Daratumumab for refractory immune-mediated thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition usually associated with IgG antibody-mediated destruction of the disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) enzyme. In the United Kingdom, acute TTP is treated with plasma exchange (PEX), methylprednisolone, rituximab and caplacizumab.1, 2 Plasma exchange is typically continued until the platelet count is ≥150 × 109/L for two consecutive days, and caplacizumab is continued until ADAMTS13 activity of 30 IU/dL or more on two consecutive occasions after completing plasma exchange.3 A small proportion of patients have a persistent low ADAMTS13 after treatment despite platelet recovery.4 The optimal immunosuppression regimen for these patients is unclear and several strategies have been tried including mycophenolate,5 azathioprine,6 bortezomib7 and more recently daratumumab.8 Van den Berg et al published a case series of two patients with relapsed/refractory TTP,8 both of whom had rapid eradication of the anti-ADAMTS13 IgG antibody titre and normalisation of ADAMTS13 activity within 2 weeks after starting daratumumab. We report the outcomes for the first two patients treated with daratumumab for refractory immune-mediated TTP in the United Kingdom. In case 1, daratumumab was started for refractory TTP because of a persistently undetectable ADAMTS13 activity 105 days after diagnosis. Daratumumab was administered subcutaneously at a standard dose of 1800 mg with 20 mg of oral dexamethasone. Montelukast 10 mg, chlorphenamine 4 mg and paracetamol 1 g were administered to prevent infusion reactions. 20 mg dexamethasone was given for 2 days after daratumumab. The dose of dexamethasone was reduced to 12 mg for the subsequent dose of daratumumab. This patient reached a partial ADAMTS13 response (ADAMTS13 activity 20 IU/dL or greater) after 32 days and was still in partial ADAMTS13 remission at 90 days. The anti-ADAMTS13 IgG antibody titre was 66 IU/mL prior to daratumumab and was undetectable at 90 days (Table 1; Figure 1). Refractory anti-ADAMTS13 IgG antibody Clinical relapse on stopping caplacizumab on day 81. Restarted caplacizumab from day 97 until day 166 Anti-ADAMTS13 IgG antibody titre 66 IU/mL Antigen 54 IU/dL Activity 0 IU/dL Anti-ADAMTS13 IgG antibody titre 129 IU/mL Antigen 53 IU/dL Activity 0 IU/dL In case 2, daratumumab was started for refractory TTP because of a persistently undetectable ADAMTS13 activity 238 days after diagnosis. Daratumumab was given weekly via the intravenous route at 16 mg/kg with dexamethasone 20 mg each time. Chlorphenamine 10 mg and paracetamol 1 g were administered to prevent infusion reactions. The anti-ADAMTS13 IgG antibody titre was 129 IU/mL prior to daratumumab and undetectable at 90 days. ADAMTS13 activity remained undetectable at 90 days. The subcutaneous 1800 mg of daratumumab and weight-based intravenous dosing have been directly compared and have been shown to have equivalent in terms of pharmacokinetics and efficacy in myeloma patients.9 Both patients provided written consent for off-label use of daratumumab. The daratumumab was funded on an individual basis by the hospital trusts. ADAMTS13 activity (TECHNOZYM® ADAMTS13 Activity ELISA Kit), ADAMTS13 antigen (TECHNOZYM® ADAMTS13 Antigen ELISA Kit) and anti-ADAMTS13 IgG antibody titres (TECHNOZYM® ADAMTS13 INH ELISA Kit) were determined by ELISA method. ADAMTS13 activity was typically performed within 24 h of sample collection, whereas ADAMTS13 antigen and anti-ADAMTS13 IgG antibody titres were analysed in batches, delaying incorporation of the results into the clinical management. Remission criteria followed the recommendations of the International Working Group for Thrombotic Thrombocytopenic Purpura consensus report.10 In both cases, the anti-ADAMTS13 IgG antibody improved after the administration of daratumumab and was negative 90 days after daratumumab. In case 1, the patient reached partial ADAMTS13 remission 38 days after two doses of daratumumab. In case 2, the anti-ADAMTS13 IgG antibody was negative by 90 days but this did not correspond with an increase in ADAMTS13 activity. In case 1, there may have been a better response if the patient had completed four doses of daratumumab. In both cases, the anti-ADAMTS13 IgG antibody titre had started falling prior to starting daratumumab and this may represent a delayed effect from the previous immunosuppressant treatments. By contrast to our results, in the Van den Berg case series,8 there was rapid improvement in ADAMTS13 activity within 2 weeks for both the patients they reported. The majority of evidence in treating relapsed/refractory TTP is for anti-CD20 therapy.11, 12 However, in patients who are refractory to these, additional therapies to bring down the anti-ADAMTS13 IgG antibody and restore ADAMTS13 activity are an unmet need. In these patients, if caplacizumab is stopped, they are at risk of clinical relapse, as was demonstrated by case 1. No therapies have clear evidence of efficacy in patients who are refractory to rituximab and oral immunosuppression. While it is an elegant proposal that targeting plasma cells rather than B cells will lead to a rapid clearance of the anti-ADAMTS13 IgG antibody, our results show that this is not the case in all patients. Xie et al.13 have recently published a case series of daratumumab used as part of initial combination treatment. In all three patients, clinical remission was achieved. Given the small numbers, it is unclear whether daratumumab improves the chance of clinical remission after initial treatment. Daratumumab is principally used as a treatment for plasma cell dyscrasias. However, there are case reports of Daratumumab being used to treat patients to remission for autoimmune haematological disorders including immune thrombocytopenia and warm autoimmune haemolytic anaemia.14 In summary, we present the data on the first two patients treated in the UK with daratumumab for refractory immune TTP. Both had a reduction in anti-ADAMTS13 IgG antibody titres after daratumumab and had negative anti-ADAMTS13 IgG antibody titres by 90 days. One patient reached partial ADAMTS13 remission and one had an unchanged ADAMTS13 activity 90 days after treatment. As daratumumab was given after other immunosuppressant therapies and in both cases the anti-ADAMTS13 IgG antibody titres were starting to fall before starting daratumumab, it is possible that they may have confounded the interpretation of response to daratumumab. Further studies are needed to ascertain the role plasma cell-directed therapy may play in the treatment of relapsed/refractory TTP. AA wrote the first draft of the manuscript and performed the analysis with input from WT and MJRD. WT and MJRD conceived the idea for the manuscript. DW performed laboratory analysis. SP, WT and MJRD managed the patients. All authors critically reviewed the manuscript. AA and MJRD had access to the full data set. We would like to thank Peter Baker and Sarah Harper for running the ADAMTS13 assays in Oxford. We would like to thank Ruth Jolley and Viv Garcia for clinical care of the patients in Cambridge. WT—advisory boards for Sanofi and Ablynx. Support to attend educational meetings from Octapharma. Advisory boards and speakers fees from Takeda are all unrelated to this work. MJRD—advisory boards or speakers' fees for Amgen, Pfizer, Portola, Sanofi and Takeda all unrelated to this work. SP—received fees for educational talks and advisory boards from Sanofi and Alexion. The other authors have no conflicts of interest to declare. Dr Desborough and Dr Thomas will consider requests to share anonymised data via email at: [email protected]. Submitted requests will require a protocol detailing hypothesis, aims, analyses and intended tables and figures. Where possible, we will perform the analyses; alternatively, de-identified data and a data dictionary will be supplied for the necessary variables for remote analysis. Any sharing will be subject to a signed data access agreement.