Lidia Usnarska-Zubkiewicz
1, Jadwiga Hołojda
2, Kazimierz Kuliczkowski
1AL Amyloidosis (Amyloidosis Antibody Light).
Part 2 – Epidemiology, Clinical Symptoms, Diagnosis
and Treatment of Amyloidosis AL
Amyloidoza AL (
amyloidosis antibody light
). Część II – epidemiologia,
objawy kliniczne, rozpoznanie i leczenie amyloidozy AL
1 Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University,
Poland
2 Hematology Department of District Specialist Hospital of Legnica, Poland
Abstract
Studies have shown that 10–20% of patients with multiple myeloma develop AL amyloidosis. AL amyloidosis can affect the kidney and the heart, as well as cause peripheral polyneuropathy and CNS impairment. The main diagnostic test to confirm amyloidosis is the staining of the adipose tissue from abdominal fat with Congo red, which demonstrates green birefringence when polarized light is used, or reveals nonbranching fibril structures with a diameter of 10 nm under an electron microscope.Oral melphalan and prednisone have been the leading drugs in the therapy of AL amyloidosis for 30 years. The patients qualified for megachemotherapy and stem cells transplantation had to be free from severe, burdening diseases and had to have less than three involved organs (Adv Clin Exp Med 2011, 20, 6, 771–788).
Key words: amyloidosis AL, epidemiology, clinical symptoms, diagnosis, treatment.
Streszczenie
Badania wykazały, że u 10–20% pacjentów chorych na szpiczaka mnogiego rozwija się amyloidoza AL. W prze-biegu tej postaci skrobiawicy najczęściej dochodzi do zajęcia nerek i serca oraz rozwoju polineuropatii obwodowej i uszkodzenia o.u.n. Podstawowym testem diagnostycznym potwierdzającym amyloidozę jest barwienie czerwienią Kongo tkanki tłuszczowej z fałdu brzusznego i wykazanie charakterystycznego zielonego, dwułomnego świecenia w świetle spolaryzowanym lub nierozgałęzionych włóknistych struktur o średnicy 10 nm w mikroskopie elektro-nowym. Od 30 lat wiodącymi lekami w terapii amyloidozy AL są melfalan i prednison. Podobnie jak w leczeniu szpiczaka mnogiego, w terapii amyloidozy zaproponowano stosowanie talidomidu, lenalidomidu i bortezomibu, w monoterapii lub w połączeniu z deksametazonem. Do megachemioterapii i przeszczepienia komórek macierzy-stych byli kwalifikowani chorzy bez poważnych, obciążających chorób, którzy mieli zajęte przez amyloidozę mniej niż trzy narządy (Adv Clin Exp Med 2011, 20, 6, 771–788).
Słowa kluczowe: amyloidoza AL, epidemiologia, objawy kliniczne, rozpoznanie, leczenie.
Adv Clin Exp Med 2011, 20, 6, 771–778 ISSN 1230-025X
REvIEWS
© Copyright by Wroclaw Medical University
Epidemiology
The prevalence of amyloidosis is difficult to es-timate, as the disease often remains undiagnosed or misdiagnosed. In AL amyloidosis, the estimations more often include mortality due to this complica-tion, while estimations of the prevalence of the AA type are based on post mortem examinations [1]. In order to evaluate the incidence of AL amyloi-dosis, Kyle and colleagues analyzed the number of
disease is 0.8–1/100000 cases/year, with patients at the age of 50–70 [4].
In Europe, there are no centers that would keep a register of amyloidosis cases. Data reported from individual countries only provides information on the incidence of amyloidosis in a given region [5].
Studies have shown that 10–20% of patients with myeloma develop AL amyloidosis [6]. vela- -Ojeda et al. analyzed 201 newly diagnosed MM patients and found that 68 of them (34%) had amyloidosis AL and poorer disease prognosis [7]. Primary AL amyloidosis also affects 7% of patients suffering from non-hematologic malignancies [8].
Amyloidosis rarely occurs before the age of 40, patients aged 50–70 constitute 60% of cases, and it more often affects men (50–65%) [4].
Clinical Symptoms
The most common clinical symptoms associat-ed with amyloidosis include: weight loss, ankle oe-dema, hoarseness, paraesthesia, tiredness, orthos-tatic hypotension, heart failure, enlargement of the liver and the tongue, and carpal tunnel syndrome [9]. The amyloidosis can also affect the kidney and the heart as well as cause peripheral polyneuropa-thy and CNS impairment [10]. According to Mül-ler et al., kidney damage in the form of nephritic syndrome affects 28% of patients, heart failure and polyneuropathy 17%, carpal tunnel syndrome 21%, orthostatic hypotension 11%, and orbital purpura 15% of the subjects [11].
The Kidney
Studies have shown that in a group of 211 newly dialyzed patients, 2% developed systemic amyloidosis [12]. Kyle et al., analyzing 474 AL pa-tients, revealed the presence of proteinuria in 73% of the subjects, out of which 28% met the criteria of nephritic syndrome and 50% developed renal failure [13]. Other authors reported Bence-Jones proteinuria in 60% of amyloidosis patients, while 10% of patients had amyloidosis without typical proteinuria. In these patients, proteinuria was re-placed by fatigue and ankle oedema [14].
The Heart
17% of amyloidosis patients develop amyloid cardiomyopathy in the type of restrictive cardio-myopathy with the symptoms of right ventricular insufficiency. The low ejection fraction observed in 13% of patients may evolve into orthostatic hy-potension [11]. Congestive heart failure is associ-ated with shorter median survival and exertional
syncope is a predictor of early death [15]. ECG (echocardiography) tracing shows low voltage QRS complex in standard leads, or traces corresponding to myocardial infarction, but without evidence of ischaemic disease. The deposits of amyloid in cor-onary vessels may also lead to arrhythmia, conduc-tion blocks, angina pectoris, or myocardial infarc-tion [16]. Unlike ECG, troponin I and N-terminal pro-brain natriuretic peptide (NT-proBNP) are objective parameters of cardiac involvement. Ac-cording to these measurements, three stages of car-diac amyloidosis have been proposed. In patients with stage I of cardiac amyloidosis, troponin T, troponin I and NT-proBNP must be within nor-mal values, while in stage II, one of them, and in stage III both of them, exceed normal values [17]. At the Mayo Clinic, the serum troponin T level was introduced as a criterion of the inclusion for stem cell transplantation (SCT) [18].
The Haematopoietic System
In AL amyloidosis, 18% of patients reveal above 20% plasmocytes in the bone marrow, and 60% – below 10% [19]. According to Merlini et al., the majority of patients with amyloidosis AL do not meet the criteria for myeloma [9]. A tendency to bleeding, ecchymoses, and periorbital extrava-sations in the type of “raccoon eyes” results from amyloid deposition in the blood vessels, which in-creases their fragility. Moreover, the bleeding ten-dency is associated with the binding of the X fac-tor by the amyloid, which leads to the formation of a faulty clot [20].
The spleen is involved in 10% of amyloido-sis patients. Amyloid may be present in the white splenic pulp and less commonly in the red pulp [13]. Hyposplenism resulting from amyloid in-filtration may cause thrombocythemia, and the presence of Howell-Jolly bodies has also been ob-served.
The Liver
Hepatomegaly is secondary to amyloid car-diomyopathy, or results from the accumulation of amyloid fibrils. Liver involvement is observed in 50% of amyloidosis patients. Laboratory stud-ies reveal significantly elevated levels of alkaline phosphatase and slightly elevated levels of amin-otransferases.
The Skin
scaling infiltrations are common. Mucous mem-branes present a similar picture. The sensation of dryness in the mouth (xerostomia) results from amyloid infiltration of the salivary glands. An evi-dent balding tendency occurs.
The Musculo-Skeletal System
Amyloid accumulation in the muscles leads to pseudohypertrophy, such as enlargement of the tongue. Macroglossia affects up to 10% of amyloi-dosis patients. Arthropathy results from amyloid depositions in the joints.
The Nervous System
20% of patients with nervous system involve-ment develop polyneuropathy. Its peripheral form is associated with peripheral sensation disturbanc-es, such as numbness, paraesthesia and piercing pains. The symptoms result from pressure exerted by the amyloid deposits on peripheral nerves, like in carpal tunnel syndrome in the course of AL am-yloidosis. Orthostatic hypotension, impotence and digestive tract motor disturbances are associated with autonomic neuropathy.
Diagnosis of Amyloidosis
The main diagnostic test to confirm amyloido-sis is the staining of adipose tissue from abdominal fat with Congo red, which demonstrates green bi-refringence when polarized light is used, or reveals nonbranching fibril structures with a diameter of 10 nm under an electron microscope. If the test is negative, it may be followed by a salivary gland, rectal mucosa, gingival, or bone marrow biopsy, or a biopsy from an organ which is assumed to con-tain accumulated amyloid fibrils [21]. The efficacy of amyloid identification in various loci varies: kid-ney, spleen and liver biopsies are positive in about 90% of cases, abdominal adipose tissue aspirates in 60–80%, rectal biopsy in 50–70%, bone marrow biopsy in 50–55%, and skin biopsy in 50–80% [22, 23]. The amyloid deposits may also be visualized by means of radioisotope methods with the use of Tc99m technetium, which is especially useful in the case of cardiac amyloidosis [24]. It is effective in very advanced cardiomyopathy, which, together with echocardiography, constitutes the basic diag-nostic test.
Amyloid deposits may be diagnosed by means of another diagnostic method – scintigraphy, which is based on the coexistence of amyloid de-posits with normal serum SAP protein, which may
be tagged with technetium or iodine (I123).
Scintig-raphy using the radioisotope combined with SAP is able to determine the locations of amyloid de-posits and amyloid fibril load in a very short time. This examination is especially useful in secondary amyloidosis and may be positive despite a negative tissue biopsy. Spleen scintigraphy may be positive in 100%, kidney in 80%, adrenals in 50% and liver in 25–50% of cases [25]. The method is of no use in cardiac amyloidosis due to the large amount of blood flowing through the organ, which may cause 100% false results [26]. In AL amyloidosis, a bone marrow aspiration biopsy is performed in order to demonstrate plasma cell infiltration. The clonal character of the plasma cells may be demonstrated by means of the immunohistochemical method with the use of anti-κ or anti-λ antibodies.
The use of electrophoresis and immunofix-ation of serum and urine proteins may help reveal the presence of light chains and monoclonal im-munoglobulin in 90% of amyloidosis patients [6]. The serum level of free light chains (FLCs) is de-termined with the immunonephelometric meth-od with the use of antibmeth-odies specific for κ and λ chains, which do not recognize light chains linked with heavy chains. The sFLCs test is more sensitive than protein electrophoresis and at least 500 times more sensitive that immunofixation [27]. With the immunofixation method, while the presence of light chains may be determined when their level is 100–500 mg/l, the immunonephelometric meth-od revealed the presence of sFLCs at the level of 3–4 mg/l. According to Katzmann, a combination of 2 parameters, i.e. the kappa/lambda ratio and serum immunofixation, gives the highest sensitiv-ity (99%) in diagnosed AL patients [28].
DNA examinations used in sequencing of the amino acids in the amyloid fibrils are indicated in patients who reveal the presence of monoclonal protein, and who at the same time present clini-cal symptoms of inborn amyloidosis [29]. In other forms of fibrilosis than AL amyloidosis, apart from a histological demonstration of amyloid deposits, other examinations are performed in order to identify the amyloid protein, immunohistochemi-cal evaluation with the use of an electron micro-scope, or spectrophotometric examinations [30].
Treatment of Amyloidosis
for solubilizing the amyloid fibril is not known at the moment. The response criteria in patients with amyloidosis AL meet both the monoclonal pro-tein, measured as a serum free light chains level, and an objective improvement in organ function [5]. The current study conducted by Kumar et al. supports the notion that FLC response is a more useful measure of hematological response than M-protein and achieving at least a 90% reduction in the FLC to improve the outcome of patients with light-chain AL [32]. According to Lachmann et al., there is a positive correlation between a hematolog-ic as well as organ response to therapy and survival [33]. The hematologic response has been defined as a 50% reduction in the precursor monoclonal protein level (PR, partial response), and survival is better in patients who have at least 50% reduction of FLC compared with those who do not fulfill this criterion. The best outcomes were observed in pa-tients with normalization of these parameters and negative immunofixation of the serum and urine (CR, complete hematologic response) [34]. An or-gan response has been defined as a 50% reduction in urinary albumin loss in patients with renal amy-loidosis, a decrease in liver size (or a 50% lowering of alkaline phosphatase in serum) in persons with hepatic amyloidosis, and echocardiographic im-provement (or a 30% abatement in the BNP level) in cardiac amyloidosis [35].
Megachemotherapy
and Stem Cells
Transplantation
In the Mayo Clinic, the patients who were qualified for megachemotherapy and stem cells transplantation had to be free from severe, bur-dening diseases and had to have less than three involved organs [35]. The conditioning therapy involved administration of high doses of mel-phalan. A multi-center study performed in the years 1998–2006 demonstrated that 25–67% of patients treated this way achieved remission of the disease, however the transplant-related mortality was high and ranged from 15 to 40% [36]. Bone marrow transplantation in patients with amyloi-dosis differs from the procedure performed in other plasma cell dyscrasias. Multi-organ dysfunc-tion occurs more commonly in amyloidosis. This leads to post-transplantation complications, such as kidney failure requiring dialysis, as well as liver and heart failure. Studies have shown that the suc-cess of transplantation is affected by the high level of expertise of the transplantation center, with
significantly better outcomes achieved in centers with over 5 years’ experience [37].
Stem cell transplantation is not a routine man-agement in amyloidosis, despite the reported fact that remission of organ involvement was achieved in up to 50% of patients [38]. Studies performed by a multi-center French group involving 100 pa-tients treated with melphalan and dexamethasone at standard doses, or megachemotherapy, revealed that the median survival for group I was 57 months, and in patients after transplantation – 49 months, and the therapeutic response was achieved in 64% and 65% of patients respectively [39]. However, according to the authors, the rejection of mega-chemotherapy as a therapeutic modality in amy-loidosis seems premature.
Treatment of Patients
not Qualified
for Transplantation
Oral melphalan has been the leading drug in the therapy of AL amyloidosis for 30 years. The drug is administered in 4-day cycles every 28 days at a daily dose of 0.22 mg/kg, in combination with prednisone. In the study by Kyle et al. involving 219 patients, the median survival was demon-strated to reach 17 months, twice as much as in the case of colchicine-treated patients [40]. Prom-ising outcomes were also achieved in 93 patients treated with dexamethasone with or without in-terferon: a complete hematological remission was achieved in 24% of patients, improved organ func-tion in 45% of patients, and median survival was 31 months [41]. The above outcomes were con-firmed in the study by Palladini et al. [42].
Thalidomide, Lenalidomide
and Bortezomib
for Amyloidosis AL
Like in myeloma therapy, amyloidosis is also treated with thalidomide, lenalidomide and bort-ezomib, in monotherapy or in combination with dexamethasone.
Adverse events of grade 3 and 4, possibly related to lenalidomide, were neutropenia, thrombocy-topenia and fatigue [44, 45].
In 2008, the National Amyloidosis Center in Great Britain presented data of a study conducted on 18 patients treated with bortezomib that had pre-viously received thalidomide-based therapy [46]. Hematologic and organ response was observed in 77% and 27% of patients, respectively. Kastritis et al. reported on AL patients, who relapsed or pro-gressed after previous therapy and persons with renal dysfunction, treated with bortezomib. This data as well as a study conducted by Lamm et al. in previously untreated patients has shown signifi-cant benefits in overall and progression-free sur-vival [47, 48].
New Therapeutic Options
New drugs, the main aim of which is to inhibit amyloid fibril formation, are being investigated and tested clinically. They include:
1. Drugs diminishing the aggregation of fi-brils and stimulating the resorption of amyloid. The effect is achieved by 4-iodo-4-deoxydoxorubi-cin (IDOX). Clinical trials have shown that a dose
of 15 mg/m2 is able to evoke a clinical response in
15% of patients [49].
2. R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo- -hexanoyl]pyrrolidine-2-carboxylicacid causes the elimination of SAP protein from the circulation and its secondary resorption from amyloid depos-its [50].
3. Etanercept – a TNF blocker, the use of which is associated with TNF-alpha activity in the devel-opment of amyloidosis [51].
4. Eprodisate (sulfated glycosaminoglycan), the use of which in the therapy for secondary amy-loidosis is tested in ongoing phase II–III clinical trials [52].
Supportive Care of Organ
Involvement in the Course
of Amyloidosis
Cardiac Amyloidosis
The therapy for cardiac amyloidosis has two aims: it is directed against light chains, and it is aimed to protect the heart. Maintaining balance between the function of the amyloidosis-affected heart muscle and the volume of the vascular bed plays a key role, thus administration of diuretics, e.g. spironolactone and metholasone, as well as
a sodium regime are important measures [53]. Such management may be limited if there is coexisting orthostatic hypotension or nephritic syndrome. In case of recurrent fainting, the patients should be qualified for pacemaker implantation [54]. In patients with paroxysmal ventricular arrhyth-mias, defibrillator implantation is advisable. The use of angiotensin inhibitors is hampered due to large differences in blood pressure. Patients with low ejection fraction may use ICE, however with extreme caution, starting from low doses. Calci-um-channel blockers are also advocated. Orthos-tatic hypotension is an important problem in pa-tients with amyloid heart disease. In such cases, the use of compression stockings and midodrine may prove useful. In cases of extreme heart failure, tri-als were undertaken to transplant the heart, which gave a symptom-free survival rate of 32 months [55]. According to recommendations of the Na-tional Amyloidosis Center in Great Britain, and the Spanish Register for Heart Transplantation, heart transplantation should follow bone marrow transplantation and be reserved for patients with or without mild systemic AL [55, 56].
Kidney Amyloidosis
A crucial role in the therapy for kidney dys-function in the course of amyloidosis is played by diuretics and a sodium regime. However this man-agement proves insufficient in the case of nephrit-ic syndrome and high loss of protein with urine. In these patients, in the terminal stage of kidney failure, ramipril remains the drug of choice [57]. The mean time lapse between the diagnosis of kid-ney amyloidosis to the onset of dialysis therapy is 14 months, and the mean survival rate of pa-tients on renal replacement therapy is assessed at 9 months. Simultaneously coexisting cardiac amy-loidosis significantly hampers the dialysis therapy. Researchers from the Mayo Clinic found out that institution of chemotherapy prior to renal trans-plantation ensures better tolerance of the transplant, however it requires the use of immunosuppressive drugs since the very onset. It was established that a positive therapeutic response to decreased doses of melphalan constitutes an indication to kidney transplantation in amyloidosis patients.
treat-ment is the improvetreat-ment of organ response. For this reason, the definition of an organ response (PR, CR) was developed.
The introduction of thalidomide, lenalidomide and bortezomib, the new agents for the
manage-ment of AL, have significantly expanded the possi-bilities of treatment of amyloidosis AL. Reduction of FLC level is associated with survival benefits, ir-respective of the chemotherapy regimen used.
References
Simms RW, Prout MN, Cohen AS:
[1] The epidemiology of AL and AA amyloidosis. Baillieres Clin Rheumatol 1994, 8, 627–634.
Kyle RA, Linos A, Beard CM, Linke RP, Gertz MA, O’Fallon WM, Kurland LT:
[2] Incidence and natural history of primary systemic amyloidosis in Olmstead County, Minnesota, 1950 through 1989. Blood 1992, 79, 1817–1822.
Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR:
[3] Amyloidosis: diagnosis and management. Clin Lymphoma Myeloma 2005, 6, 208–219.
Mayo MM, Johns GS:
[4] Serum free light chains in the diagnosis and monitoring of patients with plasma cell dyscra-sias. Contrib Nephrol Basel Karger 2007, 153, 44–65.
Gertz MA, Merlini G, Treon SP:
[5] Amyloidosis and Waldenström’s macroglobulinemia. Hematology. Am Soc Hematol Educ Program 2004, 257–282.
Kurusu A, Yamada T, Yamaji K, Nishitani M, Tashiro K, Maeda K, Horikoshi S, Shirato I, Rinno H, Tomino Y: [6]
A case of primary immunoglobulin light chain amyloidosis with a delayed appearance of Bence Jones protein in urine. Nephrology 2004, 9, 122–125.
Vela-Ojeda J, Garcia-Ruiz Esparza MA, Padilla-Gonzales Y, Sanchez-Cortez E, Garcia-Chavez J, Montiel- [7]
-Cervantes L, Reyes-Maldonado E, Majluf-Cruz A, Mavani H: Multiple myeloma-associated amyloidosis is an independent high-risk prognostic factor. Ann Hematol 2009, 88, 59–66.
Iwahashi N, Tome E, Nagasaka T:
[8] Massive hemorrhagie and pseudo-obstruction of the small intestine caused by primary AL amyloidosis associated with gastric cancer. Surg Today Rep Cause 2004, 34, 871–874.
Merlini G, Stone MJ:
[9] Dangerous small-B cell clones. Blood 2006, 349, 583–596.
Falk RH:
[10] Diagnosis and management of the cardiac amyloidoses. Circulation 2005, 112, 2047–2060.
Műller AMS, Geibel A, Neuman HPH:
[11] Primary (AL) amyloidosis in plasma cell disorders. Oncologist 2006, 11, 824–830.
Gertz MA, Kyle RA, O’Fallon WM:
[12] Dialysis support of patients with primary systemic amyloidosis. A study of 211 patients. Arch Intern Med 1992, 152, 2245–2250.
Kyle RA, Gertz MA:
[13] Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995, 32, 45–59.
Dember LM:
[14] Emerging treatment approaches for the systemic amyloidosis. Kidney Int 2005, 68, 1337–1390.
Savyer BD, Skinner M:
[15] Cardiac amyloidosis shifting our impressions to hopeful. Curr Heart Fail Rep 2006, 3, 64–71.
Dubrey S, Pollak A, Skinner M, Falk RH:
[16] Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation. Br Heart J 1995, 74, 541–544.
Dispenzieri A, Gertz MA, Kyle RA:
[17] Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a stag-ing system for primary systemic amyloidosis. J Clin Oncol 2004, 22, 3751–3757.
Gertz MA, Lacy M, Dispenzieri A, Hayman S, Kumar S, Buadi F, Leung M, Litzow M:
[18] Troponin T levels an
exclusion criterion for stem cell transplantation in light chain amyloidosis. Leuk Lymphoma 2008, 40, 36–41.
Abraham RS, Ballman KV, Dispenzieri A:
[19] Functional gene expression analysis of clonal plasma cells identifies a unique molecular profile for light chain amyloidosis. Blood 2005, 105, 794–803.
Mumford AD, Donnell J, Gillmore JD:
[20] Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis. Br J Haematol 2000, 110, 454–460.
Libbey CA, Skinner M, Cohen AS:
[21] Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch Int Med 1983, 143, 1549–1552.
Sungur C, Sungur A, Ruacan S, Arik N, Yasavul U, Turgan C:
[22] Diagnostic value of bone marrow biopsy in patients with renal disease secondary to familial Mediterranean fever. Kidney Int 1993, 44, 834–836.
Duston MA, Skinner M, Shraham T, Cohen AS:
[23] Diagnosis of amyloidosis by abdominal fat aspiration: analysis of 4 years experience. Am J Med 1987, 82, 412–441.
Falk RH, Lee VW, Rubinow A, Skinner M, Cohen AS:
[24] Cardiac technetium-99m pyrophosphate scintigraphy in familial amyloidosis. Am J Cardiol 1984, 54, 1150–1151.
Hawkins PN, Pepys MB:
[25] Imaging amyloidosis with radiolabelled SAP. Eur J Nucl Med 1995, 25, 595.
Hawkins CN:
[26] Serum amyloid P component scintigraphy for diagnosis and monitoring amyloidosis. Curr Op Nephrol Hyperten 2002, 11, 649–655.
Abraham RS, Katzman JA, Clark RJ, Bradwell AR, Kyle RA, Gertz MA:
[27] Quantitative analysis of serum free light
chains. A new marker for the diagnostic evaluation of primary systemic amyloidosis. A J Clin Pathol 2003, 119, 274–278.
Katzmann JA, Abraham RS, Dispenzieri A, Lust JA, Kyle RA:
Comenzo RL, Zhou P, Fleisher M, Clark B, Teruya-Feldstein J:
[29] Seeking confidence in the diagnosis of systemic
AL (Ig light-chain) amyloidosis: patients can have both monoclonal gammapathies and hereditary amyloid pro-teins. Blood 2006, 107, 3489–3491.
Murphy CL, Wang S, Williams T, Weiss DT, Solomon A:
[30] Characterization of systemic amyloid deposits by mass spectrometry. Meth Enzymol 2006, 412, 48–62.
Gertz MA, Zeldenrust SR:
[31] Treatment of immunoglobulin light chain amyloidosis. Curr Hematol Malig Rep 2009, 4, 91–98. Review.
Kumar SK
[32] , Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Tan T, Sinha S, Leung N, Kyle RA, Rajkumar SV, Gertz MA: Changes in serum-free light chain rather than intact monoclonal immunoglobulin levels predicts outcome following therapy in primary amyloidosis. Am J Hematol 2011, 86, 251–255.
Lachmann HJ, Gallimore R, Gillmore JD, Carr-Smith HD, Bradwell AR, Pepys MB, Hawkins PN:
[33] Outcome in
systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br J Haematol 2003, 122, 78–84.
Sanchoravala V, Seldin DC, Magnani D, Skinner M, Wright DG:
[34] Serum free light chain responses after high
dose intravenous melphalan and autologous stem cell transplantation for AL (primary) amyloidosis. Bone Marrow Transplant 2005, 36, 597–600.
Comenzo RL, Gertz MA:
[35] Autologous stem cell transplantation for primary systemic amyloidosis. Blood 2002, 99, 735–740.
Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL:
[36] High dose melphalan and autologous
stem-cell transplantation in patients with Amyloidosis AL: An 8-year study. Ann Intern Med 2004, 140, 85–93.
Gertz MA, Blood E, Vesole DH, Abonour R, Lazarus HM, Greipp PR:
[37] A multicenter phase 2 trial of stem cell
transplantation for immunoglobulin light-chain amyloidosis: an Eastern Cooperative Oncology Group Study. Bone Marrow Transplant 2004, 34, 149–154.
Seldin DC
[38] , Anderson JJ, Sanchorawala V, Malek K, Wright DG, Quillen K, Finn KT, Berk JL, Dember LM, Falk RH, Skinner M: Improvement in quality of life of patients with AL amyloidosis treated with high-dose mel-phalan and autologous stem cell transplantation. Blood 2004, 104, 1988–1993.
Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, [39]
Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP: Myélome Autogreffe (MAG) and Intergroupe Francophone du Myélome (IFM) Intergroup. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 2007, 357, 1083–1093.
Kyle RA
[40] , Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM: A trial of three regimens for primary amyloidosis: colchicines alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 1997, 336, 1202–1207.
Dhodapkar MV
[41] , Hussein MA, Rasmussen E, Solomon A, Larson RA, Crowley JJ, Barlogie B: United States Intergroup Trial Southwest Oncology Group. Clinical efficacy of high-dose dexamethasone with maintenance dexamethasone/alpha interferon in patients with primary systemic amyloidosis: results of United States Intergroup Trial Southwest Oncology Group (SWOG) S9628. Blood 2004, 104, 3520–3526.
Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, [42]
Merlini G: Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood 2004, 103, 2936–2938.
Palladini G, Perfetti V, Perlini S:
[43] The combination of thalidomide and intermediate dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis. Blood 2005, 105, 2949–2951.
Dispenzieri A, Lacy MQ, Zeldenrust SR,
[44] Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA: The activity of lenalidomide with or without dexam-ethasone in patients with primary systemic amyloidosis. Blood 2007, 109, 465–470.
Sanchorawala V, Wright DG, Rozenzweig M,
[45] Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC:
Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood 2007, 109, 492–496.
Wechalekar AD, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD:
[46] Efficacy of bortezomib in systemic AL
amyloidosis with relapsed/refractory clonal disease. Haematologica 2008, 93, 295–298.
Kastritis E, Anagnostopoulos A, Roussou M, Taumanidis S, Pamboukas C, Migkou M, Tassidou A, Xilauri J, [47]
Delibai S: Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Hematologica 2007, 92, 1351–1358.
Lamm W
[48] , Willenbacher W, Lang A, Zojer N, Müldür E, Ludwig H, Schauer-Stalzer B, Zielinski CC, Drach J:
Efficacy of the combination of bortezomib and dexamethasone in systemic AL amyloidosis. Ann Hematol 2011, 90, 201–206.
Gertz MA, Lacy MQ, Dispenzieri A:
[49] Amyloidosis. Best Pract Res Clin Haematol 2005, 18, 709–727.
Pepys MB, Herbert J:
[50] Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 2002, 417, 254–259.
Hussein MA, Juturi JV, Rybicki L:
[51] Etanercept therapy in patients with advanced primary amyloidosis. Med Oncol 2003, 20, 283–289.
Geerts H:
[52] NC-531(neurochem). Curr Opin Invest Drugs 2004, 5, 95–100.
Mathew V, Chaliki H, Nishimura RA:
Falk RH:
[54] Diagnosis and management of the cardiac amyloidosis. Circulation 2005, 112, 2047–2060.
Gillmore JD
[55] , Goodman HJ, Lachmann HJ, Offer M, Wechalekar AD, Joshi J, Pepys MB, Hawkins PN: Sequential heart and autologous stem cell transplantation for systemic AL amyloidosis. Blood 2006, 107, 1227–1229.
Roig E
[56] , Almenar L, González-Vílchez F, Rábago G, Delgado J, Gómez-Bueno M, Crespo-Leiro MG, Arizón JM, de la Fuente L, Manito N: Spanish Register for Heart Transplantation. Outcomes of heart transplantation for car-diac amyloidosis: subanalysis of the Spanish registry for heart transplantation. Am J Transplant 2009, 9, 1414–1419.
Mayr M, Dickenmann MJ:
[57] Further evidence for the renoprotective effect of ACE inhibitors: ramipril protects against the progression of chronic renal insufficiency in non-diabetic nephropathy with nephrotic proteinuria. Schweiz Med Wochenschr 2000, 130, 49–55.
Address for correspondence:
Lidia Usnarska-Zubkiewicz
Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation Wroclaw Medical University
Pasteura 4 50-367 Wrocław Poland
Tel.: +48 71 784 25 96, +48 600 642 881 E-mail: [email protected]
Conflict of interest: None declared Received: 2.08.2011
