Acquired TTP: new treatments and updated guidelines

New, effective treatments have become available for patients with acquired thrombotic thrombocytopenia (aTTP). Updated guidelines include new treatment decision trees and recommendations for the monitoring of patients in remission.

Dr María Mingot-Castellano (Hospital Universitario Virgen del Rocío, Spain) reviewed some significant changes in aTTP management in the last 5 years as a result of the introduction of new drugs, guidelines, and real-world data [1]. The evolution of therapeutic strategies started in 1975 with the introduction of corticosteroids and plasma exchange, which increased survival from 10% to 78% [2]. However, ≤42% of patients are refractory to plasma exchange and immunosuppression and the risk of relapse is 30–50%. Today, treatment strategies aim to stop inhibitor production, supply ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif) and prevent thrombus formation.

To stop inhibitor production, immunomodulation is used targeting T cells (e.g. cyclosporine A, mycophenolate, azathioprine), B cells (e.g. rituximab), plasma cells (e.g. steroids, bortezomib), and/or clearance of antibodies (e.g. plasma exchange, splenectomy). Rituximab was shown to reduce relapse rate over >50 months and increased ADAMTS13 remission in a triplet regimen with corticosteroids and caplacizumab [3,4].

To replenish ADAMTS13 levels, plasma exchange or plasma infusions are used and a recombinant ADAMTS13 is currently being investigated in a phase 2 study.

Inhibition of thrombus formation or von Willebrand factor (VWF) interaction can be achieved by caplacizumab, N-acetylcysteine, and aptamers. Caplacizumab was evaluated in the phase 3 HERCULES trial (NCT02553317) and led to fewer days in hospital and intensive care unit (ICU) compared with placebo [5]. Furthermore, refractory aTTP was reduced to 0 and recurrence was significantly lower (P<0.001). A recent integrated analysis including participants from HERCULES and the phase 2 TITAN study (NCT01151423) confirmed the superior efficacy of caplacizumab [6]. Integrated safety data showed more frequent bleeding events with caplacizumab compared with standard of care (11.3% vs 1.8%), but most bleeding events were mild to moderate. Real-world evidence also supports the good efficacy of caplacizumab [4,7].

ISTH treatment guidelines have been updated in 2020 and new concepts regarding ADAMTS13 levels, caplacizumab, and rituximab were included (see Figure). Evaluation of ADAMTS13 levels in patients in remission is recommended monthly for the first 3 months, every 3 months for the first year, and every 6–12 months when stable, and more frequently if levels begin to drop. For patients with ADAMTS13 activity <10%, the risk for relapse may be prevented by rituximab [8].

Figure: Decision tree for the treatment of aTTP patients, according to updated ISTH 2020 guidelines. Modified from [8]



In summary, the determination of ADAMTS13 is the foundation for the diagnosis and monitoring of aTTP. Recommended first-line treatment is steroids, plasma exchange, and caplacizumab ± rituximab. Patients with an ADAMTS13 plasma level of <20% are at high risk of relapse and rituximab treatment should be considered. New treatment regimens and therapeutics (e.g. recombinant ADAMTS13) might become available in the future.

1. 
   
   1. Mingot-Castellano ME. The treatment armamentarium in 2021 – from evidence to clinical practice. 5SS133-SL3, EHA 2021 Virtual Congress, 9–17 June.
   2. George JN. Blood 2021;137(6):719–20.
   3. Scully M, et al. Blood 2011;118(7):1746–53.
   4. Coppo P, et al. Blood 2021;137(6):733–42.
   5. Scully M, et al. N Engl J Med 2019;380(4):335–46.
   6. Peyvandi F, et al. Blood Adv. 2021;5(8):2137–41.
   7. Dutt T, et al. Blood 2021;137(13):1731–40.
   8. Zheng XL, et al. J Thromb Haemost. 2020;18(10):2486–95.

 

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Posted on 5 August 20215 August 2021