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AL amyloidosis is a rare and underdiagnosed entity, where pathogenic monoclonal light chains are produced by a small clone of plasma cells or, rarely, by a mature B cell clone1,2. These pathogenic proteins undergo a conformational change which renders them insoluble, favoring their deposition in tissues and eventually organ malfunction3,4. Amyloidosis has an estimated incidence of 3-14/1 million inhabitants/year, depending on the geographical area5,6.
While the whole world discusses about the new diagnostic and therapeutic tools, in Chile, and Latin America in general, we are far from that reality.
There is little information about AL amyloidosis in Chile, consisting mainly on case reports7,8. The largest report was in 2005, where 11 cases were described9.
The aim of the present study is to characterize patients with AL amyloidosis in public health centers throughout the country.
Materials and Methods
We conducted a retrospective, descriptive, multicenter study. Cases were collected between 2010 and 2018.
The public centers are members of the Chilean Monoclonal Gammopathies Cooperative Group, they were asked to search in their databases to look for patients diagnosed with AL amyloidosis.
In all centers, the diagnosis of AL amyloidosis was made with a positive Congo red stain on tissue biopsy. Affected organs were determined by biopsy or according to the definition of Gertz et al10. Epidemiological, clinical and laboratory characteristics were evaluated.
A descriptive statistical analysis was done. Overall survival (OS) was calculated with Kaplan Meier curves and a comparison was made with log Rank test.
The present study was approved by the corresponding Ethics Committee.
Results
Data was collected from 42 patients of eight public health centers.
The main characteristics are detailed on Table 1. The median age was 65 years, ranging from 22 to 84 years. The male to female ratio was 1: 0.75. Twenty four percent were diagnosed as localized AL amyloidosis; paraprotein was found in all the patients, and 64% presented with a lambda light chain clone; 47% of cases were associated with multiple myeloma (MM), and 9% with non-Hodgkin lymphoma (NHL) (Figure 1), 2 MALT lymphomas, 1 lymphoplasmacytic lymphoma, and a non-characterized low grade B cell lymphoma. The most frequently involved organ was the kidney (76%), followed by the heart (48%) (Figure 2). The analysis by group: 1.- Primary amyloidosis, 2.- MM-associated amyloidosis, and 3.-NHL-associated AL amyloidosis showed no statistical difference between them (Table 1).
Table 1 Patient's characteristics and analysis by group: primary AL amyloidosis, MM-associated AL amyloidosis and NHL-associated AL amyloidosis (p < 0,5)
| Total (n = 42) |
Primary amyloidosis (n = 18) |
MM-associated (n = 20) |
NHL-associated (n = 4) |
p value | |
|---|---|---|---|---|---|
| Male, n (%) | 24 (47) | 11 (61) | 12 (60) | 1 (25) | NS |
| Median age, years (range) | 65 (22-84) | 58 (33-84) | 65 (22-77) | 63 (56-77) | NS |
| iFLC= Lambda, n (%) | 27 (64) | 12 (67) | 13 (65) | 2 (50) | NS |
| iFLC= Kappa, n (%) | 13 (31) | 5 (28) | 7 (35) | 1 (25) | NS |
| Heavy chain only, n (%) | 2 (5) | 1 (5) | 0 (0) | 1 (25) | NS |
| Localized involvement, n (%) | 10 (24) | 5 (28) | 3 (15) | 2 (50) | NS |
| Multi-organ involvement, n (%) | 32 (76) | 13 (72) | 17 (85) | 2 (50) | NS |
| Cardiac involvement, n (%) | 20 (48) | 10 (56) | 10 (50) | 0 (0) | NS |
| Renal involvement, n (%) | 32 (76) | 14 (78) | 17 (85) | 1 (25) | NS |
NS: not significant.
Regarding diagnostic tests (Figure 3), 100% reported having performed serum protein electrophoresis (sPEP), 69% serum immunofixation (sIFE) and 43% urine IFE. Serum free light chains (sFLC) were performed in 31% of the patients.
Figure 3 Diagnostic tests. Performed test are shown in dark gray. sPEP: Serum protein electrophoresis; uPEP: Urine protein electrophoresis; sIF: Serum immunofixation; uIF: Urine immunofixation; sFLC: Serum free light chain.
Heart involvement by echocardiogram was looked for in 74%, and renal involvement was screened in 98%.
As seen in Table 2, the most frequently performed biopsies were bone marrow (52%) and subcutaneous fat tissue (38%), being these samples diagnostic in 45% and 44% of cases, respectively. Renal biopsy was performed in 33% of the cases, with a positive diagnosis in all of them.
Table 2 Most frequent performed biopsies and frequency of positive diagnosis
| Biopsy Site | Performed n (%) |
Diagnostic n (%) |
|---|---|---|
| Bone marrow | 22 (52%) | 10 (45%) |
| Subcutaneous fat | 16 (38%) | 7 (44%) |
| Kidney | 14 (33%) | 14 (100%) |
| Gastrointestinal | 11 (26%) | 6 (55%) |
Treatment was heterogeneous: 17% were treated with bortezomib based therapy, 21% with cyclophosphamide, thalidomide, and dexamethasone (CTD), 40% with melphalan based therapy, and 17% received only palliative care. No patient received a bone marrow transplant.
The median OS of the group was 19 months. The 3-year OS was 38%, and the 5-year OS 28% (Figure 5). There was no survival difference between patients with or without associated MM (5-yr OS of 22% vs 24%; p = 0.8), with or without use of novel agents (5-yr OS of 15% vs 38%; p = 0,09), localized versus systemic amyloidosis (5-yr OS of 36% vs 27%; p = 0,6) or with or without cardiac involvement (5-yr OS of 25% vs 31%; p = 0.31).
Discussion
This is to our knowledge, the larger experience published in Chile and Latin-America on this topic.
The scarce number of patients may be due to registry deficiency in our healthcare system. This is further favored by lack of clinical suspicion and reduced access to diagnostic tools.
Epidemiological and clinical characteristics
The demographic and clinical characteristics proved to be similar to what is reported in the international literature. The disease is more frequent in men, and the median age is approximately 65 years, according to series carried out in America, Europe and Asia11–13.
Half of our patients were MM-associated, when the described rate is between 10-15%. This may be attributed to the fact that the MM-amyloidosis association is-well known by general physicians, and therefore, more often suspected and diagnosed.
In 5% to 7% of patients, AL amyloidosis is associated with an underlying IgM secreting lymphoma, usually lymphoplasmocytic and MALT type14. In our cohort we found 10%. Compared with patients who have non-IgM AL amyloidosis, these patients are described to be older, having a higher prevalence of neuropathy and lymph node involvement, and a lower proportion of cardiac involvement. This was not demonstrated in this study, most likely due to the low number of recruited patients.
Twenty four percent of patients were catalogued as localized AL amyloidosis. Much more than described in literature. The lack of complete organ involvement study might explain this result.
The most frequent light chain reported is lambda, in about 80% of patients. Our cohort was not the exception, although it was observed in only 64% of the patients. One explanation could be the high percentage of MM-associated AL amyloidosis in our cohort.
The most affected organs were the kidney, followed by the heart, which coincides with other series11–13. The results obtained regarding affected organs must be analyzed with caution, since not all the patients had a complete organ study. For example, 26% of patients did not have an echocardiogram performed, despite cardiac involvement is the most frequently reported.
As described, the most characteristic signs such as macroglossia and periorbital purpura were found in a small number of patients (26% and 7%, respectively).
Screening
Appropriate screening should include sIFE15, urine IFE16, and sFLC assay17. In a recent survey conducted by our group, it was observed that only a small percentage of public health centers have these three studies available (not published). This is a serious concern and partially explains the underdiagnoses of this disease in our country.
Diagnosis
For an accurate diagnosis, the standard recommendation is to perform a biopsy/aspiration of subcutaneous fat and a bone marrow (BM) biopsy18,19, which would have a sensitivity of 85%1,20. This was not consistent with the results of our study, where the sensitivity of subcutaneous fat and BM biopsies was low, confirming the diagnosis in less than half of the cases. Larger studies are required to verify this low sensitivity of the standard anatomopathological recommended studies. Experienced pathologists are important for an accurate diagnosis, and it is a factor to take into consideration when analyzing the results of this study.
In the majority of cases, the diagnosis of AL amyloidosis was made only after biopsy of the affected organ was performed, which suggests a low level of suspicion of AL amyloidosis prior to the biopsy. Although biopsy of the affected organ increases sensitivity to 95%, being 100% in the case of renal biopsy in our cohort, this procedure should be indicated with caution due to its invasive nature.
Unequivocal amyloid typing using mass spectrometry in specialized laboratories is the basis for accurate diagnosis and subsequent treatment22,23. This technology is not available in Chile, where diagnosis relies on tissues testing positive to Congo red and immunohistochemical study. This also means that we cannot exclude other type of amyloidosis in our patients.
Prognosis
New biomarkers are currently being used for diagnosis, prognosis and follow-up. One of them is the measure of sFLC24. In 2003, Palladini et al. described the sensitivity of NT-proBNP in diagnosis and prognosis for the first time25.
The Mayo Clinic score is the main tool used to define prognosis26,27. In this score the NT-proBNP, troponin I and the difference of the involved light chain with the non-involved free light chain are included.
There is not enough data to evaluate prognosis in our studied patients, due to the lack of these markers in most of our centers.
Treatment
Unfortunately, the Chilean public health system has few treatment options. The current protocol continues being melphalan and dexamethasone, with no access to new drugs such as bortezomib. Although 17% of the patients were treated with bortezomib, the acquisition of this drug required cumbersome and time-consuming requests from each institution.
It is necessary to include bortezomib in our therapeutic arsenal as it is the drug that changed the vision of AL amyloidosis, demonstrating an excellent response of up to 71% complete response with cyclophosphamide- bortezomib- dexamethasone (CyBorD)28,29. Another effective treatment is BMDex (bortezomib, melphalan and dexamethasone), which has shown very good results, superior to CyBorD in patients with high tumor burden30,31. Moreover, a recent phase 3 study demonstrated a greater hematological and organ response with BMDex versus MDex32. This positive outcome may be due to a proven high sensitivity of the plasma cells to bortezomib33.
There are new pharmacological treatments which are unattainable in our country at this time, which include studies with carlfilzomib, ixazomib, daratumumab and even anti-fibril antibodies34–36.
Autologous stem cell transplantation
The introduction of autologous stem cell transplantation (ASCT) marked a major advance in the treatment of AL amyloidosis37 as it has improved OS through the years with a 5-year OS up to 77% and a reduction in mortality at 30 and 100 days of 3% and 5%, respectively38. One study of 629 patients showed ~ 35% of patients obtaining complete remission and a median survival approaching up to 8 years39. Unfortunately, the bone marrow transplant program in the Chilean public health system is restricted, and amyloidosis is not currently an indication of it, which explains why no patient had bone marrow transplant in our registry. Furthermore, there is just one report in Chile of 6 AL amyloidosis patients with bone marrow transplant40.
Survival
Survival has doubled worldwide in the last decade; 30 to 40% of patients are now surviving more than 10 years12. In Sweden, the median survival after diagnosis of AL amyloidosis is 3 years41. The results in Chile are far below this, with a median OS of less than 20 months, which requires further analysis of the situation. It seems that physicians often do not suspect this disease on time, leading to a delay in the diagnosis. It is also necessary to optimize and standardize the diagnostic tools in all public health centers where amyloidosis is treated. In addition, the therapeutic resources are currently also insufficient.
Continuous education regarding this pathology is peremptory, as the most important step to avoid underdiagnoses is the awareness of this disease42. An online survey from the Amyloid Research Consortium indicates that 37% of patients are not diagnosed until one year after the onset of initial symptoms, and an average of three medical appointments. Moreover, despite advances in therapeutic treatments, the frequency of sudden death within ≤ 90 days of diagnosis remains at 25% −30%43. Early detection can prevent cardiac damage and potentially reduce the risk of sudden death.
This study is limited by its retrospective nature, and small number of patients. In addition, data could not be obtained from all national public health centers nor was the requested data complete in all cases. Nevertheless, this is the reality in Chile and it is our belief that this initial report is necessary to generate a change.
Conclusion
There are shortfalls in the diagnostic study and treatment of AL amyloidosis in our public health centers. It is important to obtain realistic, national results to initiate strategies to improve both early diagnosis and management of this pathology. Improving awareness is therefore crucial.
