Systemic light chain amyloidosis: an update for treating physicians

Abstract In immunoglobulin light chain amyloidosis a small, indolent plasma cell clone synthesizes light chains that cause devastating organ damage. Early diagnosis, based on prompt recognition of “red-flags” before advanced cardiomyopathy ensues, is essential for improving outcomes. Differentiation from other systemic amyloidoses may require advanced technologies. Prognosis depends on the extent of cardiac involvement, and cardiac biomarkers guide the choice of therapy. The protean clinical presentation requires individualized treatment. Close monitoring of clonal and organ response guides therapy changes and duration. Conventional or high-dose alkylator-based chemotherapy is effective in almost two-thirds of patients. Combinations of proteasome inhibitors, dexamethasone, and alkylators achieve high response rates, although controlled studies are needed. Risk-adapted stem cell transplant and consolidation with novel agents may be considered in selected patients. Immune-modulatory drugs are good options for refractory/relapsed patients. Novel agents and therapeutic targets are expected to be exploited, in an integrated, more effective and less toxic treatment strategy.

Download Full-text

Long-Term Outcomes of Patients With Systemic Light Chain Amyloidosis (AL) Treated at Diagnosis With Risk-Adapted Stem Cell Transplant and Consolidation With Novel Agents

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2012.11.298 ◽

2013 ◽

Vol 19 (2) ◽

pp. S235-S236

Author(s):

Heather Landau ◽

Daniel Fein ◽

Hani Hassoun ◽

Christina Bello ◽

Joanne Chou ◽

...

Keyword(s):

Stem Cell ◽

Light Chain ◽

Stem Cell Transplant ◽

Novel Agents ◽

Cell Transplant ◽

Long Term Outcomes ◽

Light Chain Amyloidosis

Download Full-text

Conventional Therapy for Amyloid Light-Chain Amyloidosis

Acta Haematologica ◽

10.1159/000507072 ◽

2020 ◽

Vol 143 (4) ◽

pp. 365-372

Author(s):

Paolo Milani ◽

Giovanni Palladini

Keyword(s):

Stem Cell ◽

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Alkylating Agents ◽

Proteasome Inhibitors ◽

Response Rates ◽

Al Amyloidosis ◽

Cell Transplant ◽

Conventional Chemotherapy

The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional regimens are based on various combinations of dexamethasone, alkylating agents, proteasome inhibitors, and immunomodulatory drugs. The choice of these regimens requires a careful risk stratification, based on the extent of amyloid organ involvement, comorbidities, and the characteristics of the amyloidogenic plasma cell clone. Most patients are treated upfront with bortezomib and dexamethasone combined with cyclophosphamide or melphalan. Cyclophosphamide does not compromise stem cell mobilization and harvest and is more manageable in renal failure. Melphalan can overcome the effect of t(11;14), which is associated with lower response rates and shorter survival in subjects treated with bortezomib and dexamethasone, or in combination with cyclophosphamide. Lenalidomide and pomalidomide are the mainstay of rescue treatment. They are effective in patients exposed to bortezomib, dexamethasone, and alkylators, but deep hematologic responses are rare. Ixazomib, alone or in combination with lenalidomide, increases the rate of complete responses in relapsed/refractory patients. Conventional chemotherapy regimens will represent the backbone for future combinations, particularly with anti-plasma-cell immunotherapy, that will further improve response rates and outcomes.

Download Full-text

High Dose Therapy Improves Survival in Systemic Light Chain Amyloidosis: 14 Year Follow up

Blood ◽

10.1182/blood.v120.21.750.750 ◽

2012 ◽

Vol 120 (21) ◽

pp. 750-750

Author(s):

Simrit Parmar ◽

Joshua Howell ◽

Michael Wang ◽

Mubeen A Khan ◽

Qaiser Bashir ◽

...

Keyword(s):

Light Chain ◽

Troponin I ◽

Induction Treatment ◽

High Dose ◽

Primary Amyloidosis ◽

Cell Transplant ◽

Term Survival ◽

Light Chain Amyloidosis ◽

Number Of Patients

Abstract Abstract 750 Background: Treatment remains a challenge for systemic light chain amyloidosis (AL). Autologous stem cell transplant (AutoSCT) has been associated with long term survival. However, a recent multicenter randomized study failed to show survival benefit for AutoSCT perhaps due to high non-relapse mortality (NRM). Here we present a comparison of AutoSCT to other conventional therapies in AL patients treated at our institution with a 14-year follow up. Methods: A total of 2018 cases were identified upon pathology review from 1998–2012. AL was confirmed in 264 patients; primary amyloidosis (PA) in 147 pts and multiple myeloma with amyloidosis (AM) in 110 patients; solitary amyloidoma in 7 patients. AutoSCT was performed in 126 patients (PA=79 and AM=47). Results: The day 100 NRM was 5% and 1-year NRM was 8%. With a follow up of 14 years in surviving patients, the 10-year overall survival (OS) of AL patients was significantly better in those undergoing AutoSCT (41% vs. 17%; p<0.0001; figure 1). Involvement of more than one organ (6-yr OS 36% vs. 55%; p=0.04) and cardiac involvement (2-yr OS of 57% vs. 78%; p=0.01) were associated with poor outcome. In the patients undergoing AutoSCT: PA vs. AM, Mayo staging, Boston University (BU) staging or bone marrow plasma cells >10 % at the time of autoSCT did not have an impact on OS. Cardiac biomarkers including NT-ProBNP and Troponin-I and T levels were available in a limited number of patients and were not analyzed for survival outcomes. In multivariate analysis, superior OS was associated with: age <60yrs (HR 2.1, p=0.022); and induction treatment before AutoSCT (HR 2.7, p=0.02). Involvement of kidney as the only end organ showed a trend toward improved survival (HR 1.6, p=0.06) (Table 1). Specifically for PA patients (n=79); treatment before autoSCT was associated with improved 3-yr OS: 85% vs. 66%; p=0.02. Conclusions: AL patients should be evaluated for AutoSCT and selected patients should undergo induction therapy to decrease amyloid burden prior to AutoSCT. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Novel Therapies and Approaches to Relapsed/Refractory HL Beyond Chemotherapy

Cancers ◽

10.3390/cancers11030421 ◽

2019 ◽

Vol 11 (3) ◽

pp. 421 ◽

Cited By ~ 2

Author(s):

Alain Mina ◽

Chetan Vakkalagadda ◽

Barbara Pro

Keyword(s):

Salvage Therapy ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Novel Agents ◽

High Dose ◽

Cell Transplant ◽

Close Monitoring ◽

Early Stage Disease ◽

Early Results ◽

Stage Disease

Although Hodgkin lymphoma (HL) is highly curable with first-line therapy, relapses occur in approximately 10–20% of patients with early stage disease and 30–40% of patients with advanced stage disease. The standard approach for relapsed or refractory disease is salvage therapy, followed by consolidation with high dose therapy and autologous stem cell transplant (ASCT). Patients who achieve a complete response to salvage therapy prior to ASCT have better outcomes, thus recent studies have focused on incorporating newer agents in this setting. Major challenges in the management of relapsed patients remain how to choose and sequence the many salvage therapies that are currently available and how to best incorporate novel agents in the current treatment paradigms. In this article, we will summarize the most recent advances in the management of patients with recurrent HL and will mainly focus on the role of new agents approved and under investigation. Aside from brentuximab vedotin and checkpoint inhibitors, other novel agents and therapies are showing promising early results. However, at least with some of the newest targeted strategies, it is important to recognize that we are facing new challenges in terms of toxicities, which require very close monitoring and education of both the patient and treating physician.

Download Full-text

Nonchemotherapy Treatment of Immunoglobulin Light Chain Amyloidosis

Acta Haematologica ◽

10.1159/000507724 ◽

2020 ◽

Vol 143 (4) ◽

pp. 373-380

Author(s):

Layla Van Doren ◽

Suzanne Lentzsch

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Standard Of Care ◽

Organ Damage ◽

Current Therapy ◽

Al Amyloidosis ◽

Immunoglobulin Light Chain ◽

Light Chain Amyloidosis ◽

Immunoglobulin Light Chain Amyloidosis

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare, life-threatening disease characterized by the deposition of misfolded proteins in vital organs such as the heart, the lungs, the kidneys, the peripheral nervous system, and the gastrointestinal tract. This causes a direct toxic effect, eventually leading to organ failure. The underlying B-cell lymphoproliferative disorder is almost always a clonal plasma cell disorder, most often a small plasma cell clone of <10%. Current therapy is directed toward elimination of the plasma cell clone with the goal of preventing further organ damage and reversal of the existing organ damage. Autologous stem cell transplantation has been shown to be a very effective treatment in patients with AL amyloidosis, although it cannot be widely applied as patients are often frail at presentation, making them ineligible for transplantation. Treatment with cyclophosphamide, bortezomib, and dexamethasone has emerged as the standard of care for the treatment of AL amyloidosis. Novel anti-plasma cell therapies, such as second generation proteasome inhibitors, immunomodulators, monoclonal antibodies targeting a surface protein on the plasma cell (daratumumab, elotuzumab), and the small molecular inhibitor venetoclax, have continued to emerge and are being evaluated in combination with the standard of care. However, there is still a need for therapies that directly target the amyloid fibrils and reverse organ damage. In this review, we will discuss current and emerging nonchemotherapy treatments of AL amyloidosis, including antifibril directed therapies under current investigation.

Download Full-text

Treatment with intravenous melphalan and dexamethasone is not able to overcome the poor prognosis of patients with newly diagnosed systemic light chain amyloidosis and severe cardiac involvement

Blood ◽

10.1182/blood-2009-11-253237 ◽

2010 ◽

Vol 116 (4) ◽

pp. 522-528 ◽

Cited By ~ 64

Author(s):

Sascha Dietrich ◽

Stefan O. Schönland ◽

Axel Benner ◽

Tilmann Bochtler ◽

Arnt V. Kristen ◽

...

Keyword(s):

Light Chain ◽

Cardiac Biomarkers ◽

High Dose ◽

Hematologic Toxicity ◽

Light Chain Amyloidosis ◽

First Line Therapy ◽

Organ Response ◽

Grade 3 ◽

High Dose Melphalan ◽

Karnofsky Index

Abstract Treatment with oral melphalan and dexamethasone (M-Dex) was reported to be effective and feasible in patients with systemic light chain amyloidosis (AL) not eligible for high-dose melphalan. We report on 61 patients with advanced AL who were treated with intravenous M-Dex as first-line therapy. Estimated median overall survival (OS) was 17.5 months. Seventeen patients (28%) died within 3 months, mostly of disease-related complications. In addition, nonhematologic toxicity of Common Terminology Criteria grade 3 or 4 was observed in 20 patients, whereas hematologic toxicity was low. Twenty-seven patients (44%) had hematologic response, including complete in 7 patients (11%) and partial remission in 20 patients (33%). Organ response was observed in 15 patients (25%). The amount of the involved free light chains in serum and Karnofsky Index at diagnosis significantly influenced OS. Plasma levels of the cardiac biomarkers before start of treatment and their increase after the third M-Dex cycle also were strong negative predictors of OS. These parameters might help to identify patients who will not benefit from M-Dex chemotherapy.

Download Full-text

Role of stem cell transplant and maintenance therapy in plasma cell disorders

Hematology ◽

10.1182/asheducation.v2016.1.504.088352 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 504-511 ◽

Cited By ~ 3

Author(s):

Philip L. McCarthy ◽

Sarah A. Holstein

Keyword(s):

Stem Cell ◽

Maintenance Therapy ◽

Disease Control ◽

Stem Cell Transplant ◽

Proteasome Inhibitors ◽

Treatment Strategies ◽

High Dose Chemotherapy ◽

Novel Agents ◽

High Dose ◽

Cell Transplant

AbstractAutologous stem cell transplant (ASCT) has been an important component of therapy for myeloma patients eligible for high-dose chemotherapy. Recent studies comparing early transplant to low-dose chemotherapy support the continued use of ASCT as consolidation following induction therapy, even in the era of immunomodulatory drugs, proteasome inhibitors, and other novel agents. Despite the marked improvements in outcomes with this approach, most patients will eventually experience disease progression. Thus, inclusion of post-ASCT consolidation/maintenance strategies is used to improve long-term disease control. Multiple randomized studies support the use of lenalidomide maintenance therapy following ASCT. The next generation of clinical trials will incorporate novel agents such as monoclonal antibodies, proteasome inhibitors, and other novel pathway modulatory agents into post-ASCT treatment strategies with the goal of achieving even deeper responses and longer durations of disease control.

Download Full-text

Role of stem cell transplant and maintenance therapy in plasma cell disorders

Hematology ◽

10.1182/asheducation-2016.1.504 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 504-511 ◽

Cited By ~ 11

Author(s):

Philip L. McCarthy ◽

Sarah A. Holstein

Keyword(s):

Stem Cell ◽

Maintenance Therapy ◽

Disease Control ◽

Stem Cell Transplant ◽

Proteasome Inhibitors ◽

Treatment Strategies ◽

High Dose Chemotherapy ◽

Novel Agents ◽

High Dose ◽

Cell Transplant

Autologous stem cell transplant (ASCT) has been an important component of therapy for myeloma patients eligible for high-dose chemotherapy. Recent studies comparing early transplant to low-dose chemotherapy support the continued use of ASCT as consolidation following induction therapy, even in the era of immunomodulatory drugs, proteasome inhibitors, and other novel agents. Despite the marked improvements in outcomes with this approach, most patients will eventually experience disease progression. Thus, inclusion of post-ASCT consolidation/maintenance strategies is used to improve long-term disease control. Multiple randomized studies support the use of lenalidomide maintenance therapy following ASCT. The next generation of clinical trials will incorporate novel agents such as monoclonal antibodies, proteasome inhibitors, and other novel pathway modulatory agents into post-ASCT treatment strategies with the goal of achieving even deeper responses and longer durations of disease control.

Download Full-text