Stefan M. Hillmann1,2*†
Hendrik Brockhoff1,2Sarah Loebel1,3Suna Hentschke1,4
Dirk Arnold1,2†
Hans Salwender1,2†- 1Asklepios Tumorzentrum Hamburg, Hamburg, Germany
- 2Department of Hematology and Oncology, Asklepios Klinik Altona, Hamburg, Germany
- 3Department of Hematology, Asklepios Klinik St. Georg, Hamburg, Germany
- 4Asklepios Medical Service Center (MVZ) Internal Medicine, Oncology and Hematology, Hamburg, Germany
Evans syndrome is a rare autoimmune disorder characterized by the simultaneous or sequential occurrence of autoimmune cytopenia. The disease is chronic, relapsing, and frequently refractory to standard therapies. Typical symptoms include anemia-related fatigue, pallor, and jaundice due to hemolysis and petechiae, and purpura and mucosal bleeding due to thrombocytopenia. Treatment often involves a stepwise escalation of immunosuppressive treatments (e.g., corticosteroids, anti-CD20 monoclonal antibodies) and/or stimulants (e.g., thrombopoietin receptor agonists). However, sustained remission remains elusive in many patients. We report the case of a 69-year-old woman with a 19-year history of Evans syndrome, presenting with a life-threatening relapse marked by severe thrombocytopenia and strong hemolytic activity. The patient had previously undergone multiple treatment regimens and had developed comorbidities that both complicated disease management and treatment strategies. Despite repeated therapeutic interventions with various immunosuppressant agents, she remained transfusion-dependent and clinically unstable and experienced various treatment complications. Additionally, targeting antibody-producing plasma cells with daratumumab (anti-CD38) led to a rapid fall in transfusion dependency, clinical stabilization, and transition to outpatient care. Unfortunately, the patient later succumbed to infectious complications after a femoral fracture. This case underscores the therapeutic complexity of multirefractory Evans syndrome and the limitations of conventional therapy. The addition of daratumumab, resulting in depletion of CD38+ plasma cells, helped achieve hematologic stabilization in this refractory case.
Introduction
Evans syndrome (ES), a rare and often life-threatening autoimmune disorder, poses unique challenges in both diagnosis and treatment. It is characterized by the simultaneous or sequential occurrence of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and occasionally autoimmune neutropenia (1).
The pathophysiology of ES differs regarding age of onset: In pediatric ES, up to 60% of cases are attributed to inborn errors of immunity caused by germline mutations leading to immune dysregulation (2). In adult ES, this number is suggested to be lower than 10% (3). Up until now, the distinct pathophysiology of adult ES remains unknown, largely characterized by isolated ITP and AIHA (4). In contrast to single-lineage autoimmune cytopenia (AIC), available data suggest that adult ES reflects a broader and more severe collapse of immune tolerance, often in association with secondary autoimmune disease or lymphoproliferative neoplasia and a pro-inflammatory marrow environment affecting several hematopoietic lineages (4–7), which likely underlies its more relapsing course and higher morbidity and mortality compared to isolated ITP or AIHA (8).
The clinical presentation of ES reflects its multifaceted nature, with symptoms ranging from anemia-related fatigue, pallor, and jaundice to thrombocytopenia-associated petechiae, purpura, and mucosal bleeding. In some cases, even life-threatening hemorrhages may occur. Diagnosing ES requires a careful exclusion of alternative causes of cytopenia, including thrombotic microangiopathies, myelodysplastic syndromes, and infections (6). Notably, the prevalence of secondary ES is estimated to range between 20% and 50% of cases (5, 7). Diagnosis is confirmed when either concurrent AIC is present or when sequential development of a second AIC is observed.
Management of clinically significant ES presents challenges due to its chronic and relapsing nature. First-line treatment typically involves corticosteroids, sometimes combined with intravenous immunoglobulin (IVIG) during acute bleeding episodes. However, the often refractory or relapsing disease frequently necessitates second- and third-line therapies, such as rituximab, immunosuppressants, and thrombopoietin receptor agonists. In select cases as ultima ratio, even splenectomy may be considered (9). Long-term therapy can further be impacted by treatment-associated complications, including infections and thrombotic events, particularly in patients requiring intensive immunosuppression (7).
First consensus guidelines for ES management, which have been recently published, provide recommendations for first-line and subsequent therapies (9). Later treatment decisions in the naturally long treatment course of patients with ES—especially involving immunosuppressive agents—still remain reliant on clinical experience and off-label drug use. This is primarily due to a notable lack of comparative data on the efficacy of various immunosuppressive therapies in ES, with current knowledge largely extrapolated from studies in ITP and AIHA (10, 11).
Rituximab is embedded in current first- and second-line treatment recommendations for ES (9). It is an anti-CD20 monoclonal antibody, targeting mostly B cells and their precursor lines, whereas plasma cells are mostly spared due to low or no CD20 expression. Its limited efficacy in some cases may be attributed to persistent autoantibody production from the remaining CD20-negative plasma cells (12).
This limitation has prompted exploration of alternative agents explicitly targeting plasma cells, such as daratumumab—a CD38-targeting monoclonal antibody originally approved for treatment of multiple myeloma (13, 14).
CD38 is a receptor/ecto-enzyme expressed across B-cell maturation, with the highest expression on plasma cells. As a signaling molecule, CD38 integrates calcium/NF-κB pathways linked to B-cell activation and differentiation. Anti-CD38 therapy, therefore, is hypothesized to deplete CD38+ plasma cells by antibody-dependent cellular cytotoxicity and interrupt further B-cell activation (15).
Beyond B cells, CD38 functions as a NAD+ glycohydrolase and activation marker on T cells. CD38 blockade increases intracellular NAD+ and mitochondrial function in naive T cells and reduces IFN-γ/TNF-α production in activated effector T cells, supporting a complementary immunomodulatory mechanism relevant to autoimmunity (16).
This report is among the first to document the use of daratumumab in the treatment of ES (13). We aim to show the complexities of managing refractory ES, illustrating the therapeutic challenges and complications, highlighting the potential of emerging new treatments such as daratumumab. By contributing to the growing body of evidence, we aim to aid informed clinical decision-making in this rare and challenging condition.
Case
A 50-year-old female patient had been diagnosed with ES in 2005 with a combination of ITP and warm-type AIHA. Over nearly two decades since diagnosis, she had experienced multiple relapses of ITP and AIHA despite corticosteroids, repeated rituximab therapy, splenectomy, and long-term thrombopoietin receptor agonist therapy and had thus evolved into a heavily pretreated, multirefractory case (Table 1).
Table 1. Prior therapies before January 2024 admission.
She presented to our outpatient clinic in January 2024 for follow-up laboratory work after a recent hospitalization in December 2023 for severe ITP. Her platelet count had decreased again to 0 × 109/L. She was admitted to the ward to undergo treatment with close monitoring. Her baseline “Eastern Cooperative Oncology Group” (ECOG) performance status at admission was 0 (17).
At her current age of 69 years, she had developed extensive medical comorbidities including arterial hypertension, hypercholesterolemia, gout, type 2 diabetes with polyneuropathy, depression, obesity, and an infrarenal aortic aneurysm with a persistent endoleak after intervention. She had accumulated about 40 pack-years of cigarette smoking and continued to smoke half a pack of cigarettes per day.
Thrombocytopenic stage
After being admitted with 0 × 109/L platelets in January 2024, the patient developed severe intestinal and nasal bleeding WHO grade IV (18) and required immunoglobulins and red blood cell (RBC) transfusions alongside steroids (Supplementary Figure 2 for detailed steroid exposure). After 4 days with a count of 0 × 109/L platelets, the platelet count recovered. Because platelet counts began to fall again and the last relapse had been severe, we decided to discontinue eltrombopag and started the patient on avatrombopag 20 mg daily and fostamatinib 100 mg twice daily. Despite transient stabilization, the patient experienced a significant relapse in March 2024, once again requiring steroids and intravenous immunoglobulin therapy due to active bleeding—as a consequence, the avatrombopag dosage was doubled. A transient increase in platelet count occurred (which we most plausibly attribute clinically to the use of immunoglobulins), only to fall to 0 × 109/L again for 11 consecutive days. Given the lack of sustained response, we initiated immunosuppressive therapy by discontinuing avatrombopag and fostamatinib and starting cyclophosphamide at 100 mg daily, later increased to 150 mg daily. As there was no improvement in platelet count, a full cycle of rituximab (four weekly doses at 375 mg/m2) was administered alongside an escalation of corticosteroid dosing. Eltrombopag (75 mg) was reintroduced shortly thereafter. However, the platelet count increased only transiently, peaking at 51 × 109/L, before relapsing again at the beginning of April 2024 (Figure 1). We decided to switch the immunosuppressive therapy from cyclophosphamide to ciclosporin A (plasma-level adapted dosing).
Figure 1. Thrombocytopenic stage. Platelet count and hemoglobin (Hb) levels during the thrombocytopenic stage in 2024, with administration of key treatments and red blood cell (RBC) transfusions indicated. Singe data points indicate exact platelet-levels.
After 2 weeks, the patient developed acute renal failure and an infection. Ciclosporin A was paused due to the risk of accumulation during renal failure. The platelet counts, however, remained stable, mostly between 100 and 200 × 109/L. No platelet transfusions were administered since admission in January 2024.
Hemolytic stage
After restarting ciclosporin A, a period of strong hemolytic activity [lactate dehydrogenase (LDH) levels > 1,250 U/L] followed, which lasted for more than 10 weeks and required transfusions almost daily, requiring a total of 52 RBC transfusions (Figure 2). In an effort to control the severe hemolysis and due to the recent renal failure, we switched from ciclosporin A to mycophenolate mofetil (MMF) 500 mg twice daily and added tacrolimus (plasma-level-adapted dosing). These measures led to a normalization in laboratory hemolysis parameters (LDH, haptoglobin, bilirubin) and to a reduction but continued dependency on RBC transfusions. During this period, absolute neutrophil counts, measured intermittently, were frequently <1.5 × 109/L (Supplementary Table 2; Supplementary Figure 1), indicating recurrent neutropenia in the context of extensive comedication, intensive immunosuppression, and intercurrent infections; autoimmune neutropenia in the context of the patient’s ES is a plausible but unproven contributor; granulocyte-colony stimulating factor was not administered.
Figure 2. Hemolytic stage. Platelet count and hemoglobin (Hb) levels during the hemolytic stage in 2024, with administration of key treatments and red blood cell (RBC) transfusions indicated. Singe data points indicate exact Hb-levels.
Despite prophylactic anticoagulation with dalteparin (5,000 IU once daily), the patient developed an extensive thrombosis of the iliac and femoral veins (confirmed by sonography and CT scan), resulting in a peripheral pulmonary embolism and necessitating anticoagulation therapy. This complication was attributed to her reduced performance status and immobility, as well as the prothrombotic risk associated with the ITP component of ES. Additionally, the potential contribution of thrombopoietin receptor agonists such as eltrombopag cannot be excluded. Accordingly, we stopped eltrombopag and re-initiated fostamatinib 100 mg twice daily. Shortly after, the patient also required a re-intervention for the increasing endoleak of her aortic aneurysm.
The patient’s overall performance status deteriorated during this treatment period, leaving her bedridden and medicated with approximately 35–40 tablets per day with an ECOG performance status of 4. In view of the refractory and relapsing course, bone marrow biopsies were performed in March and June 2024, showing findings consistent with AIC histopathology and excluding myelodysplasia, lymphoproliferative disease, or other secondary bone marrow causes.
The transfusion frequency had finally dropped to 10 RBC transfusions per month in July 2024 under therapy with fostamatinib, MMF, and tacrolimus, and the patient was clinically able to transfer to an inpatient rehabilitation facility to improve her performance status.
Although the patient stabilized physically at that time point in 2024, she had been hospitalized for 169 out of the past 251 days (67%), receiving a total of 80 RBC transfusions. The initiation of therapy with MMF and tacrolimus had been ongoing for more than 12 weeks, and literature on median time to response suggested that most of the therapeutic effect should have already taken place (19–22). Although transfusion dependency had decreased, it still remained at a substantial rate with 10 RBC transfusions in August. Therefore, we decided to start therapy with daratumumab in September 2024 in an inpatient setting with 1,800 mg subcutaneously once weekly for 8 weeks.
This quickly led to a further decrease in transfusion dependency (initially just one more RBC transfusion after the sixth daratumumab injection), which also enabled treatment to be moved to an outpatient setting. This improvement most likely reflected a cumulative effect of the concurrent therapies in addition to the plasma cell depletion and immunomodulatory effect of daratumumab.
We subsequently discontinued therapy with fostamatinib, MMF, and finally, tacrolimus. The patient regained walker-assisted mobility and was able to stay in outpatient care (ECOG 2). However, her performance status remained reduced compared to her baseline at admission in January 2024 (ECOG 0), underscoring the substantial toll the disease and its treatment had taken on her overall condition.
After completing seven of eight planned subcutaneous daratumumab injections, the patient experienced a proximal femur fracture at the beginning of November, requiring surgery and postoperative RBC transfusions. Approximately 2 weeks later, she presented to the emergency room with severe pneumonia and expired within 24 h.
Discussion
This case of a 69-year-old woman with refractory, life-threatening ES exemplifies the challenges clinicians face in managing autoimmune cytopenia, particularly in patients with significant comorbidities. Over the course of nearly two decades, this patient experienced numerous disease relapses despite receiving various therapies, including corticosteroids, rituximab, splenectomy, and thrombopoietin receptor agonists. Each intervention provided only temporary relief or failed outright.
The patient’s stabilization following the addition of daratumumab to immunosuppressive therapy highlights its potential as an adjunct or subsequent therapy in refractory ES.
ES is a disease with a high risk of multiple relapses; more than 51% of patients require three or more lines of therapy (7). According to the recently published first consensus guidelines on the management of ES, there is no specific therapeutic differentiation beyond the second or third line—aside from splenectomy—other than the general recommendation to consider immunosuppressive agents, which are to be evaluated on a case-by-case basis (9). Many patients reach this point during the course of their disease, leaving clinicians with no viable decision support besides their own and others’ clinical experience.
Furthermore, conventional therapies in ES often fail to achieve long-term remission: Systemic corticosteroids often provide rapid symptom control but usually only transient benefit in ES (9). Over time, many patients accumulate substantial cumulative exposure and dose-related toxicities, including infections, osteoporosis and fragility fractures, thrombotic stroke or myocardial infarction, hypertension, obesity, and diabetes (23). In this patient, the minimum cumulative dose prednisone equivalent (mCDP) dose we could reconstruct for 2024 alone was 63.14 mg/kg, a range associated with a several-fold increase in steroid-related adverse events (24). We also consider her hypertension, diabetes, obesity, and lastly her femoral fracture due to likely osteoporosis to be at least partly attributable to prolonged high-dose corticosteroid exposure over the entire disease course.
Thrombopoietin receptor agonists can improve platelet counts but are largely ineffective in controlling hemolysis—an essential component of ES—and have known side effects, including an increased risk of thrombosis (6).
Splenectomy, while still considered a second-line option, has shown reduced efficacy in ES compared to ITP (25) and carries significant risks, including overwhelming post-splenectomy infection (OPSI) syndrome, postoperative complications, and high relapse rates (26).
Rituximab, though effective in depleting CD20+ B cells, does not directly target long-lived plasma cells, leaving the underlying autoantibody production primarily unaddressed in some cases (10, 14).
Additional immunosuppressive agents, such as those used in this patient, often show prolonged and sometimes incomplete responses and must frequently be maintained long term. However, they serve as a corticosteroid-sparing option, while evidence for their use specifically in ES remains very limited (9).
Daratumumab represents a promising addition to existing therapeutic strategies in ES, as anti-CD38-directed therapy targets long-lived CD38+ plasma cells, which are hypothesized to be responsible for persistent autoantibody production in refractory ES, even after anti-CD20-directed therapy (15). Autoantibodies produced in ES are heterogeneous and may include platelet-directed antibodies (e.g., anti-GPIb/IX or anti-GPIIb/IIIa) (27) and erythrocyte-directed antibodies, with specific antiplatelet antibodies detectable in only approximately 45% of patients (28) (specific antibody testing was not performed in this patient except for positive direct antiglobulin tests, see Supplementary Table 1).
By eliminating the remaining source of autoantibody production after CD20-directed therapy, daratumumab enabled further clinical stabilization and a rapid reduction in transfusion dependency in this patient.
In addition to its effects on plasma cells, CD38 functions as an ectoenzyme in T cells and actively regulates NAD+ metabolism, calcium signaling, and cytokine production during effector T-cell activation (16). Accordingly, CD38 blockade may have contributed to dampening pathological immune activation beyond plasma cell depletion, a mechanism that has recently been demonstrated in human immune cells in an in vivo model of graft-versus-host disease (29).
While daratumumab has shown a relatively favorable safety profile in multiple myeloma studies (30–32), its adverse effects, including cytopenia and infection risks, remain significant concerns. Daratumumab is associated with contributing to infections in 48% of patients (7% grade 3–4) in multiple myeloma (33). Translating these findings to autoimmune conditions requires caution, as the safety profile may differ in this patient population.
Other adverse effects beyond infectious complications, such as renal failure and neurotoxicity—both observed in this patient—are well-documented adverse events associated with treatments like MMF, cyclosporin A, and tacrolimus, but are much less pronounced with daratumumab treatment (33–36).
Beyond anti-CD38 therapy, further investigational treatment of ES relies on case reports/series and extrapolation from AIHA and ITP. Choices are mechanism- and context-driven, such as alemtuzumab (CD52-directed T-cell depletion), Bruton tyrosine kinase (BTK) inhibitors (B-cell receptor signaling modulation), sutimlimab (blockade of complement-mediated hemolysis), and proteasome inhibitors such as bortezomib (4). Like daratumumab, bortezomib primarily targets and eliminates antibody-producing plasma cells, however, through intracellular reversible 26S proteasome inhibition, disrupting proteasome-induced proteolysis and pro-survival signaling in highly secretory plasma cells (37). In contrast, daratumumab relies on CD38 surface expression and induces cell death mainly through complement activation, antibody-dependent cytotoxicity, and phagocytosis. Emerging pediatric and adult reports describe meaningful, sometimes durable, responses to bortezomib in refractory Evans syndrome (37–39) as well as a phase II trial in wAIHA in combination with rituximab (40). However, its toxicity profile (notably peripheral neuropathy, cytopenia, and renal complications) differs from that of daratumumab (37).
Neutropenia was also a recurrent finding in this patient and likely multifactorial, related to chronic autoimmune cytopenia, immunosuppressive therapy, and intercurrent infections; in the absence of specific antineutrophil antibody testing, autoimmune neutropenia remains a plausible but unproven contributor, representing a limitation of our diagnostic workup.
During daratumumab treatment, the patient experienced a decline in hemoglobin accompanying her femur fracture and subsequent surgery. While this is a plausible cause for the drop in hemoglobin (41, 42), we cannot rule out the new onset of hemolytic activity post-surgery, since hemolysis laboratory work was not collected after this time point and immunosuppressive therapy was sequentially stopped.
In our view, the patient’s death was likely the result of a multifactorial interplay between the severity of her ES, progressive clinical deterioration, multiple comorbidities, long-term corticosteroid use, extensive immunosuppressive therapy, and the cumulative burden of treatment, including daratumumab.
However, it is possible that an earlier initiation of daratumumab therapy, combined with either the avoidance or more rapid discontinuation of the aforementioned immunosuppressive agents, might have altered the disease trajectory, although this remains purely speculative.
This case also underscores the potential economic benefits of daratumumab. We believe that despite the high cost of daratumumab treatment, it can be cost-saving in the end by quickly stabilizing the patient’s condition and significantly reducing the duration of hospitalization. The reduction in transfusion dependency further decreases the burden on healthcare systems with respect to scarce resources such as blood products.
In our opinion, these considerations support the use of daratumumab as an additional or subsequent agent in heavily pretreated patients with ES.
Conclusion
With this case report, we demonstrate the efficacy of daratumumab given as an additional agent in a patient with multirefractory ES. By targeting CD38+ plasma cells, daratumumab addressed the core pathophysiology of the disease, resulting in rapid hematologic stabilization, minimal transfusion dependency, and a shift toward outpatient care—even after failure of multiple prior therapies.
While further evidence is needed, especially from prospective studies, this case supports the consideration of daratumumab as a valuable therapeutic option in selected, critically ill ES patients. We encourage future treatment guidelines to reflect the need for earlier access to targeted therapies in refractory cases.
Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. The raw data supporting the conclusions of this article will be made available by the authors on request, without undue reservation.
Ethics statement
Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author contributions
SMH: Conceptualization, Data curation, Investigation, Methodology, Writing – original draft, Writing – review & editing. HB: Methodology, Supervision, Writing – review & editing. SL: Writing – review & editing. SH: Writing – review & editing. DA: Writing – review & editing. HS: Funding acquisition, Supervision, Writing – review & editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Conflict of interest
HS receives honoraria for lectures/presentations from AbbVie, Amgen, AstraZeneca, BMS/Celgene, GSK, Janssen, Oncopeptides, Pfizer, Sanofi, and Stemline; travel support from Amgen, BMS/Celgene, Janssen, Pfizer, Sanofi, and Stemline; and service on advisory boards for Amgen, AstraZeneca, BMS/Celgene, GSK, Janssen, Oncopeptides, Pfizer, Sanofi, and Stemline. SH and her husband own shares of Johnson & Johnson as part of the S&P500 and MSCI World Index Exchange-Traded-Funds.
The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/frhem.2025.1719208/full#supplementary-material
Abbreviations
AIC, autoimmune cytopenia; AIHA, autoimmune hemolytic anemia; ANC, absolute neutrophil count; BTK, Bruton tyrosine kinase; CDP, cumulative dose prednisone equivalent; ECOG, Eastern Cooperative Oncology Group (performance status scale); ES, Evans syndrome; Hb, hemoglobin; IFN-γ, interferon gamma; ITP, immune thrombocytopenia; IU, international units; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; mCDP, Minimal cumulative dose prednisone-equivalent; MMF, mycophenolate mofetil; NAD+, nicotinamide adenine dinucleotide (oxidized form); NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells (transcription factor); OPSI, overwhelming post-splenectomy infection (syndrome); RBC, red blood cell(s); TNF-α, tumor necrosis factor alpha; WHO, World Health Organization.
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Keywords: anti-CD38, autoimmune hemolytic anemia (AIHA), daratumumab, Evans syndrome (ES), immune thrombocytopenia (ITP), plasma cell disorder, targeted therapy
Citation: Hillmann SM, Brockhoff H, Loebel S, Hentschke S, Arnold D and Salwender H (2026) Daratumumab in severe Evans syndrome: a case report. Front. Hematol. 4:1719208. doi: 10.3389/frhem.2025.1719208
Received: 05 October 2025; Accepted: 30 December 2025; Revised: 29 December 2025;
Published: 23 January 2026.
Edited by:
Peter Korsten, St. Josef-Stift Sendenhorst, GermanyReviewed by:
Xijuan Lin, Chinese Academy of Medical Sciences and Peking Union Medical College, ChinaRoman Schimmer, University Hospital Zürich, Switzerland
Copyright © 2026 Hillmann, Brockhoff, Loebel, Hentschke, Arnold and Salwender. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Stefan M. Hillmann, cy5oaWxsbWFubkBhc2tsZXBpb3MuY29t
†ORCID: Stefan M. Hillmann, orcid.org/0009-0005-6561-1755
Dirk Arnold, orcid.org/0000-0003-2392-599X
Hans Salwender, orcid.org/0000-0001-7803-0814