Case study 57.1
An 80-year-old man is referred to you for evaluation and treatment. The patient had been noted by his primary care doctor to have a monoclonal gammopathy of uncertain significance (MGUS) 10 years previously. Over the past year, the patient has developed dyspnea on exertion and signs of congestive heart failure, and he was placed on a diuretic and an angiotensin-converting enzyme inhibitor by his cardiologist. The cardiac evaluation has revealed increased wall thickness on echocardiography with diastolic dysfunction, and a cardiac magnetic resonance (CMR) study showed delayed gadolinium enhancement of the subendocardium consistent with amyloidosis. The cardiologist and primary care doctor have concluded the patient has light-chain amyloidosis (AL), and they are referring the patient to you for treatment.
- Start the patient as soon as possible on treatment with melphalan and prednisone
- Start the patient as soon as possible on melphalan and dexamethasone
- Start the patient as soon as possible on treatment with CyBorD, the combination of cyclophosphamide, bortezomib, and dexamethasone
- Refer the patient to a colleague for consideration of stem cell transplantation
- Carry out additional diagnostic studies
Kudos to your colleagues for identifying a possible case of cardiac AL amyloidosis, a disease that can progress rapidly and is fatal without treatment. However, it would not be appropriate to treat this patient with chemotherapy without confirmation of the diagnosis. There are two essential steps in diagnosing AL amyloidosis: proving that amyloid fibrils are present, and proving that a plasma cell dyscrasia is responsible for the disease. The demonstration of amyloidosis can be accomplished by biopsy of the involved organ, in this case the heart, or by a less invasive aspiration of abdominal fat under local anesthesia, which is positive in 66–95% of patients with systemic amyloidosis, depending upon the type.
2. An abdominal fat aspirate is performed, dried on a slide, stained with Congo red dye, and examined under polarized light microscopy. Apple-green birefringence is seen. Now that you have proven the patient has amyloidosis, what should you do?
- Start the patient as soon as possible on treatment with melphalan and prednisone
- Start the patient as soon as possible on melphalan and dexamethasone
- Start the patient as soon as possible on treatment with CyBorD
- Refer the patient to a colleague for consideration of stem cell transplantation
- Carry out additional diagnostic studies
You still have not established the diagnosis of AL amyloidosis. MGUS is not uncommon in an 80-year-old man; it occurs in about 7% of 80-year-old white males (data from Olmstead County, Minnesota), and the incidence in African Americans is 2–3 times higher. It is important to recognize that older men can develop an entity termed senile systemic amyloidosis (SSA) due to deposition of wild-type transthyretin (TTR), most commonly in the heart. The formal nomenclature for this would be ATTR(wt) to distinguish it from a hereditary form of amyloidosis due to production of a mutant TTR, ATTR(mut), a subtype of AF (familial amyloidosis). These patients should not be treated with chemotherapy. The TTR is synthesized in the liver, and chemotherapy would have no benefit.
3. How do you go about proving this is AL amyloidosis, due to aggregation and deposition of clonal immunoglobulin light chains produced by bone marrow plasma cells?
While the clinical presentation can favor one or the other (e.g., a patient whose parent had ATTRmut probably has the same diagnosis, whereas a patient who has multiorgan disease, or macroglossia, with a plasma cell dyscrasia undoubtedly has AL). In many cases, the clinical diagnosis should be confirmed using immunochemical or molecular testing. Most pathology laboratories are able to perform immunohistochemistry (IHC) for TTR, AA (secondary amyloidosis protein), and kappa and lambda light chains. If one of these is strongly positive and the others are negative, that is generally a reliable result. However, amyloid fibrils can bind antibodies nonspecifically, and if multiple antibodies are positive, the IHC is not helpful. Immunoelectron microscopy has more specificity but is not widely available. Many cases can be sorted out with mass spectrometric analysis of fibrils harvested from tissue sections using laser capture microdissection, which is available as a commercial test through the Mayo Clinical Laboratories. If the patient in question has TTR deposition by an immunochemical technique, gene sequencing should be done to distinguish a hereditable TTR mutant, versus the wild-type TTR that causes SSA.
Based on clinical presentation, there is a real possibility that this patient has two unlinked age-related conditions, MGUS and SSA, and does not need specific treatment for either. In that case, management would be supportive care to reduce heart failure symptoms. Drugs that stabilize TTR and reduce fibril formation, such as tafamidis and diflunisal, are under ongoing investigation.
4. If the workup reveals light-chain fibrils consistent with AL, what is the best treatment?
- Start the patient as soon as possible on treatment with melphalan and prednisone
- Start the patient as soon as possible on melphalan and dexamethasone
- Start the patient as soon as possible on treatment with CyBorD
- Refer the patient to a colleague for consideration of stem cell transplantation
- Tailor treatment based upon the patient’s performance status and comorbidities
There are no evidence-based guidelines for treatment of AL in older patients. In the era before the so-called novel agents for plasma cell diseases (proteasome inhibitors and immunomodulators), we were sometimes able to employ modified high-dose melphalan and autologous stem cell transplantation in patients up to age 80. However, the efficacy of the novel agents has shifted the risk–benefit ratio in older patients, and most centers would no longer consider transplant for patients this old, particularly with cardiac involvement, as risk of treatment-related mortality is high. Melphalan and prednisone is a regimen with a low response rate that largely has been superseded by melphalan + dexamethasone, as higher response rates were seen with the more intensive steroid regimen. However, in patients with cardiac amyloidosis, young or old, weekly dexamethasone is better tolerated than a consecutive 4-day regimen; even the weekly dosing may need to be modified to avoid exacerbation of congestive heart failure. I would suggest starting this 80 year old on no more than 20 mg dexamethasone weekly, with the expectation of needing to increase diuretics for a day or two after the steroid. While oral melphalan + dexamethasone is a convenient oral regimen, many hematologists now choose a bortezomib-containing regimen as first-line therapy for plasma cell diseases. Many centers would begin with bortezomib and dexamethasone on a weekly dose-reduced schedule in a patient this old (e.g., 1.3 mg/m2 of bortezomib with 20 mg of intravenous dexamethasone). Weekly dosing will be more tolerable in terms of congestive heart failure, and it also has a lower incidence of neuropathy than biweekly dosing. Pharmacokinetic and pharmacodynamic data suggest subcutaneous administration is bioequivalent to the original intravenous regimen, and is an alternative. CyBorD is a highly effective three-drug combination regimen, but the original report did not note what the oldest treated patient was.
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