Daratumumab, an original approach for treating refractory autoimmune cytopenia

2021 
Background: Patients with autoimmune cytopenias failing first- or second- line treatments have an increased morbidity and mortality, and therapeutic alternatives are needed. Daratumumab, an anti-CD38 monoclonal antibody developed for multiple myeloma, could target long-lived autoreactive plasma cells. Aims: The aim of the study was to assess safety and efficacy of daratumumab given for refractory autoimmune cytopenias. Methods: We conducted an observational, retrospective, multicenter study throughout the network of the French reference center for adult' immune cytopenias including patients receiving compassionate off-label treatment by daratumumab for either refractory immune thrombocytopenia (ITP) or warm autoimmune hemolytic anemia (wAIHA) between 2020 and 2021. Response was assessed according to international criteria. Patients who required any other treatment more than six weeks after first daratumumab infusion were considered non-responders. Results: Eight patients (5 female) with a median age of 45 years [range 34-70] were included in the study. Treatment by daratumumab was given for ITP (5 patients), wAIHA (2 patients), and acquired Glanzmann thrombastenia complicating ITP (1 patient) with a median disease duration of 84.5 months [range 18-174]. Five patients had underlying Evans syndrome and one patient had ITP secondary to antiphospholipid syndrome. Five patients were splenectomized and all 8 patients failed to respond to rituximab (median time from last infusion of 11 months [3-98]). Patients received a median number of 6 [range 4-11] weekly infusions of daratumumab at 16mg/kg of body weight with dexamethasone premedication. Median follow up after daratumumab was 6 months [range 3-9]. Three patients had a minor reaction at first daratumumab infusion. Two patients had infectious events during follow up (one bacterial pneumonia and one COVID-19 pneumonia). After exclusion of 2 patients who received regular intravenous immunoglobulin, hypogammaglobulinemia (i.e., gammaglobulins <6g/L) was observed in 5/6 patients. Median concentration of gammaglobulins was 7.1 g/L [4.8-16.2] before treatment, versus 4.2 g/L [3.5-7.6] at 3 months and 6.1g/L [6-15.5] at 9 months. Five patients were given daratumumab for ITP with low platelet counts (median 11 x109/L, [range 0-21]). Two achieved a CR after respectively 3 and 4 infusions, including one of who relapsed after 3 months. Anti- β2GP1 antibodies and lupus anticoagulant disappeared upon treatment in the patient with antiphospholipid syndrome. Another steroid dependent patient required a transient increase in corticosteroid doses one month after daratumumab, but with a definite weaning at 6 months. The remaining 2 patients had no response. Two patients had wAIHA and a positive IgG DAT (no C3). One patient received 4 daratumumab infusions associated with corticosteroids tapered during 6 weeks, resulting in a CR that lasted 9 months. The other patient had no response. Daratumumab had no clinical efficacy in the patient with an ITP that had acquired Glanzmann thrombastenia with bleeding symptoms despite normal platelet counts. Summary/Conclusion: Overall, these data suggest that daratumumab may be effective in a subset of patients with autoimmune cytopenia refractory to standard therapy. The response appears transient as some patients with CR eventually relapsed during the follow-up. As most patients experienced transient hypogammaglobulinemia, the risk of infection should be weighted in the therapeutic decision. Prospective studies are needed to confirm these preliminary data.
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