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. 2020 Jul 14;4(13):3093-3101.
doi: 10.1182/bloodadvances.2020001987.

ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP

Linus A Völker  1   2 , Jessica Kaufeld  3 , Wolfgang Miesbach  4 , Sebastian Brähler  1   2 , Martin Reinhardt  3 , Lucas Kühne  1   2 , Anja Mühlfeld  5 , Adrian Schreiber  6   7 , Jens Gaedeke  6   7 , Markus Tölle  8   9 , Wolfram J Jabs  10 , Fedai Özcan  11 , Silke Markau  12 , Matthias Girndt  12 , Frederic Bauer  13 , Timm H Westhoff  13 , Helmut Felten  14 , Martin Hausberg  14 , Marcus Brand  15 , Jens Gerth  16 , Markus Bieringer  17 , Martin Bommer  18 , Stefan Zschiedrich  19 , Johanna Schneider  19 , Saban Elitok  20 , Alexander Gawlik  20 , Anja Gäckler  21 , Andreas Kribben  21 , Vedat Schwenger  22 , Ulf Schoenermarck  23 , Maximilian Roeder  24 , Jörg Radermacher  25 , Jörn Bramstedt  26 , Anke Morgner  27 , Regina Herbst  27 , Ana Harth  28 , Sebastian A Potthoff  27   29 , Charis von Auer  30 , Ralph Wendt  31 , Hildegard Christ  32 , Paul T Brinkkoetter  1   2 , Jan Menne  3
Affiliations

ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP

Linus A Völker et al. Blood Adv. .

Abstract

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Immunosuppressive treatment led to a rapid normalization of ADAMTS13 activities (calculated median, 21 days). In 35 of 60 patients, ADAMTS13 activities started to normalize before day 30 after PEX; in 11 of 60 patients, the treatment was extended beyond day 30; and in 5 patients, it was extended even beyond day 58 due to persistent autoimmune activity. In 34 of 60 instances, caplacizumab was stopped before day 30 with a favorable outcome whenever ADAMTS13 activities were >10%. In contrast, 11 of 34 patients with ADAMTS13 activities <10% at the time of stopping caplacizumab treatment developed a nonfavorable outcome (disease exacerbation or relapse). In some cases, prolongation of the treatment interval to every other day was feasible and resulted in a sustained reduction of von Willebrand factor activity. ADAMTS13 activity measurements are central for a rapid diagnosis in the acute setting but also to tailor disease management. An ADAMTS13 activity-guided approach seems safe for identifying the individual time point when to stop caplacizumab to prevent overtreatment and undertreatment; this approach will result in significant cost savings without jeopardizing the well-being of patients. In addition, von Willebrand factor activity may serve as a biomarker for drug monitoring.

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Conflict of interest statement

Conflict-of-interest disclosure: P.T.B. reports grants from the German Research Foundation (BR2955/8) during the conduct of the study; and personal fees from Alexion, Astellas, Bayer, Sanofi Genzyme, Pfizer, and Vifor (speaker honoraria and advisory boards). L.A.V. reports grants from the Else-Kroener-Fresenius Stiftung (2015_A224); and speaker honoraria from Sanofi Genzyme. S.B. receives grant support from the German Research Foundation (BR4917/3). J.M. received personal fees from Alexion, Sanofi Genzyme, and Ablynx (speaker honoraria and advisory boards). S.A.P. received personal fees from Alexion, Sanofi Genzyme, and Ablynx (speaker honoraria and advisory boards). R.W. received personal fees from Alexion, Sanofi Genzyme, and Ablynx (speaker honoraria, advisory boards, educational materials, and review writing). W.J.J. received speaker honoraria from Alexion and Ablynx (advisory boards). W.M. received honoraria from Ablynx, Takeda, and Shire (speaker honoraria and advisory boards). M.T. reports research grants from the Sonnenfeld Stiftung, Charité3R, and Novartis; and personal fees from Baxter, Cytosorbents, Novartis, and Takeda (speaker honoraria and advisory boards). M.R. reports personal fees from Alexion, Diamed, Roche, and Sanofi Genzyme (speaker honoraria and travel support). A. Gäckler reports personal fees from Alexion and Ablynx (speaker honoraria and advisory boards), F.B. received honoraria from Amgen, Sanofi, Akcea, Hexal, MSD, AstraZeneca, Alexion, and Astellas (speaker honoraria and advisory boards). U.S. reports study fees, travel support, and consultancy fees from Alexion; and study fees and consultancy fees Ablynx. M. Bommer received honoraria from Ablynx, Alexion, Amgen, and Sanofi; and study fees from Ablynx and Amgen. C.v.A. reports personal fees from Sanofi Genzyme (advisory boards). The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Kaplan-Meier curves of patient fractions remaining without ADAMTS13 activity (>10%) recovery after the end of PEX treatment.
Figure 2.
Figure 2.
Duration of caplacizumab treatment after end of PEX in relation to outcome. Caplacizumab treatment duration after PEX stratified according to ADAMTS13 activity at the time of stopping caplacizumab. Nonfavorable outcomes include exacerbation, relapse, and death. Two cases were censored due to ongoing caplacizumab treatment and registered as being in remission at the time point of the census. It is noteworthy that in 6 cases, >1 instance of termination of caplacizumab treatment after PEX was reported. Days of caplacizumab treatment do not necessarily reflect the doses of caplacizumab because some patients were treated with a nondaily or intermittent caplacizumab regimen.
Figure 3.
Figure 3.
VWF activity as measured by a VWF:GP1bM activity assay on the first and second day after caplacizumab administration. Patients were on an alternate-day caplacizumab treatment regimen and closely monitored for signs of relapse. Normal range for VWF activity, 50% to 187%. LL, lower limit of normal; UL, upper limit of normal.
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