Long‐term complete remissions of refractory severe idiopathic immune thrombocytopenia treated with daratumumab: A case series

Immune thrombocytopenia, also called idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura (ITP), is a common acquired autoimmune-mediated thrombocytopenia. The majority of ITP cases are primary with no known underlying medical condition. Generally, primary ITP has a good response to immunomodulatory therapies with glucocorticoids and immunoglobulins. Second-line treatments include thrombopoietin receptor agonists. In later lines, SYK-inhibitor fostamatinib, monoclonal anti-CD20 antibody rituximab or splenectomy are treatment options.1, 2 Autoantibodies against platelet membrane proteins are detectable in up to 60% of all ITP cases. The use of rituximab for selective depletion of CD20-positive B cells was reported in case reports and studies.3 However, long-term remissions differ between 10% and 40%. Following B-cell depleting therapies, refractory ITP could be caused due to antibody secretion of CD20-negative, CD38-positive long-lived plasma cells.4, 5 To date, eight cases of ITP treated with the anti-CD38 antibody daratumumab have been published, including our previously published patient.6, 7 We hereby report a case series of seven patients with refractory ITP treated with daratumumab at our centre. To our knowledge, this is the largest case series reported with the longest patient follow-up. Patients' age ranged between 22 and 87 years. Five patients had primary ITP and two patients had secondary ITP. Of these, one patient had mantle cell lymphoma (MCL) with persistent ITP after achieving a complete remission of his MCL. The other patient was diagnosed with hairy cell leukaemia (HCL), with persistent ITP in complete remission for the HCL. All patients had prior dexamethasone, TPO receptor agonist and rituximab treatment. One patient had four lines of prior therapy, all other had five or more lines of prior therapy. Daratumumab was administered in all seven patients subcutaneously with 1800 mg per injection every week. Two patients received four applications; the other patients had 10, 11, 12, 16 and 17 applications respectively. The optimal number of daratumumab injections in ITP is not known. Our patients received a minimum of four doses, but at the discretion of the treating physician, daratumumab was administered up to 12 times in responding patients and even more frequently in non-responders. Four of our patients responded to therapy with a sustained complete response (platelet count >100 × 103/μL over 3 months), the time to response was measured within in weeks (1, 3, 4, 10 weeks respectively). All responding patients are in continuous remission for now 36, 19, 18 and 9 months respectively (Table 1). Platelet counts over time are shown in Figure 1. Patient 7 is under sustained treatment with now 16 applications of daratumumab, but the patient had yet no substantial response. One patient received 17 sc applications, with only short responses and no sustained remission. One patient did not respond to four applications of daratumumab and withdrew her consent for further treatment with daratumumab. Figure 1 shows daratumumab schedule and concurrent treatments for each patient. Daratumumab is currently approved for the treatment of multiple myeloma, targeting CD38 on neoplastic plasma cells.8, 9 First evidence of efficacy of daratumumab in immune cytopenias was gained in post-transplant-related autoimmune haemolytic anaemia and immune cytopenias.10, 11 Moreover, daratumumab is effective in children and young adults with autoimmune cytopenias.11 Migdady et al. reported a case of successful treatment of immune thrombocytopenia with daratumumab after allogeneic transplant and contribute a literature review of seven patients successfully treated with daratumumab in the post-transplant setting.12 Crickx and colleagues described five cases of refractory ITP (treated with daratumumab intravenous infusions) and three out of five patients responded well with a treatment response of 3 and 12 months respectively.13 Reported patients with immune thrombocytopenia and daratumumab treatment are summarized in Table 2. The DART trial (NCT04703621) investigates daratumumab in 21 primary ITP patients (age ≥18) after failure of corticosteroid therapy and at least 1 s-line therapy, the safety run-in phase (4 weekly subcutaneous daratumumab injections) with three patients was reported on abstract basis with two of three patients responding, but one relapse by study week 24. Estimated study completion date is December 2024.14 Recently, Chen and colleagues reported on a phase 1–2 study of CM313, a novel anti-CD38 monoclonal antibody, in 22 ITP patients with promising results.15 Depletion of long-lived plasma cells may be an important mechanism to induce remission in otherwise refractory ITP. However, not all of our patients respond to daratumumab, and relapses after anti-CD38 mAb treatment have been reported.14, 15 Other mechanisms, such as T-cell-dependent autoimmune responses against platelets and megakaryocytes in ITP, may play a role in potentially preventing a response to anti-CD38 treatment.16 In conclusion, daratumumab appears to be a valid treatment option for refractory ITP patients and may lead to durable responses in a proportion of treated patients. In our patient cohort, daratumumab subcutaneous administration was safe and resulted in long-term remissions in four of seven patients. Additional data from prospective clinical trials are awaited. TS performed data collection and analysis and wrote the manuscript. JH performed data acquisition and interpretation. RW performed data collection and interpretation. JJ performed data acquisition. ME performed part of the data collection and analysis. JD provided administrative support. JF provided administrative support. JD-A and RM contributed to data collection and analysis and supervised the project. All authors revised the paper critically. All authors approved the submitted and final version of the manuscript. This work was supported by Comprehensive Cancer Center Freiburg. The authors have declared no conflicts of interest. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. The datasets used and/or analysed during the current study are available upon reasonable request from the corresponding author.