Updates in the Treatment of Acquired Thrombotic Thrombocytopenic Purpura

by Carter BloodCare Specialty Services

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease in which disseminated microthrombi lead to ischemic organ injury/failure and potentially to death. Platelet-rich microthrombi form due to a lack of ADAMTS-13, an enzyme responsible for cleaving ultra-large von Willebrand (UL-VWF) multimers into smaller multimers. These UL-VWF multimers that persist are inherently stickier and avidly bind platelets, which leads to the thrombocytopenia seen in TTP. In addition, these platelet-rich microthrombi cause shearing of circulating RBCs, which leads to a microangiopathic hemolytic anemia. Other entities, such as atypical hemolytic uremic syndrome or disseminated intravascular coagulation, have very similar clinical presentations. Thus, an ADAMTS-13 activity <10% is used to confirm a diagnosis of TTP. The distinction between TTP and the other thrombotic microangiopathies is essential since more tailored therapies, such as eculizumab and caplacizumab, have become available.

Plasma exchange (PLEX) acts to replace ADAMTS-13 and remove autoantibodies, and along with corticosteroids, has been the mainstay in the treatment of acquired TTP (aTTP). More recently, use of other immunosuppressants to eradicate autoantibodies, such as rituximab, have led to improvement in the clinical course of patients with aTTP. In February 2019, the FDA approved caplacizumab-yhdp (CABLIVI, Sanofi) for treatment of adults with acquired TTP, in combination with PLEX and immunosuppressive therapy.

Caplacizumab is a nanobody that binds the A1 domain of von Willebrand factor (vWF) and blocks the binding of platelets via GPIb to this domain, which ultimately leads to a reduction in microvascular thrombosis. HERCULES, a phase 3 double-blind randomized controlled trial, demonstrated significantly shorter time to platelet count normalization and decrease in duration of PLEX and hospital stay compared to placebo. The trials and package insert doses on the first day of plasma exchange and once daily for 30 days following the last plasma exchange. The most common adverse event was bleeding, with the majority of cases being mild-moderate mucocutaneous bleeding. Bleeding was seen in both treatment and placebo groups, 65% and 48%, respectively.

Real-world use of caplacizumab has confirmed similar efficacy findings but increased rates of bleeding, and in particular, cases of severe bleeds, such as intracranial hemorrhage, have been reported.1 Questions regarding caplacizumab’s cost-effectiveness have also been debated. A single dose is $7,700; an average course of therapy would be ~$275,000. A study using ADAMTS-13 monitoring to guide duration of caplacizumab use found that 58.3% of patients did not require treatment for the full 30 days, which resulted in a cost savings of $3.4 million.2 In addition, the United Kingdom TTP forum has recommended discontinuation of caplacizumab with an ADAMTS-13 activity >30%, which could limit drug exposure and additional drug costs.

Additional studies are ongoing that will hopefully lead to better information as to how to best treat patients with aTTP.

References:

  1. Dutt T. Shaw R. Scully M. et al. Real-World Experience with Caplacizumab in the Management of Acute TTP. Blood (2021) 137(13):1731-1740.

  2. Dutt T. Shaw R. Scully M. et al. Real-World Experience with Caplacizumab in the Management of Acute TTP. Blood (2021) 137(13):1731-1740.