Daratumumab in patients with immune thrombocytopenia: a single-center, open-label, phase 2 trial.

Research in context

Evidence before this study

Before initiating this study, we searched PubMed on August 1, 2022, for articles published since the database inception, without restrictions on article type or language, using the search terms “immune thrombocytopenia”, “anti-CD38 monoclonal antibody” or “Daratumumab”. We found that the retrieved literature consisted primarily of case reports and review of the literature. Findings from case reports indicate that anti-CD38 monoclonal antibodies may have potential therapeutic efficacy in autoimmune cytopenias. In a case report of a patient with post-transplant immune thrombocytopenia treated with daratumumab, platelet levels demonstrated normalization following therapy. A pivotal phase 2 trial ( NCT04703621 ) by Galina Tsykunova and colleagues investigated daratumumab for the treatment of immune thrombocytopenia. Safety run-in data from this trial were first reported at the 2021 American Society of Hematology annual meeting. In the initial three patients enrolled, no grade 3 or higher adverse events were observed, and two of these patients achieved a treatment response. The final results of the study were published in Blood Advances in 2025. 21 patients were enrolled. Data showed that 48% (10 of 21) of patients met the primary efficacy endpoint, and 38% (8 of 21) achieved a sustained response. Regarding safety, most treatment-related adverse events were transient grade 1–2 in severity. However, large-scale clinical trials on the therapeutic potential and safety of daratumumab in ITP are still lacking.

Added value of this study

This single-center, open-label, phase 2 trial represents the largest clinical trial to date investigating the efficacy and safety of daratumumab for the treatment of immune thrombocytopenia. A total of 63 patients with immune thrombocytopenia were enrolled. 46 patients had a clinically meaningful increase in platelet counts within 1 week of the initial dose, underscoring the early onset of response. This therapeutic response was sustained after treatment discontinuation, with an overall response rate of 60% (38 of 63) at week 24. Daratumumab had a manageable safety profile.

Implications of all the available evidence

Anti-CD38 monoclonal antibody therapy demonstrates rapid and durable therapeutic effects in adults with immune thrombocytopenia. The therapeutic outcomes observed in this trial highlight daratumumab therapy as a promising therapeutic strategy for adult patients with immune thrombocytopenia, providing a novel alternative for patients with immune thrombocytopenia.

Introduction

Immune thrombocytopenia is an autoimmune bleeding disorder characterized by both immune-mediated platelet destruction and impaired platelet production. 1 The pathogenesis of immune thrombocytopenia is diverse, involving various immune and metabolic dysregulations. 2 , 3 , 4 Clinical presentations range from asymptomatic thrombocytopenia to spontaneous mucocutaneous bleeding, with approximately 5–6% of patients at risk of developing life-threatening hemorrhage. 5 These manifestations significantly impact patient wellbeing and quality of life. Immune thrombocytopenia affects approximately 9.5 per 100,000 adults, with an annual incidence of 2–4 per 100,000. 6 Although first-line therapies, including glucocorticoids, intravenous immunoglobulin (IVIg), and anti-RhD immunoglobulin, may provide transient platelet recovery in many cases, they usually fail to induce long-term remission. 7 Second-line options, such as thrombopoietin receptor agonists (TPO-RAs), anti-CD20 monoclonal antibodies, immunosuppressants, and splenectomy, offer variable efficacy but certain patients remain refractory. Emerging therapeutic strategies, including spleen tyrosine kinase inhibitors, bruton tyrosine kinase inhibitors, and neonatal Fc receptor antagonists, are under investigation. 8 , 9 , 10 Despite the diverse therapeutic strategies available for immune thrombocytopenia, the response to treatment and sustained remission in some cases remains problematic. Considering that high-affinity autoreactive plasma cells can disseminate through multiple organs in patients with immune thrombocytopenia, 11 , 12 which may contribute to partial treatment failure, we propose that depleting these plasma cells with the use of anti-CD38 monoclonal antibody may offer a novel therapeutic approach for immune thrombocytopenia.

CD38 is a type II glycoprotein that functions as an ectoenzyme, catalyzing the degradation of nicotinamide adenine dinucleotide (NAD) and mediating intracellular signaling, and as a receptor involved in cell adhesion. 13 CD38 is broadly expressed across multiple immune cell lineages, with particularly high surface density in plasma cells and neoplastic plasma cells associated with multiple myeloma. Anti-CD38 monoclonal antibodies was initially developed and approved for the treatment of relapsed or refractory multiple myeloma. Preclinical and clinical studies have suggested the therapeutic potential of anti-CD38 monoclonal antibody in autoimmune settings. Case reports have documented promising outcomes with daratumumab in refractory autoimmune diseases, including lupus nephritis, autoimmune hemolytic anemia, and immune thrombotic thrombocytopenic purpura. 14 , 15 , 16 In the context of immune thrombocytopenia, case series have preliminarily demonstrated the therapeutic potential of daratumumab. 17 , 18 , 19 Results from clinical trials of anti-CD38 monoclonal antibodies for immune thrombocytopenia have shown favorable safety profiles and treatment responses, 20 , 21 , 22 , 23 with efficacy observed even within one week after administration. Additionally, this therapeutic approach offers the convenience of not requiring long-term continuous dosing. Mechanistically, CD38-targeted therapy may facilitate long-term remission in immune thrombocytopenia by depleting antibody-secreting plasma cells and disrupting autoantibody production. It may also inhibit antibody-dependent cellular cytotoxicity mediated by natural killer (NK) cells and the mononuclear phagocytosis system to rapidly elevate platelet levels. 20 Additional reports have suggested that daratumumab may influence T cell transcriptional signatures and effector responses. 24

Daratumumab, as the pioneering and clinically approved anti-CD38 monoclonal antibody, has demonstrated preliminary therapeutic potential in immune thrombocytopenia, while robust clinical data on the therapeutic potential of daratumumab in immune thrombocytopenia remain lacking before the initiation of this study. To address this limitation, a prospective, single-arm clinical trial was initiated to assess the safety and efficacy of daratumumab in adult immune thrombocytopenia.

Methods

Study design and participants

This single-arm, open-label, phase 2 clinical trial ( NCT05562882 ) was conducted on adult patients diagnosed with immune thrombocytopenia at the Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. Eligible patients were aged 18 years or older with a diagnosis of persistent or chronic immune thrombocytopenia, as defined by internationally standardized diagnostic criteria. 25 Enrollment required a platelet count of less than 30 × 10 9 platelets per L during the screening period and documented failure to both standard first-line glucocorticoid therapy (either due to non-response, relapse during tapering, or inability to maintain efficacy) and at least one second-line immune thrombocytopenia therapy intervention including thrombopoietic agents and/or anti-CD20 monoclonal antibodies (either due to non-response, relapse during tapering, or inability to maintain efficacy). Completion of previous therapies was required at least 2 weeks before daratumumab initiation. Key exclusion criteria included secondary forms of immune thrombocytopenia, a history of venous or arterial thromboembolism within 12 months before the first dose, and clinically significant organ dysfunction. Full eligibility criteria are detailed in the Supplementary Methods . Clinical data, including demographic characteristics, were collected in the hematology ward. In this study, sex referred to biological sex and was self-reported by patients.

Ethics

The trial was implemented in accordance with the Declaration of Helsinki and the Guidelines for Quality Management of Pharmaceutical Clinical Trials. All study protocols were approved by the Medical Ethics Committee of Hematology and Blood Diseases Hospital (No. IIT2022039-EC-1). All authors had access to primary clinical trial data. All patients provided written informed consent prior to enrollment.

Procedures

The study protocol comprised a 4-week screening period, an 8-week treatment period, and a 16-week follow-up period. Daratumumab was administered intravenously by trained nurses in the hematology ward at a dose of 16 mg/kg once weekly for eight consecutive weeks, following administration protocols established in prior clinical studies. 26 All patients received prophylactic medications, including glucocorticoids, antihistamines, acetaminophen, and antiviral prophylaxis to mitigate adverse events. The recommended dose of methylprednisolone (or equivalent) was an initial dose of 100 mg prior to the first and second infusions, followed by a reduced dose of 60 mg prior to each subsequent infusion; and methylprednisolone (20 mg/day) on the first and second days following each of the initial two infusions. Additional details on pre-infusion management are provided in the Supplementary Methods . A single concomitant baseline medication was permitted if maintained at a stable dose for at least 4 weeks prior to enrollment. Rescue therapies, including TPO-RAs, IVIg, glucocorticoids, platelet transfusions, and anti-CD20 monoclonal antibodies, were permitted in cases of inadequate response or clinically significant bleeding.

Outcomes

The primary efficacy endpoint was the proportion of patients with two or more consecutive platelet counts of at least 50 × 10 9 platelets per L, separated by at least 1 day, within 8 weeks of initiating daratumumab. Primary safety endpoints included the incidence and severity of adverse events, graded according to the American Institute for Cancer Research Common Terminology Criteria for Adverse Events, version 5.0.

Overall response was categorized as complete response or partial response. Complete response was defined as two or more consecutive platelet counts of at least 100 × 10 9 platelets per L in the absence of bleeding symptoms. Partial response was defined as a platelet count at least 30 × 10 9 platelets per L and at least double the baseline count, with an interval of at least 7 days, without bleeding symptoms. Durable sustained platelet response was defined as the proportion of patients achieving platelet counts ≥30 × 10 9 platelets per L and at least double baseline levels in at least six out of eight follow-up visits between weeks 17 and 24. Relapse was defined as a platelet count of less than 30 × 10 9 platelets per L, failure to maintain double the baseline value, or recurrence of bleeding symptoms following an initial response. A full description of secondary endpoints is available in the Supplementary Methods .

Statistics

Sample size determination accounted for both efficacy and safety considerations. For efficacy, assuming a response rate of 40% (defined as achieving platelet counts ≥50 × 10 9 platelets per L within 8 weeks of initiating daratumumab) and a null hypothesis threshold of 20%, with an anticipated 20% dropout rate, a total of 60 patients was required to achieve 90% power at a two-sided significance level (α) of 0.05. For safety assessment, a sample size of 60 provided an 83.9% probability of detecting at least one treatment-related adverse event with an expected incidence of 3%. Calculations were performed using PASS 2022.

All enrolled patients were included in both efficacy and safety analyses. Baseline demographics and clinical characteristics were summarized using descriptive statistics. Categorical variables were presented as frequencies and percentages, while continuous variables were reported as medians and IQRs. The status after rescue therapy was classified as non-responders. Binary and continuous data obtained following the initiation of rescue therapy were classified as non-response and response-deficient data, respectively, and were subsequently excluded from time-to-event analyses. For the primary efficacy endpoint, 95% CIs were calculated using the Clopper-Pearson method. Group comparisons were conducted using the Chi-square test. Cumulative incidence curves were generated using the Kaplan–Meier method to evaluate time-to-response distributions. All adverse events reported throughout the study duration were tabulated. Statistical analyses were conducted using SPSS version 26.0, and data visualization was performed with GraphPad Prism v8. A two-tailed p value of less than 0.05 was considered statistically significant.

Role of the funding source

The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Results

Between December 10, 2022, and August 15, 2024, 63 eligible adults with immune thrombocytopenia were enrolled and completed both the 8-week course of daratumumab treatment and the 16-week follow-up period ( Fig. 1 ). All 63 enrolled patients were included in both the intention-to-treat (efficacy) and safety analyses. Baseline characteristics are summarized in Table 1 . The median age at enrollment was 33 years (IQR 23–47); 17 (27%) were male and 46 (73%) female. The median duration of an immune thrombocytopenia diagnosis was 24 months (IQR 12–60). The median baseline platelet count was 9 × 10 9 platelets per L (IQR 5–16), with 32 patients (51%) having a baseline platelet count of less than 10 × 10 9 platelets per L. Bleeding severity, as classified by the WHO bleeding scale, was grade 0 in 35 patients, grade 1 in 22 patients, and grade 2 in six patients.

Common previous therapeutic regimens included glucocorticoids (n = 63 [100%]), IVIg (n = 68 [92%]), thrombopoietic agents (n = 63 [100%]), anti-CD20 monoclonal antibodies (n = 20 [31.8%]), immunosuppressive agents (n = 18 [29%]), danazol (n = 15 [24%]), vindesine (n = 7 [11%]), and all-trans retinoic acid (n = 8 [13%]). All patients had received thrombopoietic agents; 47 (75%) had been treated with recombinant human thrombopoietin, and 63 (100%) were administered TPO-RAs. There were three splenectomized patients. A substantial proportion of patients (39 [62%] of 63) had received four or more previous therapies. At baseline, 32 patients (51%) were receiving concomitant medications, including glucocorticoids (n = 9) and TPO-RAs (n = 23). Platelet glycoprotein-specific (GP) autoantibodies were detected in 41 patients (65%). Among these, 24 patients had isolated anti-GPIIb/IIIa antibodies positivity, 4 had isolated anti-GPIb/IX antibodies positivity, and 13 had dual positivity for both autoantibodies.

Within the 8-week treatment window, 52 (83%) of 63 patients reached the primary efficacy endpoint, defined as two or more consecutive platelet counts of at least 50 × 10 9 platelets per L. Additionally, 55 patients (87%) attained platelet counts of at least 30 × 10 9 platelets per L with at least a 2-fold increase from baseline. The median time to initial platelet counts of at least 50 × 10 9 /L without rescue therapy was 1 week (IQR 1–1; Table 2 ). 46 patients reached this threshold within the first week ( Supplementary Figure S1 ). At week 8, 49 (78%) of 63 patients had an overall response, with 32 (51%) reaching complete response. The median platelet count at week 8 was 135.5 × 10 9 platelets per L (IQR 63.5–195.8). Longitudinal response trends are depicted in Fig. 2 and Supplementary Figure S2 .

The median cumulative response duration—defined as achieving platelet counts of at least 30 × 10 9 /L and at least double the baseline level—was 24 weeks (IQR 15–24). At week 24, 38 patients (60%) maintained an overall response. 38 (60%) also had a durable sustained platelet response. The median platelet count at this timepoint was 101 × 10 9 platelets per L (IQR 52–159; Table 2 ; Fig. 2 and Supplementary Figure S3 ).

Among those reaching the primary endpoint within 8 weeks, 13 patients had previously been treated with anti-CD20 monoclonal antibodies. Response rates were significantly lower in patients with previous anti-CD20 monoclonal antibodies exposure compared to those without within 8 weeks (65% [13 of 20] vs 91% [39 of 43]; p = 0.032), at week 8 (55% [11 of 20] vs 88% [38 of 43]; p = 0.003), and at week 24 (35% [7 of 20] vs 72% [31 of 43]; p = 0.005). Among 20 patients with previous exposure to anti-CD20 monoclonal antibodies, those with a previous response to such therapy exhibited numerically higher response rates for the primary endpoint (80% [4 of 5] vs 60% [9 of 15]) and at week 8 (60% [3 of 5] vs 53% [8 of 15]), but lower at week 24 (20% [1 of 5] vs 40% [6 of 15]) compared to previous non-responders. There was no statistically significant difference between the two groups ( Supplementary Table S1 ). All three splenectomized patients exhibited no response to daratumumab treatment.

Therapeutic response was further stratified by response status within 8 weeks, at week 8, and at week 24. Correlation analyses between baseline platelet glycoprotein autoantibodies and therapeutic response revealed a statistically significant difference in isolated GPIIb/IIIa antibody positivity between responders and non-responders at week 24 (p = 0.016; Supplementary Table S2 ).

At baseline, 32 patients (51%) were receiving concomitant medications. By the end of the study, 21 (66%) of these 32 patients had fully discontinued such treatments, and one patient had reduced the dosage. Two non-responders discontinued their baseline concomitant medications and initiated rescue therapy. Eight patients continued concomitant therapy through the study period ( Supplementary Table S3 ).

Bleeding symptoms improved markedly over the course of treatment. The proportion of patients with a WHO bleeding score of 0 increased from baseline to 90% (57 of 63) at week 8, whereas 8% (5 of 63) had a bleeding score of 1. One patient had a WHO bleeding score of 3 at week 8. At week 24, 52 patients (83%) remained free of bleeding events, and 11 patients (17%) had a score of 1. The frequency and severity of bleeding episodes declined significantly following daratumumab treatment ( Supplementary Figure S4 ).

During the study period, 22 (35%) of 63 patients required rescue interventions, including glucocorticoids (n = 2 [3%]), IVIG (n = 11 [17%]), TPO-RAs (n = 17 [27%]), anti-CD20 monoclonal antibodies [n = 9 [14%]), platelet transfusions (n = 2 [3%]), orelabrutinib (n = 1 [2%]), and splenectomy (n = 1 [2%]; Supplementary Tables S4 and S5 ).

All patients had grade 1 reductions in immunoglobulin levels following treatment ( Table 3 ). Infusion-related reactions were the most frequently observed adverse events, affecting 32% (20 of 63) of patients, predominantly during the first administration. Reported symptoms included chills (n = 12 [19%]), elevated blood pressure (n = 10 [16%]), chest tightness or dyspnea (n = 12 [19%]), and nausea (n = 7 [11%]; Supplementary Table S6 ). Most infusion-related events were resolved through temporary infusion interruption and infusion rate adjustment after administration of glucocorticoids. Infectious events were reported in 32% (20 of 63) of patients, with upper respiratory tract infections being the most common (n = 15 [24%]). Fatigue was noted in 13% (8 of 63) of patients. Most adverse events were grade 1–2 in severity. Five grade 3 adverse events were reported in four patients during the study, including two cases of pulmonary infection, one case of urinary tract infection, one case of gastrointestinal bleeding, and one case of right subclavian vein thrombosis ( Supplementary Table S7 ). Of these, infections were considered treatment-related, whereas gastrointestinal bleeding and thrombosis were not. Additional treatment-related adverse events are detailed in Supplementary Table S8 . No grade 4 or 5 adverse events occurred, and no deaths were reported. Treatment was neither interrupted nor modified due to adverse events.

A significant reduction in serum immunoglobulin (Ig) levels was observed following daratumumab treatment. IgG concentrations declined by 34.2% at week 4 and 46.6% at week 12 relative to baseline, followed by a gradual upward trend after week 12, although levels remained below baseline throughout the study period ( Supplementary Figure S5 ).

Discussion

This single-arm phase 2 trial explored the efficacy and safety of daratumumab in adult patients with immune thrombocytopenia refractory to first-line glucocorticoids and at least one second-line therapy, including thrombopoietic agents or anti-CD20 monoclonal antibodies. Daratumumab, administered at 16 mg/kg weekly for 8 weeks, was well tolerated and elicited rapid and sustained platelet responses.

In total, 83% (52 of 63) of patients reached the primary efficacy endpoint, with an overall response rate at week 8 of 78% (49 of 63). 46 patients had a clinically meaningful increase in platelet counts within 1 week of the initial dose, underscoring the early onset of response. These results demonstrate the potent activity of daratumumab in adult immune thrombocytopenia and are consistent with prior findings using the anti-CD38 monoclonal antibody CM313 20 , 21 and daratumumab in pediatric immune thrombocytopenia. 27 Similarly, interim results from a phase 2 trial of mezagitamab, a novel anti-CD38 monoclonal antibody, demonstrated rapid and sustained platelet responses post-therapy. 22 An investigator-initiated phase 2 study of daratumumab in adult immune thrombocytopenia (n = 21) also reported short-term improvements in platelet counts, with a median time of 7 days to first platelet count of at least 50 × 10 9 platelets per L. 23 Although differences in study design may contribute to variations in response rates, these findings collectively indicate the potential of daratumumab in achieving early treatment response. The results observed in this study are comparable to those reported for other established immune thrombocytopenia therapies. In clinical trials of TPO-RAs, hetrombopag induced a rapid platelet response within 1–2 weeks, with an overall response rate of 64.3%. 28 Eltrombopag achieved platelet counts ≥50 × 10 9 platelets per L in 86% of patients by week 2. 29 Fostamatinib, a Syk inhibitor, demonstrated an 43% overall response rate within the first 12 weeks in a pooled analysis of two phase 3 trials. 8 These agents are associated with rapid onset but typically require continuous administration to sustain effectiveness. 30 Rituximab, a monoclonal antibody targeting CD20, is widely used as a second-line therapy in immune thrombocytopenia. In a randomized controlled trial, the median time to response has been approximately 30 days, with an overall response rate of 67.4% at week 8 and a sustained response rate of 54.4% at month 6. 31

In this study, daratumumab achieved an overall response rate of 60% (38 of 63) at week 24, similar to the 64.0% reported for the anti-CD38 monoclonal antibody CM313. 20 In the ongoing clinical evaluation of mezagitamab for immune thrombocytopenia, platelet responses have been shown to persist for 8 weeks following the final dose through to week 16. 22 The median cumulative response duration in the present trial was 24 weeks (IQR 15–24). These findings are comparable to those reported for rituximab (54.4%), 31 TPO-RAs (67.0%), 32 and fostamatinib (65.7%). 30 However, given the heterogeneity in study design, response criteria, and patient populations, direct cross-trial comparisons were not undertaken.

Of the 63 patients enrolled, 20 had a history of anti-CD20 monoclonal antibody exposure. These individuals exhibited lower response rates to daratumumab compared to unexposed patients, with rates of 55% (11 of 20) vs 88% (38 of 43) at week 8 and 35% (7 of 20) vs 72% (31 of 43) at week 24. Among these 20 patients with prior anti-CD20 exposure, prior responders showed a numerically higher response rate to daratumumab within 8 weeks and at week 8, although the difference was not statistically significant. Previous anti-CD20 exposure may reflect a more refractory or severe disease state, which typically responds poorly to multiple conventional therapies. Taken together, these findings suggest that previous anti-CD20 exposure may be a clinical indicator of disease severity. Whether the specific response to previous anti-CD20 therapy could serve as a predictive biomarker for response to daratumumab requires further investigation in larger studies. Among the 32 patients receiving concomitant medications at baseline, 22 (69%) were able to reduce or discontinue these therapies without experiencing severe bleeding or requiring rescue intervention. In immune thrombocytopenia management, clinical benefit is not solely defined by platelet count elevation; prevention of bleeding complications remains a primary therapeutic objective. In this study, WHO bleeding scores declined significantly at both week 8 and week 24 relative to baseline.

Baseline positivity for isolated GPIIb/IIIa antibodies appeared to be associated with improved response to daratumumab at week 24, suggesting that this immunological profile may help identify a subset of patients more likely to benefit from CD38-targeted therapy. Similar observations have been reported in the CM313 trial, where patients positive for GPIIb/IIIa antibodies exhibited a lower recurrence rate compared to those positive for GPIb/IX antibodies. 20 The pathogenesis of immune thrombocytopenia is largely mediated by autoantibodies that recognize platelet membrane glycoprotein complexes. Anti-GPIIb/IIIa antibodies are thought to mediate platelet clearance via Fc-dependent mechanisms, 33 which may explain the enhanced responsiveness to IVIg. And similar results were observed in rituximab in immune thrombocytopenia. 34 , 35 In contrast, anti-GPIb/IX antibody-driven immune thrombocytopenia is considered to follow an Fc-independent pathway and has been associated with poorer treatment outcomes in previous studies. 36 In this trial, no significant association was observed between GPIb/IX antibody status and treatment response. Given the sample size and single-arm design, further validation of these immunological predictors in large-scale clinical studies is warranted.

Daratumumab had a safety profile consistent with that reported in earlier studies. 20 , 26 The most frequently observed adverse events were infusion-related reactions and infections, aligning with the findings from the phase 1/2 CM313 clinical trial. 20 Most adverse events were mild to moderate (grade 1–2), with infusion-related events occurring primarily during the initial administration. To reduce the risk of these events, all patients received pre-infusion and post-infusion prophylactic medications, including glucocorticoids and antihistamines. Infections occurred in 32% (20 of 63) of patients, commonly presenting as upper respiratory tract infections. Three grade 3 infections were reported, including two cases of pneumonia and one urinary tract infection, all of which responded to anti-infective therapies. As reductions in immunoglobulin levels were observed following treatment, prolonged hypogammaglobulinemia may increase infection risk. For patients with active infections or at high risk, strategies such as regular low-dose IVIg infusion or pre-study vaccination may help reduce this risk. However, given the effect of daratumumab on humoral immunity, vaccine efficacy may be compromised. Consequently, close monitoring for potential infections and periodic assessment of immune status are important.

Serum immunoglobulin levels, including IgG, IgM, and IgA, declined following daratumumab treatment and remained below baseline levels throughout the study period. Consistent with previous findings, 20 this reduction likely reflects depletion of antibody-secreting cells, leading to a down-regulation of autoantibody production and contributing to durable clinical responses in immune thrombocytopenia.

Several limitations should be mentioned. This was a single-arm, open-label study, lacking randomization or blinding, which may introduce bias in efficacy and safety assessment. The relatively small sample size and limited follow-up duration further constrain the generalizability of the findings. The age distribution was skewed with a median age of 33 years. Concomitant medications in some patients may still exert a synergistic effect with daratumumab, potentially influencing the efficacy assessment. The prophylactic administration of glucocorticoids may potentially affect the time to therapeutic response onset. Due to the small cohort of splenectomy-treated patients, we were unable to assess correlation between prior splenectomy response and daratumumab treatment efficacy. During the 24-week observation period in this study, the response rate showed a decreasing trend over time (from 78% [49 of 63] at week 8 to 60% [38 of 63] at week 24), and immunoglobulin levels remained below baseline levels, indicating the need for a longer follow-up period to further evaluate the long-term efficacy and safety of daratumumab treatment for immune thrombocytopenia. Therefore, large-scale, randomized controlled trials with extended follow-up are necessary to further confirm the clinical utility of daratumumab in immune thrombocytopenia. Additionally, health-related quality of life metrics, such as the Immune Thrombocytopenia Patient Assessment Questionnaire, were not collected. Moreover, this study lacked comprehensive assessment of immunological changes following daratumumab treatment in immune thrombocytopenia, including functional alterations in NK cells or monocytes/macrophages, as well as subsequent monitoring of platelet glycoprotein autoantibodies. These parameters may potentially explain observed platelet response post-treatment.

In conclusion, this single-arm, open-label study demonstrated that daratumumab had an acceptable safety profile and induced rapid and sustained therapeutic effects in adults with immune thrombocytopenia. These findings support daratumumab as a promising therapeutic candidate that warrants further investigation in controlled clinical trials.

Contributors

YFC, ZJH, YMX, JC, QW, TS and HYL contributed equally to this study as co-first authors. LZ and YFC contributed the design of the study. YFC and ZJH contributed to the literature search of the study. YMX, ZJH, JC, QW, TS, and HYL contributed to the preparation of figures for the manuscript. XFL, RFF, MKJ, FX, WL, HD, WJG, XYD, WTW, YC, XLP, and RCY contributed to the collection of the study. YFC, ZJH, and YMX contributed to the analysis and interpretation of the data. YFC, YMX, and ZJH verified the data and wrote the manuscript. All authors had full access to all the data in the study and approved the final version of the manuscript.

Data sharing statement

De-identified individual participant data will be made available to qualified researchers upon reasonable request. Data access may be granted by the corresponding author from 12 to 36 months following trial completion.

Declaration of interests

We declare no competing interests.

Acknowledgements

This work was supported by the grant from the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0500800 Z.L.), National Natural Science Foundation of China (82470136 Y.R.C., 82570173 L.H.Y.), CAMS Innovation Fund for Medical Sciences (2025-I2M-XHZY-034 Z.L., 2024-I2M-C&T-B-085 C.Y.F.), National Key Research and Development Program of China (2023YFC2507802, X.F.), Tianjin Municipal Science and Technology Commission Grant (25ZXZSSS00510, Z.L.), Joint Funds of the Natural Science Foundation of Tianjin (No. 25JCLMJC00700 S.T., No. 25JCLZJC00480, C.Y.F.), China Higher Education Institution Industry-University-Research Innovation Fund (2023JQ002, X.F.). We thank all the patients and their families for their participation and support, as well as all investigators who contributed to this study.

Footnotes

Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2026.103849 .

Supplementary data

Supplemental Information

Protocol and Statistical Analysis Plan

References

1. Cooper N. State of the art – how I manage immune thrombocytopenia. Br J Haematol. 2017;177(1):39–54. doi: 10.1111/bjh.14515.

2. Provan D., Semple J.W. Recent advances in the mechanisms and treatment of immune thrombocytopenia. eBioMedicine. 2022;76 doi: 10.1016/j.ebiom.2022.103820.

3. Liu J., Chen Y., O'Neill L. Phospholipid metabolism in innate immunity and inflammation: from basic to clinic. Immun Inflamm. 2025;1(1)

4. Hoffmann A., Cheng G., Baltimore D. NF-κB: master regulator of cellular responses in health and disease. Immun Inflamm. 2025;1(1) doi: 10.1007/s44466-025-00014-0.

5. Piel-Julian M.L., Mahévas M., Germain J., et al. Risk factors for bleeding, including platelet count threshold, in newly diagnosed immune thrombocytopenia adults. J Thromb Haemost. 2018;16(9):1830–1842. doi: 10.1111/jth.14227.

6. Lambert M.P., Gernsheimer T.B. Clinical updates in adult immune thrombocytopenia. Blood. 2017;129(21):2829–2835. doi: 10.1182/blood-2017-03-754119.

7. Wei Y., Ji X.B., Wang Y.W., et al. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016;127(3):296–370. doi: 10.1182/blood-2015-07-659656.

8. Bussel J., Arnold D.M., Grossbard E., et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921–930. doi: 10.1002/ajh.25125.

9. Newland A.C., Sánchez-González B., Rejtő L., et al. Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia. Am J Hematol. 2020;95(2):178–187. doi: 10.1002/ajh.25680.

10. David J., Kuter W.G., Cooper N., et al. Safety and efficacy of rilzabrutinib vs placebo in adults with immune thrombocytopenia the phase 3 LUNA3 study. Blood. 2025;145 doi: 10.1182/blood.2024027336.

11. Canales-Herrerias P., Crickx E., Broketa M., et al. High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura. J Clin Investig. 2022;132(12) doi: 10.1172/JCI153580.

12. Mahévas M., Patin P., Huetz F., et al. B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells. J Clin Investig. 2013;123(1):432–442. doi: 10.1172/JCI65689.

13. Piedra-Quintero Z.L., Wilson Z., Nava P., Guerau-de-Arellano M. CD38: an immunomodulatory molecule in inflammation and autoimmunity. Front Immunol. 2020;11 doi: 10.3389/fimmu.2020.597959.

14. Roccatello D., Fenoglio R., Caniggia I., et al. Daratumumab monotherapy for refractory lupus nephritis. Nat Med. 2023;29(8):2041–2047. doi: 10.1038/s41591-023-02479-1.

15. Schuetz C., Hoenig M., Moshous D., et al. Daratumumab in life-threatening autoimmune hemolytic anemia following hematopoietic stem cell transplantation. Blood Adv. 2018;2(19):2550–2553. doi: 10.1182/bloodadvances.2018020883.

16. Aggarwal A., White D., Pavord S., Thomas W., Desborough M.J.R. Daratumumab for refractory immune-mediated thrombotic thrombocytopenic purpura. Br J Haematol. 2023;202(2):429–433. doi: 10.1111/bjh.18854.

17. Strüßmann T., Jung J., Heinz J., et al. Long-term complete remission of refractory severe idiopathic immune thrombocytopenia (ITP) treated with daratumumab. Ann Hematol. 2023;102(1):245–247. doi: 10.1007/s00277-022-05035-y.

18. Migdady Y., Ediriwickrema A., Jackson R.P., et al. Successful treatment of thrombocytopenia with daratumumab after allogeneic transplant: a case report and literature review. Blood Adv. 2020;4(5):815–818. doi: 10.1182/bloodadvances.2019001215.

19. Zoubi I., Warwar A., Perek S., Preis M. Daratumumab and romiplostim combined therapy for a long-standing refractory primary immune Thrombocytopenia – case report. ImmunoTargets Ther. 2025;14:1–5. doi: 10.2147/ITT.S487895.

20. Chen Y., Xu Y., Li H., et al. A novel Anti-CD38 monoclonal antibody for treating immune thrombocytopenia. N Engl J Med. 2024;390(23):2178–2190. doi: 10.1056/NEJMoa2400409.

21. Chen Y., Xu Y., Dai J., et al. Anti-CD38 monoclonal antibody CM313 for primary immune thrombocytopenia: multicentre, randomised, placebo controlled, phase 2 trial. BMJ. 2025;391 doi: 10.1136/bmj-2025-084314.

22. Kuter DJ, Pulanic D, Partiarca A, et al. International Society on Thrombosis and Haemostasis (ISTH) Congress. 2024. Safety, tolerability, and efficacy of mezagitamab (TAK-079) in chronic or persistent primary immune thrombocytopenia: interim results from a phase 2, randomized, double-blind, placebo-controlled study. Abstract LB 01.1.

23. Tsykunova G., Holme P.A., Tran H.T.T., et al. Safety and efficacy of daratumumab in immune thrombocytopenia. Blood Adv. 2026;10(1):143–154. doi: 10.1182/bloodadvances.2025017279.

24. Ostendorf L., Burns M., Durek P., et al. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. N Engl J Med. 2020;383(12):1149–1155. doi: 10.1056/NEJMoa2023325.

25. Provan D., Arnold D.M., Bussel J.B., et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780–3817. doi: 10.1182/bloodadvances.2019000812.

26. Usmani S.Z., Weiss B.M., Plesner T., et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128(1):37–44. doi: 10.1182/blood-2016-03-705210.

27. Sun T., Chen Y., Zhang L. Daratumumab in relapsed or refractory pediatric immune thrombocytopenia. N Engl J Med. 2025;392(20):2069–2071. doi: 10.1056/NEJMc2501527.

28. Mei H., Liu X., Li Y., et al. A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia. J Hematol Oncol. 2021;14(1) doi: 10.1186/s13045-021-01047-9.

29. Wong R.S.M., Saleh M.N., Khelif A., et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017;130(23):2527–2536. doi: 10.1182/blood-2017-04-748707.

30. González-López T.J., Bermejo-Vega N., Cardesa-Cabrera R., et al. Fostamatinib effectiveness and safety for immune thrombocytopenia in clinical practice. Blood. 2024;144(6):646–656. doi: 10.1182/blood.2024024250.

31. Ni X., Li D., Yuan C., et al. Single-dose versus low-dose rituximab in corticosteroid-resistant or relapsed ITP: a multicenter, randomized, controlled study. Am J Hematol. 2022;97(4):440–447. doi: 10.1002/ajh.26473.

32. Lucchini E., Palandri F., Volpetti S., et al. Eltrombopag second-line therapy in adult patients with primary immune thrombocytopenia in an attempt to achieve sustained remission off-treatment: results of a phase II, multicentre, prospective study. Br J Haematol. 2021;193(2):386–396. doi: 10.1111/bjh.17334.

33. Zheng S.S., Ahmadi Z., Leung H.H.L., et al. Antiplatelet antibody predicts platelet desialylation and apoptosis in immune thrombocytopenia. Haematologica. 2022;107(9):2195–2205. doi: 10.3324/haematol.2021.279751.

34. Webster M.L., Sayeh E., Crow M., et al. Relative efficacy of intravenous immunoglobulin G in ameliorating thrombocytopenia induced by antiplatelet GPIIbIIIa versus GPIbα antibodies. Blood. 2006;108(3):943–946. doi: 10.1182/blood-2005-06-009761.

35. Feng R., Liu X., Zhao Y., et al. GPIIb/IIIa autoantibody predicts better rituximab response in ITP. Br J Haematol. 2018;182(2):305–307. doi: 10.1111/bjh.14782.

36. Peng J., Ma S.H., Liu J., et al. Association of autoantibody specificity and response to intravenous immunoglobulin G therapy in immune thrombocytopenia: a multicenter cohort study. J Thromb Haemost. 2014;12(4):497–504. doi: 10.1111/jth.12524.

Associated Data

Supplementary Materials

Supplemental Information

Protocol and Statistical Analysis Plan