Persistent ADAMTS13 Inhibitor May Lead to Delayed ADAMTS13 Recovery in Japanese Patients with Caplacizumab-Treated Immune-Mediated Thrombotic Thrombocytopenic Purpura

Introduction Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare condition that causes fatal ischemic end-organ damage due to autoantibodies against ADAMTS13. iTTP patients treated with caplacizumab in addition to standard treatments show a faster time to platelet recovery and fewer incidences of TTP-related organ damage and death. Caplacizumab got approval in Japan in December 2022, while it had been approved in Western countries as far back as 2018 and 2019. Recently, it has been reported that caplacizumab may delay the recovery of ADAMTS13 activity. Therefore, we analyzed the temporal changes of ADAMTS13 activity and its inhibitor in acute iTTP cases before and after the introduction of caplacizumab.

Methods iTTP was diagnosed when ADAMTS13 activity was severely decreased (<10%) and ADAMTS13 inhibitor level was ≥0.5 BU/mL. Patients with caplacizumab-treated iTTP underwent once a week or more monitoring for ADAMTS13 activity and inhibitor during the acute phase (caplacizumab group). In addition, cases not treated with caplacizumab were selected that matched the inhibitor levels of the TTP registry since 2019 (non-caplacizumab group). The activity of the plasma ADAMTS13 and its inhibitor were measured using a chromogenic ADAMTS13 activity ELISA (Kinos Laboratories, Tokyo, Japan). Anti-ADAMTS13 IgG levels were analyzed using the TECHNOZYM ADAMTS13 INH ELISA (Tecnoclone, Vienna, Austria). The ADAMTS13 activity, ADAMTS13 inhibitor, and anti-ADAMTS13 IgG antibody levels in both groups were compared on day of onset, day 7, day 14, day 21, and day 28 from the initial therapeutic plasma exchange (TPE) (error margin of ±2 days for each time point). Continuous data were statistically compared using the Mann-Whitney U test. P values of <0.05 were judged as statistically significant. This study was approved by the ethics committee of our university.

Results Of the 22 patients included in this study, 11 were treated with caplacizumab (caplacizumab group) and 11 were not (non-caplacizumab group). The median follow-up period was 55 and 74 days in the caplacizumab and non-caplacizumab groups, respectively. The demographic data for both groups are shown in Table. The median duration of caplacizumab administration in the caplacizumab group was 46 days. ADAMTS13 activity was less than 0.5% on admission in all cases. The ADAMTS13 inhibitor was detected in all cases, with no significant difference in the median titer between the caplacizumab group (7.2 BU/mL) and the non-caplacizumab group (5.0 BU/mL) (p=0.2). There was also no statistical significance in the median value of anti-ADAMTS13 IgG antibody between the caplacizumab group (133.6 U/mL) and non-caplacizumab group (73.9 U/mL) (p=0.439).

All patients received TPE and corticosteroids. The median number of TPE in the caplacizumab group was significantly lower than that in the non-caplacizumab group (8 vs. 16 days, p=0.003). There was no significant difference in the median number of days from the first TPE to the start of rituximab administration, or in the proportion of rituximab administered between the two groups. After the final TPE, the caplacizumab group took a median of 43 days compared to the non-caplacizumab group (median, 3 days; p=0.003) to achieve ≥20% ADAMTS13 activity, which was significantly longer.

The median ADAMTS13 activity level was significantly lower in the caplacizumab group than in the non-caplacizumab group on days 14 (<0.5% vs. 8.7%, p=0.029), 21 (<0.5% vs. 25.5%, p=0.003), and 28 (<0.5% vs. 27.8%, p<0.001), whereas the median ADAMTS13 inhibitor level was significantly higher in the caplacizumab group on the same days: day 14 (5.6 vs. <0.5 BU/mL, p=0.005), day 21 (2.0 vs. <0.5 BU/mL, p=0.009), and day 28 (0.8 vs. <0.5 BU/mL, p<0.001). Similarly, the median level of the anti-ADAMTS13 IgG antibody was significantly higher in the caplacizumab group compared to the non-caplacizumab group at identical time points on day 14 (55.4 vs. 8.3 U/mL, p=0.005) and 21 (median, 27.6 vs. 7.0 U/mL; p=0.016), and day 28 (median, 17.5 vs. 3.7 U/mL; p=0.008).

Conclusion We found a delay in the recovery of ADAMTS13 activity in patients treated with caplacizumab, especially after the final TPE. This is potentially due to the persistent presence of ADAMTS13 inhibitor. When administering caplacizumab, closely monitoring for ADAMTS13 activity and its inhibitor is necessary in order to discontinue caplacizumab at the appropriate time.