Free Light Chain Burden and Elevated Alkaline Phosphatase Identify Patients with Non-Cardiac AL Amyloidosis with Poor Outcome

Abstract Background. The prognosis of patients with AL amyloidosis is mainly driven by the severity of heart involvement. Cardiac amyloidosis is being extensively studied, and accurate staging systems have been developed to identify patients with different degrees of heart dysfunction who are candidates for different treatment approaches. However, little is known on the outcome of patients without heart involvement who are generally considered low-risk. In the present study we evaluated factors affecting survival of patients with non-cardiac AL amyloidosis. Patients and Methods. The subjects (n=135) without cardiac involvement (NT-proBNP <332 ng/L and mean left ventricular wall thickness at echocardiography £12 mm) and with normal troponin (Mayo Clinic stage I) were selected form the prospectively maintained database including 748 consecutive, previously untreated patients with AL amyloidosis diagnosed at our center between 2004 and 2012. Results. Median age was 61 years (range 39-80 years). Involved organs were kidney (111, 82%); with median (range) proteinuria 7.2 g/24h (0.5-23.5 g/24h) and creatinine 1.1 mg/dL (0.5-4.4 mg/dL); soft tissues (21, 16%); liver (18, 13%), with median alkaline phosphatase (ALP) 2.3 times the upper reference limit (range 1.6-7.5 times u.r.l.); peripheral nervous system (13, 10%); gastrointestinal (GI) tract (10, 7%). One hundred seven patients (79%) had more than one organ involved. Median (range) bone marrow plasma cell infiltrate was 10% (2-29%) and dFLC (difference between involved and uninvolved free light chains) 70 mg/L (0-5721 mg/dL). Fifty-two patients (38%) were treated with melphalan / dexamethasone (MDex), 42 (31%) with bortezomib-based regimens, 14 (10%) underwent stem cell transplant (ASCT), 13 (10%) received thalidomide-based regimens, and the remaining patients received treatment for IgM clones or high-dose dexamethasone alone. After a median follow-up of living patients of 51 months, 23 patients (17%) died. Survival at 5 years was 82%. Twelve patients (52%) died a cardiac death (heart failure in 8 cases, sudden death in 4), after having developed cardiac involvement. All of them had baseline dFLC >100 mg/L. In these subjects the median NT-proBNP concentration at last assessment was 2401 ng/L, with a median 1646% increase compared to baseline. Of them 7 had failed to respond to frontline therapy, and the remaining had progressed after an initial partial response (PR, 3 cases) or very good partial response (VGPR, 2 cases). Eight patients (35%) died of liver failure. Six satisfied the criteria for liver involvement at baseline, and 2 developed hepatic amyloidosis during the follow-up, but had elevated ALP at baseline (1.3 and 1.4 times the u.r.l., respectively). Among them, 5 were non-responders to first-line therapy, and 3 had relapsed after PR (1) and VGPR (2). One patient died due to GI bleeding during ASCT. In the remaining 2 patients the causes of death were not directly related to the disease: myelodysplasia (5.9 years after having achieved VGPR with 6 cycles of MDex), and colorectal cancer (6.5 years after diagnosis). Only the two deaths that were not disease-related occurred in patients who presented with normal ALP and dFLC <100 mg/L (Figure). Elevated ALP (HR 5.11, P<0.001) and dFLC (HR 4.79, P<0.001) were independent prognostic factors at multivariate analysis. Conclusion. This is the first study specifically addressing the outcome of patients with non-cardiac AL amyloidosis. Cardiac dysfunction after development of heart involvement remains the first cause of death also in patients who do not have cardiac involvement at diagnosis. Notably, fatal cardiac amyloidosis occurred only in patients in whom dFLC was >100 mg/L at diagnosis. Progressive liver involvement emerges as a significant cause of death in Stage I AL patients, and is predicted by elevated ALP. Patients with non-cardiac AL who have high dFLC and/or ALP should be treated aggressively to prevent the onset of terminal organ damage. Figure Figure. Survival of patients with non-cardiac AL amyloidosis according to baseline dFLC and alkaline phosphatase Disclosures Merlini: Millennium Takeda: Honoraria.

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Long Term Follow up of the Combination of Bortezomib with Dexamethasone as Initial Treatment for AL Amyloidosis

Blood ◽

10.1182/blood.v116.21.3048.3048 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3048-3048

Author(s):

Efstathios Kastritis ◽

Maria Roussou ◽

Magdalini Migkou ◽

Maria Gavriatopoulou ◽

Constantinos Pamboukas ◽

...

Keyword(s):

Initial Treatment ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

High Dose ◽

Al Amyloidosis ◽

Long Term Follow Up ◽

Organ Response ◽

High Dose Melphalan

Abstract Abstract 3048 Until recently, patients with AL amyloidosis had limited treatment options, especially those who were not candidates for high dose therapy, those with severe cardiac involvement or patients who relapsed after initial treatment or never responded to first line alkylators with steroids. Bortezomib (B) with dexamethasone (D) has shown significant activity in patients with AL amyloidosis in patients who relapsed or even those who were refractory to initial treatment. We and others have presented data indicating that BD is active in newly diagnosed patients with AL, inducing responses rapidly but also associated with high rates of complete responses. However, data about long-term follow-up of these patients are limited. Thus, we updated a series of 24, previously untreated patients who received frontline BD. In all patients, treatment started with B at a dose of 1.3 mg/m2 on days 1, 4, 8 & 11 and D was given for 4 consecutive days at a dose of 40 mg per day (days 1–4), every 21 days for up to 6 cycles. The median age of these patients was 70 years (range 42–82) and 46% were males. The median number of involved organs was 2; heart was involved in 83% and kidneys in 63%. Fifty-seven percent were Mayo stage II and 26% were Mayo stage III while 67% had impaired ECOG performance status ≥ 2. The first patient started treatment with BD on September 2005. A median of 5 cycles of BD was given (range 1–6) and 57% of patients received the planned 6 cycles. On intent to treat and according to criteria published by Gertz et al in 2005, 77% of patients achieved a hematologic response including 36% with a hematologic CR. Most of the responses occurred after the first cycle of BD (median time to first response <1 month), while a median of two cycles of BD was needed for CR (median time to CR was 42 days, range 21–84). In 54% of patients an organ response was recorded: 47% of patients with a cardiac involvement achieved a cardiac response and 77% had a reduction of NTproBNP ≥ 30% (which was at least 300 pg/ml), while 60% of patients with a kidney involvement achieved an organ response. Three patients received high dose melphalan with autologous stem cell transplant (HDM-ASCT) after they had completed 6 cycles of BD, 2 while in CR and one in PR. All these 3 patients had achieved organ responses before ASCT. The median follow up for all patients is 31 months. Thirteen patients (54%) have died; most of them due to complications of cardiac amyloidosis and the median survival is estimated to exceed 36 months (patients who underwent ASCT were censored at the time of HDM). Baseline NT-proBNP was the most significant factor independently associated with survival. There were no differences in the baseline characteristics of patients who achieved CR compared to those who achieved a PR as best hematologic response. The median follow up for patients who achieved a CR is 31 months (range 2–55 months). One patient died early due to complications of cardiac amyloidosis, while she had achieved a CR. Among the rest of the patients who achieved a CR but did not receive HDM, all remain alive and without progression for a median of 32 months. Similarly none of the patients who received HDM has relapsed. Among patients who achieved a PR as their best response, 4 (50%) have relapsed and the median progression free survival (PFS) for these patients is 9 months and their median survival is 34 months. In conclusion, BD induces high rates of CRs, in unselected, patients with previously untreated AL amyloidosis, most of whom had features of advanced disease and elevated cardiobiomarkers. i.e. patients that may be excluded form clinical trials. The severity of cardiac involvement remains the most important prognostic factor despite the rapid responses and the high rates of hematologic CRs. It is also of interest to note that CRs may persist even in patients who did not receive any alkylating agents or consolidation with high dose melphalan. A CR is associated with improved survival and should be the primary goal of treatment in patients with AL. Our data indicate that primary treatment with bortezomib based regimens should be evaluated in a phase III trial. Disclosures: Dimopoulos: Ortho-Biotech: Honoraria; Celgene: Honoraria; Millennium: Honoraria.

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Abnormal NT-ProBNP in AL Amyloidosis Patients without Cardiac Involvement at Diagnosis - A Predictor of Subsequent Cardiac Involvement.

Blood ◽

10.1182/blood.v110.11.1500.1500 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1500-1500

Author(s):

Ashutosh D. Wechalekar ◽

Helen J. Lachmann ◽

Julian D. Gillmore ◽

Philip N. Hawkins

Keyword(s):

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Myocardial Dysfunction ◽

Posterior Wall ◽

Left Ventricular ◽

Al Amyloidosis ◽

International Consensus ◽

Cardiac Amyloid ◽

Significant Difference

Abstract Cardiac involvement in AL amyloidosis is associated with a poor prognosis and greatly increased treatment related morbidity and mortality, and regression of cardiac amyloid deposits is extraordinarily slow following chemotherapy that suppresses the underlying aberrant light chain production. Diagnosis of cardiac amyloidosis is normally made by echocardiography, by which time significant diastolic dysfunction has usually developed. Atrial natriuretic peptides (ANP, BNP and its N-terminal fragment NT-ProBNP) are useful in early diagnosis of myocardial dysfunction. Serum NT-ProBNP concentration has been reported to be a promising marker of cardiac dysfunction in AL amyloidosis, and patients with normal NT-ProBNP values at diagnosis have superior outcomes. We report here the outcome of patients attending the UK National Amyloidosis Centre (NAC) who had elevated NT-ProBNP at diagnosis of AL amyloidosis but who did not have accompanying evidence of cardiac involvement using conventional consensus criteria. To exclude the confounding effect of renal failure which is associated with substantial elevation of NT-ProBNP, we studied patients with serum creatinine <150 μmol/L and creatinine clearance of >50ml/min at diagnosis in whom there was less than 10% change in renal function after treatment. AL type amyloidosis was confirmed in all patients histologically with corroborating genetic studies to robustly exclude hereditary amyloidosis as indicated. Organ involvement and responses/progression were defined according to recent international consensus criteria (Gertz et al 2005). 102 patients who had no evidence of cardiac involvement by these conventional parameters and who otherwise conformed with our study criteria were identified. Median creatinine was 87 μmol/L (44–128), albumin 33g/L (10–65), bilirubin 7 μmol/L (1–65) and alkaline phosphatase 89 units/L (36–2649). The median interventricular septal and left ventricular posterior wall thickness was 9 mm (7–11 mm). 62 (61%) patients had NT-ProBNP ≤ 35pMol/L at diagnosis while 40 (39%) had NT-ProBNP of >35 pMol/L. There was no significant difference in the baseline characteristics of either group. 5 patients in each group did not respond to the initial chemotherapy (p=0.46). With median follow-up of 60 months, 19/40 (47%) of patients with NT-ProBNP >35pMol/L at diagnosis developed evidence of cardiac involvement compared to only 6/62 (10%) of whose baseline NT-ProBNP was ≤ 35 pMol/L (p<0.001). The Kaplan-Meier estimated median overall survival has not been reached for either group but the estimated 7 year survival was significantly better in the group with NT-ProBNP of ≤35pMol/L compared to those with greater values (92% vs. 82%, p=0.03). In conclusion, these preliminary findings suggest that patients who have elevated NT-ProBNP concentration but no conventional evidence of cardiac involvement at diagnosis of AL amyloid appear to be at greater risk of developing cardiac amyloidosis during follow-up, and have a poorer prognosis. It reasonable to speculate that such patients have early cardiac involvement at diagnosis that cannot be identified by conventional non-invasive methods, and that their risk of subsequently developing clinically significant cardiac amyloidosis may be reduced by striving to achieve complete remission of their underling clonal plasma cell disease.

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Abstract 18297: Clinical and Prognostic Utility of Cardiac Magnetic Resonance Imaging in Multiple Myeloma Patients With Suspected Amyloidosis

Circulation ◽

10.1161/circ.130.suppl_2.18297 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Sabha Bhatti ◽

Evan Watts ◽

Fahd Syed ◽

Abdul Hakeem

Keyword(s):

Magnetic Resonance Imaging ◽

Multiple Myeloma ◽

Cardiac Mri ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Al Amyloidosis ◽

Resonance Imaging ◽

Prognostic Utility

Background: Upto 30% of patients with multiple myeloma have AL amyloidosis and cardiac involvement is associated with worse outcomes in these patients. Traditional screening modalities including EKG, echocardiography and biomarkers have limited value. The aim of this study was to evaluate the role of “screening” cardiac MRI in a large multiple myeloma population at a large specialized referral center. Methods & Results: 164 consecutive patients with multiple myeloma who underwent cardiac MRI between 6/2005 and 10/2011 were enrolled in this study. Primary endpoint was all cause death. Clinical, EKG, echocardiographic, biomarker and MRI predictors for death were analyzed. Mean age of population was 63+10 years, 40% females and 16% African Americans. 30% of the population had MRI evidence of cardiac involvement. There were 26 patients who had biopsy proven systemic amyloidosis, of whom 62% showed cardiac involvement on MRI. 81% patients with confirmed cardiac amyloidosis on endomyocardial biopsy had typical MR pattern of cardiac involvement. During a median follow up period of 702 days (mean 1019 (950) days), there were 59 deaths (36%). Amyloid pattern on cardiac MRI (OR 2.19), elevated BNP and increased LV wall thickness on MRI were significant predictors of mortality . (All p<0.05) Conclusions: This is the largest study to date evaluating the role of cardiac MRI in multiple myeloma patients with suspected cardiac amyloidosis. Cardiac MRI is a clinically robust tool for risk stratification of this subset of patients.

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Cardiac involvement Is Underdiagnosed in Patients with Biopsy-Proven Systemic AL Amyloidosis

International Cardiovascular Forum Journal ◽

10.17987/icfj.v6i0.172 ◽

2016 ◽

Vol 6 ◽

Author(s):

Haoyi Zheng ◽

Amitabha Mazumder ◽

Stuart Katz

Keyword(s):

Clinical Diagnosis ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Clinical Care ◽

Response To Therapy ◽

Cardiac Response ◽

Al Amyloidosis ◽

Limited Data ◽

Nccn Guidelines

Background: Clinical recognition of cardiac involvement and cardiac response to therapy is an important element of clinical care in patients with AL amyloidosis. The new criteria including NT-proBNP, troponin, and echocardiography for assessment of cardiac involvement in patients with systemic AL amyloidosis were proposed in 2004, but there are limited data on the utilization of these in clinical practiceMethods: We retrospectively reviewed the clinical data of 28 patients with AL amyloidosis. Clinical diagnosis of cardiac amyloidosis was based on medical record documentation of symptomatic heart failure without other causes. Then we use the criteria from the current NCCN Guidelines to reassess cardiac involvement.Results: 14 cases (50%) had clinical diagnosis of cardiac amyloidosis at the time of diagnosis and also met the NCCN criteria. An additional 6 cases without clinical diagnosis of cardiac amyloidosis met the NCCN criteria. In total, 20 patients (71.4%) met the NCCN criteria for cardiac involvement. No routine follow-up testing with echocardiography and biomarkers was documented during treatment for any of the patients.

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Efficacy and Tolerability of Daratumumab in Heavily Pretreated AL Amyloidosis: A Systematic Review

Blood ◽

10.1182/blood-2018-99-115214 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2025-2025 ◽

Cited By ~ 1

Author(s):

Muhammad Aadil Rahman ◽

Ali Younas Khan ◽

Awais Ijaz ◽

Muhammad Junaid Tariq ◽

Muhammad Usman ◽

...

Keyword(s):

Heart Failure ◽

Partial Response ◽

Light Chain ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Renal Involvement ◽

Renal Amyloidosis ◽

Al Amyloidosis ◽

Heavily Pretreated ◽

Organ Response

Abstract Introduction Light chain (AL) amyloidosis is a low burden plasma cell disorder, characterized by deposition of misfolded lambda or kappa light chains. Kidney dysfunction is present in almost two-thirds of patients at the time of initial presentation, followed by diastolic heart failure in about 50% of cases, which is responsible for 75% of deaths in these patients. Autologous stem cell transplant (auto-SCT) remains the gold standard for the management of AL amyloidosis but is often impractical to perform by virtue of patients' age, medical comorbidities including cardiac involvement. Methods We conducted a literature search using three databases (PubMed, Embase,Web of Science). Our search strategy included MeSH terms and key words such as AL amyloidosis, daratumumab and darzalex from date of inception to March 2018. After excluding duplicates, reviews and non-relevant articles, we selected eight studies, including two case reports, two phase II prospective trials and four retrospective trials. Results Data on 129 patients was included, there ages ranged from 43-83 years. Median number of prior therapies were 3 (range: 2-6), 106 (82%) received proteasome inhibitor (bortezomib) based therapy, and 69 (53.5%) received immunomodulatory (lenalidomide) based therapy. Another 41 (32%) received high dose melphalan (HDM) followed by auto-SCT. The time from the diagnosis of AL to the start of daratumumab therapy varied from 0.7-150 months. Eighty-nine (69%) patients had cardiac and 64 (49.6%) patients had renal involvement. A total of 114 (88%) patients received a daratumumab dose of 16 mg/kg weekly for 8 weeks followed by every 2 weeks for the next 8 weeks. A total of 104 patients were evaluable for hematological response, assessed by improvement in free light chain (FLC) levels. Daratumamab achieved an impressive overall response rate (ORR) of 72% (n=75). Complete remission (CR) in 15 (14%) of patients, very good partial response (VGPR) in 44 (42%) and a partial response (PR) in 16 (15%) of patients was noted. Thirty-four patients with cardiac involvement and 26 patients with renal amyloidosis were assessed for organ response across four studies. Thirteen (38%) patients with cardiac amyloidosis demonstrated an improvement in N-terminal pro brain natriuretic peptide (NT-proBNP) levels. Ten (38%) patients with renal involvement responded according to consensus criteria [Palladini et al 2014] for organ response. Another two had improvement in serum creatinine levels. Among the 129 patients treated with daratumumab for AL amyloidosis, 36 (32%) reported infusion related reactions (IRR). Most were mild (grade 1-2). Daratumumab infusion was well tolerated in patients with cardiac (n=54) and renal involvement (n=48). Only one patient needed adjustment in his diuretic dose, another one developed decompensated heart failure and one died due to progression of cardiac disease. Seven patients had worsening of their NT-proBNP levels. Similarly, no dose adjustments were required for patients with renal amyloidosis and one patient tolerated daratumumab infusion at a GFR<20 mL/min without any complications. Conclusion Daratumumab monotherapy is associated with deep and prompt hematological responses in patients with heavily pretreated AL amyloidosis, at the standard dosing regimens used for multiple myeloma, with a favorable safety profile. Furthermore, daratumumab performed well in patients with cardiac amyloidosis even though there is an increased risk of volume overload and infusion related morbidity. Given the high incidence of peripheral neuropathy with bortezomib, cardiotoxicity with carfilzomib based regimens in amyloidosis patients, daratumumab appears to be a suitable alternative. It has already been approved for relapsed amyloidosis (AL) patients in the European Union. Currently, it is being investigated as monotherapy for AL amyloidosis in phase 2 trials (NCT02841033 and NCT02816476) and in combination with bortezomib, cytoxin and dexamethasone (VCd) in a phase III trial (NCT03201965). Disclosures No relevant conflicts of interest to declare.

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A European Collaborative Study of Treatment Outcomes In 428 Patients with Systemic AL Amyloidosis

Blood ◽

10.1182/blood.v116.21.988.988 ◽

2010 ◽

Vol 116 (21) ◽

pp. 988-988 ◽

Cited By ~ 3

Author(s):

Ashutosh D Wechalekar ◽

Efstathios Kastritis ◽

Giampaolo Merlini ◽

Philip N Hawkins ◽

Meletios A. Dimopoulos ◽

...

Keyword(s):

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Median Number ◽

Cardiac Response ◽

Al Amyloidosis ◽

Line Treatment ◽

End Of Treatment ◽

Significant Difference ◽

Organ Response

Abstract Abstract 988 The treatment of patients with systemic AL amyloidosis remains challenging. Cyclical combination chemotherapy is used in majority of patients but a report that I.V. melphalan-dexamethasone may not overcome the poor prognosis for cardiac amyloidosis (Deitrich S et al, Blood, 116, 2010) has fuelled the controversy about best front line treatment. We report outcomes of 428 patients treated with oral cyclophosphamide thalidomide dexamethasone (CTD), oral melphalan dexamethasone (M-dex), bortezomib dexamethasone with or without an alkylator (BD), cyclophosphamide-lenalidomide-dexamethasone (CLD) or stem cell transplant (ASCT) as first line treatment for systemic AL amyloidosis assessed at three large European amyloid centres in London (UK), Pavia (Italy) and Athens (Greece) between 2003–2010. Patients with a full baseline data set were included in the study. Clonal and organ responses were defined according to the international amyloidosis consensus statement (Gertz et al 2005) and responses were assessed at 6 months or at the end of treatment. dFLC (difference between involved and uninvolved free light chain (FLC)) was used to assess the absolute FLC change after treatment. 204 (48%) received M-dex, 155 (36%) received CTD, 13 (3%) received ASCT, 28 (7%) received BD and 25 (6%) received CLD. The median number of cycles received was 5 for all regimens. 257 (60%) had cardiac involvement, 325 (76%) had renal and 59 (14%) had liver involvement. Cardiac involvement by regime was: BD 75%, CLD 68%, M-dex 65%, CTD 45% and ASCT 23%. 30 (7%) died within six months of diagnosis. The median number of organ involved was 2 (range 1–5) with ECOG performance status ≥2 in 123 (28%). 98 (23%) patients achieved a complete response (CR), 175 (41%) achieved a partial response (PR) and 125 (29%) did not respond to treatment. A haematological CR/PR was seen, respectively, in 22%/41% treated with CTD, 26%/44% with M-dex, 23%/46% with ASCT, 39%/42% with BD and 4%/44% with CLD. There was significantly greater reduction in dFLC after BD (median reduction 91% over starting value) compared to CTD (median 81%; p = 0.006), M-Dex (median 83%; p = 0.004) and CLD (median 72%; p = 0.03). There was no significant difference in the median dFLC reduction between patients treated with CTD and M-Dex. 100/325 (30%) had a renal organ response, 17/59 (29%) had a hepatic response and 24/257 (9%) had a cardiac response, and 61 (16%) had a cardiac response by NT-proBNP criteria. The organ and NT-proBNP responses respectively were highest in the cohort treated with BD (53% and 32%) followed by CTD (38% and 12%), ASCT (30%), M-dex (23% and 19%) and CLD (12% and nil). CTD achieved significantly better organ responses compared to M-dex (p=0.0024). At median follow up of 29 months, median overall survival (OS) for the whole cohort has not been reached with 2, 3 and 4 year estimated survival of 75%, 65% and 61%, respectively. When patients with cardiac involvement were considered, those achieving a CR have not reached median OS with an estimated 3 year survival of 89%, those with PR had an estimated median OS of 50 months and the non-responders had a median OS of 21 months. Detailed comparison by Mayo stage will be presented. There was no significant difference in the OS of patients treated with CTD or M-Dex (as compared directly or by centre). In summary, outcome of patients with AL amyloidosis across three major European centres appears comparable. BD treatment achieves significantly lower end of treatment dFLC values compared to CTD, M-dex, ASCT or CLD – which importantly translates into an organ response in over half of all patients receiving BD compared to a third of those treated with CTD and quarter of those with M-dex and further follow up may yet reveal survival differences. Organ responses appear significantly better with CTD compared to M-dex – possibly due to more rapid response to CTD since the end of treatment dFLC values are not significantly different - although this does not translate into a survival advantage. Depth of clonal response appears to be directly linked to improvement in survival of patients with cardiac amyloidosis (including in patients treated with CTD and M-dex) and organ response in general. This study supports the rational for doing urgent phase III studies confirming benefits of bortezomib combination chemotherapy for upfront treatment in AL amyloidosis and the benefit of rapid deep clonal responses in cardiac amyloidosis irrespective of the regimen. Disclosures: Off Label Use: Thalidomide, bortezomib, lenalidomide. Dimopoulos:Celgene: Honoraria; Othro Boitech: Honoraria.

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Development and validation of a survival staging system incorporating BNP in patients with light chain amyloidosis

Blood ◽

10.1182/blood-2018-06-858951 ◽

2019 ◽

Vol 133 (3) ◽

pp. 215-223 ◽

Cited By ~ 36

Author(s):

Brian Lilleness ◽

Frederick L. Ruberg ◽

Roberta Mussinelli ◽

Gheorghe Doros ◽

Vaishali Sanchorawala

Keyword(s):

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Light Chain ◽

Cardiac Involvement ◽

Staging System ◽

Stage I ◽

Stage Iiib ◽

Stage Ii ◽

Al Amyloidosis ◽

Derivation Cohort

Abstract Immunoglobulin light chain amyloidosis (AL amyloidosis) is caused by misfolded light chains that form soluble toxic aggregates that deposit in tissues and organs, leading to organ dysfunction. The leading determinant of survival is cardiac involvement. Current staging systems use N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T and I (TnT and TnI) for prognostication, but many centers do not offer NT-proBNP. We sought to derive a new staging system using brain natriuretic peptide (BNP) that would correlate with the Mayo 2004 staging system and be predictive for survival in AL amyloidosis. Two cohorts of patients were created: a derivation cohort of 249 consecutive patients who had BNP, NT-proBNP, and TnI drawn simultaneously to create the staging system and a complementary cohort of 592 patients with 10 years of follow-up to determine survival. In the derivation cohort, we found that a BNP threshold of more than 81 pg/mL best associated with Mayo 2004 stage and also best identified cardiac involvement. Three stages were developed based on a BNP higher than 81 pg/mL and a TnI higher than 0.1 ng/mL and compared with Mayo 2004 with high concordance (κ = 0.854). In the complementary cohort, 25% of patients had stage I, 44% had stage II, 15% had stage III, and 16% had stage IIIb disease with a median survival not reached in stage I, 9.4 years in stage II, 4.3 years in stage III, and 1 year in stage IIIb. This new Boston University biomarker scoring system will allow centers without access to NT-proBNP the ability to appropriately stage patients with AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00898235.

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Diagnostic approach to light-chain cardiac amyloidosis and its differential diagnosis

Acta Haematologica Polonica ◽

10.2478/ahp-2018-0002 ◽

2018 ◽

Vol 49 (1) ◽

pp. 9-14

Author(s):

Monika Adamska ◽

Anna Komosa ◽

Tatiana Mularek ◽

Joanna Rupa-Matysek ◽

Lidia Gil

Keyword(s):

Differential Diagnosis ◽

Light Chain ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Diagnosis And Treatment ◽

Diagnostic Approach ◽

Al Amyloidosis ◽

Delay In Diagnosis ◽

Light Chain Amyloidosis ◽

Novel Approaches

AbstractCardiac amyloidosis is a rare and often-misdiagnosed disorder. Among other forms of deposits affecting the heart, immunoglobulin-derived light-chain amyloidosis (AL amyloidosis) is the most serious form of the disease. Delay in diagnosis and treatment may have a major impact on the prognosis and outcomes of patients. This review focuses on the presentation of the disorder and current novel approaches to the diagnosis of cardiac involvement in AL amyloidosis.

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Effectiveness of Bortezomib in Cardiac AL Amyloidosis: A Report of Two Cases

Case Reports in Medicine ◽

10.1155/2014/627474 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Santi Nigrelli ◽

Giuseppe Curciarello ◽

Piercarlo Ballo ◽

Stefano Michelassi ◽

Francesco Pizzarelli

Keyword(s):

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Chronic Kidney Disease Stage ◽

Clinical Results ◽

Disease Stage ◽

Comorbid Condition ◽

Al Amyloidosis ◽

Therapeutic Approaches ◽

Hematologic Disease ◽

Total Remission

Cardiac involvement is a major prognostic determinant in patients with primary AL amyloidosis. The clinical results of standard therapeutic approaches are suboptimal. It has been recently shown that bortezomib, an inhibitor of the proteasome, can induce rapid favourable responses in AL amyloidosis improving cardiac function and survival. Herein we report on two patients with cardiac amyloidosis treated by bortezomib who experienced partial or total remission of hematologic disease and of cardiac involvement. However, death of one patient, suffering from chronic kidney disease stage 5, due to fulminant respiratory syndrome suggests the need for caution in bortezomib use if patients have this comorbid condition.

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A Prospective Study of Treatment Outcomes in 179 Patients with Advanced Cardiac Stage STAGE IIIb Amyloidosis

Blood ◽

10.1182/blood.v126.23.5357.5357 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5357-5357

Author(s):

Belen Sevillano ◽

Ashutosh Wechalekar ◽

Darren Foard ◽

Carol Whelan ◽

Marianna Fontana ◽

...

Keyword(s):

Partial Response ◽

Prospective Study ◽

Treatment Outcomes ◽

Cardiac Involvement ◽

Left Ventricular ◽

Stage Iiib ◽

Stage Iii ◽

Al Amyloidosis ◽

Hematological Response ◽

A Prospective Study

Abstract A PROSPECTIVE STUDY OF TREATMENT OUTCOMES IN 179 PATIENTS WITH ADVANCED CARDIAC STAGE IIIB AMYLOIDOSIS Authors: Belen Sevillano, Darren Foard, Carol Whelan, Mariana Fontana, Critina Quarta, Shameem Mahmood, Helen Lachmann, Julian Gillmore, Philip Hawkins and Ashutosh Wechalekar INTRODUCTION The prognosis of systemic light chain amyloidosis is determined by extent of cardiac involvement. The Mayo cardiac staging system (Dispenzieri et al JCO 2004) is widely used for prognosis and we defined a particularly poor prognostic subgroup within Mayo stage III patients (Wechalekar et al Blood, 121(17), 2013) characterized by NT-proBNP >8500 ng/L with a median survival of 4 months-stage IIIb disease. All such patients are excluded from clinical trials and treatment outcomes of this group are not known. We report the treatment outcomes of a cohort of stage IIIb cardiac AL patients prospectively followed up in the ALChemy study PATIENTS AND METHODS. All patients from the ALChemy study (a prospective observational study of all patients with AL amyloidosis undergoing chemotherapy) at the UK National Amyloidosis Centre (identified from first 1000 patients recruited into the study from 2009 to Jan 2015) with Mayo stage IIIb cardiac AL (defined as NT-proBNP >8500 ng/L and cardiac troponin T >0.035 μg/L) were included. All were treated according to nationally agreed protocols. Organ involvement and hematologic/amyloidotic organ responses were assessed according to 2010 amyloidosis consensus criteria. The primary outcome measure was overall survival (OS) and impact of hematological response on survival. Statistical analysis was undertaken using SPSS software package. Survival was assessed by the Kaplan-Meier method and compared by log-rank test. RESULTS A total of 179 patients were included. The median age was 65 yrs, 77 (43 %) were female and 102 (57 %) male. All patients had cardiac involvement, renal involvement was seen in 131 (73.2 %) and liver involvement in 28 (15.6 %). The median NT-proBNP was 19056 ng/L (range 8500 - 70084 ng/L). The median left ventricular (LV) wall thickness was 14.2 mm (range 11-22 mm) and median ejection fraction (EF) was 48.7 % (23-75 %). 34 % had dyspnea ≥ NYHA grade 3 and 16.8 % had ECOG performance status ≥3. Only 68 (38 %) patients managed a 6 min walk test and median distance was 130.5 m. 30 (17 %) patients died prior to treatment initiation. Initial treatment regimens were: Bortezomib combinations - 48 % (87); Thalidomide or Lenalidomide combinations in 28 % (51), alkylators based regimens - 5 % (9) and rituximab based in 1 %. The hematological best responses on an intention to treat basis were: complete response (CR) - 35w (20%), very good partial response (VGPR) 25 (13%), partial response (PR) 32 (18%) and no response (NR) 87 (47%) (NR included patients who died before treatment). The median OS for the cohort was 6 months (mo). Univariate and ROC analysis identified LVEF >55%, dFLC <400 mg/L and SBP >110 mm of Hg predictors of OS. The median OS was significantly better for patients with LVEF>55% (13 mo); for dFLC < 400 mg/L was 7 mo (vs. 3 mo for dFLC >400 mg/L); and for those with SBP > 110 mmHg was 10 mo (vs. 5 mo in those with lower SBP). Median OS for patients achieving a CR/VGPR at day 30 was 26 mo compared to 5 mo for patients with <VGPR at that time. The median OS for patients who finally achieved CR/VGPR was 38 mo, PR 7 mo and NR was 2.6 mo (log rank p<0.0001) (Fig 1). In a multivariate model, achieving a hematological CR/VGPR (HR 5.3), LVEF <55% (HR1.5), dFLC >400 mg/L (HR 1.3) and SBP <110 mm of Hg (HR 1.5) were independent predictors of outcomes. CONCLUSIONS: The survival of stage IIIb AL remains poor but has improved compared with historical reported series. The survival of patients who achieve a CR or VGPR is over 3 years. Early achievement of ≥VGPR, as early as end of cycle 1, seems to predict for a better survival challenging the practice of treating stage III patients with "low" dose chemotherapy which often leads to slower clonal responses. This study confirms that, even in this advanced group of patients, a rapid hematological response will translate into improved outcomes. Since most non-responders to the first 1 or 2 cycles succumb to progressive disease, prospective studies are urgently needed to design rapidly effective well tolerated regimes possibly with combination of anti-amyloid therapy. Disclosures No relevant conflicts of interest to declare.

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