Daratumumab can lead to long-lasting remissions in patients with refractory immune thrombocytopenia but with a high incidence of severe infections Free

Introduction Despite the increasing number of therapeutic options for immune thrombocytopenia (ITP), refractory disease remains an unmet need in clinical practice. Anti-CD38 monoclonal antibodies such as daratumumab have recently been shown to be a promising treatment in ITP. The aim of this study was to assess safety and efficacy of daratumumab given for refractory ITP.

Patients and 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 ITP (either primary or secondary) between 01/01/2020 and 01/06/2025. ITP was diagnosed according to international guidelines. Patients were excluded if daratumumab was given to treat plasma cell malignancy. Complete response (CR) was defined by platelet count >100x10⁹/L and response (R) by platelet count 30 to 100x10⁹/L with at least a 2-fold increase from baseline. Patients who required any other treatment including rescue therapy more than six weeks after first daratumumab infusion were considered non-responders regardless of platelet counts. All patients were informed and gave consent to ‘off-label’ use of daratumumab. The study received institutional review board approval (00011558, UPEC University, AP-HP).

Results Twenty-one patients (43% females) with a median age at first daratumumab infusion of 67 years [range 21-88] were included in the study. Eight had secondary ITP (38%; Evans syndrome, n=6, and/or antiphospholipid syndrome (APLS), n=2, or rheumatoid arthritis, n=1). In addition, 2 patients had antibodies against GPIIb-IIIa (acquired Glanzmann syndrome, n=1) and GPVI (n=1) responsible for chronic bleeding symptoms.

Median ITP duration was 78 months [range 4-594], and patients had previously received a median number of 8 [range, 3-12] treatment lines for ITP, including corticosteroids (100%), rituximab (100%), intravenous immunoglobulin (95%), thrombopoietin receptor agonists (95%; including eltrombopag [90%] and romiplostim [86%]), mycophenolate mofetil (81%), splenectomy (71%), fostamatinib (48%), and one or more other immunosuppressive drug (43%). Fifteen patients (71%) had bleeding symptoms despite treatment in the previous month.

Patients received a median number of 6 [range 3-20] infusions of daratumumab either at 16mg/kg of body weight intravenously (n=10) or at a fixed dose of 1800 mg subcutaneously (n=11) with dexamethasone premedication. Daratumumab was given with other ITP treatments in 15 patients (71%).

Median follow up after daratumumab was 16 months [range 1-60]. Ten (48%) patients had adverse events imputable to daratumumab, including 5 patients (24%) with infectious events requiring hospitalization (sepsis, n=2, bacterial pneumonia, n=2, acute tonsillitis, n=1), 2 patients with transient neutropenia (but without infection), and 3 patients with immediate reaction after infusion. During follow-up, 4 patients (19%) died (1 splenectomized patient had campylobacter sepsis 1 month after daratumumab initiation, 1 patient with stroke and APLS had sepsis 23 months after daratumumab, 1 patient died from refractory ITP, and 1 patient with metastatic cancer died from cardiac failure). In the 6 months following daratumumab, among the 10 patients with available gammaglobulin assessment without intravenous immunoglobulin administration, 8 (80%) had concentrations below 6g/L.

Overall response (CR+PR) was achieved in 11 patients (52%), including 9 CR (43%), and 2 PR (10%), with a median time to response of 35 days [range 7-84]. Relapses occurred in 3/7 (43%) of responders that had a follow-up >6 months after daratumumab. Four patients had long-lasting CR without any other ITP treatment, with relapses in 2 (50%) after 10 and 32 months, respectively. Two patients with initial CR and experiencing a relapse had a second course of daratumumab, resulting in 2 new initial CR but eventually with relapses in both patients.

Discussion Overall, these results suggest that daratumumab has the potential to induce durable remissions even in multirefractory ITP patients, although response appears transient in most responders. However, this came at the cost of a high rate of severe infections in this particular group of heavily treated, frequently splenectomized, immunocompromised and fragile patients. Careful assessment of benefit/risk balance is therefore warranted before daratumumab administration.