Targeted Therapeutics for Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Deposition of wild-type or mutant transthyretin (TTR) amyloid fibrils in the myocardium causes TTR amyloid cardiomyopathy (ATTR-CM). Targeted therapeutics for ATTR-CM include TTR stabilizers (tafamidis and diflunisal) and oligonucleotide drugs (revusiran, patisiran, and inotersen). TTR stabilizers prevent dissociation of transthyretin tetramers. Transthyretin monomers can misfold and form amyloid fibrils. TTR stabilizers thereby limit amyloid fibrils development and deposition. Oligonucleotide drugs inhibit hepatic synthesis of transthyretin, which decreases transthyretin protein levels and thus the amyloid fibril substrate. AREAS OF UNCERTAINTY: To study the safety and efficacy of targeted therapeutics in patients with ATTR-CM, we performed a pooled analysis. A random-effects model with the Mantel-Haenszel method was used to pool the data. DATA SOURCES: A literature search was performed using PubMed, Cochrane CENTRAL, and Embase databases using the search terms "cardiac amyloidosis" AND "tafamidis" OR "patisiran" OR "inotersen" OR "revusiran" OR "diflunisal." THERAPEUTIC ADVANCES: We identified 6 studies that compared targeted therapeutics with placebo. One study was stopped prematurely because of increased mortality in the targeted therapeutics arm. Pooled analysis included 1238 patients, of which 738 patients received targeted therapeutics and 500 patients received placebo. When compared with placebo, targeted therapeutics significantly reduced all-cause mortality [OR 0.39, 95% confidence interval (CI): 0.16-0.97, P = 0.04]. Only 2 studies reported the effect on cardiovascular-related hospitalizations. There was a trend toward an improvement in global longitudinal strain (mean difference -0.69, 95% CI: -1.44 to 0.05, P = 0.07). When compared with placebo, there was no increase in serious adverse events with targeted therapeutics (OR 1.06, 95% CI: 0.78-1.44, P = 0.72). CONCLUSION: Evidence from the pooled analysis revealed targeted therapeutics improve survival and are well-tolerated. These findings suggest a potential role for targeted therapeutics in the treatment of patients with ATTR-CM.

AL amyloidosis: The effect of fluorescent in situ hybridization abnormalities on organ involvement and survival.

BACKGROUND: Systemic light chain (AL) amyloidosis is a clonal plasma-cell neoplasm that carries a poor prognosis. Although AL amyloidosis and Multiple Myeloma (MM) can co-exist and share various cytogenetic chromosomal abnormalities, little is known about Fluorescent in situ hybridization (FISH) and its prognostic relevance in AL amyloidosis. AIM: The study aims to evaluate the most prevalent FISH cytogenetic abnormalities in AL patients as independent prognostic factors, and assess the impact of cytogenetics on the survival of high-risk cardiac AL patients. MATERIALS & METHODS: This retrospective study reviewed 113 consecutive AL patients treated at The Ohio State University (OSU). Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis. Hyperdiploidy was defined as trisomies of at least 2 chromosomal loci. Primary endpoints were progression free survival (PFS) and overall survival (OS). Kaplan Meier curves were used to calculate PFS and OS. The log-rank test and Cox proportional hazard models were used to test the equality of survival functions and further evaluate the differences between groups. RESULTS: FISH abnormalities were detected in 76% of patients. Patients with abnormal FISH trended toward lower overall survival (OS) (p=0.06) and progression free survival (PFS) (p=0.06). The two most prevalent aberrations were translocation t(11;14) (39%) and hyperdiploidy-overall (38%). Hyperdiploidy-overall was associated with worsening PFS (p=0.018) and OS (p=0.03), confirmed in multivariable analysis. Patients with del 13q most frequently had cardiac involvement (p=0.006) and was associated with increased bone marrow plasmacytosis (p=0.02). Cardiac AL patients with no FISH abnormalities had much improved OS (p=0.012) and PFS (p=0.018) CONCLUSIONS: Our findings ultimately reveal the association of hyperdiploidy on survival in AL amyloidosis patients, including the high-risk cardiac AL population.

AL Amyloidosis: The Effect of Maintenance Therapy on Autologous Stem Cell Transplantation Outcomes.

BACKGROUND: Autologous stem cell transplantation (ASCT) remains an effective treatment option for many patients with systemic light chain (AL) amyloidosis. While maintenance post ASCT in multiple myeloma is now standard, the decision to utilize maintenance in AL amyloidosis remains largely unexplored. The present study aims to determine the prognostic significance of utilizing maintenance therapy following ASCT and assess the impact of fluorescent in situ hybridization (FISH) abnormalities, bone marrow plasma cell burden (BMPC), and degree of organ involvement on this decision. METHODS AND RESULTS: This is a retrospective analysis of fifty AL amyloidosis patients who underwent ASCT at The Ohio State University. Twenty-eight patients received maintenance and twenty-two did not. Kaplan-Meier survival analysis was used to compare the effect of maintenance therapy with no significant difference in PFS (p = 0.66) and OS (p = 0.32) between the two groups. There was no difference in survival based on maintenance when further categorized by FISH, PFS (p = 0.15), and OS (p = 0.65); BMPC ≥ 10%, PFS (p = 0.49), and OS (p = 0.32); or with 2 or more organs involved, PFS (p = 0.34) and OS (p = 0.80). CONCLUSION: Maintenance therapy post ASCT did not impact PFS or OS when categorized by FISH abnormalities, increasing BMPC, or ≥2 organs involved in AL amyloidosis patients.