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Review
Immunoglobulin light chain amyloidosis Expert Review of Hematology Downloaded from informahealthcare.com by Washington University Library on 12/29/14 For personal use only.
Expert Rev. Hematol. 7(1), 143–156 (2014)
Giampaolo Merlini*1, Raymond L Comenzo2, David C Seldin3,4, Ashutosh Wechalekar5 and Morie A Gertz6 1 Department of Molecular Medicine, University of Pavia, Foundation Scientific Institute San Matteo, Amyloidosis Research and Treatment Center, V.le Golgi 19 27100, Pavia, Italy 2 Department of Medicine, Tufts Medical Center and Tufts University School of Medicine, Division of HematologyOncology, Boston, MA 02111, USA 3 Boston University School of Medicine, Amyloidosis Center, Boston, MA 02118, USA 4 Department of Medicine, Section of Hematology-Oncology, Boston Medical Center, Boston, MA 02118, USA 5 National Amyloidosis Centre, UCL Medical School (Royal Free Campus), Rowland Hill Street, London, NW3 2PF, UK 6 Division of Hematology, Mayo Clinic, 200 First Street, SW Rochester, MN 55905, USA *Author for correspondence: Tel.: +39 0382 502 995 Fax: +39 0382 502 990 [email protected]
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Primary light chain amyloidosis is the most common form of systemic amyloidosis and is caused by misfolded light chains that cause proteotoxicity and rapid decline of vital organ function. Early diagnosis is essential in order to deliver effective therapy and prevent irreversible organ damage. Accurate diagnosis requires clinical skills and advanced technologies. The disease can be halted and the function of target organs preserved by the prompt reduction and elimination of the plasma cell clone producing the toxic light chains in the bone marrow. Heart damage is the major determinant of survival, and staging with cardiac biomarkers guides treatment. Two-thirds of patients can benefit from treatment with improved quality of life and extended survival. Future efforts should be directed at early diagnosis, improving the tolerability and efficacy of anti-plasma cell therapy, accelerating recovery of organ function via promoting resorption of amyloid deposits, and developing novel approaches to counter light chain proteotoxicity. KEYWORDS: amyloid cardiomyopathy • biomarkers • novel agents • proteotoxicity
Amyloid & amyloidoses
A diagnostic feature of human amyloid diseases is extracellular cross-b-sheet amyloid fibril deposition. About 30 different proteins can cause amyloidosis; the major protein deposited determines the pathology observed [1]. Amyloid deposits display distinctive ultrastructural beta-sheet conformation and tinctorial properties such as vivid green birefringence in polarized light after staining with Congo red. The process of amyloid formation and deposition ultimately results in tissue damage and organ dysfunction. Basic research and clinical observations have identified some factors associated with the capacity of a protein to form amyloid in vivo and to give rise to disease, including: a sustained increase in the concentration of a protein with high propensity to aggregate (e.g., serum amyloid A protein (SAA) in chronic inflammation); mutations that destabilize a protein and favor its misfolding and aggregation, as occurs in the hereditary amyloidoses and in immunoglobulin light chain amyloidosis (AL); proteolytic processing of a protein, as in the case of the amyloid-b (Ab) peptides and intrinsic tendency to misfold, e.g., wild-type transthyretin and apolipoprotein A-I, both associated with age-related amyloid deposition. 10.1586/17474086.2014.858594
Frequently, a combination of these factors determines the amyloidogenicity of an individual protein, as occurs in AL amyloidosis where specific mutations in a light chain produced in excess by a plasma cell clone cause the disease. However, the inherent amyloidogenicity of a specific protein, per se, is probably not sufficient to account for amyloid deposition in vivo. Interactions with cells, extracellular matrix components and other constituents commonly found in amyloid deposits play an important role in the amyloid disease process. Serum amyloid P (SAP) component, a glycoprotein of the pentraxin family, binds all types of amyloid, making it suitable for imaging amyloid deposits [2] and as a potential therapeutic target [3]. Proteoglycans are also common in amyloid deposits and heparan sulfate (HS), in particular, is directly associated with amyloidogenesis, as shown in animal models [4]. HS accelerates not only the transition of the amyloid protein from the native state into the partially folded state [5] but also the rate of amyloid fibril formation by immunoglobulin light chains (LC) [6,7]. Heparin-binding peptides have been proposed as potential radiotracers of amyloid deposits [8]. Other common elements found in amyloid deposits are components of the extracellular matrix, such as elastin, entactin and collagen IV.
2014 Informa UK Ltd
ISSN 1747-4086
143
Review
Merlini, Comenzo, Seldin, Wechalekar & Gertz
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In vitro studies have shown that amyloid fibril formation proceeds, in many instances, through ‘nucleated growth’. After an initial lag phase, once a critical nucleus has been generated, fibril formation begins and proceeds rapidly: any amyloidogenic precursor in its aggregation-prone conformation is rapidly incorporated into the growing fibrils [9]. This seeding mechanism has clinical implications, since the process of amyloid clearance, following a response to therapy, usually leaves traces of ‘seeds’ in tissues. In the case of disease relapse, these may trigger rapid re-accumulation of amyloid deposits. AL amyloidosis: the biology of the clone
AL amyloidosis is characterized by the production, by a clonal plasma cell population in the bone marrow, of a monoclonal light chain with unique structural features causing systemic proteotoxicity. The biology of the clone that sustains this condition is poorly defined. Limited studies have been performed in AL amyloidosis where a small bone marrow plasma cell clone (the median plasma cell infiltration is only 5–7%) produces light chain only in approximately 50% of the cases [10]. There is a strikingly high frequency of the t(11;14) translocation [11–13] consistent with cyclin D1 up-regulation [14], suggesting that disruption of the heavy chain locus might also be an important mechanism in AL since half of AL patients lack an intact immunoglobulin in serum immunofixation. The low frequencies of t(4;14) and deletion 17p13 [15], aberrancies linked to rapid clonal proliferation, short remission durations and progressive drug resistance, fit with the observation of the rare progression of AL to multiple myeloma. In addition, hyperdiploidy is uncommon in AL compared with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM), consistent with the hypothesis that the amyloidogenic clone represents an early stage of monoclonal gammopathy possibly more susceptible to chemotherapy [15]. Higher sensitivity to proteasome inhibitors of AL plasma cells as compared with myeloma plasma cells has been reported [16]. Furthermore, patients with AL who undergo autologous stem cell transplantation (ASCT) enjoy a superior survival compared with MM patients undergoing the same procedure. This difference is most notable among those patients who achieve CR suggesting that AL and MM clones may have biological differences; however, it is important to note that the overall survival of AL patients with ASCT is very similar to that of patients with stage I MM [17,18]. Therefore, it is likely that both clonal plasma cell burden and biologic features shared by less proliferative plasma cell dyscrasias contribute to the differences in response to bortezomib and outcomes in ASCT observed for AL patients. The small indolent plasma cell clones responsible for AL synthesize an abnormal monoclonal light chain that causes systemic proteotoxicity by misfolding, aggregating, disturbing tissue architecture and metabolism, and depositing in vital organs. Therefore, the clinical features of AL derive primarily from the systemic toxicity of the monoclonal light chain. Unlike most other PC dyscrasias, the lambda isotype accounts 144
for 75% of the amyloidogenic light chains [10]. These misfolded light chains can target and damage practically all organs outside of the central nervous system. Mechanism of organ targeting & tissue damage
Sequence-specific interaction of LC with matrix proteins, cells, or other components of the target organ may play a role in ‘tissue tropism’, the concept that different LC have differing propensities to target and damage heart, kidney, nerves, etc. Almost all patients whose plasma cell clone expresses the l6 isotype develop renal disease [19,20]. The l1 isotype, derived from the IGLV1-44 germline gene, is particularly associated with cardiac disease [21], whereas k1 is seen more often than l isotypes in patients with bone and soft tissue deposits [22]. It is unknown what properties of the LC determine tissue tropism: the primary amino acid sequence may be critical, or posttranslational modifications could play a role. It is also unclear what organ-specific molecules in extracellular matrix or cells interact with the LC and is a fertile area for further research. The amyloid hypothesis describes the process by which proteins aggregate and form fibrils that are deposited in tissues, leading to organ failure. However, recent studies suggest that it is not just a mechanical effect of the fibrillar end product, but the activity of toxic oligomeric intermediates, that leads to cell death and tissue dysfunction. This is now well described in the neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Seminal studies from the laboratory of Ronglih Liao have described a similar process in AL amyloidosis. Initial observations showed that human amyloidogenic LC, purified from patients with severe cardiomyopathy, caused the rapid (in minutes) onset of diastolic dysfunction in the isolated mouse heart [23], and increased production of intracellular reactive oxygen species in isolated cardiomyocytes, impairing contractility [24]. Further studies revealed that this response is mediated by p38 MAPK signaling, and p38 inhibition is protective [25]. Recently, it has been shown that expression of amyloidogenic cardiotoxic LC mRNA [26] or injection of protein [27] cause cardiac dysfunction and early death in zebrafish. Thus, for the first time there is an animal model in which this process can be studied, and p38 signaling as well as other effectors of cardiomyocyte dysfunction may now be druggable targets and testable in an in vivo model. The toxic effect of the LC described in these model systems is supported by clinical observations that cardiac stress, as measured by circulating levels of the Nterminal pro-brain natriuretic peptide (NT-proBNP) or BNP itself, may be reduced in parallel with the reduction in free LC levels following chemotherapy and such reductions predict for improved survival [28]. Interestingly, protein misfolding and proteotoxicity has been linked to other common types of acquired and hereditary cardiomyopathy with chronic heart failure [29]. In the kidney, effects of LC on mesangial cell protein expression may contribute to pathogenesis in that organ. Amyloidogenic LC decrease matrix protein synthesis and increase degradation through induction of collagenase IV [30] and matrix Expert Rev. Hematol. 7(1), (2014)
Immunoglobulin AL
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metalloproteinases (MMPs) [31]. While renal involvement is not as dire as cardiac involvement in AL amyloidosis, renal failure is still a major cause of morbidity if not mortality. Thus, targeting these pathways of matrix protein turnover could be protective. Similar observations have been made about the involvement of MMPs and their inhibitors in the heart [32]; combining measurement of MMPs and their inhibitors with BNP and troponin may help to distinguish between forms of amyloid cardiomyopathy, and add prognostic information [33]. Diagnosis
Review
Clinical suspicion of systemic AL amyloidosis
Unexplained weight loss, fatigue, leg swelling, thick walled heart failure or nephrotic syndrome in a patient with M-protein or abnormal FLC, periorbital purpura, macroglossia, peripheral and autonomic neuropathy
How to make an early diagnosis of AL amyloidosis
Keeping a high index of suspicion is important for early diagnosis to avoid development of irreversible organ failure. In a patient with myeloma or MGUS, specific symptom complexes should trigger a suspicion for a diagnosis of amyloidosis such as: nephrotic syndrome with albuminuria rather than Bence Jones proteinuria; peripheral or autonomic neuropathy; diastolic heart failure with normal or low voltage ECG; or recurrent carpal tunnel syndrome. Periodic measurement of cardiac biomarkers and screening for albuminuria in a patient with MGUS may allow early diagnosis, as abnormalities of either may herald development of amyloidosis [10]. A stepwise approach to diagnosis and staging of amyloidosis is critical and involves confirmation of amyloid deposition, identification of fibril type, assessment of the underlying amyloidogenic disorder, and evaluation of amyloidotic organ involvement (FIGURE 1). Histological demonstration of amyloid deposits & confirming the fibril type
Demonstration of characteristic green birefringence under cross-polarized light following Congo red staining of a tissue biopsy remains the gold standard for confirming amyloid deposition. Abdominal fat aspiration is a simple high yield method available at the bedside for obtaining tissue for diagnosis. A negative fat aspirate does not exclude amyloidosis (sensitivity ~80%), and rectal or labial salivary glands biopsy are alternatives with high diagnostic sensitivity [34]. Biopsy of an organ suspected to be involved by amyloid deposits should only be considered if other methods do not reveal amyloid deposits due to risk of bleeding [35]. Confirmation of amyloid fibril type is critical since this will guide therapy. Immunohistochemistry, the most widely used method of choice for fibril typing, [36] is not definitive in many patients with AL amyloidosis. Immunoelectron microscopy with gold labeled anti-fibril protein antibodies is very sensitive but of limited availability [37]. Mass spectrometric analysis of amyloidotic material obtained through laser dissection of tissue sections or from fat aspirates is the gold standard [38,39] for diagnosis but needs to be done in laboratories experienced in this complex technology. Sequencing of appropriate genes is needed when there is a suspicion of hereditary amyloidosis. Hereditary amyloidosis can be suspected in cases with: family history, isolated neuropathic disease (transthyretin amyloidosis), informahealthcare.com
Diagnostic tests Fat aspirate or organ biopsy FLC, M-protein, 24-proteinuria, cardiac biomarkers, echocardiogram, bone marrow analysis
Confirm diagnosis and type Congo red stain to confirm amyloid deposition Immunohistochemistry or mass spectrometry to confirm fibril type
Prognostic markers to decide appropriate treatment pathway Cardiac biomarkers (troponin T/I; NT-proBNP/BNP) Performance status; blood pressure; renal function
Figure 1. Keeping a high index of suspicion is important for early diagnosis to avoid development of irreversible organ failure. In a patient with myeloma or monoclonal gammopathy of undetermined significance, specific symptom complexes should trigger a suspicion for a diagnosis of amyloidosis. However, in several instances signs and symptoms appear when end-organ damage is advanced and frequently irreversible. Periodic measurement of cardiac biomarkers and screening for albuminuria in a patient with monoclonal gammopathy of undetermined significance may allow early diagnosis, as abnormalities of either may herald development of amyloidosis. The diagnosis requires the histological documentation of the amyloid deposits, and their unequivocal typing. Assessing the severity of target organ damage is essential for prognostication and deciding the appropriate treatment.
isolated renal amyloidosis with no detectable clonal plasma cell dyscrasias (fibrinogen a chain amyloidosis), slowly progressive liver and renal involvement (apolipoprotein A1 amyloidosis), liver/gut involvement with dry mouth and skin rashes (lysozyme amyloidosis) and cranial nerve palsies, corneal lattice dystrophy and cutis laxa (gelsolin amyloidosis). Assessment of the underlying disorder
Assessment or identification of the underlying plasma cell disorder is the next step in evaluation of patients with AL amyloidosis. A combination of serum and urine testing with electrophoresis, immunofixation (IFE) and measurement of serum free light chain (FLC) is required to detect the monoclonal protein in AL amyloidosis [40], and will be informative in 145
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Box 1. New hematologic and cardiac response and progression criteria. Hematologic response • Complete response (negative serum and urine and normal free light chain ratio) • Very good partial response (dFLC 50%) • No response Cardiac response and progression criteria • NT-proBNP response (>30% and >300 ng/l decrease if baseline NT-proBNP ‡650 ng/l) • NT-proBNP progression (>30% and >300 ng/l increase) • Cardiac troponin progression (‡33% increase) • NYHA class response (‡2 class decrease if baseline NYHA class 3 or 4) • Ejection fraction progression (‡10% decrease) dFLC: Difference between involved and uninvolved free light chains; NT-proBNP: Amino-terminal pro-natriuretic peptide type-B; NYHA: New York Heart Association. Data taken from [43].
over 95% cases [41]. AL fibrils are four times more often of lambda than kappa light chain type. The plasma cell percentage in the bone marrow is usually low, with a median of less than 10%. Genetic study of bone marrow plasma cells and investigations to rule out symptomatic myeloma, including bone imaging, should be done at baseline [10]. Uncommonly, patients may have two possible amyloid-forming proteins. Blacks, for example, have a higher frequency of monoclonal gammopathies and also have a 4% risk of carrying a mutant transthyretin gene that can cause hereditary amyloidosis, while elderly male patients may present with monoclonal gammopathies and cardiac amyloidosis that is age-related due to wild type transthyretin [42]. In these cases, definitive typing of amyloid fibrils in a tissue biopsy is mandatory. Assessing the extent of disease
Assessment of amyloid-related end organ damage informs prognosis, supportive care needs and formulation of a risk adapted treatment plan. Consensus criteria for defining amyloidotic organ involvement have been recently published [43]. Tests of organ function and cardiac biomarkers underpin assessment of end organ damage in amyloidosis. Standard cross sectional imaging like computed tomography or MRI scanning is useful to assess localized deposits, lymph node involvement and visceral organ size. Echocardiography, including tissue Doppler and strain imaging, is important to document baseline cardiac structure and function [44]. Echocardiography shows ‘pan-cardiac’ thickening (increased thickness of left and right ventricular free walls, septum, valves and intra-atrial septum with dilation of the atria) which is rare in other infiltrative cardiomyopathies. 2-D strain mapping shows relative preservation of apical function which can be an early clue to cardiac involvement. Cardiac MRI (CMR) provides a diagnostic tool with a high specificity for diagnosis of cardiac amyloidosis, shows a typical pattern of late 146
subendocardial enhancement after gadolinium contrast, and can give accurate anatomical information including the wall thickness and LV mass, while equilibrium contrast MRI (EqCMR) [45] provides a novel tool for monitoring cardiac amyloid load by quantification of the myocardial interstitial volume fraction. SAP component scintigraphy is a specific imaging method that enables the amyloid load in liver, kidneys, spleen, adrenal glands and bones to be ascertained and monitored serially to assess response/progression after therapy but is of limited availability and cannot image amyloid in the heart [2]. 99m Tc-DPD/PYP (99m-technetium-3,3,-diphosphono-1,2propanodicarboxylic acid/pyrophosphate) scintigraphy gives a non-invasive method for potentially differentiating cardiac transthyretin amyloidosis from AL amyloidosis in elderly patients with MGUS and cardiac amyloidosis [46]. Assessing the risk & response to therapy
Many studies have demonstrated a link between hematologic responses and improved organ function and survival. Stopping the production of the toxic light chain species can translate into significant benefit for most patients except those with most advanced organ involvement, while stable hematologic disease despite therapy means it is likely that the effects of the toxic light chain species will continue. Consensus criteria for hematologic and cardiac response have been recently developed and validated (BOX 1) [43]. Advanced cardiac and extensive organ involvement limit eligibility for ASCT and can shorten survival despite treatment [47,48]. The limitation of survival despite treatment is also reflected in the outcomes of patients who are not eligible for ASCT and receive melphalan and dexamethasone, once again demonstrating the association of advanced cardiac disease and shortened survival [49,50]. To some degree, delayed diagnosis contributes to these outcomes [51]. It is hoped that bortezomibbased initial therapy with prompt and deep hematologic responses may overcome this limitation for some patients, rapidly reducing the pathologic light-chain producing clonal cells, enabling significant organ improvement, and potentially allowing young patients ineligible for ASCT due to advanced organ involvement to undergo ASCT [52,53]. Another treatment limitation is related to organ involvement predisposing patients to adverse effects of specific drugs. Two examples are the fluid retention and weight gain associated with filgrastim (G-CSF) and renal involvement during stem cell mobilization and collection, and the cardiac biomarker increases associated with lenalidomide in AL cardiac patients [54,55]. In both cases, the adverse effects are manageable and usually reversible. The impact of side effects of lenalidomide is particularly complex by affecting measuring improvement of organ involvement which is an important aspect of assessing response to therapy [43]. In AL clinical trials, it has been a challenge to distinguish drug-related side effects from disease-mediated organ dysfunction [56]. In TABLES 1 & 2, we summarize the available data on AL amyloidosis study populations reported, treatment-related and AL-related risks, hematologic and organ response rates and Expert Rev. Hematol. 7(1), (2014)
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[18]
II 60% at 5.1 years 4.5 49% at 1 year 38 (46%) 7% 83 2002–2011
83
29/54†
Not given
[107]
Retrospective Not reached at 2.3 years NR 40% 42 (42%) Not given 3% 57/43 (MEL 140 in 16 patients) 100 1998–2007
94
[58]
III 1.9 26% 50 2000–2005
50
27/10 (MEL 140)
24%
In 11 creatinine rose threefold; dialysis in 8
11 (22%)
NR
[106]
II NR NR 270 NR
NR
167/103 (MEL 100-140)
11%
Median hospitalization 9 days bacteremia 63%
94 (35%)
NR
[105]
II 6.3 2.6 52.7% 145 (34%) Creatinine >2.0 16% dialysis 5.9% 11% 231/190 (MEL 100-140) 421 1994–2008
319
Ref. Trial phase OS (years) PFS (years) Organ RR CR (% ITT) SAE TRM MEL 200/other New Dx
Although a systematic review and meta-analysis to evaluate the efficacy of ASCT for AL did not establish that high-dose therapy is superior to conventional chemotherapy in improving survival, many investigators believe that stem cell transplantation is a preferred option if it can be performed safely. Much of the transplant-related research over the past 5 years has focused on improving patient selection to ensure a safe outcome. ASCT outcomes have improved significantly when comparing patients transplanted before and after 2006 [69,70]. Much of this reduction in mortality relates to refinement in patient selection. Patients who have a troponin T >0.06 mg/l [71] or an NT-proBNP level >5000 pg/ml at diagnosis should not be considered for high-dose therapy [72]. The reported 10-year survival after ASCT is 43% [48], and in patients with hematologic CR, is 60% [73]. Patients with cardiac involvement can be safely transplanted if their biomarkers are below the thresholds listed above, and their systolic blood pressure is >100 mm Hg,
n
Risk-adapted therapy of AL amyloidosis
Time
Therapy
Table 1. Clinical trials and patient series applying melphalan and stem cell transplant to patients with light chain amyloidosis.
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time-to-event end points. The distinctive risks of therapy for AL have been an important theme in all of the major Phase II and III ASCT trials and large patient series reported in the past two decades. In the largest single-center series of ASCT in AL (n = 496), 2% of patients died during mobilization and 9% within 100 days of ASCT [57]. By contrast, in the Phase III trial reported by the French Intergroup in which AL patients were randomized to ASCT or oral melphalan and dexamethasone, the TRM was 24% in the ASCT arm and notably an additional 26% of patients in that arm were not treated as planned, the majority dying during or just after mobilization [58]. These data highlight the importance of patient selection for ASCT and of appreciating the features of the AL population being reported, as well as practice differences with respect to ASCT between the USA and the EU [59]. Oral melphalan and dexamethasone is generally well tolerated. Myelodysplasia has been reported in 1% of patients receiving melphalan and dexamethasone [60]. Patients with nephrotic syndrome or heart failure require lower doses (20 mg) of dexamethasone [49]. Given these issues, centers treating AL patients were motivated to rapidly assess non-ASCT myeloma therapies in clinical trials; see below [61–65]. Again, underlying organ disease can lead to unusual toxicities, and careful monitoring for toxicity as well as response is essential. Grade 3 peripheral neuropathy occurred in 9% of patients receiving i.v. bortezomib in consolidation post-ASCT but not in any relapsed AL patients [61,62]. With subcutaneous administration of bortezomib in initial therapy for AL, the incidence of any grade of neuropathy is less than 5%, similar to the rate of neuropathy observed with weekly i.v. administration of bortezomib [62,66]. Lenalidomide treatment in this patient population may worsen renal function [67] and lead to elevation of cardiac biomarkers, although not clearly associated with worsening heart failure [68]. Toxicities are detailed in TABLE 2.
† Patients not achieving hematologic CR post-autologous stem cell transplantation received consolidation. CR: Complete response; Dx: Diagnosis; ITT: Intention to treat; MEL: Melphalan; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; RR: Response rate; SAE: Severe adverse event; TRM: Treatment-related mortality.
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Immunoglobulin AL
147
148
148
87
46
75
34
33
49
94
17
1982–1992
1996–2003
1999–2002
2000–2005
2004–2006
2008–2010
2005–2009
2010
2007–2010
10/7
19/75
0/49
0/33
3/31
31/44
46/0
73/14
148/0
New Dx/Rel
11% (1% MDS) 52% (gr 2–4)
35% (myelosuppression)
4% 4%
3%
MEL (22 mg/kg 4d) Dex (40 mg 4d) q 28d
18% 3%
0%
0%
Pomalidomide (2 mg/day) Dex (40 mg/wk)
Bortezomib i.v. (1.6 mg/m2 d1, 8, 15, 22 q35d or 1.3 mg/m2 d1, 4, 8, 11 q21d)
Bortezomib (1.3 mg/m2 1, 4, 8, 11 q21d in 74 pts) Dex (median 80 mg/cycle)
Cyclophosphamide (300 mg/m2 po q wk) bortezomib (1.5 mg/ m2 q wk) dexamethasone (40 mg po q wk)
Lenalidomide (25 mg d1-21 q28) (Dex if NR 10–20 mg d1–4, 9– 12, 17–20 odd cycles)
2 patients gr 1– 2 neuropathy
10% (gr 2 pain PN)
16% (fatigue)
46% (cytopenias)
28% (edema)
7%
Pulse Dex (d1–4, 9–12, 17– 20 q35d) + IFN maintenance (5 MU t.i.w.)
Cyclophosphamide (500 mg d1, 8, 15) Thalidomide (200 mg/day) Dex (20 mg d1–4, 15–18) q28
5% (MDS)
NR
MEL (15 mg/kg 7d) Pred (8 mg/kg 7d) q6 wks
SAE
TRM
Therapy
71%
23 (25%)
15 (31%)
1 (3%)
7 (21%)
14 (19%)
15 (33%)
13 (15%)
NR
CR (% ITT)
50%
31%
33%
15%
21%
21%
48%
38%
18%
Organ RR (ITT)
Not given
2.1
80% at 2 year
1.2
NR
NR
3.8
2.25
NR
PFS (years)
4 died at 5, 11, 23, 30 months
80% at 1 year
71% at 4 year
2.3
NR
3.4
5.1
2.6
1.5
OS (years)
Retrospective
Retrospective
I/II
II
II
II
II
II
III
Trial phase
[111]
[70]
[62,110]
[84]
[65]
[78]
[60]
[109]
[108]
Ref.
CR: Complete response; Dex: Dexamethasone; Dx/Rel: Diagnosis/relapsed; IFN: Interferon; ITT: Intention to treat; MDS: Myelodysplastic syndrome; MelDex: Melphalan dexamethasone; MelPred: Melphalan prednisone; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; PN: Polyneuropathy; RR: Response rate; SAE: Severe adverse event; t.i.w.: Three-times a week; TRM: Treatment-related mortality.
n
Time
Table 2. Clinical trials and patient series applying conventional therapies and novel agents to patients with light chain amyloidosis.
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Immunoglobulin AL
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with a median overall survival of 52 months [74]. Incorporating refined selection criteria, treatment-related mortality can be reduced from 17 to 4% [57]. High-dose therapy does not preclude the use of highly active novel agents following transplant for patients who do not achieve an adequate response. Bortezomib–dexamethasone following stem cell transplantation improves responses, resulting in high complete response rates and organ improvement [61].
function even for patients whose amyloid does not involve the kidney [67]. Recovery in renal function has been reported in only 44%. Lenalidomide-treated patients also have a higher risk for NT-proBNP rises and early drug discontinuation compared with controls. It is unclear whether immunomodulatory-based therapy leads to increased fluid retention and cardiac toxicity, or whether cardiac response can be accurately assessed in patients on immunomodulatory drug therapy [83].
Novel agent-based chemotherapy
Pomalidomide
Melphalan and dexamethasone is considered the standard oral alkylator-based regimen. In a trial using melphalan and dexamethasone orally in patients ineligible for stem cell transplantation, the hematologic response rate was 67%, complete response rate was 33% and treatment-related mortality was 4%, with a median survival of 5.1 years [60,75]. The outcome seen in patients treated with melphalan and dexamethasone is highly dependent on the fraction of patients with advanced cardiac amyloidosis [49,50,69,76,77]. All new regimens should be compared with oral melphalan and dexamethasone.
Pomalidomide, with its higher potency, may be better tolerated in patients with light chain amyloidosis. Pomalidomide in patients with previously treated light chain amyloidosis confirmed a hematologic response rate of 48% with a rapid median time to response of 1.9 months. Pomalidomide caused rises in the NT-proBNP. The most common adverse effects, however, were neutropenia and fatigue. This drug warrants further exploration in the treatment of AL amyloidosis [84].
Thalidomide/lenalidomide
Thalidomide and lenalidomide have been used in the treatment of AL amyloidosis. Treatment-related toxicity is frequent, and the resultant median duration of therapy is often short. For patients in whom thalidomide is considered an appropriate choice, the initial dose should not exceed 50 mg nightly. Thalidomide has been combined with cyclophosphamide and dexamethasone [78]. The hematologic response rate was 74%, and the median overall survival was 41 months, but toxicity remains high. Lenalidomide has been combined with dexamethasone to treat AL. The non-hematologic toxicity is greater than reported in MM trials. Cytopenias, rash, fatigue and cramps are commonly seen [65]. A hematologic response rate of 41% has been reported [79]. Lenalidomide has been combined with melphalan and prednisone or dexamethasone. The maximum tolerated dose of lenalidomide when used in conjunction with melphalan and prednisone is 15 mg [76]. The hematologic response rate is 58%, complete in 42%. Lenalidomide responses have been reported to be durable [80]. Lenalidomide, melphalan and dexamethasone was recently reported in 16 patients. Hematologic responses were achieved by 43%, with a progression-free survival of 24 months. Grade 3–4 toxicities were experienced by 88%, and dose reductions occurred in 85% [77]. Lenalidomide has been combined with cyclophosphamide and dexamethasone and produced an overall hematologic response rate of 60%, including 40% very good partial responses or better and organ responses in 29%. The progression-free survival was 28.3 months. Non-hematologic toxicity ‡ grade 3, however, was seen in 71% with 20% of patients dying on study [81]. Lenalidomide and dexamethasone alone has a reported response rate of 41% in patients who have failed both bortezomib and thalidomide [82]. The toxicity of immunomodulatory drugs in amyloidosis patients is significant. Lenalidomide can frequently worsen renal informahealthcare.com
Bortezomib
The first Phase I dose-escalation study of bortezomib specifically excluded corticosteroids, to ensure that the response was attributable to the proteasome inhibitor, and hematologic responses were seen in 50% (20% complete) of relapsing/ refractory patients [85]. In this safety study, patients with New York Heart Association class 3–4 heart failure were excluded. Therefore, the safety of bortezomib in patients with advanced cardiac amyloidosis is difficult to gauge. Hypotension has been reported in 12–15% of myeloma patients treated with bortezomib, and congestive heart failure has been reported in up to 15% of patients; the impact on patients with cardiac amyloidosis is unknown, and caution needs to be exercised [86]. Good clonal responses to bortezomib have been reported to successfully improve cardiac function in AL amyloidosis [87]; and as alluded to earlier, post-transplant consolidation with bortezomib and dexamethasone is safe and effective. A significant advantage of bortezomib is its ability to rapidly decrease the burden of light chain with a median time to response of less than 2 months. Both weekly and twice-weekly schedules of bortezomib have been investigated with no significant differences in response rates or progression-free survival, but with significantly less side effects, particularly neuropathy, in patients treated weekly [62]. Cyclophosphamide, bortezomib and dexamethasone produce rapid and complete hematologic responses in patients with light chain amyloidosis with 71% achieving complete hematologic response, and 3 patients of 17 originally not eligible for stem cell transplantation becoming eligible [53]. Data on long-term outcomes with bortezomib are currently lacking; therefore, it cannot be directly compared with melphalan dexamethasone or high-dose therapy. A proposed therapy algorithm is reported in FIGURE 2. Novel therapies
Treatment of AL amyloidosis has remained dependent upon reducing the clonal plasma cell burden underlying the disease. 149
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Alnylam Pharmaceuticals has taken an siRNA-based approach forward. As proof Alte e l of concept, it has been shown that siRNA r b nativ gi e op Eli can reduce plasma cell synthesis of LC tions in vitro and in a plasmacytoma model in vivo [90]; as technology to target bone Mel-Dex or Age
Review
Immunoglobulin light chain amyloidosis Expert Review of Hematology Downloaded from informahealthcare.com by Washington University Library on 12/29/14 For personal use only.
Expert Rev. Hematol. 7(1), 143–156 (2014)
Giampaolo Merlini*1, Raymond L Comenzo2, David C Seldin3,4, Ashutosh Wechalekar5 and Morie A Gertz6 1 Department of Molecular Medicine, University of Pavia, Foundation Scientific Institute San Matteo, Amyloidosis Research and Treatment Center, V.le Golgi 19 27100, Pavia, Italy 2 Department of Medicine, Tufts Medical Center and Tufts University School of Medicine, Division of HematologyOncology, Boston, MA 02111, USA 3 Boston University School of Medicine, Amyloidosis Center, Boston, MA 02118, USA 4 Department of Medicine, Section of Hematology-Oncology, Boston Medical Center, Boston, MA 02118, USA 5 National Amyloidosis Centre, UCL Medical School (Royal Free Campus), Rowland Hill Street, London, NW3 2PF, UK 6 Division of Hematology, Mayo Clinic, 200 First Street, SW Rochester, MN 55905, USA *Author for correspondence: Tel.: +39 0382 502 995 Fax: +39 0382 502 990 [email protected]
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Primary light chain amyloidosis is the most common form of systemic amyloidosis and is caused by misfolded light chains that cause proteotoxicity and rapid decline of vital organ function. Early diagnosis is essential in order to deliver effective therapy and prevent irreversible organ damage. Accurate diagnosis requires clinical skills and advanced technologies. The disease can be halted and the function of target organs preserved by the prompt reduction and elimination of the plasma cell clone producing the toxic light chains in the bone marrow. Heart damage is the major determinant of survival, and staging with cardiac biomarkers guides treatment. Two-thirds of patients can benefit from treatment with improved quality of life and extended survival. Future efforts should be directed at early diagnosis, improving the tolerability and efficacy of anti-plasma cell therapy, accelerating recovery of organ function via promoting resorption of amyloid deposits, and developing novel approaches to counter light chain proteotoxicity. KEYWORDS: amyloid cardiomyopathy • biomarkers • novel agents • proteotoxicity
Amyloid & amyloidoses
A diagnostic feature of human amyloid diseases is extracellular cross-b-sheet amyloid fibril deposition. About 30 different proteins can cause amyloidosis; the major protein deposited determines the pathology observed [1]. Amyloid deposits display distinctive ultrastructural beta-sheet conformation and tinctorial properties such as vivid green birefringence in polarized light after staining with Congo red. The process of amyloid formation and deposition ultimately results in tissue damage and organ dysfunction. Basic research and clinical observations have identified some factors associated with the capacity of a protein to form amyloid in vivo and to give rise to disease, including: a sustained increase in the concentration of a protein with high propensity to aggregate (e.g., serum amyloid A protein (SAA) in chronic inflammation); mutations that destabilize a protein and favor its misfolding and aggregation, as occurs in the hereditary amyloidoses and in immunoglobulin light chain amyloidosis (AL); proteolytic processing of a protein, as in the case of the amyloid-b (Ab) peptides and intrinsic tendency to misfold, e.g., wild-type transthyretin and apolipoprotein A-I, both associated with age-related amyloid deposition. 10.1586/17474086.2014.858594
Frequently, a combination of these factors determines the amyloidogenicity of an individual protein, as occurs in AL amyloidosis where specific mutations in a light chain produced in excess by a plasma cell clone cause the disease. However, the inherent amyloidogenicity of a specific protein, per se, is probably not sufficient to account for amyloid deposition in vivo. Interactions with cells, extracellular matrix components and other constituents commonly found in amyloid deposits play an important role in the amyloid disease process. Serum amyloid P (SAP) component, a glycoprotein of the pentraxin family, binds all types of amyloid, making it suitable for imaging amyloid deposits [2] and as a potential therapeutic target [3]. Proteoglycans are also common in amyloid deposits and heparan sulfate (HS), in particular, is directly associated with amyloidogenesis, as shown in animal models [4]. HS accelerates not only the transition of the amyloid protein from the native state into the partially folded state [5] but also the rate of amyloid fibril formation by immunoglobulin light chains (LC) [6,7]. Heparin-binding peptides have been proposed as potential radiotracers of amyloid deposits [8]. Other common elements found in amyloid deposits are components of the extracellular matrix, such as elastin, entactin and collagen IV.
2014 Informa UK Ltd
ISSN 1747-4086
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In vitro studies have shown that amyloid fibril formation proceeds, in many instances, through ‘nucleated growth’. After an initial lag phase, once a critical nucleus has been generated, fibril formation begins and proceeds rapidly: any amyloidogenic precursor in its aggregation-prone conformation is rapidly incorporated into the growing fibrils [9]. This seeding mechanism has clinical implications, since the process of amyloid clearance, following a response to therapy, usually leaves traces of ‘seeds’ in tissues. In the case of disease relapse, these may trigger rapid re-accumulation of amyloid deposits. AL amyloidosis: the biology of the clone
AL amyloidosis is characterized by the production, by a clonal plasma cell population in the bone marrow, of a monoclonal light chain with unique structural features causing systemic proteotoxicity. The biology of the clone that sustains this condition is poorly defined. Limited studies have been performed in AL amyloidosis where a small bone marrow plasma cell clone (the median plasma cell infiltration is only 5–7%) produces light chain only in approximately 50% of the cases [10]. There is a strikingly high frequency of the t(11;14) translocation [11–13] consistent with cyclin D1 up-regulation [14], suggesting that disruption of the heavy chain locus might also be an important mechanism in AL since half of AL patients lack an intact immunoglobulin in serum immunofixation. The low frequencies of t(4;14) and deletion 17p13 [15], aberrancies linked to rapid clonal proliferation, short remission durations and progressive drug resistance, fit with the observation of the rare progression of AL to multiple myeloma. In addition, hyperdiploidy is uncommon in AL compared with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM), consistent with the hypothesis that the amyloidogenic clone represents an early stage of monoclonal gammopathy possibly more susceptible to chemotherapy [15]. Higher sensitivity to proteasome inhibitors of AL plasma cells as compared with myeloma plasma cells has been reported [16]. Furthermore, patients with AL who undergo autologous stem cell transplantation (ASCT) enjoy a superior survival compared with MM patients undergoing the same procedure. This difference is most notable among those patients who achieve CR suggesting that AL and MM clones may have biological differences; however, it is important to note that the overall survival of AL patients with ASCT is very similar to that of patients with stage I MM [17,18]. Therefore, it is likely that both clonal plasma cell burden and biologic features shared by less proliferative plasma cell dyscrasias contribute to the differences in response to bortezomib and outcomes in ASCT observed for AL patients. The small indolent plasma cell clones responsible for AL synthesize an abnormal monoclonal light chain that causes systemic proteotoxicity by misfolding, aggregating, disturbing tissue architecture and metabolism, and depositing in vital organs. Therefore, the clinical features of AL derive primarily from the systemic toxicity of the monoclonal light chain. Unlike most other PC dyscrasias, the lambda isotype accounts 144
for 75% of the amyloidogenic light chains [10]. These misfolded light chains can target and damage practically all organs outside of the central nervous system. Mechanism of organ targeting & tissue damage
Sequence-specific interaction of LC with matrix proteins, cells, or other components of the target organ may play a role in ‘tissue tropism’, the concept that different LC have differing propensities to target and damage heart, kidney, nerves, etc. Almost all patients whose plasma cell clone expresses the l6 isotype develop renal disease [19,20]. The l1 isotype, derived from the IGLV1-44 germline gene, is particularly associated with cardiac disease [21], whereas k1 is seen more often than l isotypes in patients with bone and soft tissue deposits [22]. It is unknown what properties of the LC determine tissue tropism: the primary amino acid sequence may be critical, or posttranslational modifications could play a role. It is also unclear what organ-specific molecules in extracellular matrix or cells interact with the LC and is a fertile area for further research. The amyloid hypothesis describes the process by which proteins aggregate and form fibrils that are deposited in tissues, leading to organ failure. However, recent studies suggest that it is not just a mechanical effect of the fibrillar end product, but the activity of toxic oligomeric intermediates, that leads to cell death and tissue dysfunction. This is now well described in the neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Seminal studies from the laboratory of Ronglih Liao have described a similar process in AL amyloidosis. Initial observations showed that human amyloidogenic LC, purified from patients with severe cardiomyopathy, caused the rapid (in minutes) onset of diastolic dysfunction in the isolated mouse heart [23], and increased production of intracellular reactive oxygen species in isolated cardiomyocytes, impairing contractility [24]. Further studies revealed that this response is mediated by p38 MAPK signaling, and p38 inhibition is protective [25]. Recently, it has been shown that expression of amyloidogenic cardiotoxic LC mRNA [26] or injection of protein [27] cause cardiac dysfunction and early death in zebrafish. Thus, for the first time there is an animal model in which this process can be studied, and p38 signaling as well as other effectors of cardiomyocyte dysfunction may now be druggable targets and testable in an in vivo model. The toxic effect of the LC described in these model systems is supported by clinical observations that cardiac stress, as measured by circulating levels of the Nterminal pro-brain natriuretic peptide (NT-proBNP) or BNP itself, may be reduced in parallel with the reduction in free LC levels following chemotherapy and such reductions predict for improved survival [28]. Interestingly, protein misfolding and proteotoxicity has been linked to other common types of acquired and hereditary cardiomyopathy with chronic heart failure [29]. In the kidney, effects of LC on mesangial cell protein expression may contribute to pathogenesis in that organ. Amyloidogenic LC decrease matrix protein synthesis and increase degradation through induction of collagenase IV [30] and matrix Expert Rev. Hematol. 7(1), (2014)
Immunoglobulin AL
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metalloproteinases (MMPs) [31]. While renal involvement is not as dire as cardiac involvement in AL amyloidosis, renal failure is still a major cause of morbidity if not mortality. Thus, targeting these pathways of matrix protein turnover could be protective. Similar observations have been made about the involvement of MMPs and their inhibitors in the heart [32]; combining measurement of MMPs and their inhibitors with BNP and troponin may help to distinguish between forms of amyloid cardiomyopathy, and add prognostic information [33]. Diagnosis
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Clinical suspicion of systemic AL amyloidosis
Unexplained weight loss, fatigue, leg swelling, thick walled heart failure or nephrotic syndrome in a patient with M-protein or abnormal FLC, periorbital purpura, macroglossia, peripheral and autonomic neuropathy
How to make an early diagnosis of AL amyloidosis
Keeping a high index of suspicion is important for early diagnosis to avoid development of irreversible organ failure. In a patient with myeloma or MGUS, specific symptom complexes should trigger a suspicion for a diagnosis of amyloidosis such as: nephrotic syndrome with albuminuria rather than Bence Jones proteinuria; peripheral or autonomic neuropathy; diastolic heart failure with normal or low voltage ECG; or recurrent carpal tunnel syndrome. Periodic measurement of cardiac biomarkers and screening for albuminuria in a patient with MGUS may allow early diagnosis, as abnormalities of either may herald development of amyloidosis [10]. A stepwise approach to diagnosis and staging of amyloidosis is critical and involves confirmation of amyloid deposition, identification of fibril type, assessment of the underlying amyloidogenic disorder, and evaluation of amyloidotic organ involvement (FIGURE 1). Histological demonstration of amyloid deposits & confirming the fibril type
Demonstration of characteristic green birefringence under cross-polarized light following Congo red staining of a tissue biopsy remains the gold standard for confirming amyloid deposition. Abdominal fat aspiration is a simple high yield method available at the bedside for obtaining tissue for diagnosis. A negative fat aspirate does not exclude amyloidosis (sensitivity ~80%), and rectal or labial salivary glands biopsy are alternatives with high diagnostic sensitivity [34]. Biopsy of an organ suspected to be involved by amyloid deposits should only be considered if other methods do not reveal amyloid deposits due to risk of bleeding [35]. Confirmation of amyloid fibril type is critical since this will guide therapy. Immunohistochemistry, the most widely used method of choice for fibril typing, [36] is not definitive in many patients with AL amyloidosis. Immunoelectron microscopy with gold labeled anti-fibril protein antibodies is very sensitive but of limited availability [37]. Mass spectrometric analysis of amyloidotic material obtained through laser dissection of tissue sections or from fat aspirates is the gold standard [38,39] for diagnosis but needs to be done in laboratories experienced in this complex technology. Sequencing of appropriate genes is needed when there is a suspicion of hereditary amyloidosis. Hereditary amyloidosis can be suspected in cases with: family history, isolated neuropathic disease (transthyretin amyloidosis), informahealthcare.com
Diagnostic tests Fat aspirate or organ biopsy FLC, M-protein, 24-proteinuria, cardiac biomarkers, echocardiogram, bone marrow analysis
Confirm diagnosis and type Congo red stain to confirm amyloid deposition Immunohistochemistry or mass spectrometry to confirm fibril type
Prognostic markers to decide appropriate treatment pathway Cardiac biomarkers (troponin T/I; NT-proBNP/BNP) Performance status; blood pressure; renal function
Figure 1. Keeping a high index of suspicion is important for early diagnosis to avoid development of irreversible organ failure. In a patient with myeloma or monoclonal gammopathy of undetermined significance, specific symptom complexes should trigger a suspicion for a diagnosis of amyloidosis. However, in several instances signs and symptoms appear when end-organ damage is advanced and frequently irreversible. Periodic measurement of cardiac biomarkers and screening for albuminuria in a patient with monoclonal gammopathy of undetermined significance may allow early diagnosis, as abnormalities of either may herald development of amyloidosis. The diagnosis requires the histological documentation of the amyloid deposits, and their unequivocal typing. Assessing the severity of target organ damage is essential for prognostication and deciding the appropriate treatment.
isolated renal amyloidosis with no detectable clonal plasma cell dyscrasias (fibrinogen a chain amyloidosis), slowly progressive liver and renal involvement (apolipoprotein A1 amyloidosis), liver/gut involvement with dry mouth and skin rashes (lysozyme amyloidosis) and cranial nerve palsies, corneal lattice dystrophy and cutis laxa (gelsolin amyloidosis). Assessment of the underlying disorder
Assessment or identification of the underlying plasma cell disorder is the next step in evaluation of patients with AL amyloidosis. A combination of serum and urine testing with electrophoresis, immunofixation (IFE) and measurement of serum free light chain (FLC) is required to detect the monoclonal protein in AL amyloidosis [40], and will be informative in 145
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Box 1. New hematologic and cardiac response and progression criteria. Hematologic response • Complete response (negative serum and urine and normal free light chain ratio) • Very good partial response (dFLC 50%) • No response Cardiac response and progression criteria • NT-proBNP response (>30% and >300 ng/l decrease if baseline NT-proBNP ‡650 ng/l) • NT-proBNP progression (>30% and >300 ng/l increase) • Cardiac troponin progression (‡33% increase) • NYHA class response (‡2 class decrease if baseline NYHA class 3 or 4) • Ejection fraction progression (‡10% decrease) dFLC: Difference between involved and uninvolved free light chains; NT-proBNP: Amino-terminal pro-natriuretic peptide type-B; NYHA: New York Heart Association. Data taken from [43].
over 95% cases [41]. AL fibrils are four times more often of lambda than kappa light chain type. The plasma cell percentage in the bone marrow is usually low, with a median of less than 10%. Genetic study of bone marrow plasma cells and investigations to rule out symptomatic myeloma, including bone imaging, should be done at baseline [10]. Uncommonly, patients may have two possible amyloid-forming proteins. Blacks, for example, have a higher frequency of monoclonal gammopathies and also have a 4% risk of carrying a mutant transthyretin gene that can cause hereditary amyloidosis, while elderly male patients may present with monoclonal gammopathies and cardiac amyloidosis that is age-related due to wild type transthyretin [42]. In these cases, definitive typing of amyloid fibrils in a tissue biopsy is mandatory. Assessing the extent of disease
Assessment of amyloid-related end organ damage informs prognosis, supportive care needs and formulation of a risk adapted treatment plan. Consensus criteria for defining amyloidotic organ involvement have been recently published [43]. Tests of organ function and cardiac biomarkers underpin assessment of end organ damage in amyloidosis. Standard cross sectional imaging like computed tomography or MRI scanning is useful to assess localized deposits, lymph node involvement and visceral organ size. Echocardiography, including tissue Doppler and strain imaging, is important to document baseline cardiac structure and function [44]. Echocardiography shows ‘pan-cardiac’ thickening (increased thickness of left and right ventricular free walls, septum, valves and intra-atrial septum with dilation of the atria) which is rare in other infiltrative cardiomyopathies. 2-D strain mapping shows relative preservation of apical function which can be an early clue to cardiac involvement. Cardiac MRI (CMR) provides a diagnostic tool with a high specificity for diagnosis of cardiac amyloidosis, shows a typical pattern of late 146
subendocardial enhancement after gadolinium contrast, and can give accurate anatomical information including the wall thickness and LV mass, while equilibrium contrast MRI (EqCMR) [45] provides a novel tool for monitoring cardiac amyloid load by quantification of the myocardial interstitial volume fraction. SAP component scintigraphy is a specific imaging method that enables the amyloid load in liver, kidneys, spleen, adrenal glands and bones to be ascertained and monitored serially to assess response/progression after therapy but is of limited availability and cannot image amyloid in the heart [2]. 99m Tc-DPD/PYP (99m-technetium-3,3,-diphosphono-1,2propanodicarboxylic acid/pyrophosphate) scintigraphy gives a non-invasive method for potentially differentiating cardiac transthyretin amyloidosis from AL amyloidosis in elderly patients with MGUS and cardiac amyloidosis [46]. Assessing the risk & response to therapy
Many studies have demonstrated a link between hematologic responses and improved organ function and survival. Stopping the production of the toxic light chain species can translate into significant benefit for most patients except those with most advanced organ involvement, while stable hematologic disease despite therapy means it is likely that the effects of the toxic light chain species will continue. Consensus criteria for hematologic and cardiac response have been recently developed and validated (BOX 1) [43]. Advanced cardiac and extensive organ involvement limit eligibility for ASCT and can shorten survival despite treatment [47,48]. The limitation of survival despite treatment is also reflected in the outcomes of patients who are not eligible for ASCT and receive melphalan and dexamethasone, once again demonstrating the association of advanced cardiac disease and shortened survival [49,50]. To some degree, delayed diagnosis contributes to these outcomes [51]. It is hoped that bortezomibbased initial therapy with prompt and deep hematologic responses may overcome this limitation for some patients, rapidly reducing the pathologic light-chain producing clonal cells, enabling significant organ improvement, and potentially allowing young patients ineligible for ASCT due to advanced organ involvement to undergo ASCT [52,53]. Another treatment limitation is related to organ involvement predisposing patients to adverse effects of specific drugs. Two examples are the fluid retention and weight gain associated with filgrastim (G-CSF) and renal involvement during stem cell mobilization and collection, and the cardiac biomarker increases associated with lenalidomide in AL cardiac patients [54,55]. In both cases, the adverse effects are manageable and usually reversible. The impact of side effects of lenalidomide is particularly complex by affecting measuring improvement of organ involvement which is an important aspect of assessing response to therapy [43]. In AL clinical trials, it has been a challenge to distinguish drug-related side effects from disease-mediated organ dysfunction [56]. In TABLES 1 & 2, we summarize the available data on AL amyloidosis study populations reported, treatment-related and AL-related risks, hematologic and organ response rates and Expert Rev. Hematol. 7(1), (2014)
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[18]
II 60% at 5.1 years 4.5 49% at 1 year 38 (46%) 7% 83 2002–2011
83
29/54†
Not given
[107]
Retrospective Not reached at 2.3 years NR 40% 42 (42%) Not given 3% 57/43 (MEL 140 in 16 patients) 100 1998–2007
94
[58]
III 1.9 26% 50 2000–2005
50
27/10 (MEL 140)
24%
In 11 creatinine rose threefold; dialysis in 8
11 (22%)
NR
[106]
II NR NR 270 NR
NR
167/103 (MEL 100-140)
11%
Median hospitalization 9 days bacteremia 63%
94 (35%)
NR
[105]
II 6.3 2.6 52.7% 145 (34%) Creatinine >2.0 16% dialysis 5.9% 11% 231/190 (MEL 100-140) 421 1994–2008
319
Ref. Trial phase OS (years) PFS (years) Organ RR CR (% ITT) SAE TRM MEL 200/other New Dx
Although a systematic review and meta-analysis to evaluate the efficacy of ASCT for AL did not establish that high-dose therapy is superior to conventional chemotherapy in improving survival, many investigators believe that stem cell transplantation is a preferred option if it can be performed safely. Much of the transplant-related research over the past 5 years has focused on improving patient selection to ensure a safe outcome. ASCT outcomes have improved significantly when comparing patients transplanted before and after 2006 [69,70]. Much of this reduction in mortality relates to refinement in patient selection. Patients who have a troponin T >0.06 mg/l [71] or an NT-proBNP level >5000 pg/ml at diagnosis should not be considered for high-dose therapy [72]. The reported 10-year survival after ASCT is 43% [48], and in patients with hematologic CR, is 60% [73]. Patients with cardiac involvement can be safely transplanted if their biomarkers are below the thresholds listed above, and their systolic blood pressure is >100 mm Hg,
n
Risk-adapted therapy of AL amyloidosis
Time
Therapy
Table 1. Clinical trials and patient series applying melphalan and stem cell transplant to patients with light chain amyloidosis.
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time-to-event end points. The distinctive risks of therapy for AL have been an important theme in all of the major Phase II and III ASCT trials and large patient series reported in the past two decades. In the largest single-center series of ASCT in AL (n = 496), 2% of patients died during mobilization and 9% within 100 days of ASCT [57]. By contrast, in the Phase III trial reported by the French Intergroup in which AL patients were randomized to ASCT or oral melphalan and dexamethasone, the TRM was 24% in the ASCT arm and notably an additional 26% of patients in that arm were not treated as planned, the majority dying during or just after mobilization [58]. These data highlight the importance of patient selection for ASCT and of appreciating the features of the AL population being reported, as well as practice differences with respect to ASCT between the USA and the EU [59]. Oral melphalan and dexamethasone is generally well tolerated. Myelodysplasia has been reported in 1% of patients receiving melphalan and dexamethasone [60]. Patients with nephrotic syndrome or heart failure require lower doses (20 mg) of dexamethasone [49]. Given these issues, centers treating AL patients were motivated to rapidly assess non-ASCT myeloma therapies in clinical trials; see below [61–65]. Again, underlying organ disease can lead to unusual toxicities, and careful monitoring for toxicity as well as response is essential. Grade 3 peripheral neuropathy occurred in 9% of patients receiving i.v. bortezomib in consolidation post-ASCT but not in any relapsed AL patients [61,62]. With subcutaneous administration of bortezomib in initial therapy for AL, the incidence of any grade of neuropathy is less than 5%, similar to the rate of neuropathy observed with weekly i.v. administration of bortezomib [62,66]. Lenalidomide treatment in this patient population may worsen renal function [67] and lead to elevation of cardiac biomarkers, although not clearly associated with worsening heart failure [68]. Toxicities are detailed in TABLE 2.
† Patients not achieving hematologic CR post-autologous stem cell transplantation received consolidation. CR: Complete response; Dx: Diagnosis; ITT: Intention to treat; MEL: Melphalan; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; RR: Response rate; SAE: Severe adverse event; TRM: Treatment-related mortality.
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Immunoglobulin AL
147
148
148
87
46
75
34
33
49
94
17
1982–1992
1996–2003
1999–2002
2000–2005
2004–2006
2008–2010
2005–2009
2010
2007–2010
10/7
19/75
0/49
0/33
3/31
31/44
46/0
73/14
148/0
New Dx/Rel
11% (1% MDS) 52% (gr 2–4)
35% (myelosuppression)
4% 4%
3%
MEL (22 mg/kg 4d) Dex (40 mg 4d) q 28d
18% 3%
0%
0%
Pomalidomide (2 mg/day) Dex (40 mg/wk)
Bortezomib i.v. (1.6 mg/m2 d1, 8, 15, 22 q35d or 1.3 mg/m2 d1, 4, 8, 11 q21d)
Bortezomib (1.3 mg/m2 1, 4, 8, 11 q21d in 74 pts) Dex (median 80 mg/cycle)
Cyclophosphamide (300 mg/m2 po q wk) bortezomib (1.5 mg/ m2 q wk) dexamethasone (40 mg po q wk)
Lenalidomide (25 mg d1-21 q28) (Dex if NR 10–20 mg d1–4, 9– 12, 17–20 odd cycles)
2 patients gr 1– 2 neuropathy
10% (gr 2 pain PN)
16% (fatigue)
46% (cytopenias)
28% (edema)
7%
Pulse Dex (d1–4, 9–12, 17– 20 q35d) + IFN maintenance (5 MU t.i.w.)
Cyclophosphamide (500 mg d1, 8, 15) Thalidomide (200 mg/day) Dex (20 mg d1–4, 15–18) q28
5% (MDS)
NR
MEL (15 mg/kg 7d) Pred (8 mg/kg 7d) q6 wks
SAE
TRM
Therapy
71%
23 (25%)
15 (31%)
1 (3%)
7 (21%)
14 (19%)
15 (33%)
13 (15%)
NR
CR (% ITT)
50%
31%
33%
15%
21%
21%
48%
38%
18%
Organ RR (ITT)
Not given
2.1
80% at 2 year
1.2
NR
NR
3.8
2.25
NR
PFS (years)
4 died at 5, 11, 23, 30 months
80% at 1 year
71% at 4 year
2.3
NR
3.4
5.1
2.6
1.5
OS (years)
Retrospective
Retrospective
I/II
II
II
II
II
II
III
Trial phase
[111]
[70]
[62,110]
[84]
[65]
[78]
[60]
[109]
[108]
Ref.
CR: Complete response; Dex: Dexamethasone; Dx/Rel: Diagnosis/relapsed; IFN: Interferon; ITT: Intention to treat; MDS: Myelodysplastic syndrome; MelDex: Melphalan dexamethasone; MelPred: Melphalan prednisone; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; PN: Polyneuropathy; RR: Response rate; SAE: Severe adverse event; t.i.w.: Three-times a week; TRM: Treatment-related mortality.
n
Time
Table 2. Clinical trials and patient series applying conventional therapies and novel agents to patients with light chain amyloidosis.
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Immunoglobulin AL
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with a median overall survival of 52 months [74]. Incorporating refined selection criteria, treatment-related mortality can be reduced from 17 to 4% [57]. High-dose therapy does not preclude the use of highly active novel agents following transplant for patients who do not achieve an adequate response. Bortezomib–dexamethasone following stem cell transplantation improves responses, resulting in high complete response rates and organ improvement [61].
function even for patients whose amyloid does not involve the kidney [67]. Recovery in renal function has been reported in only 44%. Lenalidomide-treated patients also have a higher risk for NT-proBNP rises and early drug discontinuation compared with controls. It is unclear whether immunomodulatory-based therapy leads to increased fluid retention and cardiac toxicity, or whether cardiac response can be accurately assessed in patients on immunomodulatory drug therapy [83].
Novel agent-based chemotherapy
Pomalidomide
Melphalan and dexamethasone is considered the standard oral alkylator-based regimen. In a trial using melphalan and dexamethasone orally in patients ineligible for stem cell transplantation, the hematologic response rate was 67%, complete response rate was 33% and treatment-related mortality was 4%, with a median survival of 5.1 years [60,75]. The outcome seen in patients treated with melphalan and dexamethasone is highly dependent on the fraction of patients with advanced cardiac amyloidosis [49,50,69,76,77]. All new regimens should be compared with oral melphalan and dexamethasone.
Pomalidomide, with its higher potency, may be better tolerated in patients with light chain amyloidosis. Pomalidomide in patients with previously treated light chain amyloidosis confirmed a hematologic response rate of 48% with a rapid median time to response of 1.9 months. Pomalidomide caused rises in the NT-proBNP. The most common adverse effects, however, were neutropenia and fatigue. This drug warrants further exploration in the treatment of AL amyloidosis [84].
Thalidomide/lenalidomide
Thalidomide and lenalidomide have been used in the treatment of AL amyloidosis. Treatment-related toxicity is frequent, and the resultant median duration of therapy is often short. For patients in whom thalidomide is considered an appropriate choice, the initial dose should not exceed 50 mg nightly. Thalidomide has been combined with cyclophosphamide and dexamethasone [78]. The hematologic response rate was 74%, and the median overall survival was 41 months, but toxicity remains high. Lenalidomide has been combined with dexamethasone to treat AL. The non-hematologic toxicity is greater than reported in MM trials. Cytopenias, rash, fatigue and cramps are commonly seen [65]. A hematologic response rate of 41% has been reported [79]. Lenalidomide has been combined with melphalan and prednisone or dexamethasone. The maximum tolerated dose of lenalidomide when used in conjunction with melphalan and prednisone is 15 mg [76]. The hematologic response rate is 58%, complete in 42%. Lenalidomide responses have been reported to be durable [80]. Lenalidomide, melphalan and dexamethasone was recently reported in 16 patients. Hematologic responses were achieved by 43%, with a progression-free survival of 24 months. Grade 3–4 toxicities were experienced by 88%, and dose reductions occurred in 85% [77]. Lenalidomide has been combined with cyclophosphamide and dexamethasone and produced an overall hematologic response rate of 60%, including 40% very good partial responses or better and organ responses in 29%. The progression-free survival was 28.3 months. Non-hematologic toxicity ‡ grade 3, however, was seen in 71% with 20% of patients dying on study [81]. Lenalidomide and dexamethasone alone has a reported response rate of 41% in patients who have failed both bortezomib and thalidomide [82]. The toxicity of immunomodulatory drugs in amyloidosis patients is significant. Lenalidomide can frequently worsen renal informahealthcare.com
Bortezomib
The first Phase I dose-escalation study of bortezomib specifically excluded corticosteroids, to ensure that the response was attributable to the proteasome inhibitor, and hematologic responses were seen in 50% (20% complete) of relapsing/ refractory patients [85]. In this safety study, patients with New York Heart Association class 3–4 heart failure were excluded. Therefore, the safety of bortezomib in patients with advanced cardiac amyloidosis is difficult to gauge. Hypotension has been reported in 12–15% of myeloma patients treated with bortezomib, and congestive heart failure has been reported in up to 15% of patients; the impact on patients with cardiac amyloidosis is unknown, and caution needs to be exercised [86]. Good clonal responses to bortezomib have been reported to successfully improve cardiac function in AL amyloidosis [87]; and as alluded to earlier, post-transplant consolidation with bortezomib and dexamethasone is safe and effective. A significant advantage of bortezomib is its ability to rapidly decrease the burden of light chain with a median time to response of less than 2 months. Both weekly and twice-weekly schedules of bortezomib have been investigated with no significant differences in response rates or progression-free survival, but with significantly less side effects, particularly neuropathy, in patients treated weekly [62]. Cyclophosphamide, bortezomib and dexamethasone produce rapid and complete hematologic responses in patients with light chain amyloidosis with 71% achieving complete hematologic response, and 3 patients of 17 originally not eligible for stem cell transplantation becoming eligible [53]. Data on long-term outcomes with bortezomib are currently lacking; therefore, it cannot be directly compared with melphalan dexamethasone or high-dose therapy. A proposed therapy algorithm is reported in FIGURE 2. Novel therapies
Treatment of AL amyloidosis has remained dependent upon reducing the clonal plasma cell burden underlying the disease. 149
Review
Merlini, Comenzo, Seldin, Wechalekar & Gertz
Alnylam Pharmaceuticals has taken an siRNA-based approach forward. As proof Alte e l of concept, it has been shown that siRNA r b nativ gi e op Eli can reduce plasma cell synthesis of LC tions in vitro and in a plasmacytoma model in vivo [90]; as technology to target bone Mel-Dex or Age
