In an intriguing new case report, Pavan K. Bendapudi, MD, and colleagues describe the off-label use of purified, virally inactivated, recombinant human ADAMTS13 (rADAMTS13) to treat a patient with immune thrombotic thrombocytopenic purpura (iTTP) who was refractory to standard therapies. This treatment has been found highly effective in patients with congenital thrombotic thrombocytopenic purpura, and is now approved by the U.S. Food and Drug Administration for this indication.1 However, its use in iTTP remains off-label only and is currently under active study.
The patient described in this case report is a 28-year-old woman who, approximately three months postpartum, presented with severe microangiopathic hemolytic anemia and thrombocytopenia. A diagnosis of iTTP was ultimately confirmed through the finding of severe ADAMTS13 deficiency and detection of anti-ADAMTS13 immunoglobulin G antibodies. She received standard-of-care treatment for iTTP consisting of daily plasma exchange (PLEX) treatments, prednisone, rituximab, and caplacizumab.2,3 Despite this, the patient’s thrombocytopenia persisted and her clinical status continued to deteriorate.
The authors obtained rADAMTS13 from the manufacturer for compassionate use and administered it at a dose of 80 IU/kg every 12 hours starting on day 14 following the patient’s presentation. To assess treatment response, the authors rigorously tracked ADAMTS13 activity and other key laboratory parameters (including platelet count and lactate dehyrogenase). To provide a “typical” iTTP treatment course for comparison to the study patient, the authors extracted data from the Harvard TMA Research Collaborative registry on 102 consecutive patients with iTTP. As shown in the figure below, the study patient experienced rapid and sustained laboratory improvement accompanied by clinical improvement (including resolution of bleeding). The patient was eventually transitioned from this experimental approach back to standard care, with rADAMTS13 therapy discontinued on day 46.
Trajectory of laboratory values for the study patient in relation to noted clinical events
The vertical red marks and arrows denote the initiation of rADAMTS13 treatment. Blue lines and shaded areas represent corresponding means and 95% confidence intervals for 102 consecutive patients with iTTP from an established registry.
Figure reproduced from Bendapudi et al., with permission.
The vertical red marks and arrows denote the initiation of rADAMTS13 treatment. Blue lines and shaded areas represent corresponding means and 95% confidence intervals for 102 consecutive patients with iTTP from an established registry.
Figure reproduced from Bendapudi et al., with permission.
In Brief
Although this publication’s Diffusion section does not typically highlight case reports, I felt this one was noteworthy for the novelty and promise of the described treatment, as well as the rigor with which the case is discussed and the documented effectiveness of the treatment. The findings of this single-patient, proof-of-concept clinical study echo those of a phase II randomized, placebo-controlled multicenter trial of rADAMTS13 for iTTP presented at the 2023 European Hematology Association Hybrid Congress, which demonstrated increased ADAMTS13 activity and platelet counts in patients treated with rADAMTS13 as compared to placebo.4 Of note, the maximum dose used in this study (40 U/kg rADAMTS13 post-PLEX and repeated 12 hours later) was half that used to treat the patient described in the case report (80 U/kg every 12 hours). The authors of this case report hypothesize that the high rADAMTS13 dose used may functionally “overwhelm” the anti-ADAMTS13 autoantibodies and promote autoantibody clearance independent of PLEX. While some data are provided to support this conjecture, such findings can only be viewed as hypothesis-generating at this stage. Another actively recruiting phase II trial (NCT05714969) aims to study the effect of rADAMTS13 at different dose levels. If these findings are confirmed, they could yield another effective treatment option for patients with iTTP, both in the relapsed-refractory setting and upfront/adjunct setting. Additional study will be needed to fully define the role of rADAMTS13 for iTTP. Perhaps even more excitingly, these studies could point the way toward another candidate for PLEX-free treatment of iTTP following in the footsteps of caplacizumab, which has already been employed in this fashion.5
Competing Interests
Dr. Scott indicated no relevant conflicts of interest.
Acknowledgment
Dr. Scott would like to acknowledge Dr. Katerina Pavenski for her helpful comments and feedback on this article.
