Yohannan, Binoy

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 R 2 D 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.

Introduction: Light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by tissue deposition of misfolded immunoglobulin light chains in the form of amyloid, leading to organ dysfunction. Halting the production of the amyloidogenic free light chains by achieving a deep hematologic response (HemR) is key to improving organ function, however, variation in organ responses exists. In this work, we investigated variables associated with liver response (LivR) in a large cohort of patients with AL amyloidosis. Methods: Retrospective study of newly diagnosed AL amyloidosis patients with liver involvement seen at Mayo Clinic within 90 days of diagnosis between January 2000 and December 2021. Patients were eligible if they (1) had liver involvement, defined as a baseline alkaline phosphatase (ALP) ≥ 1.5 x upper limit of normal (ULN) and (2) had LivR measurements at least twice annually in the first year from treatment and annually afterward. LivR was defined as a &gt;50% reduction in alkaline phosphatase (ALP) from baseline value or normalization of ALP. LivR was recorded at 6, 12, and 24 months from treatment initiation and at the best LivR achieved. Patients who died prior to landmark assessment were considered non-responders at subsequent milestone assessments. Covariates associated with LivR were identified by univariate and multivariable logistic regression analyses and a proportional subdistribution hazard (Fine-Gray) model for competing risk (treating death as a competing event). Multivariable logistic regression models for LivR were created using best subset selection, with calculation of odds ratio (OR) and 95% confidence interval (CI). Results: A total of 130 patients were included, with a median age of 60 years (IQR 53-66), male predominance (69%), and a median follow-up of 8.8 years. Sixty percent of patients had lambda isotype, the median ALP was 368 IU/mL (IQR 279-589), with 48% of patients having ALP ≥3 fold the upper limit of normal (ULN). Median bilirubin was 0.7 mg/dL (IQR 0.5-1.1). Forty-three percent of patients received front-line autologous stem cell transplant (ASCT) with or without prior induction therapy, and 5% received daratumumab-based therapy as their front-line treatment. Liver response rate increased with time, with 36 patients (28%) achieving a LivR at 6 months, 47 (36%) at 12 months, 63 (48%) at 24 months, and 94 (72%) at best response. The median time to liver response was 14 months (7.22-32.67). At the 24-month landmark, age &lt;60 years, ALP ≥3 fold ULN, and front-line ASCT were significantly associated with achieving a LivR on univariate logistic regression. On univariate logistic regression at best liver response, age &lt;60 years, ALP ≥3 fold the ULN, kappa isotype, ≥HemVGPR within 6 months, and front-line ASCT were significantly associated with obtaining a LivR. On multivariable logistic regression, at 24 months, ALP ≥3 folds of ULN (OR=2.9, 95% CI 1.4-6.3, P=0.004) was significantly associated with an increased likelihood of LivR. Achieving ≥HemVGPR and front-line ASCT were also associated with increased LivR likelihood, although not statistically significant (p=0.094, p=0.078, respectively). At best liver response, achieving ≥HemVGPR within 6 months (OR=5.2, 95% CI 1.9-14.8), kappa isotype (OR=3.2, 95% CI 1.1-10.0), ALP ≥3 folds of ULN (OR=3.3, 95% CI 1.3-9.9), and front-line ASCT (OR=5.3, 95% CI 1.9-16.7) were factors significantly associated with LivR. The Fine-Gray model demonstrated kappa isotype (HR=1.7), baseline ALP ≥3 folds of ULN (HR=2.1), ≥HemVGPR within 6 months (HR=1.9), and age &lt;60 years at diagnosis (HR=1.9) to be positively associated with achieving LivR (P&lt;0.05). Conclusions: In this large cohort of liver AL amyloidosis, LivR was achieved in 72% of patients, and amongst responders, the median time to response was 14 months from therapy initiation. Predictors of LivR included kappa isotype, deep hematological response in the first 6 months of initial therapy, ASCT usage, and higher baseline ALP levels. These findings better inform clinicians on the likelihood of achievement of liver response and may enable ways to improve its achievement.

The therapeutic landscape of the management of stage III non-small cell lung cancer (NSCLC) has drastically evolved with the incorporation of immunotherapy and targeted therapy. Stage III NSCLC accounts for one-third of the cases and the treatment strategy of these locally advanced presentations are diverse, ranging from surgical to non-surgical options; with the incorporation of chemo-immunotherapy, radiation, and targeted therapies wherever applicable. The staging of this disease has also changed, and it is essential to have a strong multidisciplinary approach to do justice to patient care. In this article, we aim to navigate the nuanced approaches in the diagnosis and treatment of stage III NSCLC and expand on the evolution of the management of this disease.