobulin ◽  
Variable Domains ◽  
Β Sheets ◽  
Amyloid Diseases

ABSTRACTSystemic light chain amyloidosis (AL) is a disease caused by overexpression of monoclonal immunoglobulin light chains that form pathogenic amyloid fibrils. These amyloid fibrils deposit in tissues and cause organ failure. Proteins form amyloid fibrils when they partly or fully unfold and expose segments capable of stacking into β-sheets that pair forming a tight, dehydrated interface. These structures, termed steric zippers, constitute the spines of amyloid fibrils. Here, we identify segments within the variable domains of Ig light chains that drive the assembly of amyloid fibrils in AL. We demonstrate there are at least two such segments. Each one can drive amyloid fibril assembly independently of the other. Thus these two segments are therapeutic targets. In addition to elucidating the molecular pathogenesis of AL, these findings also provide an experimental approach to identify segments that drive fibril formation in other amyloid diseases.

Prospective Randomized Trial of Melphalan and Prednisone Versus Vincristine, Carmustine, Melphalan, Cyclophosphamide, and Prednisone in the Treatment of Primary Systemic Amyloidosis

1999 ◽  
Vol 17 (1) ◽  
pp. 262-262 ◽  
Author(s):  
Morie A. Gertz ◽  
Martha Q. Lacy ◽  
John A. Lust ◽  
Philip R. Greipp ◽  
Thomas E. Witzig ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Survival Time ◽  
Conventional Therapy ◽  
Cardiac Involvement ◽  
Response Rate ◽  
Alkylating Agents ◽  
Systemic Amyloidosis ◽  
Light Chains ◽  
Primary Amyloidosis ◽  
To Receive

PURPOSE: Primary systemic amyloidosis is an immunoglobulin deposition disorder in which insoluble light chains cause organ dysfunction and death. The established conventional therapy is treatment with melphalan and prednisone. We investigated whether treatment with multiple alkylating agents improved the response rate or survival time, compared with melphalan and prednisone therapy. PATIENTS AND METHODS: We treated 101 patients with biopsy-proven primary amyloidosis. The patients were randomly assigned to receive melphalan and prednisone (52 patients) or vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (49 patients). Patients were stratified according to the presence of cardiac involvement, time from diagnosis to randomization, serum beta2-microglobulin level, and whether peripheral neuropathy was the major manifestation of the disease. RESULTS: The median duration of survival after randomization was 29 months, with no differences in survival time between the two groups. There were 29 patients who fulfilled the response criteria: 15 in the vincristine, carmustine, melphalan, cyclophosphamide, and prednisone arm and 14 in the melphalan and prednisone arm. CONCLUSION: Therapy with multiple alkylating agents did not result in a higher response rate or longer survival time, compared with standard melphalan and prednisone treatment in patients with primary systemic amyloidosis.

scholarly journals Clinical features of the disease course in patients with solitary plasmacytoma and extramedullary multiple myeloma

2020 ◽  
pp. 43-50
Author(s):  
Zh. M. Kozich ◽  
V. N. Martinkov ◽  
Zh. N. Pugacheva ◽  
M. Yu. Zhandarov ◽  
L. A. Smirnova
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Clinical Laboratory ◽  
Young Age ◽  
Light Chains ◽  
Bone Lesions ◽  
Solitary Plasmacytoma ◽  
Immunoglobulin Light Chains ◽  
Development Of Resistance ◽  
Abnormal Ratio

Objective: to study the clinical laboratory features of the course of solitary plasmacytoma (SP) and extramedullary multiple myeloma (EMM).Material and methods. The study included 42 people (22 patients newly diagnosed with EMM and 20 patients diagnosed with SP of various localization). The results were evaluated after 3 years of the study. The median age in the SP group was 61.5 years, in the EMM group — 65 years.Results. A comparative analysis of the SP and EMM groups in terms of the clinical and laboratory parameters has found no statistical differences in the distribution of immunochemical variants. Significant differences were found in the frequency of determination of the abnormal ratio of immunoglobulin light chains (p = 0.046).In EMM, extramedullary lesions were the most common for patients with multiple lytic bone lesions of the skeleton. SP was the most frequently detected in lesions of the peripheral skeletal bones and vertebral bodies.Clinically, EMM was characterized by a more aggressive course if additional factors of an unfavorable prognosis (translocations, mutations) or unfavorable immunophenotypic markers (a combination of signs — expression of markers CD56 > 20 % and CD95 < 20 %) were identified or if the disease had been diagnosed at a young age.The presence of even a minimal number of tumor or aberrant plasma cells in the bone marrow of SP patients, an abnormal ratio of immunoglobulin light chains, paraprotein detected in blood serum or urine were all poor prognostic factors.Conclusion. The clinical course of SP and EMM combined with a young age, the presence of translocations or mutations, unfavorable immunophenotypic markers, is characterized by an increased frequency of progression or the development of resistance to the performed therapy.

Sign in / Sign up

Export Citation Format

Share Document