Trials of treatment for AL amyloidosis have had disappointing results; they show only modest benefit from the currently available therapies [2, 3]. This reflects the limited success obtained to date in slowing or "turning off" production of light-chain fragments, which are the precursors of amyloid deposition.

In a few patients, the signs and symptoms caused by amyloid infiltration appear to have been reversed. Almost all of the information on these patients has been presented in individual case reports that detail renal [4], gastrointestinal [5], or neurologic recovery [6]. Long-term survival in patients who have AL amyloidosis that affects the heart is extremely unusual [7, 8], and no echocardiographic details have been reported for patients in whom cardiac symptoms of AL amyloidosis have been alleviated.

We describe the clinical features of three patients whose cardiac symptoms of amyloidosis were substantially alleviated, and we correlate this alleviation with echocardiographic features and objective evidence of disease activity.

Methods

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All patients were examined by a cardiologist at initial and subsequent evaluations. Twelve-lead and 24-hour Holter electrocardiography, transthoracic echocardiography, and Doppler echocardiography were done. Disease activity was determined on the basis of bone marrow plasma cell percentages, evidence of monoclonal bands on serum protein electrophoresis, and the presence of light chains in serum or urine.

Echocardiograms were read by blinded investigators to assess features of amyloid involvement. Left ventricular mass was calculated, and the ratio of voltage to mass was derived from the electrocardiographic voltage for the limb leads (mean QRS amplitude in leads I, II, III, aV_F [augmented V lead, left leg], and aV (_L) [augmented V lead, left arm]) divided by the left ventricular mass [9].

Results

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Of 249 patients with AL amyloidosis, 140 (56%) had congestive heart failure (median predicted survival, 7 months). Of these 140 patients, 78 (56%) received colchicine alone and 56 (40%) received melphalan (5 received high-dose melphalan therapy and autologous stem cell rescue). Six patients (4%) received no treatment. Heart failure was alleviated in 3 of the 140 patients who had congestive heart failure (2.1%), and all 3 of these patients had received melphalan as part of their treatment regimen. None of the 78 patients who had received colchicine alone had clinical alleviation of heart failure (P = 0.07). One of the 3 patients whose heart failure was alleviated is described below, and the clinical details from this patient and from the other two patients are shown in Table 1.

Case Reports

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Patient 1

A previously healthy 52-year-old man presented with a 1-year history of increasing shortness of breath on exertion. A diagnosis of AL amyloidosis was suspected on the basis of free light chains in the serum. Examination of the bone marrow showed that 7% of the cells were plasma cells (Table 2). On examination, the jugular venous pressure was markedly elevated (15 cm), and leg edema and hepatomegaly were seen. Increasingly severe heart failure developed, and the patient had dyspnea on minimal exertion. Cardiac catheterization showed normal coronary arteries, but during preparations for a right ventricular biopsy, the patient developed profound bradycardia and electromechanical dissociation that required open-chest cardiac massage. Pleural biopsy at this time confirmed amyloidosis. After further episodes of syncope, which occurred without warning, a permanent pacemaker was implanted and the symptoms resolved. Therapy for heart failure included 80 mg of furosemide and 5 mg of metolazone per day. An echocardiogram showed a small left ventricular cavity with mild wall thickening and increased echogenicity compatible with heart disease due to AL amyloidosis (Table 2).

During the next 8 months, the patient's condition continued to deteriorate. He had increasing heart failure and recurrent pleural effusions, and admission to a terminal care hospice was arranged. Throughout this period, the patient received a daily regimen of melphalan and prednisone to a total melphalan dosage of 860 mg per day. Thereafter, the symptoms of heart failure began to gradually resolve (Table 1). Cardiovascular examination 6 years after initial evaluation showed resolution of the edema and hepatic congestion with persistent mild elevation of jugular venous pressure. The patient's heart failure, initially New York Heart Association (NYHA) class IV, had improved to NYHA class I. The patient has returned to full-time employment. At an evaluation done 82 months after the initial symptoms of heart failure (80 months after tissue diagnosis), no light chains were detectable in the patient's serum or urine and the results of a bone marrow examination were normal. These findings suggest that the disease was in remission or that the patient had been cured (Table 2).

Patients 2 and 3

Detailed data for patients 2 and 3 are given in Table 1 and Table 2. Briefly, patient 2 had NYHA class IV heart failure at presentation and required large doses of diuretics and repeated thoracenteses. Her symptoms completely resolved after she received several courses of chemotherapy, and she returned to full-time employment 24 months after receiving the diagnosis of amyloidosis.

Patient 3 had evidence of severe right ventricular infiltration with amyloid and required repeated thoracenteses for right heart failure. Chemotherapy was associated with gradual alleviation of symptoms, cessation of thoracenteses, and a decrease in previously marked macroglossia. Patient 3 is now free of heart failure, 65 months after receiving the diagnosis of amyloidosis.

Discussion

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We describe 3 patients with documented AL amyloidosis and congestive heart failure whose symptoms were clearly alleviated. The rarity of such alleviation is apparent from the fact that these 3 patients made up only 2.2% of 140 consecutive patients who had congestive heart failure caused by AL amyloidosis. All 3 had received multiple courses of melphalan. In contrast, no improvement was seen in any of the patients who had received colchicine alone. This suggests that chemotherapy was responsible for the improvement in these patients, and this is further supported by a previously described survival difference between a small group of patients who had AL amyloidosis and heart failure and were treated with chemotherapy and a group of patients with the same conditions who were treated with colchicine alone [2, 3].

Only a few reports of improvement in patients with AL amyloidosis and cardiac involvement have been published [8, 10, 11]. In a review of 153 patients, Gertz and colleagues [8] briefly mention 2 patients with such improvement, but they provide no laboratory or echocardiographic details. A single patient described by Brown and Walls [11] also appears to have recovered from heart failure, but the evidence for this is confounded by the fact that the patient was in atrial fibrillation at the time of diagnosis and was in sinus rhythm when heart failure resolved. All 3 of these patients also received chemotherapy.

The resolution of symptoms seen in our patients was accompanied by the disappearance of light chains from serum and urine, suggesting either disease remission or cure. The eventual resolution of symptoms was characterized in all three cases by an initial worsening despite the initiation of therapy.

Inconsistencies between clinical improvement and the lack of evidence for a reduction in organ involvement with amyloidosis have been described in the nephrotic syndrome, in which persistent amyloid deposition is frequently seen on repeated renal biopsies [12]. Notably, in all reported cases, resolution of the nephrotic syndrome was associated with the disappearance of light chains [12]. Furthermore, all of these patients had been treated with melphalan. These observations suggest that something other than the simple physical presence of amyloid in the kidney may be responsible for the heavy proteinuria; light-chain toxicity in both kidney and muscle has been proposed [13-16].

The use of melphalan and prednisone has modestly improved the prognosis of patients with AL amyloidosis [17, 18], even those with congestive heart failure [3, 17]. Our three cases may only be examples of the most dramatic responses to chemotherapy, and we cannot exclude the possibility that disease progression was slowed in other patients with heart failure who received chemotherapy, even though these patients ultimately died of cardiac disease. The number of courses of chemotherapy received appears to be critical to achieving disease regression; because the median period of treatment required for a clinical response is 1 year [8], most patients with cardiac symptoms of amyloidosis probably do not survive long enough to receive an effective therapeutic regimen of melphalan. We show that heart failure can be reversed in some patients with AL amyloidosis, and we suggest that more intensive chemotherapy—such as that recently developed using high-dose melphalan and autologous stem cell rescue—might increase the number of patients responding to therapy.

Dr. Skinner: Arthritis Research Center, Boston University School of Medicine, Boston, MA 02118.