iTTP loses TPE

In this issue of Blood, Kühne et al present a retrospective cohort study demonstrating that a treatment regimen that omits therapeutic plasma exchange (TPE) and uses immunosuppression and upfront caplacizumab alone is safe and effective for patients with immune thrombotic thrombocytopenic purpura (iTTP).¹ 

Since the seminal study by Rock et al in 1991 which demonstrated that TPE significantly reduces mortality in TTP,² urgent initiation of TPE with immunosuppression has been the mainstay of therapy for iTTP.³ In iTTP, TPE removes circulating anti-ADAMTS13 antibodies and ultralarge von Willebrand factor (VWF) multimers while simultaneously restoring ADAMTS13 levels and normal VWF via infusion of donor plasma.⁴ In 2019, caplacizumab was approved by the US Food and Drug Administration for adults with iTTP in combination with TPE and immunosuppressive therapy. Caplacizumab is a humanized, bivalent nanobody that targets the A1 domain of VWF to reduce interactions with platelet glycoprotein Ib-IX-V. In randomized, controlled trials, early administration of caplacizumab in combination with TPE and immunosuppression induced more rapid normalization of platelet counts and lowered the incidence of recurrent iTTP, thromboembolism, and iTTP-related death vs placebo with TPE and immunosuppression.^5,6 

In their study, Kühne et al used the Austrian Thrombotic Microangiopathy Registry and the German REACT-2020 TTP registry to compare laboratory and clinical outcomes between 41 patients with iTTP who received a TPE-free treatment regimen of immunosuppression and upfront caplacizumab vs 59 control patients with iTTP who received a standard treatment regimen of TPE, immunosuppression, and caplacizumab. The authors found no difference in the primary outcome of time to platelet count normalization or in key secondary outcomes such as clinical response, clinical exacerbation, refractory disease, and iTTP-related death. In the TPE-free cohort, both time to recovery of ADAMTS13 activity ≥20% and length of hospitalization were significantly shorter. Four patients in the TPE cohort had serious complications related to TPE, including anaphylaxis and cardiac arrest, whereas major bleeding was seen in 2 patients in the TPE-free arm. Overall, safety outcomes did not differ between the 2 groups.

Since 2019, multiple case reports and case series have described success in treating iTTP patients with regimens that omit TPE and rely solely on caplacizumab and immunosuppression.^7,8 The study by Kühne et al represents the largest real-world cohort of patients with iTTP treated with a TPE-free regimen, which included 24 (57.1%) patients who had at least 1 neurological symptom at the time of presentation. Results from the study not only show that a TPE-free regimen is safe and effective in iTTP, but also highlight some important points: (1) Absence of an increase in platelet count after caplacizumab initiation should prompt investigation into a contributing or secondary cause of thrombocytopenia, such as infection. (2) ADAMTS13 activity can guide decisions for duration of caplacizumab treatment. Consistent with prior studies,^5,6 most clinical exacerbations (10 of 11) were associated with early termination of caplacizumab when ADAMTS13 activity was still <10%. (3) Although it is well established that caplacizumab increases the risk of bleeding,^5,6 2 patients in the TPE-free cohort developed major bleeding, which emphasizes the known risk of bleeding complications with caplacizumab. (4) As seen in the TPE cohort, TPE is associated with risk. Four patients had TPE-related complications, including anaphylaxis, cardiac arrhythmias, and cardiac arrest.

Despite the fact that Kühne et al strongly challenge the existing tenet that emergent initiation of TPE is mandatory for iTTP, several questions remain. Although caplacizumab impedes ultralarge VWF-platelet interactions, it does not affect the underlying disease or autoantibody production. The effect of TPE-free regimens on the increasingly recognized chronic sequelae of iTTP, including cognitive impairment, silent cerebral infarction, or cardiovascular disease,^9,10 remains unknown. In addition, the cost effectiveness of a TPE-free regimen that uses upfront caplacizumab is unknown and potentially prohibitive. Kühne et al demonstrate that omission of TPE significantly reduces hospital length of stay, and this may offset the cost incurred with caplacizumab usage, but remains to be determined. Finally, due to the retrospective nature of the study, no uniform treatment regimen or laboratory monitoring protocol was applied to the patients in the TPE-free cohort. Prospective, protocolized studies will be required before routine implementation of a TPE-free approach can be considered for patients with iTTP, and we eagerly await the results of the ongoing MAYARI trial (Caplacizumab and Immunosuppressive Therapy Without Firstline Therapeutic Plasma Exchange in Adults With Immune-Mediated Thrombotic Thrombocytopenic Purpura; ClinicalTrials.gov identifier: NCT05468320).

Kühne et al raise the possibility that a TPE-free approach may be safe and effective in patients with iTTP. Their study demonstrates a viable option in clinical scenarios where TPE is not available, there are delays in the initiation of TPE, or there is an inability to administer blood products to the patient. In the meantime, there remains a need for prospective studies using a standard TPE-free approach.

Conflict-of-interest disclosure: G.M.L. declares no competing financial interests.