Abstract
Introduction Acquired haemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against factor VIII (FVIII). The most common IST treatment used are Steroids-based regimens. However, patients with AHA are often elderly with comorbidities. Steroids-based regimens have significant side effects in patients with AHA. In particular, the risk of dying from infection appears to be higher than the risk of fatal bleeds today. This dilemma highlights the lack of safe and rapid response IST therapy in AHA. Bortezomib targets plasma cells rather than B cells and has reported efficacy in refractory AHA. It is an attractive agent because it depletes plasma cells that can continue to produce autoantibody even after CD20-positive B cells have been depleted by rituximab. The combination of bortezomib and rituximab regimen showed rapid response without severe adverse event in refractory and relapsed warm autoimmune hemolytic anemia. This phase 2, prospective, single-center study was designed to evaluate the efficacy and safety of rituximab and bortezomib (RB) treatment regimen in newly diagnosed AHA patients.
Methods All patients 18 years of age or older who met the following criteria were considered as eligible candidates for this study: 1) plasma FVIII activity (FVIII:C) <50 l/dl, detectable inhibitor to FVIII. 2) newly diagnosed without any IST treatment.
After obtaining the written informed consent from the patients, the information of demographic and medical history were collected and laboratory tests were performed.The patients were received the following regimens: Rituximab 375mg/m2 intravenous infusion on day 0 and bortezomib 1.3 mg/m2 subcutaneous on day 1,4,8,11. Best supportive care, including administration of hemostatic treatment and blood product transfusions if needed were used. Safety was evaluated according to NCI-CTCAE v4.0.
Results From March 2018 to May 2022, 30 patients were eligible for the study. The baseline characteristics of the patients are summarized in Table 1. Overall, 19 patients were male (63.3%). The median age was 53.5 years (range 22 - 90 years). The underlying disorders that could be associated with AHA included rheumatoid arthritis, systemic lupus erythematosus and pemphigus. One patient was diagnosed at her postpartum. One patient was diagnosed soon after surgery. Traditional Chinese medicine was suspected as the inducement in one patient. No patient in our cohort was reported to have coexisting malignancy. 24 patients (80.0%) were regarded as idiopathic AHA. The median time from disease onset to the diagnosis was 36.5 days (range 10-249 days). The median FVIII activity at baseline was 1.5 IU/ml (range 0 to 10.4 IU/ml), and the median inhibitor concentration was 25.6 BU/ ml (range 2.7 to 600 BU/ ml).
The bleeding event that precipitated diagnosis was reported as spontaneous in 27 patients (90.0%), by surgery in 3 patients (10.0%). All patients presented with bleeding diathesis as listed in Table 1. Sixteen patients (61.5%) received haemostatic treatment for initial bleeding, all of them received prothrombin complex concentrate (PCC). Nine patients experienced further bleeding after the treatment of BR.
All patients completed protocol treatment. Overall, 23 patients (76.7%) achieved CR, 6 patients (20.0%) achieved PR and 1 patients died of cardiac events 3 month after last dose of bortezomib. The ORR was 96.7%. Median time to CR was 74 days (range 12-179 days). After a median follow-up of 39 months (range 3-50 months), one patient had relapse of the disease, 2 months after achieved CR.
Major toxicities and adverse events are summarized in Table 2. One patient (3.8%) had grade 3 neutropenia; One patient (3.8%) had grade 4 thrombocytopenia and grade 3 thrombocytopenia each. Eight patients experienced infectious fever, including 2 grade 3 and 2 (7.7%) grade 4. Five patients (19.2%) developed grade 1-2 peripheral neuropathy.No treatment-related deaths occurred.
Conclusion Here we report the results of a phase 2 prospective study of newly diagnosed AHA. This study confirmed that rituximab plus bortezomib was an efficient and safe regimen with ORR of 96.7%, and the median time to CR was 74 days.This trial was registered at www.clinicaltrials.gov as #NCT03700229.
Disclosures
No relevant conflicts of interest to declare.
