The extension of caplacizumab application intervals from daily to alternate-day dosing may be safely considered after three to four weeks of daily treatment in selected patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP), according to study findings published in the Journal of Thrombosis and Haemostasis. Further, the modification of established protocols not only offers a cost-saving strategy that limits the economic burden associated with this drug – median cost savings per patient was US$77,240 (range = US$15,448-US$463,440) – but also holds the potential for a more individualized therapy for patients with iTTP.
The anti-von Willibrand factor (VWF) nanobody caplacizumab directly prevents the fatal microthrombi formation in iTTP. The drug, in combination with therapeutic plasma exchange (PEX), steroids, and rituximab, is the current standard of care for iTTP. This study sought to define more clearly the timing and duration of this treatment regimen and to investigate the economic effects of such modifications.
“Based on the published pharmacodynamics of caplacizumab (Titan study), many treating physicians decided to individualize the treatment protocol and to administer the drug only every other day, especially in patients who needed an extension of treatment due to persistent autoimmune activity,” said study co-author Paul T. Brinkkoetter, MD, of the University of Cologne in Germany.
To assess the risks and benefits of an alternate-day dosing regimen for caplacizumab, the retrospective cohort study analyzed the timing and outcome of this approach in patients with iTTP who were treated with caplacizumab at seven medical centers in Austria and Germany between 2018 and 2021. In total, 25 patients (21 female) with median age at diagnosis of 42 (range 17-93) were identified who had periods in which caplacizumab was not given daily but every other day or every third day. A successful use of non-daily caplacizumab therapy (alternate-day or >2-day dosing intervals) was defined as persisting normal platelet counts during non-daily treatment and the respective follow-up period.
Close monitoring of platelet counts and LDH levels is required on alternate-day dosing.
All patients were initially treated with daily caplacizumab injections, as well as rituximab and steroids. Four patients were treated without PEX. Researchers noted an increase in platelet counts in all patients after caplacizumab therapy was initiated with a median time to platelet count normalization (≥150×109/L) of three days (range 2-7). Lactate dehydrogenase (LDH) levels improved similarly to platelet counts.
Findings showed that alternate-day dosing of caplacizumab led to persistent normal platelet counts without any sign of iTTP exacerbation or relapse in most patients (n=20). Exacerbations and relapses associated with alternate-day dosing occurred solely in patients with a delayed recovery of ADAMTS13 activity (>24 days post-PEX) and in whom alternate-day dosing was introduced or terminated early.
“For this reason, we recommend considering alternate-day dosing only in patients with a stable clinical course and three to four weeks after the end of PEX,” Dr. Brinkkoetter said.
Anti-VWF activity was repeatedly measured in 16 of 25 patients and documented sufficient suppression by caplacizumab after 24 and 48 hours in line with published pharmacodynamics. Measuring VWF activity did not allow researchers to identify patients at risk of early relapse. In two patients who relapsed, sufficient suppression of VWF activity was documented on the day physicians noted a critical decrease in platelet count and decided to resume daily dosing. These findings indicate that close monitoring of platelet counts and LDH levels is required on alternate-day dosing, and dynamics of VWF activity may have a limited influence on clinical decision making.
Limitations of the study include its retrospective nature, as there were no clear criteria for those that received intermittent caplacizumab dosing and when. However, this generally followed an ADAMTS13 activity-guided approach. Additionally, not all patients were treated with PEX.
“On the basis of our retrospective observational analysis, it seems safe to individualize caplacizumab treatment modalities to every other day in patients with evidence of persistent autoimmune activity (>30 days after the end of PEX),” Dr. Brinkkoetter said. “Future studies may help us to further individualize our iTTP treatment approaches, e.g., the use of ADAMTS13 activities to define the treatment duration, measuring VWF activities for therapeutic drug monitoring, and thrombocyte dynamics to define the overall need for plasma exchange.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Kühne L, Kaufeld J, Völker LA, et al. Alternate-day dosing of caplacizumab for immune-mediated thrombotic thrombocytopenic purpura [published online 2022 Jan 9]. J Thromb Haemost. doi: 10.1111/jth.15637.
