Predictors of Liver Response in Light Chain (AL) Amyloidosis: A Study with 130 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 >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 <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 <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 <60 years at diagnosis (HR=1.9) to be positively associated with achieving LivR (P<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.

Gertz:Ionis/Akcea: Honoraria; Alexion: Honoraria; Dava Oncology: Honoraria; Medscape: Honoraria; Janssen: Other: personal fees; Alnylym: Honoraria; Prothena: Other: personal fees; Sanofi: Other: personal fees; Astra Zeneca: Honoraria; Johnson & Johnson: Other: personal fees; Abbvie: Other: personal fees for Data Safety Monitoring board . Dispenzieri:Pfizer: Research Funding; HaemaloiX: Research Funding; Janssen: Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Alnylam: Research Funding; Alexion: Consultancy, Research Funding. Kapoor:X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Ichnos: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Angitia Bio: Membership on an entity's Board of Directors or advisory committees; CVS Caremark: Consultancy; Keosys: Consultancy. Kourelis:Pfizer: Research Funding; Novartis: Research Funding. Leung:AbbVie: Current holder of stock options in a privately-held company; Checkpoint Therapeutics: Current holder of stock options in a privately-held company. Dingli:MSD: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Genentech: Consultancy; Regeneron: Consultancy, Honoraria; K36 Therapeutics: Research Funding; Sorrento: Consultancy, Honoraria; Apellis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Alexion: Consultancy, Honoraria. Cook:Geron Corp: Other: Held $600 Geron Stock for one week and sold without profit . Kumar:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune/AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche: Research Funding; Oncopeptides: Other: Independent review committee participation; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Muchtar:Protego: Consultancy.