Abstract
Treatment-refractory autoimmune cytopenias (AIC) including immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome (ES) lack therapies providing durable remission. We conducted a retrospective cohort study of 22 adults with refractory primary AIC who received single low-dose daratumumab (100 mg, day 0) combined with rituximab (100 mg weekly ×4 doses) and glucocorticoids. Primary endpoints were overall response rate (ORR), complete response rate (CRR), relapse-free survival (RFS), and safety. Among participants (median age 63.0 years; 81.8% female), 95.5% achieved initial response (CRR 27.3%; partial response rate 68.2%) with median time-to-response 7 days. At median follow-up 322 days, sustained ORR was 81.8% with CRR 59.1%. with disease-specific rates: CRR/ORR of 60.0%/80.0% (AIHA), 60.0%/70.0% (ITP), and 57.1%/100.0% (ES). Cumulative CRR by subtype were 75% (AIHA), 80% (ITP), and 65.7% (ES) (P = 0.031). The median RFS was not reached during the follow-up period. Averse events occurred in 36.4% of patients, primarily infections (27.8%; herpesvirus, urinary/respiratory tract) and rash (9.1%); all resolved with intervention. In conclusion, this dual-pathway targeting regimen induced rapid, durable hematologic responses in refractory AIC with manageable toxicity. The single low-dose daratumumab approach demonstrates significant clinical feasibility, potentially redefining therapeutic paradigms for antibody-mediated autoimmune disorders.
Keywords: Autoimmune cytopenia, CD20 monoclonal antibody, Rituximab, CD38-targeting antibody, Daratumumab
Introduction
Autoimmune cytopenias (AIC), encompassing autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), Evans syndrome (ES) and autoimmune neutropenia (AIN), represent a group of disorders characterized by immune-mediated destruction of one or more hematopoietic cell lineages. Although bone marrow involvement—such as complement activation and T‑cell‑mediated immunity in immune thrombocytopenia (ITP) or complement cascade activation leading to reticulocytopenia in autoimmune hemolytic anemia (AIHA)—has been described, most cases of autoimmune cytopenias (AIC) result from destruction of mature cells in the peripheral blood [1]. These conditions can lead to significant morbidity, including profound anemia and thrombocytopenic bleeding. Although infections have been reported in patients with AIC, the increased risk is primarily related to treatment rather than the disease itself, substantially impacting patients’ quality of life and survival [2–6]. The standard first-line treatment for AIC typically involves corticosteroids, which induce remission in a significant proportion of patients [7]. However, 30–50% of patients exhibit corticosteroid dependence, experience intolerable side effects from prolonged steroid use or become refractory to this first-line approach [8–10]. For these patients, second-line therapies are essential. Rituximab, a monoclonal antibody targeting CD20 on B lymphocytes, has emerged as a widely used and often effective first- or second-line agent, demonstrating response rates in the range of 50–80% across various AIC subtypes [2, 9, 11, 12]. However, responses are often transient, relapse rates remain substantial—especially in refractory disease or ES—and not all patients respond [2–4, 9, 10, 13]. A primary mechanism underlying treatment failure involves the persistence of long-lived plasma cells (LLPCs), which are CD20-negative and thus resistant to rituximab. In AIC, B-cell depletion can induce splenic short-lived plasma cells to reprogram into LLPCs, contributing to relapses and refractory disease [14–16]. Therefore, therapies capable of targeting plasma cells directly are urgently needed to achieve deeper and more durable responses [4, 5, 17].
Daratumumab, a human IgG1κ monoclonal antibody targeting CD38, depletes CD38-expressing plasma cells and has revolutionized multiple myeloma therapy [5, 13, 17, 18]. Its high specificity for CD38—highly expressed on plasma cells, including those producing pathogenic autoantibodies—makes it a compelling candidate for antibody-mediated autoimmune diseases such as AIC [4, 5, 13, 18]. More recently, daratumumab has shown encouraging activity in relapsed/refractory AIC, supported by prospective studies such as the DART trial in immune thrombocytopenia (ITP) [15] as well as multiple small series and case reports [4, 5, 17–19]. The emerging efficacy of novel anti‑CD38 antibodies has been further demonstrated by a phase 1‑2 trial of CM313 in refractory ITP (95% overall response rate) [20] and a phase 2 study of mezagitamab in chronic/persistent primary ITP [21]. However, although both daratumumab and rituximab have been studied individually, their combination has not been systematically evaluated in AIC. Furthermore, existing studies have used myeloma-adapted daratumumab dosing (16 mg/kg); the use of low-dose daratumumab in combination with rituximab constitutes a novel therapeutic strategy that remains unreported [4, 5, 13, 18, 19, 22].
This combination offers a compelling biologic rationale: rituximab depletes autoreactive B cells [9], while daratumumab targets LLPCs responsible for continuous autoantibody production [4, 17]. Given the unmet need for regimens that deliver deeper and more durable responses with acceptable toxicity, we conducted this retrospective study to evaluate the feasibility, efficacy, and safety of a novel low-dose daratumumab and rituximab regimen, combined with glucocorticoids, in patients with primary AIC (AIHA, ITP, and ES).
Methods
Patients
We conducted a retrospective cohort study of adults (> 18 years) with primary AIC (AIHA, ITP, or ES) diagnosed per international criteria [2, 3, 8, 23]. All participants met the following inclusion criteria: 1) Confirmed primary AIC after exclusion of secondary causes (connective tissue diseases, lymphoproliferative disorders, chronic lymphocytic leukemia, primary immunodeficiency, drug-induced, post-thymectomy, hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, EBV/CMV-associated, or post-transplant AIC); 2)Relapsed or refractory disease following ≥ 1 standard first-line therapy; 3) For ITP: platelet count < 30 × 10⁹/L at screening. 4) Consecutive patients receiving daratumumab plus rituximab with glucocorticoids at our institution (January 2022–December 2024) were included. Institutional review board approval was obtained with waiver of informed consent for retrospective data collection; all patients provided written consent for off-label biologic use. Patients declining data sharing were excluded.
Conditioning regimen
Patients received intravenous dexamethasone 20 mg daily on days 0–3, followed by oral prednisone 1 mg/kg/day on days 4–28 with subsequent planned glucocorticoid taper. Daratumumab 100 mg was administered on day 0, while rituximab 100 mg was infused weekly for four consecutive weeks on days 0, 7, 14, and 21. All patients underwent screening for hepatitis B virus (HBV) prior to treatment. For those with prior HBV exposure (positive hepatitis B core antibody), prophylactic antiviral therapy was administered in accordance with standard guidelines for patients receiving B‑cell–depleting therapies. Routine prophylaxis for herpetic infections or Pneumocystis jirovecii pneumonia (PJP) was not administered. This approach was based on the absence of clear evidence supporting routine herpesvirus prophylaxis in patients receiving daratumumab or rituximab outside of high‑risk settings, and the relatively short duration of daratumumab and glucocorticoid exposure in the present regimen, which did not meet the threshold for routine PJP prophylaxis. Efficacy criteria were described in supplementary material.
Efficacy criteria
Efficacy criteria were defined as follows: for ITP, complete response (CR) required platelet count ≥ 100 × 10⁹/L without bleeding; partial response (PR) required platelet count ≥ 30 × 10⁹/L without bleeding or ≥ 2-fold increase from baseline without bleeding; no response (NR) was platelet count < 30 × 10⁹/L or < 2-fold increase from baseline. For AIHA, CR required hemoglobin normalization without transfusions or hemolysis; PR required hemoglobin ≥ 100 g/L or ≥ 20 g/L increase from baseline; NR was hemoglobin < 100 g/L or < 20 g/L increase. For ES, CR required meeting both ITP and AIHA CR criteria; PR required meeting either ITP or AIHA PR criteria; NR met neither PR criteria. Overall response (OR) comprised CR or PR, while relapse was defined as loss of previously achieved CR/PR during follow-up. RFS was defined as the duration from daratumumab infusion to first disease relapse or death from any cause, whichever occurred first. Patients without relapse who remained alive during follow-up were censored at their last assessment date.
Statistical analysis
Statistical analyses were performed using SPSS 27.0 and R 4.4.2. Descriptive statistics summarized categorical variables as frequencies (percentages) and continuous variables as medians (ranges), with results rounded to one decimal place. Group comparisons employed χ² or Fisher exact tests for categorical data, while logistic regression analyzed predictors of treatment efficacy and recurrence. RFS was assessed using Kaplan-Meier curves. All tests were two-sided, with P < 0.05 considered statistically significant.
Results
Clinical data
This study included 22 patients: 5 (22.7%) with AIHA, 10 (45.5%) with ITP, and 7 (31.8%) with ES (Table 1). The cohort comprised 81.8% females (18/22) and 18.2% males (4/22), with the ES subgroup being exclusively female (100.0%) whereas the ITP subgroup had the highest male proportion (30.0%); no significant gender differences existed among subgroups (P = 0.286). Median age at diagnosis was 63.0 years (IQR: 47.0-70.8) overall, with AIHA patients being older (median 68 years) and ES patients younger (median 41 years), though intergroup differences were non-significant (P = 0.327). Previous treatment histories are detailed in Table 1. Initial laboratory parameters showed no significant intergroup differences, and median follow-up duration was 322 days (IQR: 23.5-565.5). In addition to an increase in the median proportion of CD8-positive T cells in patients with ES and a decrease in the median proportion of CD19-positive B cells, the median lymphocyte subset ratios in patients with AIHA or ITP remained within the normal range.
Table 1.
Patient baseline characteristics
| Patient characteristics | Total(N = 22) | AIHA(N = 5) | ITP(N = 10) | Evans(N = 7) | P-value |
|---|---|---|---|---|---|
| Sex, n(%) | 0.286 | ||||
| Male | 4(18.2%) | 1(20.0%) | 3(30.0%) | 0(0.0%) | |
| Female | 18(81.8%) | 4(80.0%) | 7(70.0%) | 7(100.0%) | |
| Age at diagnosis, years, median (IQR) | 63.0(47.0-70.8) | 68.0(64.0-74.5) | 61.0(49.0-71.2) | 41.0(25.0–70.0) | 0.327 |
| Median body-mass index (IQR) | |||||
| Previous therapies, n(%) | 0.260 | ||||
| Glucocorticoid | 19(86.4%) | 5(22.7%) | 7(31.8%) | 7(31.8%) | - |
| Intravenous immune globulin | 3(13.6%) | 0(0.0%) | 2(20%) | 1(14.3%) | - |
| Thrombopoietin-receptor agonists | 5(22.7%) | 0(0.0%) | 4(40%) | 1(14.3%) | - |
| Splenectomy | 1(4.5%)) | 0(0.0%) | 1(10%)) | 0(0.0%) | - |
| Laboratory data at initial | |||||
| Hb, g/L, median (IQR) | 84.0(52.5-107.2) | 66.0(42.0-85.5) | 112.5(86.5-135.3) | 63.0(51.0–89.0) | 0.412 |
| PLT, ×109/L, median (IQR) | 17.0(3-107.3) | 207.0(116.5-395.5) | 3.0(2.0-12.3) | 38.0(7.0–66.0) | 0.157 |
| Reticulocyte percentage ,%, median (IQR) | 2.8(1.6–18.8) | 8.9(1.8–28.8) | 2.5(1.7–2.9) | 5.1(1.6–23.0) | 0.353 |
| Total bilirubin, µmol/L, median (IQR) | 10.8(7.6–30.3) | 19.9(6.6-111.7) | 9(7.5–12.3) | 22.5(8.3–70.5) | 0.375 |
| Direct bilirubin, µmol/L, median (IQR) | 4.1(3.0-10.9) | 8.0(2.0-14.3) | 3.4(2.8–4.2) | 8.1(4.2–17.0) | 0.287 |
| Indirect bilirubin, umol/L, median (IQR) | 7.0(4.1–18.1) | 11.9(4.6–97.4) | 6.1(3.1–8.5) | 14.5(4.1–53.5) | 0.436 |
| Lymphocyte subpopulation | 0.371 | ||||
| CD4(+)CD8(-),%,median (IQR) | 52.8(43.4–64.9)_ | 72.7(55.3–76.1) | 52.0(47.6–58.6) | 41.7(37.4–60.3) | |
| CD8(+)CD4(-),%,median (IQR) | 40.9(28.3–49.4) | 25.3(21.8–33.5) | 41.3(32.7–47.0) | 49.4(34.2–53.7) | |
| CD3(+),%,median (IQR) | 66.8(55.8–78.2) | 53.7(47.9–68.3) | 62.6(50.7–74.6) | 78.2(64.5–86.5) | |
| CD19(+),%,median (IQR) | 20.4(7.4–29.3) | 20.4(6.8–45.4) | 22.9(7.6–32.6) | 14.3(6.4–26.0) | |
| Follow-up time, days, median (IQR) | 322.0(23.5-565.5) | 320.0(15.5-331.5) | 422.5(21.0-570.5) | 298.0(183.0-804.0) | 0.232 |
Clinical efficacy
Treatment responses across serial follow-up intervals (days 7 and 21, week 12, months 6 and 12, and final assessment) are detailed in Table 2. Among 22 patients, 21 (95.5%) achieved an initial response, including CR in 6 (27.3%) and PR in 15 (68.2%), with a median time to response of 7 days (IQR, 6.8–14.0). One patient discontinued treatment after a single rituximab dose despite attaining PR and was lost to follow-up. Among the 15 patients (68.2%) followed for more than 6 months, CR and ORR were 60% and 80%, respectively. In the subgroup of 7 patients (31.8%) with less than 6 months of follow-up, 3 achieved CR, 3 PR, and 1 experienced relapse after a 14-day CR (Fig. 1). The cohort’s peak CR rate (CRR) was observed at 6 months, while the peak ORR occurred at 12 weeks, reflecting similar patterns in AIHA. In contrast, ES showed peaks at 6 months (CRR) and 21 days (ORR), and ITP peaked at 21 days (CRR) and 12 weeks (ORR) (Table 3).
Table 2.
Patient response at different follow-up times, and adverse events
| Response during follow-up | Adverse event | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient no. | Disease | 7 days | 21 days | 12 weeks | 6 months | 1 year | End | Follow-up time,days | Manifestation | Grade |
| 1 | AIHA | NR | PR | - | - | - | CR | 24 | ||
| 2 | Evans | PR | PR | PR | CR | - | CR | 298 | ||
| 3 | ITP | NR | CR | - | - | - | CR | 21 | ||
| 4 | ITP | CR | NR | NR | NR | NR | NR | 713 | ||
| 5 | AIHA | NR | PR | CR | CR | - | CR | 324 | ||
| 6 | Evans | PR | PR | - | - | - | PR | 38 | Herpes virus infection | 1 |
| 7 | ITP | NR | CR | PR | PR | PR | CR | 359 | Intracranial Respiratory infection | 2 |
| 8 | ITP | NR | CR | CR | CR | CR | CR | 486 | Rash | 1 |
| 9 | ITP | PR | CR | CR | CR | CR | CR | 541 | ||
| 10 | AIHA | NR | NR | NR | NR | NR | NR | 320 | Urethral infection | 1 |
| 11 | Evans | PR | PR | CR | CR | - | CR | 183 | ||
| 12 | Evans | NR | PR | CR | CR | CR | CR | 818 | ||
| 13 | ITP | CR | CR | CR | CR | NR | CR | 659 | ||
| 14 | Evans | PR | PR | CR | CR | CR | CR | 639 | ||
| 15 | ITP | NR | PR | - | - | - | PR | 22 | Urethral infection | 1 |
| 16 | ITP | CR | CR | - | - | - | CR | 21 | Rash | 1 |
| 17 | Evans | PR | PR | PR | PR | PR | PR | 804 | Herpes virus infection | 1 |
| 18 | AIHA | NR | NR | PR | CR | CR | CR | 339 | ||
| 19 | ITP | NR | NR | PR | NR | NR | NR | 521 | ||
| 20 | Evans | PR | PR | PR | PR | - | PR | 294 | Respiratory infection | 2 |
| 21 | ITP | CR | NR | - | - | - | NR | 21 | ||
| 22 | AIHA | PR | - | - | - | - | PR | 7 | ||
Fig. 1.
Duration of response after daratumumab infusion within 180 days
Table 3.
The response rate during the follow-up time
| Response rate | Disease | Follow-up time | |||||
|---|---|---|---|---|---|---|---|
| 7 days | 21 days | 12 weeks | 6 months | 1 year | End | ||
| CRR(%) | Total | 18.2 | 23.8 | 46.7 | 60.0 | 45.5 | 59.1 |
| AIHA | 0.0 | 0.0 | 33.3 | 66.7 | 50.0 | 60.0 | |
| ITP | 40.0 | 50.0 | 50.0 | 50.0 | 33.3 | 60.0 | |
| Evans | 0.0 | 0.0 | 50.0 | 60.0 | 66.7 | 57.1 | |
| ORR(%) | Total | 54.5 | 71.4 | 86.7 | 80.0 | 63.6 | 81.8 |
| AIHA | 20.0 | 50.0 | 66.7 | 66.7 | 50.0 | 80.0 | |
| ITP | 50.0 | 60.0 | 83.3 | 66.7 | 50.0 | 70.0 | |
| Evans | 85.7 | 100.0 | 100.0 | 80.0 | 100.0 | 100.0 | |
| P-value | CRR | 0.006 | 0.004 | 0.710 | 0.504 | 0.600 | 0.401 |
| ORR | 0.073 | 0.114 | 0.364 | 0.287 | 0.308 | 0.286 | |
Durable responses were predominant, despite relapses in 1 AIHA patient, 5 ITP patients (20% of the 15 ITP patients followed for more than 6 months), and 1 ES patient. Two patients achieved CR following glucocorticoid re-treatment. Hematologic improvements included mean hemoglobin increases of 45.2 ± 21.9 g/L in AIHA and 46.9 ± 23.6 g/L in ES. Additionally, platelet counts increased by 198.7 ± 202.2 × 10⁹/L in ITP and 182.4 ± 105.8 × 10⁹/L in ES. Cumulative CR rates by subtype were 75% (AIHA), 80% (ITP), and 65.7% (ES) (P = 0.031; Fig. 2A), with ITP exhibiting significantly higher early CR rates at days 7 (P = 0.004) and 21 (P = 0.006) (Table 3). Responses peaked within 120 days and remained stable thereafter. At the final follow-up, CR was observed in 13 patients (59.1%) and PR in 5 patients (22.7%), with disease-specific CRR/ORR rates of 60.0%/80.0% for AIHA, 60.0%/70.0% for ITP, and 57.1%/100.0% for ES (Table 3). Cumulative relapse rates were 33.3% for AIHA, 68.0% for ITP, and 20.0% for ES (P = 0.10, Fig. 2B). The median RFS was not attained, as more than half of patients remained relapse-free throughout follow-up; however, 25% of patients experienced relapse by approximately 180 days. Subgroup analyses revealed a median RFS of 101 days (95% CI, 21–260 days) among patients with ITP. In contrast, only one relapse occurred in the AIHA group, at 281 days, and median RFS was not reached (> 339 days). Similarly, among patients with ES, only one of seven relapsed (at 259 days), with median RFS exceeding 804 days.
Fig. 2.
Cumulative relapse curves (a) and CR curves (b) of patients with different diseases
Univariate logistic regression analysis explored potential predictors of treatment efficacy (Table 4), revealing no significant associations between clinical outcomes and patient characteristics including age, gender, disease subtype, or baseline laboratory parameters (hemoglobin, platelet count, total bilirubin)—neither for CR attainment nor relapse occurrence during follow-up.
Table 4.
Risk factor analysis
| Potential risk factors | CR | Non-CR | P-value | Relapse | Non-relapse | P-value |
|---|---|---|---|---|---|---|
| Female sex | 12(80.0%) | 6(85.7%) | 0.582 | 5(71.4%) | 13(86.7%) | 0.989 |
| Age at diagnosis, years | 69.0(37.0-73.0) | 55.0(49.0-74.0) | 0.628 | 59.0(26.5-75.3) | 66.5(50.5-72.3) | 0.173 |
| Hb,g/L | 89.0(63.0-123.0) | 53.0(48.0-92.0) | 0.708 | 89.0(63.0-123.0) | 53.0(48.0-92.0) | 0.451 |
| PLT, ×109/L | 6.0(3.0-82.0) | 51.0(13.0-135.0) | 0.237 | 93.0(60.8-149.0) | 65.0(48.0-95.8) | 0.343 |
| Total bilirubin, μmol/L | 10.6(7.6-58.4) | 10.9(6.0-13.2) | 0.146 | 8.0(3.0-62.3) | 36.0(6.3-467.3) | 0.605 |
| AIHA | 3(20.0%) | 2(28.6%) | 0.381 | 1(14.3%) | 4(26.7%) | 0.359 |
| ITP | 8(53.3%) | 2(28.6%) | 0.396 | 5(71.4%) | 5(33.3%) | 0.153 |
| ES | 4(26.7%) | 3(42.9%) | 0.192 | 1(14.3%) | 6(40.0%) | 0.375 |
Safety
Adverse events are summarized in Table 2. In total, 8 patients (36.4%) experienced adverse reactions, with no patient experiencing more than one event. According to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, all events were graded as 1 or 2. The most common adverse events were infections (27.8%), which included herpesvirus, urinary tract infections (UTI) and respiratory tract infections (RTI). Additionally, 2 patients (9.1%) developed a rash. Most adverse events occurred within 3 months after treatment and responded well to medical intervention.
Discussion
This study represents the first systematic evaluation of low-dose daratumumab (anti-CD38), rituximab (anti-CD20), and glucocorticoid combination therapy for primary AIC (AIHA, ITP, ES). Our findings suggest that this multi-targeted approach demonstrates promising clinical activity: an initial ORR of 95.5% (27.3% CR, 68.2% PR) with a rapid median time to response of 7 days (IQR: 6.8–14.0). The cohort’s peak CRR was observed at 6 months, while the peak ORR occurred at 12 weeks. Despite relapses in 7 patients during follow-up, durability outcomes appear encouraging—sustained ORR of 81.8%, CRR of 59.1%, and median RFS was not reached during the follow-up period. The safety profile was manageable, with infections (27.8%; predominantly herpes, UTI, RTI) and rash (9.1%) as the most common adverse events. No new safety signals were identified, supporting acceptable tolerability.
Our regimen showed superior initial efficacy compared to conventional therapies, where nearly 80% of patients require second-line treatment due to corticosteroid failure [8]. Rituximab monotherapy yields suboptimal responses (ORR < 50% in AIHA; ORR 55.4%/CR 21.4% in ITP), while rituximab-corticosteroid combinations typically achieve 30%–50% response rates with high relapse [9, 10, 13]. In contrast, our combination maintained 81.8% ORR at final follow-up with median RFS not reached, suggesting enhanced durability. Compared to other second-line options—splenectomy (surgical risks) [8, 10], fostamatinib (limited response) [24–26], BTK inhibitors (off-target toxicity) [27], or thrombopoietin receptor agonists (high relapse after discontinuation, thrombotic events and bone marrow fibrosis) [28]—our limited-course protocol offers durable treatment-free remission while reducing long-term dependence and toxicity [29].
Anti-CD38 therapy effectively eliminates LLPCs that producing pathogenic autoantibodies, targeting the “resistant/relapse source” untouched by rituximab [5, 13, 14, 20]. Beyond direct plasma cell depletion, the efficacy of anti‑CD38 antibodies also depends on immune effector mechanisms, particularly natural killer (NK) cell‑mediated antibody‑dependent cellular cytotoxicity (ADCC). Indeed, NK cell phenotype and functionality have been shown to correlate with response and resistance to daratumumab in multiple myeloma [30]. To date, only a limited number of successful cases using daratumumab monotherapy in heavily pretreated adult patients with severe ITP and AIHA have been published [4, 5, 13, 18, 20, 31, 32]. Crickx and colleagues described 5 ITP patients who received 4–7 intravenous injections of daratumumab. Three of 5 achieved CR with sustained responses lasting 3–12 months [5]. In a case report of a patient with multiply refractory ITP, 12 doses of daratumumab produced a durable remission lasting at least 20 months [32]. In another case, a patient with multi-line relapsed ITP treated with daratumumab and romiplostim maintained efficacy beyond 42 weeks [19]. Additionally, Daratumumab combined with avatrombopag induced early and durable responses in 3 pediatric patients with refractory ITP [33]. Recently, a phase 1–2 trial reported that a novel CD38 antibody (CM313) achieved a 95% ORR in 22 patients with refractory ITP, with a median cumulative response duration of 23 weeks [20]. Additionally, a phase 2 study of mezagitamab, another anti‑CD38 monoclonal antibody, in patients with chronic/persistent primary ITP demonstrated promising activity and an acceptable safety profile [21]. Daratumumab has also shown remarkable efficacy in treating refractory AIHA. Among 4 patients with wAIHA resistant to rituximab who received 3–6 doses of daratumumab, 1 achieved symptom control while 2 relapsed; 1 patient with ES had effective disease control after 6 doses [13]. Crickx and colleagues reported 2 wAIHA patients who received 4 and 11 doses of daratumumab respectively, with 1 achieving CR [5]. In a study including 19 heavily pretreated adults with refractory AIHA, the ORR was 50% among 12 patients with R/R wAIHA treated with daratumumab, with a median response duration of 5.5 months; 2 of 12 patients maintained ongoing remission. Among the 6 non-responders, 4 had ES. In 7 patients with cold antibody type AIHA (cAIHA), daratumumab showed an overall response rate of 57%, with 3 of 7 patients achieving sustained responses [4].
Our daratumumab dosing strategy differed markedly from prior reports in several key aspects. Notably, we administered a single low-dose infusion (100 mg), contrasting with myeloma-adapted regimens (16 mg/kg) involving 4–13 cycles or extended maintenance therapy [4, 5, 13, 17–19]. This approach achieved durable remission while reducing healthcare utilization and immunosuppressive risks [1, 14]. The rationale stems from pathophysiologic differences between AIC and multiple myeloma [1, 14]—in AIC, LLPCs are rare and non-clonal [14, 34], requiring selective immunomodulation rather than broad cytoreduction. Low-dose daratumumab sufficiently saturates sparse CD38 expression and engages effector mechanisms without excess toxicity [15, 33, 35]. Furthermore, early use alongside rituximab may maximize cytotoxicity while immune effector function remains intact, contrasting with delayed use in salvage settings where immune exhaustion may impair efficacy [5, 13, 17, 19].
Cumulative complete response rate (CRR) differed significantly among subgroups (P = 0.031), being lowest in Evans syndrome (ES) at 65.7%. Our evaluation of individual patient data indicates that this lower CRR was primarily driven by suboptimal platelet responses, whereas hemoglobin responses were relatively robust. However, this observation should not be interpreted as isolated “platelet‑axis failure.” ES is inherently a multi‑lineage autoimmune disorder, and treatment failure in non‑responders—among whom ES was overrepresented—likely reflects synergistic immune attack across multiple hematopoietic lineages rather than deficiency in a single axis. Concurrent hemolysis and platelet destruction may reinforce each other through shared B‑cell/T‑cell pathways or complement activation [2], rendering the condition less sensitive to CD38/CD20 dual targeting alone. The differential response in ES points to underlying immunopathological heterogeneity, and future combination strategies should be guided by individual immune profiling rather than a one‑size‑fits‑all approach [2]. For example, when rituximab fails due to immunogenicity or neutralizing antibodies, structurally distinct anti‑CD20 agents such as obinutuzumab may serve as an effective alternative [36]. In relapsed cold agglutinin disease, the complement inhibitor sutimlimab has demonstrated efficacy [2]. For patients with a history of thrombotic events, fostamatinib is recommended as second‑line or later therapy [2]. Additionally, azathioprine (AZA) and mycophenolate mofetil (MMF) have shown favorable efficacy in refractory ES, and their inclusion in combination regimens may be considered [2, 11]. More broadly, emerging evidence supports pathophysiology‑driven subtyping of ES—incorporating lymphocyte subsets, cytokine profiles, and other immune parameters—to optimize combination strategies that may integrate B‑cell targeting, complement inhibition, or JAK pathway modulation. Time-to-peak response also varied: AIHA peaked at 6 months (CRR) and 12 weeks (ORR), while ITP showed earlier peaks (3 weeks CRR, 12 weeks ORR). Relapse rates were 33.3% (AIHA), 68.0% (ITP), and 20.0% (ES). ITP exhibited a “high response–high relapse” pattern, potentially due to additional pathogenic mechanisms beyond antibody-mediated destruction, including megakaryocyte defects and T cell–mediated cytotoxicity [11]. In contrast, ES showed a “difficult-to-induce yet durable remission” pattern, suggesting that once its complex immune dysregulation is overcome, responses are profound and sustained.
The overall adverse event incidence was 36.4%, primarily infections (27.8%), consistent with reported rates for rituximab-containing regimens (20%–40%) [9, 12, 13, 26, 37]. All events were grade 1–2 (CTCAE v5.0), controllable and reversible. In contrast, multi-cycle daratumumab (16 mg/kg) in AIC has been associated with severe adverse events [4, 5, 13, 31, 32], confirming the superior safety profile of our low-dose strategy [4, 12, 13, 15, 17, 31].
Beyond clinical efficacy and safety, this limited-course, low-dose regimen confers significant practical and economic advantages. By dramatically reducing cumulative drug exposure and obviating the need for prolonged or indefinite therapy, our strategy has the potential to lower direct treatment costs, decrease healthcare resource utilization (including the frequency of hospital visits and length of stays), and mitigate the long-term risks and costs associated with chronic immunosuppression. These attributes address not only patient-centered outcomes but also broader healthcare system priorities, enhancing the feasibility and sustainability of this therapeutic approach in real-world settings.
This study has certain limitations. Firstly, the sample size is small, and it is a single-center study, which may result in some bias in the results. Secondly, the follow-up period is relatively short (median 322 days, approximately 10.7 months; only seven patients had follow-up exceeding one year), which limits our ability to fully assess the durability of remission and long-term safety. We will continue to follow this cohort and report extended outcomes in future studies. In addition, this study did not conduct a detailed analysis of the patients’ immune status, which may affect the in-depth understanding of the treatment mechanism. Future research requires large-sample, longer follow-up prospective studies to further validate its efficacy.
Conclusions
This study provides preliminary evidence that the daratumumab-rituximab-glucocorticoid regimen achieves high initial response rates, encouraging durability, and manageable toxicity in AIC (AIHA, ITP, ES). The novel dual-pathway targeting strategy—simultaneously eliminating B-cells and antibody-secreting plasma cells—addresses a critical unmet need in refractory/relapsing disease, while reduced-dose daratumumab demonstrates clinical feasibility with potential immunologic and cost-saving benefits. Larger prospective studies should validate these findings, assess long-term outcomes, and identify predictive biomarkers to guide personalized treatment intensity in autoimmune disorders.
Acknowledgements
We are grateful to all the physicians, nursing staff of the Department of Hematology, and the patients who participated in this study.
Author contributions
Xiao Long and Xinyi Qin: data curation, formal analysis, project administration, validation, writing-original draft, methodology. Chun Cao: conceptualization, data curation, funding acquisition, investigation, project administration, supervisionwriting - original draft. Yun Luo: conceptualization, project administration, supervision, Writing - review & editing, data curation, Investigation. Hui Ke: methodology, validation, writing - review & editing. Yanfang Zhang: formal analysis, software, writing - review & editing.Li Tang: formal analysis, software, writing - review & editing. Hanqing Zeng: methodology, resources, writing - review & editing. Jianchuan Deng: investigation, writing - review & editing.
Funding
This work was supported by the Scientific Research Projects of the Nanan District Health and Wellness Committee and Nanan District Science and Technology Bureau (2024-11).
Data availability
Data is available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent for participate
This retrospective study was carried out using the opt-out method for the case series of our hospital. The study was approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University and was conducted in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was waived by our Institutional Review Board because of the retrospective nature of our study.
Consent for publication
All authors have contributed to the preparation of this manuscript and have approved its submission for publication. The order of authors listed in the manuscript has been agreed upon by all authors.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Xiao Long and Xinyi Qin contributed equally to this work.
Contributor Information
Yun Luo, Email: 300333@cqmu.edu.cn.
Chun Cao, Email: 303774@hospital.cqmu.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data is available from the corresponding author upon reasonable request.