Caplacizumab Therapy in Immune Thrombotic Thrombocytopenic Purpura
Authors: Réti Marienn , Sinkovits György , Várkonyi Andrea , Király Ágnes , Farkas Zita , Bogsch Luca , Icleanu Andreea-Adela , Masszi Tamás , Vályi-Nagy István , Prohászka Zoltán , Reményi Péter Pál 
Published: December 2023

Introduction: Plasma exchange (PEX) plus immunosuppression (ISU) became the standard of care (SOC) in the immune thrombotic thrombocytopenic purpura (iTTP), which turned the fatal disease into a curable one in &gt;80% of cases. Direct blocking of microvascular thrombosis by a novel anti-von Willebrand factor therapy, caplacizumab (CAPLA), improved clinical outcomes. However, the newest data showed that CAPLA prolongs the ADAMTS13 (AD13) normalisation time; the reason is not yet apparent.
Design and methods: From 2017 till July 2023, 51 acute episodes of 45 iTTP patients (pts) were treated in our Department. Four pts were transferred to their local hospitals in haematologic remission (HR); one patient died within one day. These 5 cases were excluded.
37/46 pts received SOC (daily PEXs + high dose corticosteroid + rituximab and/or other ISU) therapy only: 19/37 treatments were due to the first acute episode (FEP) and 18/37 because of relapse (REL). CAPLA was added to SOC in 9/46 cases (FEP:6 and REL:3). Small dose rituximab was given to two-thirds of pts, tipically at 4x100 mg. CAPLA was started on the median day 3 (range: 1-10). AD13 markers were regularly checked. We compared the outcome of SOC-ONLY and CAPLA therapy.
Results: The first clinical response was fast and similar in all groups: HR was achieved, and PEX could be stopped after a median of 6 PEXs (range: 3-20) in SOC-ONLY-FEP pts; after a median of 5 PEXs (range: 2-15) in SOC-ONLY-REL pts; and after a median of 5 PEXs (range: 3-11) in CAPLA pts. However, this HR was durable only in the CAPLA pts; further series of PEXs had to be started for half of SOC-ONLY pts on the median post-PEX day 5 (range: 2-15) due to early exacerbations (EX). SOC-ONLY-FEP pts needed a median of 12 PEXs (range: 3-21) in total, and SOC-ONLY-REL pts required a median of 7 PEXs (range: 3-20) in total for complete remission (CR). There was no EX needing further PEXs in the CAPLA group. We noticed a pronounced anti-AD13 antibody (AD13ab) rebound in all groups after the initial PEX series were stopped, approaching or exceeding the initial value, especially in the CAPLA pts (post-PEX/pre-PEX AD13ab level ratio: median 1,02, range:0,85-1,56). Further PEXs effectively decreased the AD13ab level in most SOC-ONLY pts with EXs. Pts without clinical EX did not receive further PEXs; instead, ISU was optimised. The pre-PEX AD13 activity was deficient in all cases. Partial AD13 remission (AD13 activity &gt;20%) occurred significantly faster in SOC-ONLY (median day: 16, range: 4-88) than in CAPLA (median day: 27, range: 18-89) pts. 95% of SOC-ONLY pts and 86% of CAPLA pts achieved AD13 CR (AD13 activity &gt;67%) during similar periods (SOC-ONLY median day: 41, range: 8-1077; CAPLA median day: 51, range: 39-126). The treatment of two CAPLA pts is still ongoing. One patient (who was excluded due to death &lt;1 day) died (2,4%) only. There were six late relapses (15%), all in the SOC-ONLY group; however, the length of follow-up is extremely different (SOC-ONLY median 3,45 years, range: 0,28-6,05; CAPLA median 0,55 years, range: 0,05-2,20).
Conclusion: Adding CAPLA to the SOC therapy significantly decreased the number of PEXs needed for CR and effectively prevented early exacerbations requiring PEX restarting. However, CAPLA prolonged the time till partial AD13 remission but not for AD13 CR. The reduced number of PEXs due to the prevented EXs in the CAPLA group may play a role in the early prolongation of AD13 normalisation.