TY - JOUR
T1 - New Validated Staging System for Light Chain (AL) Amyloidosis With Stage IIIC Defining Ultra-Poor Risk
T2 - AL International Staging System
AU - Khwaja, Jahanzaib
AU - Kirkwood, Amy A
AU - Milani, Paolo
AU - Yohannan, Binoy
AU - Theodorakakou, Foteini
AU - Weverling, Flores
AU - Di Simone, Valeria
AU - Ravichandran, Sriram
AU - Kumar, Shaji
AU - Petropoulos, Ioannis
AU - Mussinelli, Roberta
AU - Cohen, Oliver
AU - Oerlemans, Marish Ifj
AU - Muchtar, Eli
AU - Stamatelopoulos, Kimon
AU - Lachmann, Helen J
AU - Gillmore, Julian D
AU - Briasoulis, Alexandros
AU - Gertz, Morie
AU - Whelan, Carol
AU - Venneri, Lucia
AU - Fontana, Marianna
AU - Mahmood, Shameem
AU - Schwotzer, Rahel
AU - Minnema, Monique C
AU - Dispenzieri, Angela
AU - Palladini, Giovanni
AU - Kastritis, Efstathios
AU - Wechalekar, Ashutosh
N1 - Publisher Copyright:
© 2025 American Society of Clinical Oncology
PY - 2026/2
Y1 - 2026/2
N2 - PURPOSE – Outcomes in systemic light chain (AL) amyloidosis have improved with modern therapy limiting utility of existing risk stratification models. We validate a new staging system, incorporating longitudinal strain (LS) to the biomarker-based (NT-proBNP and Troponin-T) staging system in the contemporary treatment era (2015-2024).METHODS – AL International Staging System (AL-ISS) was derived from a cohort of patients with AL amyloidosis from the UK National Amyloidosis Centre (2015-2019). The model was validated in patient cohorts from Europe (Greece, Italy, the Netherlands, and Switzerland), the United States (2015-2024), and the United Kingdom (2020-2024).RESULTS – In total, 2, 493 patients were included (derivation, n = 573; validation n = 1, 920). In a multivariable model for the derivation cohort, LS ≥ –9% and cardiac biomarkers at previously validated thresholds (NT-proBNP 332 ng/L and 8, 500 ng/L and high-sensitivity troponin T ≥ 50 ng/L) were independent poor prognostic factors stratifying patients into stages I, II, IIIA, IIIB, and IIIC. In the validation cohort, the patient stages were stage I: 317 (17%), II: 782 (41%), IIIA: 551 (29%), IIIB: 174 (9%), and IIIC: 96 (5%), respectively (first-line daratumumab treated: 826; 43%). With a median follow-up of 34 months, median overall survival (OS) was not reached (NR); estimated 1-year, 2-year, and 3-year OS was 82%, 74%, and 70% respectively. The median survival for stages I to II, IIIA, IIIB, and IIIC were NR, 67, 26, and 7 months (1-year OS IIIC 53% v 68% for IIIB in the daratumumab-treated patients), respectively (P < .001). External validation exhibited good predictive performance: 12-month calibration slope was 1.09, Harrell C 0.69, Royston D 1.19, and R2D 0.25. Stage IIIC independently discriminated the poorest outcome across all cohorts.CONCLUSION – This defines and validates a new staging system from systemic AL amyloidosis with robust identification of an ultra-poor risk stage (IIIC) in contemporarily treated patients.
AB - PURPOSE – Outcomes in systemic light chain (AL) amyloidosis have improved with modern therapy limiting utility of existing risk stratification models. We validate a new staging system, incorporating longitudinal strain (LS) to the biomarker-based (NT-proBNP and Troponin-T) staging system in the contemporary treatment era (2015-2024).METHODS – AL International Staging System (AL-ISS) was derived from a cohort of patients with AL amyloidosis from the UK National Amyloidosis Centre (2015-2019). The model was validated in patient cohorts from Europe (Greece, Italy, the Netherlands, and Switzerland), the United States (2015-2024), and the United Kingdom (2020-2024).RESULTS – In total, 2, 493 patients were included (derivation, n = 573; validation n = 1, 920). In a multivariable model for the derivation cohort, LS ≥ –9% and cardiac biomarkers at previously validated thresholds (NT-proBNP 332 ng/L and 8, 500 ng/L and high-sensitivity troponin T ≥ 50 ng/L) were independent poor prognostic factors stratifying patients into stages I, II, IIIA, IIIB, and IIIC. In the validation cohort, the patient stages were stage I: 317 (17%), II: 782 (41%), IIIA: 551 (29%), IIIB: 174 (9%), and IIIC: 96 (5%), respectively (first-line daratumumab treated: 826; 43%). With a median follow-up of 34 months, median overall survival (OS) was not reached (NR); estimated 1-year, 2-year, and 3-year OS was 82%, 74%, and 70% respectively. The median survival for stages I to II, IIIA, IIIB, and IIIC were NR, 67, 26, and 7 months (1-year OS IIIC 53% v 68% for IIIB in the daratumumab-treated patients), respectively (P < .001). External validation exhibited good predictive performance: 12-month calibration slope was 1.09, Harrell C 0.69, Royston D 1.19, and R2D 0.25. Stage IIIC independently discriminated the poorest outcome across all cohorts.CONCLUSION – This defines and validates a new staging system from systemic AL amyloidosis with robust identification of an ultra-poor risk stage (IIIC) in contemporarily treated patients.
UR - https://www.scopus.com/pages/publications/105027382111
U2 - 10.1200/JCO-25-02558
DO - 10.1200/JCO-25-02558
M3 - Article
C2 - 41353737
SN - 0732-183X
VL - 44
SP - 311
EP - 320
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
ER -