Case Report: Inotersen reintroduction after thrombocytopenia in hereditary transthyretin amyloidosis: a case series

ATTRv amyloidosis is a progressive multisystem disease caused by pathogenic variants in the transthyretin (TTR) gene. Inotersen is approved for the treatment of polyneuropathy in adults with hereditary transthyretin mediated amyloidosis, but thrombocytopenia is a clinically relevant adverse event that may require treatment interruption or discontinuation. Evidence guiding reintroduction of inotersen after thrombocytopenia is limited.

We retrospectively reviewed two men with genetically confirmed ATTRv treated at two centers in Argentina who developed treatment-emergent thrombocytopenia during inotersen therapy. Patient 1 was a 71-year-old man with late-onset mixed neurologic and cardiac ATTRv due to TTR p.Val50Met who developed grade 2 thrombocytopenia after 22 weeks of treatment, with a platelet nadir of 58 × 10^9/L. Patient 2 was a 52-year-old man with early-stage neuropathic ATTRv due to TTR p.Val50Met who developed grade 4 thrombocytopenia after 65 weeks, with platelet counts below 20 × 10^9/L, and had recurrent thrombocytopenia during an initial reintroduction attempt.

After platelet recovery and exclusion of alternative causes of thrombocytopenia, both patients underwent a structured 7-day stepwise short-term reintroduction protocol under close hematologic monitoring. Following protocol completion, inotersen was resumed at 284 mg every 2 weeks. During follow-up, neither patient developed recurrent severe thrombocytopenia, and both maintained biochemical evidence of transthyretin suppression.

In this small case series, inotersen reintroduction after thrombocytopenia was feasible in two ATTRv patients when implemented with a structured stepwise protocol and close platelet monitoring, but these findings are hypothesis-generating and not generalizable. One reintroduction occurred outside prescribing recommendations for severe thrombocytopenia and should not be interpreted as a recommended strategy.