The Novel Use of Daratumumab for Pediatric TTP: A Case Series of Two Pediatric Patients with Refractory TTP

Thrombotic thrombocytopenic purpura (TTP) is a rare microangiopathy in children due to either a congenital or acquired functional deficiency of the ADAMTS13 protein, which cleaves von Willebrand factor (vWF) multimers. Excess vWF causes microthrombi to form within the vasculature causing organ damage, most notably renal and neurologic dysfunction. Acquired TTP is due to anti-ADAMTS13 IgG autoantibodies, which can be triggered by infections, autoimmune diseases, and neoplasms, although over 50% of cases are idiopathic. Treatment includes high dose steroids, plasma exchange, and immune modulators such as rituximab and caplacizumab. Even so, acquired TTP is difficult to treat and refractory disease is common, which is further complicated by the rarity of TTP in children and lack of evidence to guide treatment options. Thus, treatment of refractory TTP relies on the off-label use of certain immune modulators, such as daratumumab. Daratumumab is an anti-CD38 antibody, which has been shown to normalize ADAMTS13 levels in a case series of adult patients with TTP (van den Berg, 2022). The current case series presents two pediatric patients with refractory acquired TTP who required extensive therapy with a variety of agents, with one patient receiving daratumumab, and another requiring long-standing immunosuppression. To our knowledge, this is the first published case of a pediatric patient receiving daratumumab for the treatment of acquired TTP.

We reviewed two cases of pediatric TTP at our children's hospital. Case 1 is a 10-year-old previously healthy male. Case 2 is a 16-year-old previously healthy female. Charts were reviewed for provider notes, lab results, such as complete blood count, comprehensive metabolic panel, ADAMTS13 activity level, inhibitor level, brain imaging results if available, and type of treatment agent utilized.

Case 1 discusses a 10-year-old male who developed acquired TTP after he was found to be thrombocytopenic. His course was complicated by seizures, altered mental status, hypertension, and membranous nephropathy. He was initially treated with IV steroids, plasma exchange, and rituximab, as caplacizumab was not the standard of care at that time. He was also started on antihypertensives. However, his ADAMTS13 levels continued to be low at follow-up and therefore he was re-started on IV steroids. Ultimately, he was continued on rituximab, weaned off steroids, and mycophenolate mofetil (MMF) was added. One year after diagnosis, his ADAMTS13 levels remained >100%, and thus, rituximab was discontinued and MMF was decreased. Two years after diagnosis, he remained in remission on the decreased dose of MMF with plans to taper off MMF over the course of the year.

Case 2 discusses a 16-year-old female who also developed acquired TTP and was initially treated with IV steroids, plasma exchange, rituximab, MMF, and a 28-day course of caplacizumab. However, she also experienced an acute relapse, requiring re-admission for plasmapheresis and IV steroids. She was continued on rituximab, MMF, and re-started caplacizumab. A lymphocyte subset panel was ordered to help dictate treatment and showed CD19 B cells were minimally present. Therefore, rituximab was discontinued and in turn, she was started on a 4-week course of daratumumab with notable increases in her ADAMTS13 levels. Given her response, she remains on daratumumab every 3 months.

These two cases demonstrate the prolonged treatment course and multiple immune modulators needed to treat refractory TTP, highlighting the challenges of treating refractory TTP in children. Further, TTP has a high morbidity and mortality rate, with complications arising from prolonged hospital stays, central lines needed for plasmapheresis, and immunosuppression. Therefore, future studies are needed to help guide treatment options for acquired and refractory TTP. This case series demonstrates novel treatment regimens, including daratumumab. Case 2 reveals the promising effects of daratumumab in treating refractory TTP and to our knowledge, is the first published case in the United States in which daratumumab was used as an adjunct therapy for refractory TTP in a pediatric patient. While encouraging, further research is needed to investigate the efficacy and adverse effects of daratumumab in this population.

Panigrahi:Alexion Pharmaceuticals: Speakers Bureau.

This presentation discussed the off-label use of Daratumumab for the treatment of Pediatric refractory TTP.