Highlight
• The AL International Staging System (AL-ISS) combines standard cardiac biomarkers (NT-proBNP, high-sensitivity troponin T) with left ventricular longitudinal strain (LS) and classifies patients into five prognostic stages (I, II, IIIA, IIIB, IIIC).
• AL-ISS identifies a reproducible ultra‑poor‑risk group (Stage IIIC) with median overall survival ~7 months and markedly worse outcomes even in patients treated with contemporary regimens including daratumumab.
• The model was derived in a UK cohort (2015–2019) and externally validated across multicenter European, US and UK cohorts (2015–2024), showing acceptable calibration and discrimination (Harrell’s C 0.69).
Background
Systemic immunoglobulin light-chain (AL) amyloidosis is a proteotoxic plasma cell disorder in which misfolded light chains deposit in organs, most critically the myocardium. Cardiac involvement is the main determinant of prognosis, and early, accurate risk stratification remains essential to guide treatment intensity, candidacy for autologous stem cell transplantation, timing of cardiac support measures, and enrollment in clinical trials.
Existing biomarker-based staging systems—most notably the Mayo Clinic staging schemas developed in the early 2000s and revised in 2012—use cardiac biomarkers (troponin and NT-proBNP) and, in revised models, serum free light-chain metrics (difference between involved and uninvolved FLC, dFLC). Those systems retain clinical utility but were derived before wide adoption of modern plasma cell therapies (including proteasome inhibitors and anti-CD38 monoclonal antibodies such as daratumumab) and do not incorporate sensitive echocardiographic markers of myocardial dysfunction such as longitudinal strain (LS). Echocardiographic global longitudinal strain correlates with myocardial amyloid burden and provides incremental prognostic information over biomarkers alone.
Study design
This study by Khwaja and colleagues (J Clin Oncol 2025) reports derivation and external validation of the AL International Staging System (AL-ISS). Key features:
- Derivation cohort: 573 patients from the UK National Amyloidosis Centre (2015–2019).
- Validation cohorts: 1,920 patients from multiple centers in Europe (Greece, Italy, Netherlands, Switzerland), United States (2015–2024), and the UK (2020–2024).
- Predictors considered: cardiac biomarkers using validated thresholds (NT-proBNP at 332 ng/L and 8,500 ng/L; high-sensitivity troponin T >50 ng/L) and echocardiographic longitudinal strain (LS) with a cutoff at ≥−9% (less negative values indicate worse strain).
- Endpoints: Overall survival (OS) with median follow-up of 34 months in the validation cohort; model performance assessed by calibration slope, Harrell’s C index, Royston’s D and R2D.
Key findings
Model derivation and variables
In multivariable modelling of the derivation cohort, LS ≥−9% (meaning worse/less negative strain) and established cardiac biomarker thresholds were independent predictors of poor outcome. These variables were integrated to define five stages:
- Stage I
- Stage II
- Stage IIIA
- Stage IIIB
- Stage IIIC (ultra‑poor risk)
Validation cohort distribution and survival outcomes
Among 1,920 validation patients, stage distribution was: I 17% (n=317), II 41% (n=782), IIIA 29% (n=551), IIIB 9% (n=174), IIIC 5% (n=96). First-line daratumumab-containing therapy was used in 826 patients (43%).
With median follow-up of 34 months, overall median survival for the cohort was not reached; estimated OS at 1, 2 and 3 years was 82%, 74% and 70% respectively. When stratified by AL-ISS stage, median OS was:
- Stages I–II: not reached
- Stage IIIA: 67 months
- Stage IIIB: 26 months
- Stage IIIC: 7 months
This gradient was statistically significant (p < 0.001). Even within the subset receiving first-line daratumumab, Stage IIIC carried a markedly worse prognosis (1‑year OS 53% for IIIC vs 68% for IIIB), indicating that the ultra‑poor risk designation identifies patients at high immediate mortality risk despite contemporary therapy.
Model performance
External validation demonstrated reasonable predictive performance: 12‑month calibration slope 1.09 (close to ideal 1.0), Harrell’s C = 0.69 (moderate discrimination), Royston’s D = 1.19, and R2D = 0.25. Across diverse cohorts the model reproducibly identified Stage IIIC as the group with the poorest outcomes.
Clinical and practical implications
- Incorporating LS improves risk stratification by combining a sensitive imaging marker of myocardial dysfunction with established biomarkers; LS captures structural and functional myocardial compromise that may not be fully reflected by natriuretic peptide elevation alone.
- Identification of a discrete Stage IIIC group facilitates clinical decision-making: patients in this category have a very high short‑term mortality risk and should be prioritized for rapid therapeutic intervention, intensive monitoring, consideration of non‑standard supportive measures, early goals-of-care discussions, and urgent trial referral where appropriate.
- For multidisciplinary teams, the AL-ISS provides a reproducible framework to triage patients for escalation (e.g., combination therapies, urgent hematology–cardiology collaboration) or palliative strategies when appropriate.
Expert commentary and context
The AL-ISS is an important advance because it recognizes the value of modern echocardiographic indices alongside biomarkers in a therapeutic era transformed by daratumumab and other targeted therapies. Historically, biomarker-based Mayo systems have been central to risk stratification; the 2012 revised Mayo staging incorporated cardiac biomarkers and light-chain burden and remains widely used. However, the changing therapeutic landscape has prompted re-evaluation of prognostic models to ensure ongoing clinical relevance.
Several practical points deserve emphasis:
- Longitudinal strain measurement requires standardized acquisition and analysis. Inter‑vendor and inter‑observer variability can influence absolute LS values. The cutoff of −9% is pragmatic but should be applied with awareness of local strain measurement conventions and quality control.
- NT‑proBNP and high‑sensitivity troponin assays have assay-specific thresholds and may vary between laboratories; using the specified thresholds from the AL-ISS derivation/validation cohorts preserves fidelity.
- Stage IIIC identifies patients at extreme short‑term risk; for such patients, the therapeutic goal may shift from curative-intent aggressive cytoreduction alone to combined strategies that include urgent organ support, early palliative care involvement, or evaluation for advanced cardiac therapies (in selected candidates) and clinical trials of novel agents designed for high‑risk disease.
Limitations
Caveats include the observational derivation and validation design, which is inherently susceptible to selection bias and heterogeneity in imaging protocol, treatment patterns, and supportive care across centers. Although the external validation is reassuring, prospective implementation studies would clarify how use of AL-ISS changes management and outcomes. The model does not explicitly include serum free light-chain metrics (dFLC) in the published description; whether adding dFLC would further refine prediction remains an open question. Finally, LS requires adequate echocardiographic windows and may be unavailable in a minority of patients.
Conclusion
The AL International Staging System (AL-ISS) is a validated, contemporary prognostic tool for systemic AL amyloidosis that integrates cardiac biomarkers with echocardiographic longitudinal strain. Its principal advance is robust identification of an ultra‑poor‑risk Stage IIIC group with median survival of approximately 7 months despite modern therapies. AL-ISS should help clinicians triage patients, inform therapeutic urgency, and select candidates for trials or advanced supportive care. Prospective studies and standardized strain protocols will help optimize implementation and assess whether early, stage-directed changes in management can improve outcomes for the highest-risk patients.
Funding and clinical trials
The primary study reported was supported by the contributing institutions; funding statements and trial registrations are provided in the original publication (Khwaja et al., J Clin Oncol 2025). Clinicians should consult trial registries (e.g., clinicaltrials.gov) for contemporary trials enrolling high‑risk AL amyloidosis patients, particularly those testing novel agents or combination regimens for refractory or advanced cardiac involvement.
References
1. Khwaja J, Kirkwood AA, Milani P, et al. A new validated staging system for AL amyloidosis with Stage IIIC defining ultra‑poor risk: AL International Staging System (AL-ISS). J Clin Oncol. 2025 Dec 7:101200JCO2502558. doi: 10.1200/JCO-25-02558 IF: 41.9 Q1 . PMID: 41353737 IF: 41.9 Q1 .
2. Kumar S, Dispenzieri A, Lacy M, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30(9):989–995. doi:10.1200/JCO.2011.37.8506 .
3. Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet. 2013;381(9862):1984–1995. doi:10.1016/S0140-6736(13)60622-8 .