Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis

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thalidomide 6 endocrinologydiseasesdrugs
amyloidosis 68 endocrinologydiseases
bortezomib 4 endocrinologydiseasesdrugs
cyclophosphamide 2 endocrinologydiseasesdrugs
dexamethasone 12 endocrinologydiseasesdrugs
lenalidomide 2 endocrinologydiseasesdrugs
melphalan 6 endocrinologydiseasesdrugs
prednisone 2 endocrinologydiseasesdrugs

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bortezomib 19261 (and BNP) response independently predicted survival in 94 patients with AL amyloidosis treated with bortezomib (Bor) or Bor plus dexamethasone (BDex). Palladini et al.[49] demonstrated that post-treatment NT-proBNP
bortezomib 27199 to NT-proBNP response in an ongoing phase 3 trial comparing melphalan-dexamethasone with melphalan- bortezomib -dexamethasone (NCT01277016).Figure 5Estimated time required to complete a trial in patients with AL
bortezomib 28459 risk-adapted BDex~45 months~10 monthsAbbreviations: ASCT, autologous stem cell transplantation; BDex, bortezomib plus dexamethasone; Bor, bortezomib; CyTDex, cyclophosphamide plus thalidomide and dexamethasone; Dex,
bortezomib 28495 monthsAbbreviations: ASCT, autologous stem cell transplantation; BDex, bortezomib plus dexamethasone; Bor, bortezomib ; CyTDex, cyclophosphamide plus thalidomide and dexamethasone; Dex, high-dose dexamethasone; L, lenalidomide;
cyclophosphamide 19507 predicted patient survival in a study of 113 patients with AL amyloidosis treated primarily with MDex, Dex, cyclophosphamide plus thalidomide and dexamethasone (CyTDex) or ASCT. Kastritis et al.[56] reported that NT-proBNP response
cyclophosphamide 28515 autologous stem cell transplantation; BDex, bortezomib plus dexamethasone; Bor, bortezomib; CyTDex, cyclophosphamide plus thalidomide and dexamethasone; Dex, high-dose dexamethasone; L, lenalidomide; MDex, melphalan plus
dexamethasone 18839 1).Palladini et al.[54] documented, in 51 patients with cardiac AL amyloidosis treated with melphalan plus dexamethasone (MDex), thalidomide plus dexamethasone (TDex), dexamethasone (Dex), melphalan plus prednisone (MP) or
dexamethasone 18878 patients with cardiac AL amyloidosis treated with melphalan plus dexamethasone (MDex), thalidomide plus dexamethasone (TDex), dexamethasone (Dex), melphalan plus prednisone (MP) or thalidomide (T), that achievement of
dexamethasone 18900 amyloidosis treated with melphalan plus dexamethasone (MDex), thalidomide plus dexamethasone (TDex), dexamethasone (Dex), melphalan plus prednisone (MP) or thalidomide (T), that achievement of NT-proBNP response predicted
dexamethasone 19290 independently predicted survival in 94 patients with AL amyloidosis treated with bortezomib (Bor) or Bor plus dexamethasone (BDex). Palladini et al.[49] demonstrated that post-treatment NT-proBNP response independently predicted
dexamethasone 19545 patients with AL amyloidosis treated primarily with MDex, Dex, cyclophosphamide plus thalidomide and dexamethasone (CyTDex) or ASCT. Kastritis et al.[56] reported that NT-proBNP response predicted survival in 85 patients
dexamethasone 27170 al.[11]Figure 4Survival according to NT-proBNP response in an ongoing phase 3 trial comparing melphalan- dexamethasone with melphalan-bortezomib-dexamethasone (NCT01277016).Figure 5Estimated time required to complete a
dexamethasone 27210 NT-proBNP response in an ongoing phase 3 trial comparing melphalan-dexamethasone with melphalan-bortezomib- dexamethasone (NCT01277016).Figure 5Estimated time required to complete a trial in patients with AL cardiomyopathy
dexamethasone 28475 BDex~45 months~10 monthsAbbreviations: ASCT, autologous stem cell transplantation; BDex, bortezomib plus dexamethasone ; Bor, bortezomib; CyTDex, cyclophosphamide plus thalidomide and dexamethasone; Dex, high-dose dexamethasone;
dexamethasone 28553 BDex, bortezomib plus dexamethasone; Bor, bortezomib; CyTDex, cyclophosphamide plus thalidomide and dexamethasone ; Dex, high-dose dexamethasone; L, lenalidomide; MDex, melphalan plus high-dose dexamethasone; MP, melphalan
dexamethasone 28583 dexamethasone; Bor, bortezomib; CyTDex, cyclophosphamide plus thalidomide and dexamethasone; Dex, high-dose dexamethasone ; L, lenalidomide; MDex, melphalan plus high-dose dexamethasone; MP, melphalan plus prednisone; NT-proBNP,
dexamethasone 28646 thalidomide and dexamethasone; Dex, high-dose dexamethasone; L, lenalidomide; MDex, melphalan plus high-dose dexamethasone ; MP, melphalan plus prednisone; NT-proBNP, N-terminal fragment of the pro-brain natriuretic peptide;
dexamethasone 28818 fragment of the pro-brain natriuretic peptide; T, thalidomide; TDex, thalidomide plus intermediate-dose dexamethasone .aCardiac involvement=percentage of patients with New York Heart Association class ⩾2.bMedian survival
lenalidomide 20117 both in testing (n=816) and in validation (n=374) populations treated primarily with MDex, T-based, lenalidomide (L)-based, Bor-based, Dex, MP or ASCT treatments (Figure 3).[11] Notably, this international study in
lenalidomide 28601 bortezomib; CyTDex, cyclophosphamide plus thalidomide and dexamethasone; Dex, high-dose dexamethasone; L, lenalidomide ; MDex, melphalan plus high-dose dexamethasone; MP, melphalan plus prednisone; NT-proBNP, N-terminal
melphalan 18824 (Table 1).Palladini et al.[54] documented, in 51 patients with cardiac AL amyloidosis treated with melphalan plus dexamethasone (MDex), thalidomide plus dexamethasone (TDex), dexamethasone (Dex), melphalan plus
melphalan 18921 with melphalan plus dexamethasone (MDex), thalidomide plus dexamethasone (TDex), dexamethasone (Dex), melphalan plus prednisone (MP) or thalidomide (T), that achievement of NT-proBNP response predicted both overall
melphalan 27160 Palladini et al.[11]Figure 4Survival according to NT-proBNP response in an ongoing phase 3 trial comparing melphalan -dexamethasone with melphalan-bortezomib-dexamethasone (NCT01277016).Figure 5Estimated time required
melphalan 27189 according to NT-proBNP response in an ongoing phase 3 trial comparing melphalan-dexamethasone with melphalan -bortezomib-dexamethasone (NCT01277016).Figure 5Estimated time required to complete a trial in patients
melphalan 28621 cyclophosphamide plus thalidomide and dexamethasone; Dex, high-dose dexamethasone; L, lenalidomide; MDex, melphalan plus high-dose dexamethasone; MP, melphalan plus prednisone; NT-proBNP, N-terminal fragment of the pro-brain
melphalan 28665 dexamethasone; Dex, high-dose dexamethasone; L, lenalidomide; MDex, melphalan plus high-dose dexamethasone; MP, melphalan plus prednisone; NT-proBNP, N-terminal fragment of the pro-brain natriuretic peptide; T, thalidomide;
prednisone 18936 plus dexamethasone (MDex), thalidomide plus dexamethasone (TDex), dexamethasone (Dex), melphalan plus prednisone (MP) or thalidomide (T), that achievement of NT-proBNP response predicted both overall survival and
prednisone 28680 high-dose dexamethasone; L, lenalidomide; MDex, melphalan plus high-dose dexamethasone; MP, melphalan plus prednisone ; NT-proBNP, N-terminal fragment of the pro-brain natriuretic peptide; T, thalidomide; TDex, thalidomide
thalidomide 18861 documented, in 51 patients with cardiac AL amyloidosis treated with melphalan plus dexamethasone (MDex), thalidomide plus dexamethasone (TDex), dexamethasone (Dex), melphalan plus prednisone (MP) or thalidomide (T), that
thalidomide 18955 (MDex), thalidomide plus dexamethasone (TDex), dexamethasone (Dex), melphalan plus prednisone (MP) or thalidomide (T), that achievement of NT-proBNP response predicted both overall survival and progression-free survival
thalidomide 19529 a study of 113 patients with AL amyloidosis treated primarily with MDex, Dex, cyclophosphamide plus thalidomide and dexamethasone (CyTDex) or ASCT. Kastritis et al.[56] reported that NT-proBNP response predicted
thalidomide 28537 transplantation; BDex, bortezomib plus dexamethasone; Bor, bortezomib; CyTDex, cyclophosphamide plus thalidomide and dexamethasone; Dex, high-dose dexamethasone; L, lenalidomide; MDex, melphalan plus high-dose dexamethasone;
thalidomide 28764 melphalan plus prednisone; NT-proBNP, N-terminal fragment of the pro-brain natriuretic peptide; T, thalidomide ; TDex, thalidomide plus intermediate-dose dexamethasone.aCardiac involvement=percentage of patients
thalidomide 28783 prednisone; NT-proBNP, N-terminal fragment of the pro-brain natriuretic peptide; T, thalidomide; TDex, thalidomide plus intermediate-dose dexamethasone.aCardiac involvement=percentage of patients with New York Heart
Select Disease Character Offset Disease Term Instance
amyloidosis 151 qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis Alternative Title: NT-proBNP in AL amyloidosis trialsG MerliniI LousadaY AndoA DispenzieriM A GertzM
amyloidosis 197 point in pivotal clinical trials in patients with AL amyloidosisAlternative Title: NT-proBNP in AL amyloidosis trialsG MerliniI LousadaY AndoA DispenzieriM A GertzM GroganM S MaurerV SanchorawalaA WechalekarG PalladiniR
amyloidosis 461 10/2016Publication date (epreprint): 07/2016Publication date (epub): 08/2016AbstractAmyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients
amyloidosis 477 (epreprint): 07/2016Publication date (epub): 08/2016AbstractAmyloid light-chain (LC) amyloidosis (AL amyloidosis ) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis,
amyloidosis 581 amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis , LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal
amyloidosis 804 the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis , as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional
amyloidosis 1273 Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP)
amyloidosis 1528 clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis . Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in
amyloidosis 2005 cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis . Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated,
amyloidosis 2198 analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.IntroductionAmyloid light-chain (LC) amyloidosis
amyloidosis 2298 amyloidosis specialists, as a surrogate end point for survival.IntroductionAmyloid light-chain (LC) amyloidosis (AL amyloidosis), a rare, progressive and fatal disease, is the most common form of systemic amyloidosis,[1],
amyloidosis 2314 specialists, as a surrogate end point for survival.IntroductionAmyloid light-chain (LC) amyloidosis (AL amyloidosis ), a rare, progressive and fatal disease, is the most common form of systemic amyloidosis,[1], [2] and
amyloidosis 2403 amyloidosis (AL amyloidosis), a rare, progressive and fatal disease, is the most common form of systemic amyloidosis ,[1], [2] and it affects an estimated 8–12 per 1 000 000 persons annually.[3], [4] Systemic amyloidosis
amyloidosis 2512 amyloidosis,[1], [2] and it affects an estimated 8–12 per 1 000 000 persons annually.[3], [4] Systemic amyloidosis is characterized by the accumulation of abnormal, misfolded protein (amyloid) in various tissue and
amyloidosis 2955 the heart is affected, and is the primary cause of death.[1], [5] As many as 70% of patients with AL amyloidosis have predominantly cardiac amyloid deposition.[2], [5] The prevalence of all types of cardiac amyloidosis
amyloidosis 3061 amyloidosis have predominantly cardiac amyloid deposition.[2], [5] The prevalence of all types of cardiac amyloidosis is assumed to be underestimated because of missed diagnoses, given that the symptoms of cardiac amyloidosis
amyloidosis 3169 amyloidosis is assumed to be underestimated because of missed diagnoses, given that the symptoms of cardiac amyloidosis often mimic those of other far more common conditions.[6], [7], [8]There are no approved therapies for
amyloidosis 3287 mimic those of other far more common conditions.[6], [7], [8]There are no approved therapies for AL amyloidosis . That said, frequently used treatment options, such as high-dose chemotherapy in combination with autologous
amyloidosis 4819 analytically validated and clinically qualified for a specific context of use'.[14]The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP)
amyloidosis 5074 clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis . This consensus is supported by the consistent demonstration of the predictive value of NT-proBNP in
amyloidosis 6299 Accelerated Approval, the following qualifying criteria for using a surrogate end point are met for AL amyloidosis :‘…treats a serious condition…'—this is relevant for the substantial morbidity and mortality
amyloidosis 6430 serious condition…'—this is relevant for the substantial morbidity and mortality associated with AL amyloidosis . ‘…demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical
amyloidosis 6774 likely to predict an effect on IMM…'—hematologic response, a commonly used efficacy measure for AL amyloidosis patients, may not capture the specific impact on heart dysfunction, which causes death. Consistent evidence
amyloidosis 7256 could be confirmatory.Without acceptance of surrogate end points for survival, a primary obstacle of AL amyloidosis clinical trials is their long duration and large study size, necessary because of the need for end points
amyloidosis 8180 interpretation of multiple treatments). This will lead to more drug-industry investment into the study of AL amyloidosis . At present, ‘source therapies' are being used off-label, and few manufacturers are pursuing regulatory
amyloidosis 8764 this reason, using NT-proBNP as a surrogate end point for pivotal clinical trials in patients with AL amyloidosis will advance therapeutic treatments that save lives. Here, we present the data and rationale for the
amyloidosis 9061 directly modulated by LC-elicited signal transduction pathways in cardiomyocytes and accepted by AL amyloidosis specialists as a surrogate end point for survival.Cardiac amyloidosisIn AL amyloidosis, misfolded LCs
amyloidosis 9131 cardiomyocytes and accepted by AL amyloidosis specialists as a surrogate end point for survival.Cardiac amyloidosis In AL amyloidosis, misfolded LCs predominantly affect the heart (~70% of patients), kidneys (70% of patients)
amyloidosis 9148 accepted by AL amyloidosis specialists as a surrogate end point for survival.Cardiac amyloidosisIn AL amyloidosis , misfolded LCs predominantly affect the heart (~70% of patients), kidneys (70% of patients) or both,
amyloidosis 9511 The extent of cardiomyopathy is the most important determinant of outcome in patients with systemic amyloidosis .[2], [5], [17] As mentioned, no therapies have been specifically approved for the treatment of patients
amyloidosis 9635 [17] As mentioned, no therapies have been specifically approved for the treatment of patients with AL amyloidosis , and optimal treatment regimens remain undefined.[9], [18]Extracellular amyloid deposits in the heart
amyloidosis 10750 deposits addresses a critical unmet need to reverse or attenuate cardiomyopathy in patients with AL amyloidosis . The use of NT-proBNP will facilitate the emergence of such novel therapies.Biological significance
amyloidosis 11362 assess outcome and cardiac progression. NT-proBNP has been clinically qualified to a great extent in AL amyloidosis , and AL amyloidosis specialists agree that it predicts cardiac response and improved clinical outcome
amyloidosis 11382 cardiac progression. NT-proBNP has been clinically qualified to a great extent in AL amyloidosis, and AL amyloidosis specialists agree that it predicts cardiac response and improved clinical outcome after intervention.
amyloidosis 12189 77–108) and the biologically inactive peptide NT-proBNP (amino acids 1–76).[31], [32] Notably for AL amyloidosis , MAPK signaling mediates BNP transcription,[33], [34], [35] supporting a direct connection between LC
amyloidosis 12623 cardiovascular diseases and makes BNP levels directly reflective of the LC-induced cardiac pathology in AL amyloidosis . Ventricular dysfunction is indicated by increased serum BNP and NT-proBNP, which are secreted at a
amyloidosis 14438 NT-proBNP has been established in the biomarker field; however, studies performed in patients with AL amyloidosis have primarily used NT-proBNP. This might be because NT-proBNP has a longer half-life, is more sensitive
amyloidosis 15110 found on echocardiography.[41] NT-proBNP is the most sensitive marker of cardiac involvement in AL amyloidosis ; it has 100% sensitivity for detecting cardiac involvement estimated by clinical signs, electrocardiography
amyloidosis 15382 332 ng/l (0.33 mg/ml or 39.2 pmol/l).[42]Application of cardiac biomarkers to patients with AL amyloidosis Several studies demonstrate that cardiac biomarkers, particularly NT-proBNP, are powerful predictors
amyloidosis 15513 demonstrate that cardiac biomarkers, particularly NT-proBNP, are powerful predictors of prognosis in AL amyloidosis .[42], [43] Current staging systems for this disease are based on serum levels of NT-proBNP, cardiac
amyloidosis 16232 demonstrate that baseline NT-proBNP level predicts clinical outcome in patients with newly diagnosed AL amyloidosis . Palladini et al.[42] first reported an association between baseline NT-proBNP levels with cardiac involvement
amyloidosis 16392 association between baseline NT-proBNP levels with cardiac involvement and survival in 152 patients with AL amyloidosis (Figure 1). In separate publications, Dispenzieri et al.[53] demonstrated that baseline NT-proBNP levels
amyloidosis 16565 demonstrated that baseline NT-proBNP levels predicted survival in 242 patients with newly diagnosed amyloidosis and in 98 patients before they underwent autologous stem cell transplantation (ASCT).[51] Kristen et
amyloidosis 16794 demonstrated that baseline NT-proBNP level was an independent predictor of survival in 163 patients with AL amyloidosis . In an analysis of 1998 patients seen over a 30-year period at the Mayo Clinic compared with 313 contemporary
amyloidosis 17225 that presenting NT-proBNP correlated with survival in a group of 346 patients with newly diagnosed AL amyloidosis who subsequently were treated with hematologic therapies. Kristen et al.[46] showed that baseline NT-proBNP
amyloidosis 17414 showed that baseline NT-proBNP level was a univariate predictor of survival in 185 patients with AL amyloidosis . Banypersad et al.[47] demonstrated, in 100 patients with AL amyloidosis, that cardiac disease revealed
amyloidosis 17487 survival in 185 patients with AL amyloidosis. Banypersad et al.[47] demonstrated, in 100 patients with AL amyloidosis , that cardiac disease revealed by nuclear magnetic resonance imaging correlated with NT-proBNP levels.
amyloidosis 17761 associated with both NT-proBNP and cardiac troponin T predicted 1-year mortality in 125 patients with AL amyloidosis . These 9 independent studies in 3722 treatment-naive patients show that NT-proBNP responses consistently
amyloidosis 17955 responses consistently reflect changes in cardiac function and predict survival in patients with AL amyloidosis .NT-proBNP response after intervention predicts clinical outcomeIn the context of interventional therapy,
amyloidosis 18799 inhibitors, and alkylating agents (Table 1).Palladini et al.[54] documented, in 51 patients with cardiac AL amyloidosis treated with melphalan plus dexamethasone (MDex), thalidomide plus dexamethasone (TDex), dexamethasone
amyloidosis 19236 post-treatment NT-proBNP (and BNP) response independently predicted survival in 94 patients with AL amyloidosis treated with bortezomib (Bor) or Bor plus dexamethasone (BDex). Palladini et al.[49] demonstrated that
amyloidosis 19461 post-treatment NT-proBNP response independently predicted patient survival in a study of 113 patients with AL amyloidosis treated primarily with MDex, Dex, cyclophosphamide plus thalidomide and dexamethasone (CyTDex) or ASCT.
amyloidosis 19673 ASCT. Kastritis et al.[56] reported that NT-proBNP response predicted survival in 85 patients with AL amyloidosis treated with BDex or with L-based or risk-adapted BDex. On the basis of these results, in 2012 the International
amyloidosis 19944 validated NT-proBNP response as an indicator of organ response and as a surrogate marker of survival in AL amyloidosis . NT-proBNP response predicted a significant survival benefit both in testing (n=816) and in validation
amyloidosis 20653 responses consistently reflect changes in cardiac function and predict survival in patients with AL amyloidosis . However, these studies were retrospective. Prospectively, the response criteria are being used in an
amyloidosis 21046 analysis indicates that NT-proBNP response translates into a significant survival benefit (Figure 4).AL amyloidosis is an exceedingly rare disease. To put it in context, AL amyloidosis with cardiac involvement is diagnosed
amyloidosis 21115 survival benefit (Figure 4).AL amyloidosis is an exceedingly rare disease. To put it in context, AL amyloidosis with cardiac involvement is diagnosed in ~3000 new patients each year in the US[57] The post-intervention
amyloidosis 22256 have been validated as surrogate markers of cardiac response and clinical outcome in patients with AL amyloidosis . There is no clear correlation between reductions in NT-proBNP with improvements in cardiac anatomy,[54]
amyloidosis 22867 on biomarkers at baseline, but this application requires systematic study in patients with cardiac amyloidosis , and there is no useful precedent for monitoring response to therapy (reviewed in studies by Gertz et
amyloidosis 23137 studies[61] have proposed cardiac magnetic resonance imaging as an additional prognostic tool in cardiac AL amyloidosis , but no study has yet explored cardiac magnetic resonance imaging in response assessment. Notable additional
amyloidosis 23708 pro-adrenomedullin[65] and osteoprotegerin[66]) measured at diagnosis are prognostic factors in patients with AL amyloidosis , they have not yet been predictive of survival based on response after interventional treatment. More
amyloidosis 24110 response. Increased cardiac troponin indicated disease progression and poor survival in patients with AL amyloidosis , but the role for troponin in the definition of response remains less established.[11], [49], [62],
amyloidosis 24388 use in assessing cardiac response in patients with both mutated and wild-type cardiac transthyretin amyloidosis .Summary and conclusionNT-proBNP is a unique biomarker of cardiac amyloid involvement in patients with
amyloidosis 24505 amyloidosis.Summary and conclusionNT-proBNP is a unique biomarker of cardiac amyloid involvement in patients with AL amyloidosis . It is of fundamental importance for establishing diagnosis, prognosis, and response to therapy in AL
amyloidosis 24938 unambiguous marker of amyloid cardiac disease. The use of NT-proBNP as a surrogate efficacy end point for AL amyloidosis trials using current, validated definitions of response is not controversial. NT-proBNP level should
amyloidosis 25167 adopted to evaluate the effectiveness of new treatments targeting cardiac dysfunction in patients with AL amyloidosis as an accepted primary outcome. Experts agree that NT-proBNP is the only surrogate end point for survival
amyloidosis 26030 anticancer agents using biomarker-based tactics. This approach is now feasible and necessary in AL amyloidosis . Now is a pivotal moment for many novel drugs in the pipeline that promise to address unmet needs in
amyloidosis 26538 and is a validated and qualified surrogate marker of efficacy for interventions for patients with AL amyloidosis .Figure 1NT-proBNP levels indicate cardiac involvement (a) and predict overall survival (b) in Palladini

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