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How to Manage…

How to manage primary amyloidosis


Immunoglobulin light chain amyloidosis is a protein deposition disorder where the precursor protein represents a monoclonal immunoglobulin light or heavy chain. Deposition in viscera results in restrictive cardiomyopathy, nephrotic range proteinuria, demyelinating peripheral neuropathy, hepatomegaly and malabsorption syndrome. Diagnosis requires biopsy with Congo red staining. Invasive biopsies are not required generally. It is essential that after a histologic diagnosis is obtained, the tissue is validated to have an immunoglobulin light chain composition so patients are spared unnecessary chemotherapy. The disease prognosis and patient monitoring are linked to serialized measurement of cardiac biomarkers and immunoglobulin-free light chains. Most patients require cytotoxic chemotherapy. For some patients, this therapy involves stem cell collection and myeloablative chemotherapy; for others, chemotherapy includes an alkylator and a corticosteroid; and for some, it involves addition of a novel agent in the form of an immunomodulatory drug or a proteasome inhibitor. Delays in diagnosis continue to be an obstacle to initiating effective therapy. Early mortality rates remain high. Effective chemotherapy can result in reversal of organ dysfunction and recovery. Reductions in light chain production translate to improved survival.


Immunoglobulin light chain amyloidosis (AL) is characterized by the production of clonal immunoglobulin light chains by a clonal population of plasma cells in the bone marrow. The amyloid deposits may consist of a light chain, a light chain fragment or a heavy chain fragment.1 Misfolding of the light chain into the β-pleated sheet configuration results in the classic Congo red positivity,2 showing apple-green birefringence under polarized light.

Making the diagnosis of AL

A patient can be referred to an oncologist for management of AL in one of three typical clinical scenarios.

Clinical scenario 1: the patient is referred with biopsy-proved AL

When a new patient is seen with a diagnosis of AL, the clinician should not assume that this patient immediately requires chemotherapy. AL often appears as a localized phenomenon with no risk of systemic visceral dysfunction, and these patients have a normal life expectancy. The first important question the oncologist must ask is, ‘Is the patient's AL localized?’3

Localized AL is often first suspected on the basis of its location. Typical sites where AL is a localized, nonsystemic phenomenon are the skin,4 brain, bladder,5 ureter,6 urethra and renal pelvis.7 Other sites typically associated with localized AL include the conjunctiva,8 larynx,9 vocal cords and tracheobronchial tree.10 Solitary pulmonary nodules typically represent localized nodular AL and do not require systemic therapy.11 In all these clinical presentations, the patients have no evidence of a systemic monoclonal immunoglobulin disorder. In addition, immunofixation of the serum, immunofixation of the urine, immunoglobulin-free light chain analysis of the serum and analysis of bone marrow will fail to show evidence of a monoclonal plasma cell disorder.

If the patient has localized AL, systemic treatment is not indicated and the patient should be referred for localized therapy. Bladder AL is typically treated with laser resection12 and, occasionally, installation of dimethyl sulfoxide.13 Tracheobronchial AL is treated with bronchoscopic laser therapy14 or external beam radiation to the deposits.15 In these cases, recurrences are common. Life-long monitoring is necessary; chemotherapy is never indicated. A particularly important finding that may represent localized AL is amyloid detected on endoscopic biopsy16 or colonoscopic biopsy.17 This finding can be particularly confusing because these biopsies are often taken to validate the presence of light chain AL. A patient who has an incidental finding of AL on an endoscopic biopsy,18 particularly when the biopsy was taken from the edge of an ulcer or in a polyp, should be considered to have localized disease until proved otherwise; care should be exercised before committing the patient to any form of systemic therapy.

If the patient referred with AL has systemic, nonlocalized disease, it is important to ensure that the AL is neither familial, senile nor secondary. Some patients have nonimmunoglobulin forms of systemic AL, although it is uncommon. At autopsy—beyond age 90 years—nearly 25% of patients have senile amyloid deposits in the heart19 that may contribute to cardiac dysfunction and are not amenable to chemotherapy. Sporadically, cardiac AL develops on an inherited basis without evidence of a family history.20 The consideration that AL may be familial is particularly important in the African-American population, where the prevalence of mutant transthyretin VAL122ILE approaches 3%21 and an accurate family history of late-onset cardiomyopathy may be difficult to obtain.

Occasionally, patients are seen with secondary AL because of a well-defined rheumatic disorder, such as spondyloarthropathy or long-standing inflammatory, symmetrical polyarthritis, but often, less well-defined connective tissue disorders with sustained systemic inflammation can result in the development of secondary AL.22 These patients do not have evidence of a monoclonal gammopathy unless an incidental monoclonal gammopathy of uncertain significance is present.

Verification of the type of amyloid in the tissue biopsy specimen is critical. When the result of immunohistochemistry is definitive, it is an acceptable alternative for classifying the AL.23 However, the gold standard is mass spectroscopic analysis24 of the tissue and direct sequencing to identify the amyloid protein.25 This analysis is now standard for all pathologic specimens that are positive on Congo red stain seen at Mayo Clinic. The distinction between immunoglobulin and nonimmunoglobulin AL is important because nonimmunoglobulin AL not only does not benefit from chemotherapy, but also new trials are under way with drugs, including both eprodisate, for slowing the decline of renal function in secondary AL,26 and tafamidis,27 which has potential utility in the management of senile and familial AL. In addition, studies of experimental preclinical therapies are exploring transthyretin interfering RNAs.28 For selected patients, liver transplantation for transthyretin inherited AL is an appropriate consideration.29

If systemic AL is confirmed, the patient needs to be evaluated as outlined in Table 1. Tests of immunoglobulin-free light chain levels and a bone marrow sample are indicated, as is a serum troponin test, a B-natriuretic peptide test and echocardiography. A summary of how to treat patients in scenario 1, referred with biopsy-proved AL, is given in Table 2.

Table 1 Suggested diagnostic evaluation of suspected light chain amyloidosis
Table 2 Scenario 1: patient referred to hematologist with biopsy-proved amyloidosis

Scenario 2: the patient has a known plasma cell dyscrasia. Should the patient be assessed for AL?

When a patient with a known plasma cell proliferative disorder has bone marrow plasma cells ranging from 5 to 20% without typical features of multiple myeloma, such as cases of lytic bone disease or high urinary light chain levels, the clinician should ask whether the patient has any of the following signs and symptoms:

  • Signs of ‘atypical’ multiple myeloma with substantial fatigue disproportionate to the level of anemia (considering amyloid heart disease).

  • A peripheral neuropathy. Although this finding has the potential to be associated with multiple myeloma, the possibility of amyloid neuropathy must not be overlooked, particularly when the patient has a λ monoclonal protein.

  • Heavy albuminuria. Electrophoresis of the urine of a patient with multiple myeloma usually shows only small amounts of albumin, with substantial excretion of urinary monoclonal light chains. By comparison, a patient with amyloid has predominant albuminuria and the light chain fraction is relatively modest.

  • The patient has unexplained edema, which could be due to hypoalbuminemia, to urinary protein loss or to restrictive cardiomyopathy30 and high filling pressures on the right side of the heart.

If the clinician is caring for a patient with myeloma with any of these unusual features, the bone marrow that showed the plasma cell dyscrasia should be stained for amyloid deposits, and a subcutaneous fat aspirate should be obtained and evaluated for amyloid. Table 3 lists the treatment steps for a patient with a known plasma cell dyscrasia but also with atypical features that do not suggest classic multiple myeloma. Routine Congo red staining of the bone marrow of a patient with typical multiple myeloma is not indicated.31

Table 3 Scenario 2: patient has a known plasma cell dyscrasia

Scenario 3: the patient is sent by a subspecialist with the request, ‘please rule out AL’

As AL occurs in only eight persons per 1 million per year,32 the clinician should be familiar with the presenting syndromes that indicate whether an evaluation is appropriate. For example, chronic pain is not consistent with AL. Enlargement of the tongue and periorbital purpura, as well as periarticular infiltration (shoulder pad sign), are well-recognized features of AL. Yet, these signs occur in only 15% of patients.33 Physical signs are not a sensitive method of excluding the diagnosis. The oncologist should look for any of the following syndromes: (1) nephrotic range proteinuria, (2) fatigue or dyspnea that could potentially be due to an unrecognized cardiomyopathy, (3) sensorimotor peripheral neuropathy and (4) hepatomegaly without imaging defects.34 The most subtle among these four syndromes is cardiomyopathy. As the cardiomyopathy is restrictive, these patients have no evidence of coronary artery disease and lack cardiomegaly on chest radiography.35 The thickening of the ventricle wall may be misinterpreted as hypertrophy. An electrocardiogram may show a pseudoinfarction pattern that may be interpreted as silent ischemic heart disease.

If the patient has none of the four syndromes, the clinician should question why AL was suspected. If the symptoms are consistent, immunofixation and electrophoresis of the serum, urine, and free light chains should be done. If any of these studies are positive, then biopsy of the subcutaneous fat and bone marrow and, if necessary, an organ biopsy should be performed to confirm AL. However, if the light chain studies are negative, the likelihood that the patient has light chain AL is small; unless there is a clear history of an inherited or inflammatory disorder, further diagnostic testing is not indicated. Table 4 lists the steps to undertake for a patient referred with a ‘rule out AL’ request. Table 1 lists the recommended diagnostic evaluation for patients who have histologic proof of AL.

Table 4 Scenario 3: patient referred with the request ‘please rule out amyloidosis’


Prognosis in AL is intimately linked to the severity of the cardiac involvement. One reason that the outcomes in AL continue to be poor is late diagnosis of amyloid cardiomyopathy. The cause of death in >70% of patients with AL is progressive cardiac failure or sudden death,36 which usually represents asystolic arrest related to cardiac hypoperfusion or sudden arrhythmia.

The ability to assess amyloid cardiomyopathy has been refined over time. Cardiac failure was defined historically by clinical symptoms and the chest radiograph. The introduction of echocardiography allowed recognition of wall and valvular thickening, the granular sparkling appearance,37 and, with the introduction of Doppler,38 relaxation abnormalities leading to a rapid rise in filling pressures during diastole. Ten years ago, the first studies were reported on the use of magnetic resonance imaging to demonstrate wall thickening and the specificity of subendocardial enhancement after gadolinium infusion.39 None of these techniques are quantitative, and the introduction of cardiac biomarkers—both troponin and the N terminal of prohormone brain natriuretic peptide type B (NT-proBNP)40—has been found to be useful in defining prognosis and estimating survival, as well as providing a method to serially determine whether myocardial function is improving, stable, or progressing after therapy. A high troponin T level should serve as an exclusionary criterion for undertaking stem cell transplantation.41 Other important prognostic factors include the percentage of bone marrow plasma cells before therapy42 and the level of immunoglobulin-free light chains43 at diagnosis, as well as the serum uric acid level.44

Assessing response

In multiple myeloma, outcome is determined by reductions in the tumor mass, with the M protein acting as a surrogate for bone marrow plasma cell burden. The same cannot be said for AL.

The median number of plasma cells in the bone marrow in patients with AL is approximately 4%, and the tumor mass does not accurately predict outcomes.45 Death is the ultimate result of the inexorable deposition of immunoglobulin light chains as amyloid deposits, leading to progressive visceral infiltration and organ dysfunction. Reducing monoclonal immunoglobulin light chain production is critically important to ensuring a good outcome. Changes in the serum-free light chain, rather than the intact monoclonal immunoglobulin, appear to be the key end point for evaluating therapy in primary AL.46

Response criteria are under development by a consensus panel for AL treatment. The proposed new criteria require a partial response, defined as a decrease in >50% in the difference between involved and uninvolved immunoglobulin light chain. A very good partial response would be defined as a difference in the involved and uninvolved immunoglobulin-free light chain of <4 mg/dl, and a complete response would be negative immunofixation serum and urine and a normal-free light chain ratio.47 With respect to cardiac organ response and progression, NT-proBNP criteria were defined as a change of 30% and at least 300 ng/l, using a minimum NT-proBNP of 650 ng/l to be considered evaluable, for response and progression reporting. Figure 1 shows the survival of patients using the four categories of response as proposed.

Figure 1

Survival by the new staging system in immunoglobulin light chain amyloidosis. CR, complete response; NR, no response; PR, partial response; py, patient-year; VGPR, very good partial response (adapted from Palladini et al.47 Used with permission).


Pending the development of strategies that destabilize the amyloid fibril, either by preventing the binding of serum amyloid P component or by using agents that interfere with the misfolding of a soluble light chain to an amyloid confirmation, the treatment involves cytotoxic chemotherapy designed to disrupt the production of the immunoglobulin light chain precursor protein. Mayo Clinic investigators have reported recently on two cohorts of patients seen before and after 1 September 2006, and have recognized the steady improvement in 4-year overall survival from 21 to 42%. However, early mortality rate continues to be 44% at 1 year, and this statistic has remained unchanged for 30 years.48 Some of this improvement in survival may reflect lead time bias because of earlier diagnosis and improved recognition. The predictors of early death were troponin, NT-proBNP and uric acid; 1-year death ranged from a low of 19% with none of these factors to 80% with all of the factors. Despite the possibility of lead time bias, improvement in therapy—the use of both stem cell transplantation and novel agents—has had an important role in enhancing the outcomes for this patient population. Alkylator-based chemotherapy for AL was first used 39 years ago in a case report.49 The use of melphalan and prednisone was reported subsequently in three studies to show response rates (measured before the introduction of the light chain assay) of approximately 20% with survival benefit compared with colchicine, a treatment that was introduced in the 1970s and subsequently abandoned as ineffective.50, 51, 52 The advantage of chemotherapy based on melphalan and prednisone was that virtually any patient was eligible to receive the therapy, and we consider a trial of this well-tolerated treatment an option for virtually all patients without regard to the extent of cardiac involvement or performance status.

Alone, corticosteroids have activity in the treatment of AL. Three studies on the use of dexamethasone have shown objective responses and regression of renal AL, although little impact was seen in patients with advanced cardiac involvement.53, 54, 55

Stem cell transplantation for AL was introduced 15 years ago. This technique has been shown to produce high responses and substantial survival prolongation. However, no >20% of patients are eligible for the technique because of advanced age, renal insufficiency, advanced cardiac failure or multiorgan involvement. Table 5 gives Mayo Clinic's criteria for stem cell transplantation eligibility. Stem cell transplantation has limited application because of a high treatment-related mortality rate if patients are not carefully selected. However, Mayo Clinic investigators have shown declining mortality rates in patients who have received a transplant. After 2006, a day-100 all-cause mortality rate of <7% was seen. From 1 January 2010, through 1 April 2011, no treatment-related deaths (any cause before day 100) at Mayo Clinic in Rochester, MN, USA, occurred in the 46 patients with AL who received a transplant.56 It is our hope that this survival relates to the implementation of stricter selection criteria using troponin, assessment of cardiac reserve and severity of noncardiac organ involvement.

Table 5 Exclusion criteria for high-dose chemotherapy in AL

An important predictor of stem cell transplantation outcome is the selection of patients. Patients with high levels of troponin should not be considered eligible for transplantation.41 One series recently showed a complete response rate of 49%, higher than that reported with melphalan and dexamethasone therapy.57 However, one prospective randomized study58 and one published meta-analysis59 do not demonstrate a survival advantage for stem cell transplantation. Yet, these studies included patients who should not have been selected for transplantation, and the resultant high treatment-related mortality rate resulted in no difference between groups.60

Mayo Clinic investigators recently reported results of 430 patients with AL.61 The patients with a complete response have not attained median survival yet. For those with a partial response, median survival was 107 months; for those with no response, it was 32 months. In this study group, cardiac stage was the sole predictor of survival. A quarter of the patients had >13% plasma cells in the bone marrow. The overwhelming majority were diagnosed through either bone marrow or fat aspiration (86%), showing that biopsy of liver, heart and kidney is generally unnecessary when the diagnosis is suspected. Neutrophil engraftment occurred at a median of 13.5 days and platelet engraftment at 17.5 days. The median length of hospital stay was 8 days, with 19% of patients completing their stem cell transplantation as an outpatient. Responses were seen in all organ systems, including cardiac, renal and hepatic. The day+100 all-cause mortality rate was 10.1% going back to the beginning of the program. Organ responses were seen in 47% of patients overall. We continue to believe that stem cell transplantation is the preferred technique for patients in whom the mortality risk is thought to be low, at <10%.

Chemotherapy treatment for AL in 2011

As the majority of patients with AL are not eligible for stem cell transplantation, controversy exists as to the optimal therapy. With the knowledge that melphalan and prednisone, as well as single-agent dexamethasone, were effective in treatment of AL, investigators combined melphalan with dexamethasone in the treatment. In the largest reported series, patients ineligible for stem cell transplantation received cyclic melphalan and dexamethasone therapy, with an actuarial survival of 50% at 6 years and a progression-free survival of 40%.62, 63 However, other studies have not shown as good a result, presumably because they had a higher proportion of patients with cardiomyopathy.64, 65 In a study of 48 evaluable patients with AL who survived to return for a follow-up visit in Boston, 13% achieved a complete response and 25% a partial hematologic response. Median survival for 70 evaluable patients was not reached with a median follow-up of 17 months. Melphalan and dexamethasone can lead to hematologic responses and improvement in survival.66

Interpreting the results of clinical trials of patients with AL requires knowledge of cardiac staging, to ensure the comparability of the patient population. High proportions of enrolled patients with advanced cardiac AL will result in poor study outcomes. A low prevalence of cardiac AL will likely result in better reported response rates and survival. This impact of patient selection on the outcome must be kept in mind when interpreting published results.67

In the opinion of Mayo Clinic physicians who specialize in AL, melphalan and dexamethasone is still considered the standard for nonstudy, nontransplantation patients because of its low toxicity profile, its oral availability, and the ability to produce hematologic responses in patients with advanced AL. Subsequent studies have been designed to build on the melphalan–dexamethasone treatment backbone.

Novel agents in the treatment of AL


Thalidomide is used in AL treatment, but as a single agent, it shows low activity. In the first published case series of its use in patients with AL, no organ responses were seen.68 In a subsequent study, hematologic responses were reported in 48%—including 19% with complete response—but the agent was poorly tolerated.69 Melphalan–thalidomide–dexamethasone combination therapy has been used for 22 patients, resulting in eight hematologic responses (36%).70

The best reported results have been with the combination of thalidomide, cyclophosphamide and dexamethasone.71 The hematologic response rate appears to be 74%, with a complete response in 21% and a median overall survival of 41 months. The treatment-related mortality rate was 3%. When thalidomide is used, the initial dose should probably not exceed 50 mg per day. In a review of 428 patients with AL, 155 patients (36%) received cyclophosphamide–thalidomide–dexamethasone combination treatment.72 A hematologic complete response and partial response were seen in 22% and 41%, respectively, with a median reduction of 72% in the difference between involved free light chain and uninvolved free light chain. There was no significant difference in the overall survival of patients treated with cyclophosphamide–thalidomide–dexamethasone therapy or melphalan–dexamethasone therapy.


Lenalidomide has been combined with dexamethasone in the treatment of AL. Toxicities were substantial and included cramps, fatigue, rash and cytopenias. In the first published study of lenalidomide–dexamethasone treatment of AL, hematologic response rate was 41% and median overall survival was 31 months.73 In an update, progression-free survival of patients with complete response was 49.8 months.74 In a second study, 41% of patients with renal amyloid had a reduction in urinary protein, but the response duration and overall survival were not reported.75 In that study, high-risk patients were less likely to respond to lenalidomide.

Lenalidomide also has been combined with melphalan and dexamethasone.76 The maximum tolerated dose of lenalidomide is 15 mg. This three-drug oral combination produced hematologic responses in 58% and complete responses in 42%. The 2-year event-free survival and the overall survival were 54% and 81%, respectively. In addition, lenalidomide was combined with cyclophosphamide and dexamethasone in the treatment of 35 patients.77 Hematologic response rate was 60%. In those patients receiving at least four treatment cycles, the response rate was 87%. Median overall survival was 16.1 months.

A randomized study of cyclophosphamide–thalidomide–dexamethasone treatment compared with melphalan–dexamethasone treatment suggested a greater complete response rate with the three-drug regimen, albeit with greater toxicity.78 One cautionary note when using lenalidomide or thalidomide in patients with AL is that the NT-proBNP level appears to increase after the initiation of therapy. Recognition of potential immunomodulatory drug-induced cardiac toxicity is important when these agents are used. High levels of NT-proBNP are predictive of an inability to tolerate immunomodulatory agents for AL.79, 80


Pomalidomide, a derivative of thalidomide with structural similarity to thalidomide and lenalidomide, was given to 29 evaluable patients in one study.81 All patients received treatment previously and 13 of the patients received a prior autologous stem cell transplantation. Previously, an immunomodulatory agent was given to 15 patients and bortezomib to 12. Twenty-nine patients evaluable for hematologic response were seen. The overall response rate was 11 (38%) of the 29 patients. Combined treatment with pomalidomide and dexamethasone is promising.81 One-year survival and progression-free survival was 77% and 56%, respectively. Pomalidomide was considered effective and safe for patients, including those in whom prior lenalidomide or thalidomide therapy had failed.


Of evaluable patients in the first reported study of bortezomib in AL treatment, 80% had a hematologic response.82 Among 18 patients, the hematologic response was 77%, with a complete response of 16%. A phase 1 dose-escalation study of bortezomib given either twice weekly on days 1, 4, 8 and 11 every 21 days or on days 1, 8, 15 and 22 every 35 days reported hematologic responses in 50% of patients.83 The weekly regimen was associated with less neurotoxicity. The 1-year hematologic progression-free rate was 72.2% and 74.6% and the 1-year survival rate was 93.8% and 84%, respectively, for the twice-weekly and once-weekly doses. Among 70 patients, there were 29% renal responses and 13% cardiac responses. Discontinuation and dose reduction because of the toxicity were higher with the twice-weekly dose than the once-weekly dose. Both dose schedules represent active, well-tolerated regimens in relapsed AL.84

The combination of bortezomib and dexamethasone has been used to render a patient eligible for stem cell transplantation after organ improvement was seen with bortezomib treatment. Bortezomib was also used successfully after relapse following stem cell transplantation.85 Twenty-six patients with AL received bortezomib and dexamethasone, and 31% achieved a complete response and 12% an organ response.86 A multicenter study of 94 patients receiving bortezomib and dexamethasone showed hematologic responses in 71%, of which 25% were complete responses.87 Cardiac response was seen in 29% of patients. NT-proBNP analysis predicted survival. In a study of bortezomib–dexamethasone therapy in 26 patients with AL, the overall response rate was 54% and the complete response rate was 31%.86 Median time to response was 7.5 weeks, but the median progression-free and overall survival was 5.0 and 18.7 months, respectively, suggesting short response durability with bortezomib combined with dexamethasone. No grade 3/4 neuropathy was seen. Recommended treatment for newly diagnosed AL and relapsed AL is given in Figures 2 and 3. Reported regimens for the nontransplantation treatment of AL are given in Table 6.

Figure 2

Approach to treatment of transplant-eligible patients with AL. aHigh risk indicates stage III. FLC-diff, the difference between involved (amyloidogenic) free light chain and uninvolved free light chain; MBD, melphalan–bortezomib–dexamethasone; SCT, stem cell transplantation; Vd, bortezomib ± dexamethasone (adapted from

Figure 3

Approach to treatment of transplant-ineligible patients with AL. aHigh risk indicates stage III. Consider upfront Vd or MBD in younger patients. bStart alternative therapy if organ progression has occurred at this point. FLC-diff, the difference between involved (amyloidogenic) free light chain and uninvolved free light chain; MBD, melphalan–bortezomib–dexamethasone; Mel-Dex, melphalan–dexamethasone; Vd, bortezomib ± dexamethasone (adapted from

Table 6 Nontransplantation treatment options for amyloidosis


Chemotherapy is capable of producing a hematologic response, as well as improvement in organ function of patients with AL. Hematologic response has been shown to translate into improved survival. When a patient is seen with a compatible syndrome, studies to exclude localized, inherited and secondary AL should be performed. Mass spectroscopy is the gold standard for confirming the type of AL. After the diagnosis is confirmed, the prognosis should be assessed with use of echocardiography and testing for cardiac biomarkers. Some patients will be appropriate candidates for stem cell transplantation. For others, melphalan–dexamethasone treatment, with the possible addition of an immunomodulatory drug or a proteasome inhibitor, should be considered.


  1. 1

    Baden EM, Sikkink LA, Ramirez-Alvarado M . Light chain amyloidosis: current findings and future prospects. Curr Protein Pept Sci 2009; 10: 500–508.

    CAS  Article  Google Scholar 

  2. 2

    Randles EG, Thompson JR, Martin DJ, Ramirez-Alvarado M . Structural alterations within native amyloidogenic immunoglobulin light chains. J Mol Biol 2009; 389: 199–210.

    CAS  Article  Google Scholar 

  3. 3

    Biewend ML, Menke DM, Calamia KT . The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature. Amyloid 2006; 13: 135–142.

    Article  Google Scholar 

  4. 4

    Santos-Briz A, Canueto J, Antunez P, Bravo J, Garcia-Sanz R, de Unamuno P . Primary cutaneous localized amyloid elastosis. Am J Dermatopathol 2010; 32: 86–90.

    Article  Google Scholar 

  5. 5

    DeSouza MA, Rekhi B, Thyavihally YB, Tongaonkar HB, Desai SB . Localized amyloidosis of the urinary bladder, clinically masquerading as bladder cancer. Indian J Pathol Microbiol 2008; 51: 415–417.

    Article  Google Scholar 

  6. 6

    Takahashi T, Miura H, Matsu-ura Y, Iwana S, Maruyama R, Harada T . Urine cytology of localized primary amyloidosis of the ureter: a case report. Acta Cytol 2005; 49: 319–322.

    Article  Google Scholar 

  7. 7

    Merrimen JL, Alkhudair WK, Gupta R . Localized amyloidosis of the urinary tract: case series of nine patients. Urology 2006; 67: 904–909.

    CAS  Article  Google Scholar 

  8. 8

    Caggiati A, Campanella A, Tenna S, Cogliandro A, Potenza C, Persichetti P . Primary amyloidosis of the eyelid: a case report. In Vivo 2010; 24: 575–578.

    PubMed  Google Scholar 

  9. 9

    Neuner GA, Badros AA, Meyer TK, Nanaji NM, Regine WF . Complete resolution of laryngeal amyloidosis with radiation treatment. Head Neck 2010; e-pub ahead of print 10 November 2010.

  10. 10

    Santos JW, Schneider Filho A, Bertolazzi A, Michel GT, Silva LV, Melo CR et al. Primary tracheobronchial amyloidosis. J Bras Pneumol 2008; 34: 881–884. English, Portuguese.

    Article  Google Scholar 

  11. 11

    Gaurav K, Panda M . An uncommon cause of bilateral pulmonary nodules in a long-term smoker. J Gen Intern Med 2007; 22: 1617–1620.

    Article  Google Scholar 

  12. 12

    Caglar K, Kibar Y, Tahmaz L, Safali M . Laser therapy in patient with intractable haemorrhage due to the bladder involvement of systemic amyloidosis. Nephrol Dial Transplant 2001; 16: 1724.

    CAS  Article  Google Scholar 

  13. 13

    Malek RS, Wahner-Roedler DL, Gertz MA, Kyle RA . Primary localized amyloidosis of the bladder: experience with dimethyl sulfoxide therapy. J Urol 2002; 168: 1018–1020.

    Article  Google Scholar 

  14. 14

    Brill AK, Woelke K, Schadlich R, Weinz C, Laier-Groeneveld G . Tracheobronchial amyloidosis: bronchoscopic diagnosis and therapy of an uncommon disease: a case report. J Physiol Pharmacol 2007; 58 Suppl 5(Pt 1): 51–55.

    PubMed  Google Scholar 

  15. 15

    Poovaneswaran S, Razak AR, Lockman H, Bone M, Pollard K, Mazdai G . Tracheobronchial amyloidosis: utilization of radiotherapy as a treatment modality. Medscape J Med 2008; 10: 42.

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Wu D, Lou JY, Chen J, Fei L, Liu GJ, Shi XY et al. A case report of localized gastric amyloidosis. World J Gastroenterol 2003; 9: 2632–2634.

    Article  Google Scholar 

  17. 17

    Kyle RA, Gertz MA, Lacy MQ, Dispenzieri A . Localized AL amyloidosis of the colon: an unrecognized entity. Amyloid 2003; 10: 36–41.

    Article  Google Scholar 

  18. 18

    Rotondano G, Salerno R, Cipolletta F, Bianco MA, De Gregorio A, Miele R et al. Localized amyloidosis of the stomach: a case report. World J Gastroenterol 2007; 13: 1877–1878.

    Article  Google Scholar 

  19. 19

    Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 2008; 40: 232–239.

    CAS  Article  Google Scholar 

  20. 20

    Kestenbaum B, Belozeroff V . Mineral metabolism disturbances in patients with chronic kidney disease. Eur J Clin Invest 2007; 37: 607–622.

    CAS  Article  Google Scholar 

  21. 21

    Buxbaum J, Alexander A, Koziol J, Tagoe C, Fox E, Kitzman D . Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J 2010; 159: 864–870.

    CAS  Article  Google Scholar 

  22. 22

    Silva L, Sampaio L, Terroso G, Almeida G, Lucas R, Rios E et al. Amyloidosis secondary to rheumatic diseases: 16 cases. Acta Reumatol Port 2010; 35: 518–523.

    CAS  PubMed  Google Scholar 

  23. 23

    Picken MM . Amyloidosis: where are we now and where are we heading? Arch Pathol Lab Med 2010; 134: 545–551.

    PubMed  Google Scholar 

  24. 24

    Sethi S, Theis JD, Leung N, Dispenzieri A, Nasr SH, Fidler ME et al. Mass spectrometry-based proteomic diagnosis of renal immunoglobulin heavy chain amyloidosis. Clin J Am Soc Nephrol 2010; 5: 2180–2187.

    CAS  Article  Google Scholar 

  25. 25

    Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen III HR, Dogan A . Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood 2009; 114: 4957–4959.

    CAS  Article  Google Scholar 

  26. 26

    Manenti L, Tansinda P, Vaglio A . Eprodisate in amyloid A amyloidosis: a novel therapeutic approach? Expert Opin Pharmacother 2008; 9: 2175–2180.

    CAS  Article  Google Scholar 

  27. 27

    Ratner M . Spotlight focuses on protein-misfolding therapies. Nat Biotechnol 2009; 27: 874.

    CAS  Article  Google Scholar 

  28. 28

    Kurosawa T, Igarashi S, Nishizawa M, Onodera O . Selective silencing of a mutant transthyretin allele by small interfering RNAs. Biochem Biophys Res Commun 2005; 337: 1012–1018.

    CAS  Article  Google Scholar 

  29. 29

    Moini M, Mistry P, Schilsky ML . Liver transplantation for inherited metabolic disorders of the liver. Curr Opin Organ Transplant 2010; 15: 269–276.

    Article  Google Scholar 

  30. 30

    Halwani O, Delgado DH . Cardiac amyloidosis: an approach to diagnosis and management. Expert Rev Cardiovasc Ther 2010; 8: 1007–1013.

    Article  Google Scholar 

  31. 31

    Siragusa S, Morice W, Gertz MA, Kyle RA, Greipp PR, Lust JA et al. Asymptomatic immunoglobulin light chain amyloidosis (AL) at the time of diagnostic bone marrow biopsy in newly diagnosed patients with multiple myeloma and smoldering myeloma: a series of 144 cases and a review of the literature. Ann Hematol 2011; 90: 101–106.

    CAS  Article  Google Scholar 

  32. 32

    Kyle RA, Linos A, Beard CM, Linke RP, Gertz MA, O’Fallon WM et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood 1992; 79: 1817–1822.

    CAS  PubMed  Google Scholar 

  33. 33

    Cohen AD, Comenzo RL . Systemic light-chain amyloidosis: advances in diagnosis, prognosis, and therapy. Hematology Am Soc Hematol Educ Program 2010; 2010: 287–294.

    Article  Google Scholar 

  34. 34

    Perfetto F, Moggi-Pignone A, Livi R, Tempestini A, Bergesio F, Matucci-Cerinic M . Systemic amyloidosis: a challenge for the rheumatologist. Nat Rev Rheumatol 2010; 6: 417–429.

    CAS  Article  Google Scholar 

  35. 35

    Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR . Amyloidosis: diagnosis and management. Clin Lymphoma Myeloma 2005; 6: 208–219.

    CAS  Article  Google Scholar 

  36. 36

    Dispenzieri A, Merlini G, Comenzo RL . Amyloidosis 2008 BMT Tandem Meetings (February 13–17, San Diego). Biol Blood Marrow Transplant 2008; 14 (Suppl 1): 6–11.

    Article  Google Scholar 

  37. 37

    Wang J, Kong X, Xu H, Zhou G, Chang D, Liu D et al. Noninvasive diagnosis of cardiac amyloidosis by MRI and echochardiography. J Huazhong Univ Sci Technolog Med Sci 2010; 30: 536–540.

    CAS  Article  Google Scholar 

  38. 38

    Koyama J, Falk RH . Prognostic significance of strain Doppler imaging in light-chain amyloidosis. JACC Cardiovasc Imaging 2010; 3: 333–342.

    Article  Google Scholar 

  39. 39

    Syed IS, Glockner JF, Feng D, Araoz PA, Martinez MW, Edwards WD et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging 2010; 3: 155–164.

    Article  Google Scholar 

  40. 40

    Palladini G, Campana C, Klersy C, Balduini A, Vadacca G, Perfetti V et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation 2003; 107: 2440–2445.

    CAS  Article  Google Scholar 

  41. 41

    Gertz M, Lacy M, Dispenzieri A, Hayman S, Kumar S, Buadi F et al. Troponin T level as an exclusion criterion for stem cell transplantation in light-chain amyloidosis. Leuk Lymphoma 2008; 49: 36–41.

    CAS  Article  Google Scholar 

  42. 42

    Kumar S, Dispenzieri A, Katzmann JA, Larson DR, Colby CL, Lacy MQ et al. Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features. Blood 2010; 116: 5126–5129.

    CAS  Article  Google Scholar 

  43. 43

    Dispenzieri A, Lacy MQ, Katzmann JA, Rajkumar SV, Abraham RS, Hayman SR et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 2006; 107: 3378–3383.

    CAS  Article  Google Scholar 

  44. 44

    Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Leung N, Zeldenrust SR et al. Serum uric acid: novel prognostic factor in primary systemic amyloidosis. Mayo Clin Proc 2008; 83: 297–303.

    CAS  Article  Google Scholar 

  45. 45

    Paiva B, Vídriales MB, Perez JJ, Lopez-Berges MC, Garcia-Sanz R, Ocio EM et al. The clinical utility and prognostic value of multiparameter flow cytometry immunophenotyping in light-chain amyloidosis. Blood 2011; 117: 3613–3616.

    CAS  Article  Google Scholar 

  46. 46

    Kumar SK, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR et al. 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.

    CAS  Article  Google Scholar 

  47. 47

    Palladini G, Dispenzieri A, Gertz MAA, Wechalekar A, Hawkins PN, Schonland SO et al. Validation of the criteria of response to treatment in AL amylodiosis [abstract]. Blood 2010, 116.

  48. 48

    Kumar SK, Gertz MA, Lacy MQ, Dingli D, Hayman SR, Buadi FK et al. Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score. Mayo Clin Proc 2011; 86: 12–18.

    Article  Google Scholar 

  49. 49

    Jones NF, Hilton PJ, Tighe JR, Hobbs JR . Treatment of ‘primary’ renal amyloidosis with melphalan. Lancet 1972; 2: 616–619.

    CAS  Article  Google Scholar 

  50. 50

    Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 1997; 336: 1202–1207.

    CAS  Article  Google Scholar 

  51. 51

    Skinner M, Anderson J, Simms R, Falk R, Wang M, Libbey C et al. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med 1996; 100: 290–298.

    CAS  Article  Google Scholar 

  52. 52

    Kyle RA, Greipp PR, Garton JP, Gertz MA . Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med 1985; 79: 708–716.

    CAS  Article  Google Scholar 

  53. 53

    Palladini G, Anesi E, Perfetti V, Obici L, Invernizzi R, Balduini C et al. A modified high-dose dexamethasone regimen for primary systemic (AL) amyloidosis. Br J Haematol 2001; 113: 1044–1046.

    CAS  Article  Google Scholar 

  54. 54

    Gertz MA, Lacy MQ, Lust JA, Greipp PR, Witzig TE, Kyle RA . Phase II trial of high-dose dexamethasone for untreated patients with primary systemic amyloidosis. Med Oncol 1999; 16: 104–109.

    CAS  Article  Google Scholar 

  55. 55

    Gertz MA, Lacy MQ, Lust JA, Greipp PR, Witzig TE, Kyle RA . Phase II trial of high-dose dexamethasone for previously treated immunoglobulin light-chain amyloidosis. Am J Hematol 1999; 61: 115–119.

    CAS  Article  Google Scholar 

  56. 56

    Gertz MA, Lacy MQ, Dispenzieri A, Kumar SK, Buadi FK, Dingli D et al. Trends in day 100 and 2-year survival after auto-SCT for AL amyloidosis: outcomes before and after 2006. Bone Marrow Transplant 2011; 46: 970–975.

    CAS  Article  Google Scholar 

  57. 57

    Jimenez-Zepeda VH, Franke N, Delgado D, Winter A, Stewart K, Mikhael JR et al. High-dose melphalan for AL amyloidosis: the importance of case selection to improve clinical outcomes [abstract]. Blood 2010, 116.

  58. 58

    Mhaskar R, Kumar A, Behera M, Kharfan-Dabaja MA, Djulbegovic B . Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review. Biol Blood Marrow Transplant 2009; 15: 893–902.

    CAS  Article  Google Scholar 

  59. 59

    Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 2007; 357: 1083–1093.

    CAS  Article  Google Scholar 

  60. 60

    Mehta J, Dispenzieri A, Gertz MA . High-dose chemotherapy with autotransplantation in AL amyloidosis: a flawed meta-analysis. Biol Blood Marrow Transplant 2010; 16: 138–140.

    Article  Google Scholar 

  61. 61

    Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Kumar SK, Dingli D et al. Autologous stem cell transplant for immunoglobulin light chain amyloidosis: a status report. Leuk Lymphoma 2010; 51: 2181–2187.

    Article  Google Scholar 

  62. 62

    Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L et al. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood 2007; 110: 787–788.

    CAS  Article  Google Scholar 

  63. 63

    Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F et al. 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.

    CAS  Article  Google Scholar 

  64. 64

    Dietrich S, Schonland SO, Benner A, Bochtler T, Kristen AV, Beimler J et al. Treatment with intravenous melphalan and dexamethasone is not able to overcome the poor prognosis of patients with newly diagnosed systemic light chain amyloidosis and severe cardiac involvement. Blood 2010; 116: 522–528.

    CAS  Article  Google Scholar 

  65. 65

    Elzawawy A . Treatment of 5-fluorouracil-induced stomatitis by allopurinol mouthwashes. Oncology 1991; 48: 282–284.

    CAS  Article  Google Scholar 

  66. 66

    Sanchorawala V, Seldin DC, Berk JL, Sloan JM, Doros G, Skinner M . Oral cyclic melphalan and dexamethasone for patients with Al amyloidosis. Clin Lymphoma Myeloma Leuk 2010; 10: 469–472.

    CAS  Article  Google Scholar 

  67. 67

    Gertz MA . I don’t know how to treat amyloidosis. Blood 2010; 116: 507–508.

    CAS  Article  Google Scholar 

  68. 68

    Seldin DC, Choufani EB, Dember LM, Wiesman JF, Berk JL, Falk RH et al. Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis. Clin Lymphoma 2003; 3: 241–246.

    CAS  Article  Google Scholar 

  69. 69

    Dispenzieri A, Lacy MQ, Rajkumar SV, Geyer SM, Witzig TE, Fonseca R et al. Poor tolerance to high doses of thalidomide in patients with primary systemic amyloidosis. Amyloid 2003; 10: 257–261.

    CAS  Article  Google Scholar 

  70. 70

    Palladini G, Russo P, Lavatelli F, Nuvolone M, Albertini R, Bosoni T et al. Treatment of patients with advanced cardiac AL amyloidosis with oral melphalan, dexamethasone, and thalidomide. Ann Hematol 2009; 88: 347–350.

    CAS  Article  Google Scholar 

  71. 71

    Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD . Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood 2007; 109: 457–464.

    CAS  Article  Google Scholar 

  72. 72

    Wechalekar AD, Kastritis E, Merlini G, Hawkins PN, Dimopoulos MA, Gillmore JD et al. A European collaborative study of treatment outcomes in 428 patients with systemic AL amyloidosis [abstract]. Blood 2010, 116.

  73. 73

    Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB et al. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood 2007; 109: 492–496.

    CAS  Article  Google Scholar 

  74. 74

    Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB et al. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood 2010; 116: 1990–1991.

    CAS  Article  Google Scholar 

  75. 75

    Waites KB, Duffy LB, Dowzicky MJ . Antimicrobial susceptibility among pathogens collected from hospitalized patients in the United States and in vitro activity of tigecycline, a new glycylcycline antimicrobial. Antimicrob Agents Chemother 2006; 50: 3479–3484.

    CAS  Article  Google Scholar 

  76. 76

    Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F et al. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood 2010; 116: 4777–4782.

    CAS  Article  Google Scholar 

  77. 77

    Kumar S, Hayman SR, Buadi F, Allred J, Laumann K, Roy V et al. A phase II trial of lenalidomide, cyclophophamide and dexamethasone (RCD) in patients with light chain amyloidosis [abstract]. Blood 2009, 114.

  78. 78

    Gillmore J, Cocks K, Gibbs SDJ, Sattianayagam PT, Lane T, Lachmann H et al. Cyclophosphamide, thalidomide and dexamethasone (CTD) versus melphalan plus dexamethasone (MD) for newly-diagnosed systemic AL amyloidosis: results from the UK Amyloidosis Treatment Trial [abstract]. Blood 2009, 114.

  79. 79

    Dispenzieri A, Dingli D, Kumar SK, Rajkumar SV, Lacy MQ, Hayman S et al. Discordance between serum cardiac biomarker and immunoglobulin-free light-chain response in patients with immunoglobulin light-chain amyloidosis treated with immune modulatory drugs. Am J Hematol 2010; 85: 757–759.

    CAS  Article  Google Scholar 

  80. 80

    Tapan U, Seldin DC, Finn KT, Fennessey S, Shelton A, Zeldis JB et al. Increases in B-type natriuretic peptide (BNP) during treatment with lenalidomide in AL amyloidosis. Blood 2010; 116: 5071–5072.

    CAS  Article  Google Scholar 

  81. 81

    Dispenzieri A, Gertz MA, Hayman SR, Buadi F, Kumar S, Reeder CR et al. A phase-2 study of pomalidomide and dexamethasone in previously-treated light-chain (AL) amyloidosis [abstract]. Blood 2010, 116.

  82. 82

    Wechalekar AD, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD . Efficacy of bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease. Haematologica 2008; 93: 295–298.

    CAS  Article  Google Scholar 

  83. 83

    Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP et al. VALCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood 2009; 114: 1489–1497.

    CAS  Article  Google Scholar 

  84. 84

    Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Blade J et al. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood 2011; 118: 865–873.

    CAS  Article  Google Scholar 

  85. 85

    Brunvand MW, Bitter M . Amyloidosis relapsing after autologous stem cell transplantation treated with bortezomib: normalization of detectable serum-free light chains and reversal of tissue damage with improved suitability for transplant. Haematologica 2010; 95: 519–521.

    Article  Google Scholar 

  86. 86

    Lamm W, Willenbacher W, Lang A, Zojer N, Muldur E, Ludwig H et al. Efficacy of the combination of bortezomib and dexamethasone in systemic AL amyloidosis. Ann Hematol 2011; 90: 201–206.

    CAS  Article  Google Scholar 

  87. 87

    Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol 2010; 28: 1031–1037.

    CAS  Article  Google Scholar 

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Correspondence to M A Gertz.

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The author receives honoraria from Celgene and Millennium.

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Gertz, M. How to manage primary amyloidosis. Leukemia 26, 191–198 (2012).

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  • amyloidosis
  • chemotherapy
  • immunoglobulin light chains
  • nephrotic syndrome
  • restrictive cardiomyopathy
  • stem cell transplantation

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