Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy (TMA) caused by a severe lack of activity of ADAMTS13 caused by autoantibodies. It is characterized by microangiopathic hemolytic anemia, decreased depletion of platelet aggregation, and organ damage (eg, kidneys, central nervous system, etc.) caused by microthrombosis. Until effective treatment is available, the case fatality rate exceeds 90%. With the clinical application of plasma exchange (PE), the prognosis has greatly improved, and the case fatality rate has dropped to 10 to 20%. But at least 30% of patients relapse after the first treatment. Current administration of iTTP includes plasmapheresis, corticosteroid immunosuppression, and rituximab (anti-CD20 antibody).
Caplacizumab is a recently introduced anti-VWF nanoantibody that helps with faster remission and reduces morbidity and mortality. Rituximab reduces the risk of recurrence, but still fails to normalize ADAMTS13 activity in 15% of cases. Treatment of relapsed or refractory iTTP remains a challenge. These patients receive additional cycles of rituximab, second-generation cd20 monoclonal antibody, bortezomib, cyclosporine, cyclophosphamide, or splenectomy. On February 4, 2022, an article was published on blood advances, which first reported Daratumumab's treatment of iTTP, resulting in a rapid and complete remission of ADAMTS13 activity in 2 patients, and the inhibition of ADAMTS13 disappeared. One patient had frequent relapse of iTTP and the other had primary refractory iTTP.
Case data
Case 1:
The patient, a 32-year-old male, was successfully treated with PE and corticosteroids in 2014 with severe ADAMTS13 deficiency < due to the first episode of iTTP with suppressive autoantibodies. The first and second relapses occurred 20 months and 54 months after the initial episode, respectively. Remission is achieved by PE and corticosteroids, while rituximab is given 4 times (375 mg/m2) after the first recurrence, adamts13 activity > 90% until the next recurrence. The 3rd recurrence occurred after another 20 months (Table 1; Figure 1A). In addition to PE and corticosteroids, patients were treated with Caplacizumab and received 4 more doses of rituximab (375 mg/m2). Despite achieving a clinical response, severe ADAMTS13 deficiency and inhibitors persisted over the next 4 months. Considering the high risk of clinical recurrence of the disease, the researchers decided to infuse Daratumumab 4 times a week.
Case 2:
The patient, female, 31 years old, was diagnosed with acute TMA at the 38th week of the second pregnancy. HELLP (hemolytic, elevated liver enzymes, hypoplatelet) syndrome, caesarean section is suspected, but laboratory signs and symptoms of TMA persist. Severe ADAMTS13 deficiency (<5%) due to the detection of inhibitor presence confirms iTTP (Table 1; Figure 1B). The researchers began giving patients PE and corticosteroids. The platelet count rose to 50×109/L but did not return to normal until Caplacizumab was added on day 14 of PE, and by day 29, 4 doses of rituximab (375 mg/m2) had been given. The administration of the drug is suspended because the patient wishes to breastfeed. Despite documented depletion of B cells, ADAMTS13 failed to improve and Caplacizumab must be continued to prevent clinical recurrence. After that, the researchers decided to infuse Daratumumab 6 times a week.
Table 1 Patient characteristics of acute onset of iTTP and treatment including Daratumumab
Figure 1 Anti-CD38 antibody Daratumumab treated with iTTP. Clinical course and selected laboratory parameters of 2 patients from hospitalization to the most recent follow-up. Treatment is started with high-dose corticosteroids and then tapered gradually. In patient 2, the daily administration of Caplacizumab was reduced to once every other day after 90 days. (A) Patient 1 recurrent iTTP; shows the course of his recent iTTP recurrence. (B) Patient 2 has the first episode of refractory iTTP. The red line indicates the titer of the ADAMTS13 inhibitor (Bethesda unit [BU]/mL; truncated to 2); the blue line indicates the ADAMTS13 activity (%); and the gray line indicates the platelet count (×109/L).
Case discussion
In the above two patients, the administration of Daratumumab, an anti-CD38 antibody approved for the treatment of multiple myeloma, rapidly clears the ADAMTS13 inhibitor and restores normal ADAMTS13 activity (Figure 1). In Patient 1, investigators observed inhibitor disappearance and normalization of ADAMTS13 activity 1 week after the first infusion. 14 weeks after completion of Treatment with Daratumumab, a complete clinical response to the patient's ADAMTS13 is underway. In patient 2, a partial response to ADAMTS13 (increase in activity to 25%) was observed 1 week after the second infusion, and a complete response to ADAMTS13 was observed after 2 weeks. Caplacizumab discontinued the drug after 121 days. 10 weeks after completion of Daratumumab treatment, the patient's complete clinical response to ADAMTS13 is still underway.
Due to Daratumumab's good safety profile, Daratumumab was chosen as a plasma cell-targeted therapy over other options such as bortezomib. In both cases, Daratumumab was indeed well tolerated, with only during the first infusion that patient 1 developed a grade 1 adverse reaction (mild chest compression) and patient 2 developed a grade 2 reaction (flushing, hoarseness, nausea).
Despite previous treatment, the researchers speculate that Daratumumab's response is due to Daratumumab's depletion of CD381 cells (usually plasma cells and most plasma blast cells) that produce pathogenic ADAMTS13 antibodies and may have additional immunomodulatory activity. This is based on evidence that severe ADAMOTS13 deficiency observed in 2 patients 30 days after rituximab application predicts a lack of response to rituximab in the later stages. After the first relapse, patient 1 receives rituximab therapy, which is effective at the time. Rituximab therapy is ineffective after the most recent relapse, as has been shown in the spleen of immune thrombocytopenia and frequent relapses of iTTP treated with rituximab. Rapid remission and clearance of autoantibodies after administration of Daratumumab has also been observed in other autoimmune diseases and graft-versus-host patients, consistent with trials involving patients with multiple myeloma. At the investigator's institution, the patients tolerated Daratumumab well and no complications of infection were observed.
summary
This is the first time that Daratumumab has been reported to normalize ADAMTS13 activity rapidly in 2 patients with iTTP, the inhibitors disappear, and it is stable for 14 and 10 weeks after completion of treatment, with no associated adverse events. The researchers speculate that the addition of Daratumumab to standard therapy, thereby targeting pathogenic plasma cells that produce inhibitors, is conducive to the clearance of inhibitory autoantibodies of ADAMTS13 in relapsed or refractory iTTP and the recovery of ADAMTS13 activity. In the future, long-term efficacy and safety studies of Daratumumab plasma cell targeted therapy in patients with iTTP are required.
bibliography
Jana van den Berg,1,2 Johanna A. Kremer Hovinga, et al. Daratumumab for immune thrombotic thrombocytopenic purpura. Blood advances, 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3.