Management of AL amyloidosis in 2020 Palladini, Giovanni; Milani, Paolo; Merlini, Giampaolo
Blood,
12/2020, Volume:
136, Issue:
23
Journal Article
Peer reviewed
Open access
In amyloid light chain (AL) amyloidosis, a small B-cell clone, most commonly a plasma cell clone, produces monoclonal light chains that exert organ toxicity and deposit in tissue in the form of ...amyloid fibrils. Organ involvement determines the clinical manifestations, but symptoms are usually recognized late. Patients with disease diagnosed at advanced stages, particularly when heart involvement is present, are at high risk of death within a few months. However, symptoms are always preceded by a detectable monoclonal gammopathy and by elevated biomarkers of organ involvement, and hematologists can screen subjects who have known monoclonal gammopathy for amyloid organ dysfunction and damage, allowing for a presymptomatic diagnosis. Discriminating patients with other forms of amyloidosis is difficult but necessary, and tissue typing with adequate technology available at referral centers, is mandatory to confirm AL amyloidosis. Treatment targets the underlying clone and should be risk adapted to rapidly administer the most effective therapy patients can safely tolerate. In approximately one-fifth of patients, autologous stem cell transplantation can be considered up front or after bortezomib-based conditioning. Bortezomib can improve the depth of response after transplantation and is the backbone of treatment of patients who are not eligible for transplantation. The daratumumab+bortezomib combination is emerging as a novel standard of care in AL amyloidosis. Treatment should be aimed at achieving early and profound hematologic response and organ response in the long term. Close monitoring of hematologic response is vital to shifting nonresponders to rescue treatments. Patients with relapsed/refractory disease are generally treated with immune-modulatory drugs, but daratumumab is also an effective option.
New drugs are emerging as treatment options for patients with light-chain (AL) amyloidosis. In this timely review, Palladini et al first remind us of the importance of ensuring a precise diagnosis and then discuss a framework for care of newly diagnosed patients and those with relapsed or refractory disease.
Display omitted
Light chain (AL) amyloidosis is caused by a usually small plasma cell clone producing a misfolded light chain that deposits in tissues. Survival is mostly determined by the severity of heart ...involvement. Recent studies are clarifying the mechanisms of cardiac damage, pointing to a toxic effect of amyloidogenic light chains and offering new potential therapeutic targets. The diagnosis requires adequate technology, available at referral centers, for amyloid typing. Late diagnosis results in approximately 30% of patients presenting with advanced, irreversible organ involvement and dying in a few months despite modern treatments. The availability of accurate biomarkers of clonal and organ disease is reshaping the approach to patients with AL amyloidosis. Screening of early organ damage based on biomarkers can help identify patients with monoclonal gammopathy of undetermined significance who are developing AL amyloidosis before they become symptomatic. Staging systems and response assessment based on biomarkers facilitate the design and conduction of clinical trials, guide the therapeutic strategy, and allow the timely identification of refractory patients to be switched to rescue therapy. Treatment should be risk-adapted. Recent studies are linking specific characteristics of the plasma cell clone to response to different types of treatment, moving toward patient-tailored therapy. In addition, novel anti-amyloid treatments are being developed that might be combined with anti-plasma cell chemotherapy.
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.
Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart ...involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy map and molecular model of amyloid fibrils extracted from the heart of an AL amyloidosis patient with severe amyloid cardiomyopathy. The helical fibrils are composed of a single protofilament, showing typical 4.9 Å stacking and cross-β architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (V
) fit the fibril density. Despite V
high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic V
, highlighting structural motifs that may be common to misfolding-prone LCs. Our data shed light on the architecture of LC amyloids, correlate amino acid sequences with fibril assembly, providing the grounds for development of innovative medicines.
The combination of cyclophosphamide/bortezomib/dexamethasone (CyBorD) showed early promise of high rates of hematologic responses tempered by studies showing the inability to overcome poor prognosis ...of advanced cardiac amyloidosis. Large studies are needed to clarify its role in light chain (AL) amyloidosis. We report the outcome of 230 patients treated frontline with CyBorD. Overall hematologic response rate was 60–, and in the 201 patients with measurable disease it was 62–, with 43– achieving at least very good partial response (VGPR). Cardiac response was reached in 17– of patients and renal response in 25– of patients. Advanced cardiac stage III patients (amino-terminal pro-natriuretic peptide type B >8500 ng/L) had lower response rates (42–, ≥ VGPR 23–) and poorer survival (median, 7 months). Nevertheless, hematologic response improved survival in these subjects (67– at 2 years), showing the importance of striving for a good response even in this group.
•CyBorD achieves excellent outcome in noncardiac patients with AL amyloidosis and can rescue subjects with reversible heart damage.•The outcome of high-risk patients remains poor, but response to CyBorD can also improve survival in this group.
Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis Gillmore, Julian D; Maurer, Mathew S; Falk, Rodney H ...
Circulation (New York, N.Y.),
2016-June-14, 2016-Jun-14, 2016-06-14, 20160614, Volume:
133, Issue:
24
Journal Article
Peer reviewed
Open access
BACKGROUND—Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed ...because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease.
METHODS AND RESULTS—Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0–100).
CONCLUSIONS—Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.
The kidney is involved in 70% of patients with immunoglobulin light-chain (AL) amyloidosis, but little is known on progression or reversibility of renal involvement, and criteria for renal response ...have never been validated. Newly diagnosed patients from the Pavia (n = 461, testing cohort) and Heidelberg (n = 271, validation cohort) centers were included. Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50 mL/min predicted progression to dialysis best. Proteinuria below and eGFR above the thresholds indicated low risk (0 and 4% at 3 years in the testing and validation cohorts, respectively). High proteinuria and low eGFR indicated high risk (60% and 85% at 3 years). At 6 months, a ≥25% eGFR decrease predicted poor renal survival in both cohorts and was adopted as criterion for renal progression. A decrease in proteinuria by ≥30% or below 0.5 g/24 h without renal progression was the criterion for renal response, being associated with longer renal survival in the testing and validation populations. Hematologic very good partial or complete remission at 6 months improved renal outcome in both populations. We identified and validated a staging system for renal involvement and criteria for early assessment of renal response and progression in AL amyloidosis that should be used in clinical practice and trial design.
•A staging system based on proteinuria and glomerular filtration rate discriminates patients at different risk of progression to dialysis.•Changes in proteinuria and glomerular filtration rate allow early assessment of renal response to therapy.
To identify the criteria for hematologic and cardiac response to treatment in immunoglobulin light chain (AL) amyloidosis based on survival analysis of a large patient population.
We gathered for ...analysis 816 patients with AL amyloidosis from seven referral centers in the European Union and the United States. A different cohort of 374 patients prospectively evaluated at the Pavia Amyloidosis Research and Treatment Center was used for validation. Data was available for all patients before and 3 and/or 6 months after initiation of first-line therapy. The prognostic relevance of different criteria for hematologic and cardiac response was assessed.
There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival. This allowed the identification of four levels of response: amyloid complete response (normal FLC ratio and negative serum and urine immunofixation), very good partial response (difference between involved and uninvolved FLCs dFLC < 40 mg/L), partial response (dFLC decrease > 50%), and no response. Cardiac involvement is the major determinant of survival, and changes in cardiac function after therapy can be reliably assessed using the cardiac biomarker N-terminal natriuretic peptide type B (NT-proBNP). Changes in FLC and NT-proBNP predicted survival as early as 3 months after treatment initiation.
This study identifies and validates new criteria for response to first-line treatment in AL amyloidosis, based on their association with survival in large patient populations, and offers surrogate end points for clinical trials.
PDF
