Clinical Outcomes of Immune-Mediated Thrombotic Thrombocytopenic Purpura from a Multinational Patient Population

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disease caused by a severe, autoantibody-mediated, deficiency of the von Willebrand factor-cleaving protease ADAMTS13. ADAMTS13 deficiency results in platelet-rich microthrombi and platelet consumption leading to thrombocytopenia and multiorgan failure. Treatment approaches for iTTP include plasma exchange (PEX), immunosuppression, and anti-von Willebrand factor therapies. Gaining greater insights into the natural history of iTTP, clinical outcomes, disease burden, and treatment utilization may help to improve patient care.

Aims: The primary objectives were to describe patient characteristics, the prevalence and incidence of iTTP clinical manifestations, and disease related complications. The secondary objectives were to describe treatment utilization and health care resource utilization among patients with iTTP.

Methods: This multinational, retrospective chart review was conducted in 16 sites in Europe, Japan, and the United States using de-identified patient-level data collected during the study period (January 1, 2009 to December 31, 2020). Eligible patients were diagnosed with iTTP and had an index event between January 1, 2009 and December 31, 2017. Index events included: iTTP-related clinical events, a diagnosis of iTTP, receiving preemptive treatment, and receiving treatment for an acute iTTP event (defined as a decrease in platelet count ≥50% of baseline or <100,000/µL, and lactate dehydrogenase levels >2 × the upper limit of normal). Patients were followed from their first qualifying index event until loss to follow-up, enrollment in a clinical trial, death, or the end of the study. Descriptive statistics summarized the results. Ethics approval and informed consent were obtained where required.

Results: The study included 183 patients with a mean (SD) follow-up of 7.0 (3.1) years. The majority were female (n=129, 70.5%) and White (n=92, 50.3%). Mean (SD) age at study index was 44.2 (16.5) years and at initial iTTP diagnosis was 43.0 (16.8) years. A history of refractoriness to iTTP treatments was reported in 27 (14.8%) patients. During the study period, 263 acute iTTP events were reported in 175 (95.6%) patients, resulting in an event rate of 0.206 events per person year. Most acute iTTP events resolved (n=248, 94.3%; n=2/263 missing data); 197 (74.9%) events resolved without complications, 32 (12.2%) with short-term complications, and 19 (7.2%) with organ damage. Thirteen (4.9%) acute iTTP events did not resolve, resulting in death. Platelet counts normalized (platelet levels >150,000/µL) in 244 (92.8%) acute iTTP events. Exacerbations (defined as relapse within 30 days) were reported for 34 acute iTTP events in 31 patients. Most acute iTTP events required hospitalization (n=245, 93.2%) with 133 (54.3%) requiring intensive care unit (ICU) admission. The median (IQR) duration of hospitalization in wards was 14.0 (8.0-21.0) days and in an ICU was 6.0 (2.0-14.0) days. Of 245 hospitalizations, 185 (75.5%) involved care by >1 specialty and 21 (8.6%) required ≥10 specialties. Hematologists (n=212, 86.5%) and transfusionists (n=94, 38.4%) were the most common specialties involved during acute iTTP events. Treatment information was available for 248 acute iTTP events. In total, 191 (77.0%) acute iTTP events required >1 treatment type. Complications due PEX occurred in 44 acute iTTP events, including allergic reactions (n=32, 72.7%), fever/chills (n=7, 15.9%), and itching (n=6, 13.6%). Central vein catheter insertion was required in 203 (77.2%) acute events, of which 33 (16.3%) had complications. During the study 19 patients died, of which 12 (63.2%) deaths were iTTP related.

Conclusions: The burden of iTTP bears significant consequences for patients and health systems. Although beneficial, standard treatments can result in adverse events, including allergic reactions, which add to the treatment burden. ADAMTS13 deficiency is the hallmark of iTTP. Novel treatments that can effectively and efficiently normalize ADAMTS13 levels may provide additional benefit for patients with iTTP and help to alleviate treatment burden.

Coppo:Sanofi: Honoraria, Other: Member of CAB, speakers fees; Takeda: Honoraria, Other: Member of CAB, speakers fees; Alexion: Honoraria, Other: Member of CAB, speakers fees. Peyvandi:Novo Nordisk: Honoraria, Research Funding; CSL Behring: Honoraria; Bayer: Honoraria; Baxter: Honoraria. Scully:Shire (a Takeda company): Research Funding; Alexion: Other: received speakers fees, Research Funding; Octapharma: Other: received speakers fees; Sanofi: Other: received speakers fees; Takeda: Honoraria, Other: received speakers fees, Research Funding; Baxalta (a Takeda company): Research Funding. Kremer Hovinga:Roche, Sanofi, Sobi, Takeda (all honoraria go to employer: Insel Gruppe AG, Bern, Switzerland): Speakers Bureau; Baxter/Takeda: Research Funding; Sobi, Takeda: Other: Travel support to congresses; Federal Office of Public Health of Switzerland, Novo Nordisk, Roche, Sobi, Takeda (all honoraria go to employer: Insel Gruppe AG, Bern, Switzerland): Consultancy. Saad:Takeda Development Center Americas, Inc.: Current Employment, Current equity holder in publicly-traded company. Jose Aragon:HCD Economics: Current Employment; Takeda Development Center Americas, Inc: Research Funding. Ferri Grazzi:HCD Economics: Current Employment; Takeda Development Center Americas, Inc: Research Funding. Du:Takeda Development Center Americas, Inc.: Ended employment in the past 24 months. Cuccia:Takeda Development Center Americas, Inc.: Current Employment, Current equity holder in publicly-traded company. Ferdosi:Takeda Development Center Americas, Inc.: Current Employment, Current equity holder in publicly-traded company.