Systemic amyloidosis journey from diagnosis to outcomes: a twelve-year real-world experience of a single center in a middle-income country

One hundred and seventy-one patients were identified with a diagnosis of systemic amyloidosis between 2009 and 2020. Twenty-eight did not have a confirmatory biopsy and were excluded, and 143 patients were eligible for analysis.

Clinical characteristics, medical history, and patient's journey

Most patients were male (54%; n = 77), median age was 60 years (22–87) and 57% had performance status ≥ 2 according to ECOG scale.

Renal and cardiac disorders were the main clinical presentations (54% and 41%, respectively), and 36% of the patients had cachexia.

Until the diagnosis of amyloidosis was established, most of the patients (52%; n = 74) were seen by 3 or more physicians. After general practitioners (57%), nephrologists and cardiologists were the main specialties consulted (45% and 38%, respectively). A median delay in diagnosis of 10.9 months (0.5–114.5) was observed for the entire cohort. Patients with AL subtype were diagnosed earlier than those with non-AL subtype [9.0 (0.5–90.3) months versus 30.5 (0.9- 108.0), p < 0.001].

Diagnosis data

In 72% (n = 103) of the cases, two or more biopsies were required for diagnosing amyloidosis. The most common sites of biopsy were bone marrow (57%; n = 81), kidney (42%; n = 60), and fat pad (38%; n = 55). Additional file 1: Table S1 describes other biopsied sites and their positivity for amyloid deposit. More than half of the patients (56%; n = 80) underwent a diagnostic method to identify the precursor protein, namely: indirect immunofluorescence (66%; n = 53), IHC (36%; n = 29) and mass spectrometry (6%; n = 5). Mutations in genes related to amyloidosis were found in 15% (n = 22) of patients, being: transthyretin (TTR) (59%; n = 13); fibrinogen (27%; n = 6); and Mediterranean Fever (MEFV) gene (14%; n = 3). Other diagnostic tools were also performed to investigate the amyloidosis subtype: screening for monoclonal gammopathy (97%, n = 139; FLC unavailable in 55% of them), Tc-PYP scintigraphy in patients with cardiac involvement (18%, n = 19), and assessment of serum amyloid A protein (SAA) levels in patients with suspected AA subtype (67%, n = 8).

The following subtypes of amyloidosis were identified: AL (68%, n = 97), ATTR (13%, n = 19), AA (8%, n = 12), and fibrinogen amyloid protein (AFib) amyloidosis (4%, n = 6). Inconclusive cases comprised 7% (n = 9) of the patients. Table 1 summarizes patients´ general characteristics.

Table 1 General characteristics of patients by amyloidosis subtype (n = 143)Organ involvement

In most of the patients (75%; n = 107), advanced disease was observed at diagnosis, with ≥ 2 organs involved. Heart and kidney were the main organs affected (75% and 54%, respectively), followed by soft tissue (41%) and autonomic nervous system (24%). Sixteen (11%) patients were on renal replacement therapy. Tables 2 and Additional file 1: Table S2 describe the number and types of organs involved per patient, respectively, according to the amyloidosis subtypes.

Table 2 Number of involved organs per patient by amyloidosis subtypesAcquired subtypes of amyloidosisAL amyloidosis: clinical and laboratory characteristics, prognostic assessment, and treatment

Among patients with AL amyloidosis, 8% (n = 8) had a previous diagnosis of multiple myeloma. In 5% (n = 5), a small clonal lymphoplasmacytic infiltrate was found in the bone marrow biopsy. Specific signs of AL subtype such as macroglossia and periorbital purpura were present in 17% (n = 16) and 7% (n = 7) of patients, respectively. Lambda light chain was the predominant causative protein (75%; n = 73). Median values of monoclonal protein in serum and urine electrophoresis were 0.9 g/dL (0.2–2.56) and 270 mg/L (10–5520), respectively. Among the 53 patients with available FLC, the median difference between involved and uninvolved FLC was 90.8 mg/L (14.1–3110.6). The median percentage of bone marrow infiltration by plasma cells was 15% (0.8–100%). Fluorescent in situ hybridization analysis was not available in any patient.

Standard Mayo Clinic staging was assessed in 69% (n = 67) of patients. Most of them (66%; n = 44) were stage III, and among them, 55% (n = 24) were stage IIIb according to the European staging of advanced cardiac involvement. Revised Mayo Clinic staging was available in 34% (n = 33) of patients, 58% (n = 19) of them being classified as stages III or IV. Renal staging was evaluated in 97% (n = 94) of patients. A predominance of stages I to II (80%; n = 75) was observed and 16% (n = 15) of the patients were on renal replacement therapy.

Chemotherapy was administered to most patients (84%; n = 81), and the main regimens were alkylating-based (melphalan 48%, n = 39 and cyclophosphamide 47%, n = 38). Thalidomide was used in 19% (n = 15) of cases, and bortezomib in 16% (n = 13). The median number of chemotherapy cycles per patient was 4 (1–13). Autologous stem cell transplantation (ASCT) was performed in 14% (n = 14) of patients, and 93% of them had received prior chemotherapy. Only one patient (1%) underwent kidney transplantation. Exclusive supportive measures were offered to 15% (n = 15) of patients. Among 55 patients with hematological response assessment, 15% (n = 8) achieved complete response, 9% (n = 5) very good partial response, 25% (n = 14) partial response, 25% (n = 14) no response, and 25% (n = 14) had disease progression.

Wild-type ATTR amyloidosis and “de novo” ATTR-PN: clinical and laboratory characteristics, and treatment

Two patients were diagnosed with confirmed ATTRwt amyloidosis based on endomyocardial and fat pad biopsies showing TTR positive amyloid deposit by IHC and mass spectrometry, respectively, with no TTR mutation. Isolated heart failure was the clinical manifestation in both cases. The first patient was treated with doxycycline and the other with tafamidis.

Two other patients were diagnosed with probable “de novo” ATTR-PN. Both had received a domino liver transplantation from donors with known ATTRv and developed sensorimotor peripheral neuropathy 10 and 13 years after the transplant. Nerve biopsies confirmed amyloid deposition, and genetic sequencing had not been performed. One patient was treated with a second liver transplantation, and the other received supportive treatment.

AA amyloidosis: clinical and laboratory characteristics, and treatment

All 12 patients with AA subtype had a probable etiologic diagnosis due to an underlying inflammatory condition, and absence of features of other subtypes. Of the 8 patients with SAA assessment, 75% (n = 6) had elevated levels. Half of the patients presented with kidney involvement, and 42% (n = 5) had amyloid cardiomyopathy. Familial Mediterranean Fever was the underlying condition in 25% (n = 3) of patients with AA amyloidosis. All of them harbored mutations linked to severe phenotypes, in homozygous or compound heterozygous status, in cys or transposition, along the MEFV gene (p.Met694Val and p.Val726Ala). One patient with a monogenic form of AA amyloidosis was successfully treated with interleukin 1 inhibitor, while the others had clinical and laboratory resolution with colchicine. The other patients had the following inflammatory diseases: rheumatoid arthritis (17%; n = 2), non-specified autoinflammatory diseases (17%; n = 2), and immunoglobulin G4-related disease, vasculitis, combined polymyositis/primary biliary cholangitis, TRAPS syndrome, and Sweet syndrome (8%; n = 1 each). One patient was treated with interleukin 6 inhibitor with a laboratory response, another with anti-tumor necrosis factor agents, and the others received different immunosuppressive regimens, such as corticosteroids, cyclophosphamide, azathioprine, mycophenolate, and rituximab.

Hereditary subtypes of amyloidosisHereditary/variant ATTR amyloidosis: clinical and laboratory characteristics, and treatment

Thirteen patients had ATTRv, with the following mutations identified: p.Val50Met (54%; n = 7), p.Val142Ile (38%; n = 5), and p.Glu109Lys (8%; n = 1). Among patients with p.Val50Met mutation, the median age at diagnosis was 42 years (30–75). All of them had sensorimotor polyneuropathy, 71% autonomic dysfunction, 57% had ATTR-CM and 14% kidney involvement. Liver transplantation was performed in 43% (n = 3) of the cases and 29% (n = 2) received tafamidis. The other patients received immunosuppressive agents as treatment for a misdiagnosed inflammatory polyneuropathy. Patients carrying p.Val142Ile mutation had a median age of 67 years (54–69) at diagnosis, all of them presented with ATTR-CM, 20% had ATTR-PN, and 40% carpal tunnel syndrome, and the patient with p.Glu109Lys mutation was diagnosed by the age of 45 years and had a mixed phenotype of ATTR-CM and ATTR-PN. They received supportive therapy.

AFib amyloidosis: clinical and laboratory characteristics, and treatment

All patients with AFib amyloidosis (n = 6) had a confirmed diagnosis by the presence of amyloid deposit in a kidney biopsy and a p.Glu545Val mutation in the fibrinogen A alpha-chain gene. Kidney was the only organ involved. No patient was on renal replacement therapy at diagnosis. Supportive treatment was performed in 83% (n = 5) of patients, and one (17%) received bortezomib and dexamethasone as AL amyloidosis before confirming AFib. Progression to end-stage renal disease occurred in all patients with an interval from diagnosis ranging from 2 to 94 months.

Outcomes

The median follow-up time was 56.3 months (Q1-Q3 22.6–106.8). In the non-AL subgroup, a median OS of 74.3 months (95% CI 32.6–not reached) was observed. Among patients with AL subtype, the median OS was 18.5 months (95% CI 10.7 – 28.4), as shown in Fig. 1. Patients with cardiac stage III according to the standard Mayo Clinic staging had a decreased OS compared to stages I–II [8.6 (95% CI 4.7–14.8) months versus 52.3 (95% CI 25.2–73.6), respectively, p < 0.001], as shown in Fig. 2.

Fig. 1figure 1

Overall survival of patients with light chain amyloidosis

Fig. 2figure 2

Overall survival of patients with light chain amyloidosis stratified by the standard Mayo Clinic cardiac staging

Early mortality in the first year after the diagnosis of amyloidosis occurred in approximately one third of patients (31%, n = 44), most of them (86%; n = 38) being of the AL subtype.

Regarding renal outcomes in the AL subgroup, 18% (n = 15) of patients progressed to renal replacement therapy. Patients with stage III renal disease had a higher rate of progression to dialysis in 2 years compared to stages I–II [44.1% (95% CI 21.0–76.0) versus 20.6% (95% CI 11.1—36.5), respectively].

As shown in Table 3, we identified ECOG ≥ 2, AL subtype, and cardiac involvement as independent risk factors for decreased OS [HR 1.68 (95% CI 1.04–2.72), HR 2.44 (95% CI 1.26–4.72), and HR 3.27 (95% CI 1.55–6.90), respectively].

Table 3 COX regression model to evaluate risk factors associated with overall survival

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