Efficacy of daratumumab in treatment of relapsed and/or refractory warm autoimmune hemolytic anemia in children

Abstract Introduction: Severe warm autoimmune hemolytic anemia (wAIHA) in children carries a high mortality rate. While steroids remain the first-line treatment for wAIHA, achieving sustained response is challenging in majority of cases due to steroid refractoriness/side effects. Treatment options for steroid dependent, refractory/relapsed (r/r) wAIHA include rituximab, mycophenolate mofetil (MMF), and other immunosuppressants with splenectomy reserved for select cases. Though the therapeutic landscape of wAIHA has drastically expanded with the advent of several targeted agents, consensus and guidelines are lacking on the optimal treatment approach. Daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells, approved for multiple myeloma treatment, has recently been successfully used for treatment of post-transplant r/r autoimmune cytopenias including wAIHA, immune thrombocytopenia (ITP), Evans syndrome, and red cell aplasia in pediatric and adult patients. Additionally, successful off-label use of daratumumab was described in a prospective study of adult patients with r/r primary or non-post-transplant secondary wAIHA. We present our experience with daratumumab in 4 pediatric patients with r/r wAIHA (1 with remote cardiac transplant and 3 in non-transplant settings). To our knowledge, it is the first case series of this sort in pediatric population. Methods: Case series, retrospective chart review. Patient 1: A 20 years old female with r/r wAIHA initially diagnosed at age 12 with underlying RELA haploinsufficiency. She was treated with steroids, rituximab, cyclosporine A (CSA), MMF, bortezomib, abatacept, sirolimus, and fostamatinib with multiple relpases. She received 8 weekly doses of daratumumab (16mg/kg) with good response seen in 3 weeks, remained transfusion independent for 13 months followed by a relapse and received a second similar course of daratumumab with excellent response; remains transfusion free at 11 months follow up. Patient 2: A 14 years old female, with orthotopic heart transplant at age 8 months. Two years following transplant, she had post-transplant EBV negative lymphoproliferative disease with associated ITP and wAIHA which responded to withdrawal of tacrolimus and rituximab. She remained in remission until 12 years of age when she was diagnosed with wAIHA, refractory to multiple treatments (steroids, sirolimus, rituximab, bortezomib, CSA, intravenous (IV) immune globulin, darbepoetin). She received daratumumab with excellent response in 1 week; remains transfusion independent at 26 months. Patient 3: A 10 years old male, with history of ITP and subsequent wAIHA (Evans syndrome), initially responded to high-dose IV steroids, however developed rapid worsening of hemolysis upon attempt to switch to oral prednisone. He was deemed a poor candidate for rituximab due to hypogammaglobulinemia and suspected underlying immunodeficiency. He was started on MMF and daratumumab with remarkable recovery of hemolysis within 1 week; remains transfusion independent at 1 month follow-up. Patient 4: A Caucasian girl diagnosed at 5 months of age with immunoglobulin G & complement mediated wAIHA initially responsive to prednisone and rituximab; she developed nephrotic syndrome and lupus nephritis by 1 year of age, complicated by renal failure. Multiple relapses of wAIHA were treated with rituximab, cyclophosphamide, CSA, MMF, sirolimus, eculizumab, raviluzimab, and pegcetacoplan. She received 3 doses of daratumumab towards end of life but succumbed to her disease without signs of hematological response. Results: In our cohort (n=4) of r/r wAIHA, 3/4 patients (75%) responded to daratumumab. Time to response was 7-21 days (median=7, mean=11) and demonstrated transfusion independence at a median follow-up of 12 months. Relapse occurred in 1/4 patients (25%). All patients received other immunosuppressive treatments before or with daratumumab. Conclusions: In our experience daratumumab showed remarkable efficacy in treating r/r wAIHA in children. Responses were seen, both in heavily pretreated patients and when daratumumab was used as second-line agent. Additionally, repeat course of daratumumab was found effective in achieving disease control. In conclusion, this case series demonstrates daratumumab as a potential second-line as well as adjunct upfront therapeutic option for r/r and acute severe wAIHA respectively. We emphasize the need for prospective clinical trials and standardized guidelines for wAIHA treatment.