Complete responses in AL amyloidosis are unequal: the impact of free light chain mass spectrometry in AL amyloidosis.

ABSTRACT: Amyloidogenic serum free light chains (sFLCs) drive disease progression in AL amyloidosis. Matrix-assisted laser desorption/ionization time of flight mass spectrometry-based FLC assay (FLC-MS) has greater sensitivity than conventional sFLC assays allowing for the detection of serological residual disease. We report the utility of FLC-MS in a large series of patients with AL amyloidosis assessing the impact of FLC-MS negativity after treatment on overall survival (OS) and organ response rates. Serum samples were analyzed using FLC-MS at diagnosis and at 6 and 12 months after treatment. The impact of FLC-MS negativity over standard hematologic responses on survival and organ response was assessed. A total of 487 patients were included; 290 (59%) and 349 (71.5%) had cardiac and renal involvement, respectively. There was 100% concordance between the light chain (LC) fibril type and LC isotype identified by FLC-MS. At 6 and 12 months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional hematologic complete response (CR) at 6 and 12 months, 45 (27.7%) and 64 (39%) were FLC-MS negative. At 12 months, median OS for CR + FLC-MS negative was not reached vs 108 months in CR + FLC-MS positive (P = .024). At 12 months, 70% of patients with FLC-MS negativity (vs 50% FLC-MS positive) achieved a cardiac response (P = .015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional hematologic CR. FLC-MS assessment promises to be a new standard for response assessment in AL amyloidosis.

Response rates to second-line treatment with daratumumab bortezomib dexamethasone (DVD) in relapsed/refractory light chain amyloidosis (AL) after initial Bortezomib-based regime.

Bortezomib is regularly used as frontline therapy for systemic AL amyloidosis. We assess the efficacy of second-line daratumumab-bortezomib-dexamethasone (DVD) in AL amyloidosis in bortezomib-exposed patients. A total of 116 patients treated with second-line DVD were identified from a prospective observational study of newly diagnosed AL amyloidosis (ALchemy). DVD was initiated in both the relapsed setting or where there was an inadequate response defined as very good partial response (VGPR) or VGPR with organ progression/lack of organ improvement. A complete response (CR)/VGPR to second-line DVD was achieved in 81 (69.8%) patients. A CR/VGPR was achieved in 67 (79.7%) in those who achieved a VGPR/CR to first line versus 14/32 (43.8%) in those who did not. Where DVD was initiated due to an inadequate response to first line (vs. at relapse), the median event-free survival (EFS) was 18 vs. 34 months (p = 0.002). If a CR/VGPR was achieved to DVD, the 2-year EFS was still lower in those with prior inadequate response 54% vs. 66% (p = 0.062). DVD is an efficacious second-line treatment in systemic AL amyloidosis in a bortezomib-exposed population. However, the response to DVD is poorer in those with an inadequate response to first-line bortezomib.

Linking changes in quality of life to haematologic response and survival in systemic immunoglobulin light-chain amyloidosis.

This study reports health-related quality of life (HRQL) among newly-diagnosed immunoglobulin light-chain (AL) patients (n = 914) treated with a bortezomib-based regimen and its association with response depth and survival. Haematologic response/HRQL were assessed over 24 months in an ongoing, prospective study. HRQL change was calculated across haematologic/cardiac response levels. The relationship between baseline HRQL and survival was evaluated by the Cox proportional-hazard model (PH). Shared-random-effects models (SREMs) estimated time-to-death conditional on current HRQL/longitudinal HRQL trajectory. At 3 months, there was consistent decline in 5/8 HRQL domains across all haematologic response levels. By 12 months, 3/5 declining domains improved among complete response (CR) patients. In contrast, the mean change in less-than-CR patients did not indicate improvement. Under the Cox PH, having a baseline HRQL score five points higher than the sample mean was associated with 20% lower mortality risk. SREMs indicated a five-point greater HRQL score at the event time correlated with an approximately 30% decrease in mortality risk. For each one-point increase in HRQL score trajectory slope, mortality risk decreased by approximately 88%. Only CR patients had HRQL improvement, while partial response patients had less decline but no meaningful improvements. These data show the importance of HRQL serial assessments of AL patients and its importance as an end-point.

Characteristics and natural history of early-stage cardiac transthyretin amyloidosis.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural history of early-stage ATTR-CM remains poorly characterized. METHODS AND RESULTS: A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of <0.75 mg/kg and an NT-proBNP ≤500 ng/L or ≤1000 ng/L in the presence of atrial fibrillation, and NAC ATTR Stage Ib comprising all remaining Stage I patients. Median estimated survival among the 88% NAC ATTR Stage Ib patients was 75 (95% CI 57-93) months compared with >100 months in the 12% with Stage Ia disease [hazard ratio for death 5.06 (95% confidence interval 1.23-20.87); P = 0.025] despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297). CONCLUSION: Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.

Longitudinal strain is an independent predictor of survival and response to therapy in patients with systemic AL amyloidosis.

AIMS: Cardiac involvement, a major determinant of prognosis in AL (light-chain immunoglobulin) amyloidosis, is characterized by an impairment of longitudinal strain (LS%). We sought to evaluate the utility of LS% in a prospectively observed series of patients. METHODS AND RESULTS: A total of 915 serial newly diagnosed AL patients with comprehensive baseline assessments, inclusive of echocardiography, were included. A total of 628/915 (68.6%) patients had cardiac involvement. The LS% worsened with advancing cardiac stage with mean -21.1%, -17.1%, -12.9%, and -12.1% for stages I, II, IIIa, and IIIb, respectively (P < 0.0001). There was a highly significant worsening of overall survival (OS) with worsening LS% quartile: LS% ≤-16.2%: 80 months, -16.1% to -12.2%: 36 [95% confidence interval (CI) 20.9-51.1] months, -12.1% to -9.1%: 22 (95% CI 9.1-34.9) months, and ≥-9.0%: 5 (95% CI 3.2-6.8) months (P < 0.0001). Improvement in LS% was seen at 12 months in patients achieving a haematological complete response (CR) (median improvement from -13.8% to -14.9% in those with CR and difference between involved and uninvolved light chain <10 mg/L). Strain improvement was associated with improved OS (median not reached at 53 months vs. 72 months in patients without strain improvement, P = 0.007). Patients achieving an LS% improvement and a standard N-terminal pro-brain natriuretic peptide-based cardiac response survived longer than those achieving a biomarker-based cardiac response alone (P < 0.0001). CONCLUSION: Baseline LS% is a functional marker that correlates with worsening cardiac involvement and is predictive of survival. Baseline LS% and an absolute improvement in LS% are useful additional measures of prognosis and response to therapy in cardiac AL amyloidosis, respectively.

Haematologic responses and survival do not significantly decrease with subsequent lines of therapy in systemic immunoglobulin light chain amyloidosis: results from an analysis of real-world longitudinal data.

Systemic immunoglobulin light chain amyloidosis (AL) is an incurable disorder, and the natural history is incompletely understood. In this study, we describe its natural history based on an analysis of real-world longitudinal data. All patients seen at the National Amyloidosis Centre, UK, between February 2010 and August 2019 and treated with up-front bortezomib are included. In all, 1 276 patients received the first-line treatment; 259, 85, and 32 patients received second, third, and fourth treatment lines, respectively. Among patients requiring further treatment after the first line, 77·2% started the second line within two years of the first line; 50·5%, 50·6%, 40·1% and 40·6% of patients had achieved at least very good partial response after the first, second, third and fourth treatment lines. Median overall survival (OS) from first, second, third and fourth lines was 45 months, 56 months, 37 months and not reached, respectively (P = 0·109). In summary, although relapses occur in AL amyloidosis, the outcomes and responses do not worsen with each subsequent relapse, making it attractive to design therapeutics with curative intent.

A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib.

Bortezomib is a standard therapy in light-chain amyloidosis (AL), but little is known about response duration. A difference in involved amyloidogenic and uninvolved serum-free light chains (dFLC) < 10 mg/L (low dFLC response) predicts survival in AL patients with low presenting dFLC (20-50 mg/L). We report outcomes in the largest AL cohort treated with upfront bortezomib and explore the impact of posttreatment dFLC < 10 mg/L ("stringent dFLC response"). A total of 915 newly diagnosed AL patients treated with bortezomib and assessed at our center were included. Hematologic responses, 6-month dFLC, organ responses, overall survival (OS), and time-to-next-treatment (TNT) (excluded patients who died without starting second-line treatment) were evaluated. Overall response rate (intent-to-treat) was 65%, with 49% complete response (CR)/very good partial response/low dFLC response and with a stringent dFLC response, dFLC 10-40 mg/L, and dFLC > 40 mg/L was 30%, 22%, and 48%, respectively. Median OS was 72 months. A total of 289 patients died without progressing to second-line treatment. Median TNT was not reached, and 55% had not progressed to further treatment at 7 years. Patients with stringent dFLC responses had significantly better OS and TNT than did those with lesser responses. A total of 72% of CR patients did not progress to further treatment at 3 years compared with 84% with stringent dFLC responses. Cardiac responses were better in those with stringent dFLC responses (61%) compared with lesser responses (45%; P = .005). Upfront bortezomib confers durable hematologic responses. A stringent dFLC response predicts prolonged TNT and impressive organ responses.

Challenges of antithrombotic therapy in the management of cardiovascular disease in patients with inherited bleeding disorders: A single-centre experience.

INTRODUCTION: Cardiovascular events in patients with inherited bleeding disorders are challenging to manage. The risk of bleeding secondary to antithrombotic treatment must be balanced against the risk of thrombosis secondary to haemostatic therapy. METHODS: Patients with inherited bleeding disorders with coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI) or atrial fibrillation (AF) from a single centre (2010-2018) are included. RESULTS: A total of 11 patients undergoing CABG (n = 3), PCI (n = 5) or with AF (n = 3) and a diagnosis of haemophilia A (n = 8), haemophilia B (n = 1), factor XI deficiency (n = 1) and von Willebrand disease (n = 1) managed by a multidisciplinary team are reported. In patients undergoing CABG, factor levels were normalized for 7-10 days with trough levels of 70-80% with severe patients continuing high-dose factor prophylaxis (trough 20-30%) three weeks post-operatively with daily aspirin. In a patient with mild haemophilia A and an inhibitor, recombinant factor VIIa dosing was monitored with thromboelastometry. For PCI, a 3rd-generation drug-eluting stent with one month of dual antiplatelet therapy in addition to high-dose prophylaxis as needed was preferred. Patients with AF and severe haemophilia did not receive antithrombotic treatment, and a thrombin generation assay was used to guide heparin dosing in mild haemophilia. CONCLUSION: Our experience demonstrates the importance of interdisciplinary communication to identify strategies that decrease the risk of bleeding and thrombosis. The use of extended, increased intensity prophylaxis facilitated antiplatelet therapy. Global assays may help balance the intensity of haemostatic and antithrombotic treatment.

Renal transplant outcomes in amyloidosis.

BACKGROUND: Outcomes after renal transplantation have traditionally been poor in systemic amyloid A (AA) amyloidosis and systemic light chain (AL) amyloidosis, with high mortality and frequent recurrent disease. We sought to compare outcomes with matched transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy (DN), and identify factors predictive of outcomes. METHODS: We performed a retrospective cohort study of 51 systemic AL and 48 systemic AA amyloidosis patients undergoing renal transplantation. Matched groups were generated by propensity score matching. Patient and death-censored allograft survival were compared via Kaplan-Meier survival analyses, and assessment of clinicopathological features predicting outcomes via Cox proportional hazard analyses. RESULTS: One-, 5- and 10-year death-censored unadjusted graft survival was, respectively, 94, 91 and 78% for AA amyloidosis, and 98, 93 and 93% for AL amyloidosis; median patient survival was 13.1 and 7.9 years, respectively. Patient survival in AL and AA amyloidosis was comparable to DN, but poorer than ADPKD [hazard ratio (HR) = 3.12 and 3.09, respectively; P < 0.001]. Death-censored allograft survival was comparable between all groups. In AL amyloidosis, mortality was predicted by interventricular septum at end diastole (IVSd) thickness >12 mm (HR = 26.58; P = 0.03), while survival was predicted by haematologic response (very good partial or complete response; HR = 0.07; P = 0.018). In AA amyloidosis, recurrent amyloid was associated with elevated serum amyloid A concentration but not with outcomes. CONCLUSIONS: Renal transplantation outcomes for selected patients with AA and AL amyloidosis are comparable to those with DN. In AL amyloidosis, IVSd thickness and achievement of deep haematologic response pre-transplant profoundly impact patient survival.

Lymph node core biopsies reliably permit diagnosis of lymphoproliferative diseases. Real-World Experience from 554 sequential core biopsies from a single centre.

INTRODUCTION: Whilst excision biopsy is traditionally preferred, advances in radiological and histological techniques warrant a re-look at core biopsy as a viable primary diagnostic method. METHOD: Over a 3-year period, all patients who underwent core biopsy to investigate lymphoma at our centre were included. RESULTS: 554 consecutive patients were included (40.1% prior lymphoma and 59.4% new presentations). Three or more cores were taken in 420 (75.8%) cases. Median time from request to biopsy and biopsy to histology report was 2 (0-40) days and 7 (1-24) days, respectively. 510/544 (93.8%) biopsies were diagnostic. There was no difference in whether the biopsy was diagnostic based on indication (new vs. relapsed lymphoma) (P = .445), whether biopsy was PET-directed (P = .507), for T-cell lymphoma (P = .468) or nodal vs. extra-nodal (P = .693). Thirty-eight patients (6.9%) required a second biopsy due to inadequate tissue. In a patient experience survey, only 13.9% reported any complications (1 self-limiting minor bleeding, 4 bruising) whilst 16.7% reported any discomfort beyond 12 hours. CONCLUSION: Core biopsy performed by experienced radiologists and analysed by expert haemato-pathologists is a reliable, well-tolerated method for diagnosing lymphoma and confirming relapse. Multiple cores can be obtained under local anaesthetic yielding sufficient material in the majority of cases.

Autologous stem cell transplantation vs bortezomib based chemotheraphy for the first-line treatment of systemic light chain amyloidosis in the UK.

OBJECTIVES: The benefit of autologous stem cell transplantation (ASCT) in the treatment of light chain (AL) amyloidosis requires re-evaluation in the modern era. This retrospective case-matched study compares ASCT to bortezomib for the treatment of patients with AL amyloidosis. METHODS: Newly diagnosed patients with AL amyloidosis treated with ASCT or bortezomib between 2001 and 2018 were identified. Patients were excluded if the time from diagnosis to treatment exceeded 12 months. Patients were matched on a 1:1 basis, using a propensity-matched scoring approach. RESULTS: A total of 136 propensity score-matched patients were included (ASCT n = 68, bortezomib n = 68). There was no significant difference in overall survival at two years (P = .908, HR: 0.95, CI: 0.41-2.20). For ASCT vs bortezomib: overall haematological response rate at 6 months was 90.6% vs 92.5%; organ response at 12 months: cardiac (70.0% vs 54%, P > .999), renal (74% vs 24%, P = .463) liver (21% vs 22%, P = .048); median progression-free survival (50 vs 42 months P = .058, HR: 0.61, CI: 0.37-1.02) and time to next treatment (68 vs 45 months, P = .145, HR: 0.61, CI: 0.31-1.19). More patients required treatment in the bortezomib group compared to ASCT group at 24 months (41 vs 23, Chi-squared P = .004) and 48 months (57 vs 41, Chi-squared P = .004). CONCLUSIONS: This small retrospective study suggests that there is no clear survival advantage of ASCT over bortezomib therapy. A prospective randomised controlled trial evaluating ASCT in AL amyloidosis is critically needed.

Use of ixazomib, lenalidomide and dexamethasone in patients with relapsed amyloid light-chain amyloidosis.

With improving outcomes in amyloid light-chain (AL) amyloidosis, there is a need to study novel agents in this setting. We report outcomes of 40 patients with relapsed AL amyloidosis treated with ixazomib + lenalidomide + dexamethasone (IRd). Haematological responses were assessed on an intention-to-treat basis at three months: complete response (CR) - 8 (20·5%), very good partial response (VGPR) - 8 (20·5%), partial response (PR) - 7 (17·9%) and no response (NR) - 16 (41·0%). One patient had missing data. Six patients subsequently improved response. Best responses were: CR - 10 (25·6%), VGPR - 8 (20·5%), PR - 7 (17·9%), NR - 14 (35·9%). Cardiac and renal organ responses occurred in 5·6% and 13·3% respectively. Median progession-free survival (PFS) was 17·0 months (95% CI 7·3-20·7 months), improving to 28·8 months (95% CI 20·6-37·0 months) in those achieving CR/VGPR. Median overall survival was 29·1 months (95% CI 24-33 months). Serious adverse events were seen in 14 (35·0%) patients inclusive of 15 admissions due to: infection (6/15, 40·0%), fluid overload (5/15, 33·3%), cardiac arrhythmia (2/15, 13·3%), renal dysfunction (1/15, 6·6%) and anaemia (1/15, 6·6%). In summary, IRd is an oral treatment option with a manageable toxicity profile leading to deep responses in 47% of patients with relapsed AL amyloidosis.

The value of screening biopsies in light-chain (AL) and transthyretin (ATTR) amyloidosis.

INTRODUCTION: Systemic amyloidosis is a histological diagnosis, often achieved via critical organ biopsy. Screening biopsies represent a low-risk approach to diagnosis. OBJECTIVES AND METHODS: All patients with systemic AL and ATTR amyloidosis who underwent abdominal fat aspiration (AFA) and either a bone marrow (BM) or gastrointestinal (GI) biopsy at the UK National Amyloidosis Centre (2006-2019) were identified. We sought to determine diagnostic sensitivity in relation to whole body amyloid burden, amyloid type and organ involvement. RESULTS: Diagnostic sensitivity established in 471 patients with AL (n = 321) and ATTR (n = 150) amyloidosis, respectively, was 73.2% and 27.3% for AFA (P< .001), 59.7% and 42.2% for BM (P< .001), and 74.6% and 44.6% for GI biopsy (P< .001). ATTR amyloid deposits were detected in 35.4% BMs and 33.3% of GI biopsies when AFA did not demonstrate amyloid. In AL amyloidosis, sensitivity of combined AFA and BM biopsy in AL amyloidosis was 82.9%. There was a strong association between whole body amyloid burden and sensitivity of each screening biopsy method. The diagnostic sensitivity of screening biopsies ranged from 80.0% to 90.5% for patients with a large amyloid load on 123 I-SAP scintigraphy in comparison with 53.9%-79.0% in those with no visceral amyloid visible on imaging. CONCLUSION: Performing both AFA and BM biopsy should be considered in suspected AL amyloidosis to substantially reduce the clinical risk associated with critical organ biopsy. The sensitivity of screening biopsies in ATTR amyloidosis is poor.

Graded Organ Response and Progression Criteria for Kidney Immunoglobulin Light Chain Amyloidosis.

Importance: Kidney light chain (AL) amyloidosis is associated with a risk of progression to kidney replacement therapy (KRT) and death. Several studies have shown that a greater reduction in proteinuria following successful anticlonal therapy is associated with improved outcomes. Objective: To validate graded kidney response criteria and their association with kidney and overall survival (OS). Design, Setting, and Participants: This retrospective, multicenter cohort was conducted at 10 referral centers for amyloidosis from 2010 to 2015 and included patients with kidney AL amyloidosis that was evaluable for kidney response and who achieved at least hematologic partial response within 12 months of diagnosis. The median follow-up was 69 (54-88) months. Data analysis was conducted in 2023. Exposure: Four kidney response categories based on the reduction in pretreatment 24-hour urine protein (24-hour UP) levels: complete response (kidCR, 24-hour UP ≤200 mg), very good partial response (kidVGPR, >60% reduction in 24-hour UP), partial response (kidPR, 31%-60% reduction), and no response (kidNR, ≤30% reduction). Kidney response was assessed at landmark points (6, 12, and 24 months) and best kidney response. Main Outcomes and Measures: Cumulative incidence of progression to KRT and OS. Results: Seven-hundred and thirty-two patients (335 women [45.8%]) were included, with a median (IQR) age of 63 (55-69) years. The median (IQR) baseline 24-hour proteinuria and estimated glomerular filtration rate was 5.3 (2.8-8.5) g per 24 hours and 72 (48-92) mL/min/1.73m2, respectively. In a competing-risk analysis, the 5-year cumulative incidence rates of progression to KRT decreased with deeper kidney responses as early as 6 months from therapy initiation (11%, 12%, 2.1%, and 0% for kidNR, kidPR, kidVGPR, and kidCR, respectively; P = .002) and were maintained at 12 months and 24 months and best kidney response. Patients able to achieve kidCR/kidVGPR by 24 months and at best response had significantly better OS compared with kidPR/kidNR. Kidney progression, defined as a 25% or greater decrease in estimated glomerular filtration rate, was associated with cumulative incidence of progression to KRT and OS. Conclusions and Relevance: The results of this cohort study suggest that graded kidney response criteria offers clinically and prognostically meaningful information for treating patients with kidney AL amyloidosis. The response criteria potentially inform kidney survival based on the depth of reduction in 24-hour proteinuria levels and demonstrate an OS advantage for those able to achieve kidCR/kidVGPR compared with kidPR/kidNR. Taken together, achievement of at least kidVGPR by 12 months is needed to ultimately improve kidney and patient survival.

Redefining Cardiac Involvement and Targets of Treatment in Systemic Immunoglobulin AL Amyloidosis.

Importance: Cardiac amyloid infiltration is the key determinant of survival in systemic light-chain (AL) amyloidosis. Current guidelines recommend early switching therapy in patients with a nonoptimal or suboptimal response regardless of the extent of cardiac amyloid infiltration. Objective: To assess the differences between serum biomarkers, echocardiography, and cardiovascular magnetic resonance (CMR) with extracellular volume (ECV) mapping in characterizing cardiac amyloid, the independent prognostic role of these approaches, and the role of ECV mapping to guide treatment strategies. Design, Setting, and Participants: Consecutive patients newly diagnosed with systemic AL amyloidosis (2015-2021) underwent echocardiography, cardiac biomarkers, and CMR with ECV mapping at diagnosis. Data were analyzed from January to June 2024. Main Outcomes and Measures: The primary outcomes of the study were all-cause mortality and hematological response as defined according to validated criteria: no response (NR), partial response (PR), very good partial response (VGPR), and complete response (CR). Secondary outcomes were the depth and speed of hematological response and overall survival according to ECV. Results: Of 560 patients with AL amyloidosis, the median (IQR) age was 68 years (59-74 years); 346 patients were male (61.8%) and 214 female (38.2%). Over a median (IQR) 40.5 months 9-58 months), ECV was independently associated with mortality. In the landmark analysis at 1 month, long-term survival was independent of the achieved hematological response in ECV less than 0.30% and ECV of 0.31% to 0.40%, while it was dependent on the depth of the hematological response in ECV greater than 0.40%. In the landmark analysis at 6 months, survival was independent of the achieved hematological response in ECV less than 0.30% and dependent on achieving at least PR in ECV of 0.31% to 0.40%. Survival was dependent on achieving CR in ECV of 0.41% to 0.50% and ECV greater than 0.50%. Achieving a deep hematological response at 1 month was associated with better survival compared with 6 months in patients with ECV greater than 0.40% but not with ECV less than 0.40%. Conclusions and Relevance: This study found that ECV mapping, in systemic AL amyloidosis, is an independent predictor of prognosis, can help define the hematological response associated with better long-term outcomes for each patient and potentially inform treatment strategies.

Graded Cardiac Response Criteria for Patients With Systemic Light Chain Amyloidosis.

PURPOSE: Binary cardiac response assessment using cardiac biomarkers is prognostic in light chain amyloidosis. Previous studies suggested four-level cardiac responses using N-terminal prohormone of brain natiuretic peptide improves prognostic prediction. This study was designed to validate graded cardiac response criteria using N-terminal prohormone of brain natiuretic peptide/brain natiuretic peptide. PATIENTS AND METHODS: This retrospective, multicenter study included patients with light chain amyloidosis who achieved at least a hematologic partial response (PR) and were evaluable for cardiac response. Four response criteria were tested on the basis of natriuretic peptide response depth: cardiac complete response (CarCR), cardiac very good partial response (CarVGPR), cardiac PR (CarPR), and cardiac no response (CarNR). Response was classified as best response and at fixed time points (6, 12, and 24 months from therapy initiation). The study primary outcome was overall survival. RESULTS: 651 patients were included. Best CarCR, CarVGPR, CarPR, and CarNR were achieved in 16%, 26.4%, 22.9%, and 34.7% of patients, respectively. Patients in cardiac stage II were more likely to achieve CarCR than patients in cardiac stage IIIA and IIIB (22% v 13.5% v 3.2%; P < .001). A deeper cardiac response was associated with a longer survival (5-year overall survival 93%, 79%, 65%, and 33% for CarCR, CarVGPR, CarPR, and CarNR, respectively; P < .001). Fixed time-point analyses and time-varying covariates Cox regression analysis, to minimize survivorship bias, affirmed the independent survival advantage of deeper cardiac responses. Four-level response performed better than two-level response as early as 12 months from therapy initiation. CONCLUSION: Graded cardiac response criteria allow better assessment of cardiac improvement compared with the traditional binary response system. The study re-emphasizes the importance of early diagnosis, which increases the likelihood of deep cardiac responses.

Outcomes of renal transplantation in patients with AL amyloidosis: an international collaboration through The International Kidney and Monoclonal Gammopathy Research Group.

Effective systemic therapies suppress toxic light chain production leading to an increased proportion of patients with light chain (AL) amyloidosis who survive longer albeit with end-stage renal disease. There is a critical need to identify patients in this population who benefit from renal transplantation. This multicenter, observational study from five countries includes 237 patients with AL amyloidosis who underwent renal transplantation between 1987 and 2020. With a median follow-up of 8.5 years, the median overall survival from renal transplantation was 8.6 years and was significantly longer in patients with complete and very good partial hematologic responses (CR + VGPR) compared to less than VGPR (9 versus 6.8 years; HR: 1.5, P = 0.04 [95% CI: 1-2.1]) at renal transplantation. Median graft survival was 7.8 years and was better in the CR + VGPR group (8.3 vs 5.7 years, HR: 1.4, P = 0.05 [95% CI: 1-2]). The frequency and time to amyloid recurrence in the graft was also lower (16% vs 37%, p = 0.01) and longer (median time not achieved vs 10 years, p = 0.001) in the CR + VGPR group. Comparing CR vs. VGPR there was no difference in overall or graft survival. Although 69 patients (29%) experienced hematologic relapse, treatment effectively prevented graft loss in the majority (87%). Renal transplantation in selected AL amyloidosis patients is associated with extended overall and renal graft survival. Patients with hematologic CR or VGPR have the most favorable outcomes, and these patients should be considered for renal transplantation.

Prognostic importance of the 6 min walk test in light chain (AL) amyloidosis.

OBJECTIVES: In AL amyloidosis, organ response assessment is based on surrogates (eg, cardiac biomarkers). An objective functional test, such as the 6 min walk test (6MWT), capturing overall clinical improvement, is required. We aimed to evaluate the prognostic impact of the 6MWT at baseline and change following chemotherapy. METHODS: This study evaluated the outcomes of patients who enrolled in a prospective observational study at the UK National Amyloidosis Centre (2012-2017). Patients underwent comprehensive assessments inclusive of blood testing, echocardiogram and 6MWT at baseline and annually thereafter. RESULTS: In total, 799 patients were included within the study. Median baseline 6 min walk distance (6MWD) was 362 m (IQR: 231 m). 6MWD progressively decreased with worsening cardiac disease stage (458 m, 404 m, 331 m and 168 m for cardiac Mayo stages I, II, IIIa and IIIb, respectively (p<0.0001)). In patients with a baseline 6MWT of ≥350 m, the median overall survival was not reached (vs 30.0 (95% CI 23.2 to 36.8) months if <350 m and 5.0 (95% CI 2.8 to 7.2) months if unable to attempt 6MWT (p<0.0001). Following chemotherapy, only patients in a complete haematological response improved their 6MWD by 12 months (p=0.001). Improvement in 6MWD prolonged survival in patients with cardiac amyloidosis (p=0.005). CONCLUSION: The 6MWT is prognostic in AL amyloidosis. A baseline distance of ≥350 m independently predicts better survival. These data suggest that 6MWT has utility in AL amyloidosis for baseline prognosis and assessing response.