The American Society of Hematology (ASH) has released new Clinical Practice Guidelines on the diagnosis of light chain (AL) amyloidosis, a rare and life-threatening bone marrow disorder. The guidelines present 12 evidence-based recommendations designed to help clinicians and facilitate early and accurate diagnosis of AL amyloidosis. Participating in the two-year research was a large group of multi-disciplinary amyloidosis experts, as well as Deb Boedicker from Mackenzie’s Mission/Amyloidosis Speakers Bureau. Below we summarize the 12 recommendations, followed by a link to the full publication. In addition, at the end you’ll find a link to a comprehensive Resource Center which support these Clinical Practice Guidelines.

 

The primary goals of these guidelines are to review, critically appraise and implement evidence-based recommendations that will enhance early detection, timeliness and accuracy of diagnosis of AL amyloidosis. Through improved provider and patient education of the available evidence and creation of evidence-based recommendations, these guidelines aim to provide clinical decision support that will result in clear diagnostic decision making with known potential outcomes and enable timely diagnosis of AL amyloidosis by multidisciplinary teams.

ENHANCING CLINICAL SUSPICION

Should serum and urine immunofixation (SIFE and UIFE) and serum free light chains (sFLC) be used to increase suspicion of AL amyloidosis in individuals with cardiac symptoms?
Recommendation 1
For individuals with suspected cardiac amyloidosis, the ASH Guideline Panel recommends the use of serum and urine immunofixation (SIFE and UIFE) and serum free light chain (sFLC) assay to increase clinical suspicion of cardiac AL amyloidosis.

Should serum and urine immunofixation (SIFE and UIFE) and serum free light chains (sFLC) be used to increase suspicion of AL amyloidosis in individuals with unexplained proteinuria?
Recommendation 2
For individuals with unexplained proteinuria, the ASH Guideline Panel suggests performing paraprotein testing (SIFE/UIFE/sFLC) to increase clinical suspicion of AL amyloidosis.

Should cardiac MRI (CMR) be used to diagnose cardiac AL amyloidosis in individuals suspected of having cardiac amyloidosis (positivity in any of the following studies: SIFE, UIFE, or sFLC, abnormal cardiac biomarkers, and non-diagnostic echocardiographic findings)?
Recommendation 3
For individuals with positivity in any of the following studies SIFE, UIFE, or sFLC, and abnormal cardiac biomarkers, and non-diagnostic echocardiography, the ASH Guideline Panel suggests performing cardiac magnetic resonance (CMR) rather than not performing CMR to increase clinical suspicion of cardiac amyloidosis.

Should cardiac MRI (CMR) be used to diagnose cardiac AL amyloidosis in individuals with abnormal cardiac biomarkers, echocardiography, and positivity in any of the following studies: SIFE, UIFE, or sFLC?
Recommendation 4
For individuals with positivity in any of the following studies SIFE, UIFE, or sFLC, and abnormal cardiac biomarkers, and echocardiography consistent with amyloidosis, the ASH Guideline Panel suggests against performing cardiac magnetic resonance (CMR) and instead performing tissue biopsy to diagnose cardiac AL amyloidosis.

DIAGNOSIS

Should Bone Scintigraphy with technetium 99m – pyrophosphate (PYP), technetium 99 m – 3, 3 diphosphono –1,2 propranodicarboxylic (DPD) and technetium 99 m-hydroxymethylene Diphosphonate (HMDP) be used to diagnose amyloidosis in suspected individuals?
Recommendation 5
For individuals with a suspicion of AL amyloidosis, the ASH Guideline Panel recommends against the use of bone scintigraphy (PYP, DPD, HMDP) for the diagnosis of AL cardiac amyloidosis.

Should Bone Scintigraphy (PYP, DPD, HMDP) be used to diagnose ATTR amyloidosis in suspected individuals?
Recommendation 6
For patients without evidence of a plasma cell disorder (normal serum free light chain levels and no monoclonal proteins on serum and urine immunofixation) and suspicion of cardiac amyloidosis, the ASH Guideline Panel recommends the use of bone scintigraphy (PYP, DPD, HMDP) for the diagnosis of Cardiac ATTR amyloidosis.

Should surrogate biopsy vs. cardiac biopsy be used to diagnose AL amyloidosis in individuals suspected to have cardiac amyloidosis?
Recommendation 7
For individuals with suspected AL cardiac amyloidosis with abnormal cardiac biomarkers, diagnostic echocardiogram, and positivity in any of the following studies: SIFE, UIFE, or sFLC, the ASH Guideline Panel suggests either starting with performing both fat pad sampling and bone marrow biopsy or with endomyocardial biopsy.

Should surrogate biopsy vs renal biopsy be used to diagnose AL amyloidosis in individuals suspected to have renal amyloidosis?
Recommendation 8
For individuals with suspected light chain renal amyloidosis and positivity in any of the following studies SIFE, UIFE, or sFLC, the ASH Guideline Panel suggests starting with performing both abdominal fat pad sampling and bone marrow biopsy over renal biopsy.

Should surrogate biopsy vs. peripheral nerve biopsy be used to diagnose AL amyloidosis in individuals suspected to have neurological amyloidosis?
Recommendation 9
For individuals with a monoclonal gammopathy and generalized small or large fiber peripheral neuropathy or autonomic neuropathy suspected of having AL amyloidosis, the ASH Guideline Panel suggests performing both fat pad sampling and bone marrow biopsy over nerve biopsy.

Should surrogate biopsy vs target organ biopsy be used to diagnose AL amyloidosis in individuals suspected to have AL amyloidosis with multiorgan presentation?
Recommendation 10
For individuals with suspected multiorgan AL amyloidosis, the ASH Guideline Panel suggests starting with surrogate biopsies (combination of fat pad sampling and bone marrow biopsy) over target organ biopsy if surrogate biopsies can be performed expeditiously. If endomyocardial biopsy or renal biopsy are more feasible than fat pad sampling and bone marrow biopsy, these symptomatic target tissues should be preferentially biopsied.

Should Congo Red Staining on bone marrow biopsy that has already been performed be used to diagnose AL amyloidosis in individuals with Multiple Myeloma and Smoldering Myeloma?
Recommendation 11
For individuals with plasma cell dyscrasias (multiple myeloma and smoldering multiple myeloma), the ASH Guideline Panel suggests performing Congo red staining on bone marrow biopsies that may have already been performed.

ORGAN INVOLVEMENT

In individuals with AL amyloidosis with no cardiac symptoms, should clinicians use cardiac biomarkers/investigations [BNP, NT-proBNP, troponin (I,C,T, Highly Sensitive), 2D Echo with strain, Cardiac MRI] or not to evaluate for cardiac involvement?
Recommendation 12
For individuals with proven AL amyloidosis and with no cardiac symptoms, the ASH Guideline Panel recommends performing cardiac biomarkers (high sensitivity troponin, and BNP or NT-proBNP) and cardiac imaging rather than not performing these tests to define the presence and extent of cardiac involvement at diagnosis.

KEY CONCLUSIONS

The use of serum immunofixation, urine immunofixation and serum free light chains enhances the clinical suspicion of AL amyloidosis. The diagnosis of AL amyloidosis can be made effectively through surrogate biopsies which require both a bone marrow biopsy and fat pad sampling. However, target organ biopsies may be favoured in certain clinical situations.

Overarching good practice statements:
1. The ASH panel agreed that it is essential to assess for major organ involvement in patients with confirmed AL amyloidosis, as this guides further management and risk stratification.
2. A multidisciplinary team is typically required for the timely and accurate diagnosis and management of AL amyloidosis.

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The red flag signs and symptoms provide a summarized way to elevate suspicion and hopefully accelerate the diagnostic timeline.

RED FLAG SIGNS AND SYMPTOMS FOR CARDIAC INVOLVEMENT

1. HFpEF (heart failure with preserved ejection fraction)
2. Moderate or Severe LVH in absence of a significant history of untreated hypertension on imaging.
3. Echocardiogram: Severe left ventricular hypertrophy, advanced diastolic dysfunction, reduced left ventricular global longitudinal strain with an apical sparing pattern
4. EKG/Arrhythmia: Low voltage and/or discordance between voltage on EKG and left ventricular wall thickness on imaging, pseudo-infarct pattern, and arrhythmias including atrial fibrillation, heart block, and ventricular tachycardia/ventricular fibrillation
5. Elevated biomarkers (Troponin and NT-Pro BNP) in absence of CAD
6. Constellation of symptoms suggesting cardiac, renal, and peripheral nervous system disease
7. Low Flow, Low Gradient Aortic Stenosis

RED FLAG SIGNS AND SYMPTOMS FOR RENAL INVOLVEMENT

1. Inability to tolerate ACE/ARB
2. Change in hypertension status unexplained by medication i.e. intolerance/hypotension on previously tolerated therapy.
3. Unexplained proteinuria (albumin predominant) without diabetes (or not thought to be related to be diabetes or any other reason) and positive laboratory tests (monoclonal proteins and/or abnormal light chains (must be clonal or above renal limits)
4. Proteinuria in diabetic with positive monoclonal protein

RED FLAG SIGNS AND SYMPTOMS FOR NEUROLOGICAL INVOLVEMENT

1. Small fiber neuropathy: pain and temperature impairments, allodynia and hyperalgesia
2. Autonomic neuropathy: orthostatic hypotension, erectile dysfunction, diarrhea and/or constipation, gastroparesis, urinary dysfunction, sweating abnormalities, pupillary dysfunction and dry eye and mouth.
3. Sensorimotor neuropathy: numbness, paresthesia, imbalance, weakness and atrophy.
4. Autonomic, Small fiber or sensorimotor neuropathy unexplained by other causes, including diabetes.
5. Abnormal nerve conduction studies/ electromyography, typically a sensory or sensorimotor neuropathy with axonal pattern.
6. Carpal Tunnel Syndrome – bilateral, particularly with heart disease and a monoclonal protein
7. Peripheral neuropathy with positive monoclonal gammopathy
8. Rapid progression of neuropathy
9. Constellation of symptoms suggesting cardiac, renal, and peripheral nervous system disease

RED FLAG SIGNS AND SYMPTOMS – OTHER

Liver Presentation

1. Cholestatic (associated with raised serum alkaline phosphatase) not related to other disorders.
2. Hepatomegaly not related to other disorders.

Gastrointestinal tract Presentation

1. Unexplained diarrhea and/or constipation, weight loss, loss of appetite, early satiety, nausea, vomiting, abdominal pain, gastrointestinal bleeding

Other

1. Easy Bleeding and bruising (associated with acquired factor X deficiency)

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LINK TO PUBLICATION IN BLOOD ADVANCES

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In addition, ASH provides a comprehensive Resource Center to support the Clinical Practice Guidelines. In this center, clinicians will find a significant library of resources including the following.

• A snapshot of the ASH Clinical Practice Guidelines — “Diagnosis of Light Chain (AL) Amyloidosis: What You Should Know”
  • What it covers
  • Why it matters
  • Who it affects
  • What are the highlights
• A Disease State Infographic
• A Visual Summary: a concise visual aid intended to support understanding of the recommendations and to aid in clinical decision-making.
• A Pocket Guide: a brief, evidence-based pocket guide intended to help physicians provide quality care to patients.
• Teaching Slides: educational slides intended to teach about the diagnosis of amyloidosis.
• Audit Report: A set of metrics intended to assess compliance with the ASH Clinical Practice Guidelines on Diagnosis of Light Chain Amyloidosis. This audit report can be used to identify quality gaps at your institution and improve care for patients with light chain amyloidosis.

LINK TO RESOURCE CENTER