Session: 331. Thrombotic Microangiopathies/Thrombocytopenias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Bleeding and Clotting, Clinical Research, Diseases, Therapy sequence, Real-world evidence, Thrombotic disorders, Treatment Considerations
Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy (TMA). It is caused by inhibitory autoantibodies to ADAMTS13 leading to deficient ADAMTS13 activity, persistence of ultra-large von Willebrand factor (VWF) and enhanced interaction of VWF and platelets resulting in microthrombus formation. These VWF/platelet-rich microvascular thrombi cause thrombocytopenia, microangiopathic hemolytic anemia and tissue ischemia. Management of acute iTTP consists of daily therapeutic plasma exchange (TPE), administration of the anti-VWF nanobody caplacizumab and immunosuppression with corticosteroids. Additional anti-CD20 therapy with rituximab is administered early to prevent relapsing iTTP which occurs in at least 30% of patients. Some patients are refractory to treatment with persistence of ADAMTS13 deficiency and inhibitor, or show a frequently relapsing course (r/r iTTP). Management of these patients is challenging. Several immunosuppressive or immunomodulatory interventions are applied, some with considerable side effects but no clear recommendations exist. Daratumumab, an anti-CD38 antibody, has emerged as an efficacious and safe therapeutic option for a variety of autoimmune diseases, including single patients with iTTP. We present a series of patients with r/r iTTP which we have treated with daratumumab with a median follow-up of 43 months.
Methods
This retrospective analysis was conducted across 3 Swiss centres including 8 treatment episodes with daratumumab in 5 patients (4 treatments in 3 patients, University Hospital Zurich; 3 in 1 patient, University Hospital Bern; 1 in 1 patient, University Hospital Basel). Patient-level data from January 1st, 2014 through July 1st, 2024 were abstracted from medical records. Data on basic demographic characteristics, disease course, treatment with response and adverse reactions, ADAMTS13 activity and inhibitor levels were collected. ADAMTS13 recovery following treatment was defined as partial (ADAMTS13 activity >20%) and complete (>50%).
Results
We evaluated 8 treatment episodes with daratumumab in 5 r/r iTTP patients. Prior to daratumumab, a median of 2 (range, 2-6) other immunosuppressive therapies were given. All patients had received rituximab as one of the prior treatment regimens. A median number of 6 (range: 4-8) daratumumab doses was administered per patient, either as an intravenous infusion (16 mg/kg body weight) or subcutaneous injection (1800 mg). One patient received continuing monthly daratumumab injections of 1800 mg subcutaneous following his initial six weekly injections. In all cases, daratumumab was initiated to reverse ADAMTS13 deficiency (< 5%) while the patients were still in clinical remission. Infusion-related adverse events were observed in 2 episodes with grades 1 and 2, respectively. No other adverse events related to daratumumab were observed. ADAMTS13 response was observed in 87.5% (7/8 treatment episodes). 85.6% (6/7 episodes) had complete ADAMTS13 responses whereas 1 had near-complete response (ADAMTS13 activity 48%). The mean ADAMTS13 activity at response was 70% (n = 7, SD 23.1%). The median time to response was 2.5 weeks (range, 2-4). The median duration of this response was 19 months (max. 37 months, 1 patient was no longer responsive during his last treatment episode). After a median follow-up of 43 months, 85.7% of those patients who had been responsive (6/7 cases) maintained this response at 12 months and 28.5% of patients (2/7) at 24 months. Ultimately, relapse following daratumumab therapy was seen in 85% of patients (6/7 cases).
Discussion and Outlook
Following daratumumab, most patients that responded achieved complete ADAMTS13 recovery. At 12 months this response was maintained in the majority of patients and at 24 months only in some. Our retrospective evaluation indicates that daratumumab could be an efficacious and safe option for r/r iTTP patients failing to respond to rituximab. Prospective studies are warranted to confirm the long-term efficacy and safety of daratumumab treatment in such patients.
Disclosures: Kremer Hovinga: Federal Office of Public Health of Switzerland, Novo Nordisk, Roche, Sobi, Takeda (all honoraria go to employer: Insel Gruppe AG, Bern, Switzerland): Consultancy; Roche, Sanofi, Sobi, Takeda (all honoraria go to employer: Insel Gruppe AG, Bern, Switzerland): Speakers Bureau; Sobi, Takeda: Other: Travel support to congresses; Baxter/Takeda: Research Funding.
OffLabel Disclosure: Daratumumab is an anti-CD38 monoclonal antibody targeting plasma cells and is commonly used in the treatment of autoimmune diseases as well as plasma cell dyscrasias.