Successful eradication of de novo HLA antibodies with daratumumab in immune-mediated cytopenias after allogeneic stem cell transplantation: a case report.

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for severe aplastic anemia (SAA) [ 1 ]. Because human leukocyte antigen (HLA)-matched sibling donors are available for only a minority of patients, alternative donor transplantation has become increasingly common [ 2 – 4 ]. However, mismatched or unrelated donor transplantation carries higher risks of primary graft failure, poor graft function, delayed hematopoietic recovery, and second graft failure—complications frequently linked to anti-HLA antibodies, including donor-specific antibodies (DSAs) and non-donor-specific antibodies (NDSAs) [ 5 – 7 ].

While the detrimental impact of preexisting DSAs on engraftment is well established and pretransplant HLA antibody screening is widely implemented, the clinical significance and mechanistic role of de novo HLA antibodies arising after transplantation remain poorly defined. Emerging data suggest that de novo HLA antibodies are not uncommon and may be associated with adverse outcomes such as severe acute graft-versus-host disease (aGVHD) and inferior survival [ 8 , 9 ]. It remains unclear whether de novo HLA antibodies contribute to posttransplant immune-mediated cytopenias (IMCs).

Posttransplant IMCs are defined as otherwise unexplained cytopenia(s) occurring after allo-HSCT in the setting of immune dysregulation, with exclusion of relapse, graft failure, infection, drug toxicity, and thrombotic microangiopathy [ 10 ]. IMCs occur in up to 22% of allo-HSCT recipients [ 10 , 11 ]. Increasingly recognized across malignant and nonmalignant diseases, these allo- or autoimmune complications can present as hemolytic anemia, thrombocytopenia, and/or neutropenia, either alone or in combination [ 10 ]. Identified risk factors include younger age, non-malignant hematologic diseases (such as SAA), alternative donors, the use of lymphodepleting agents, reduced-intensity conditioning regimens, stem cell source, GVHD, and viral infections. Management of refractory posttransplant IMCs is challenging. Conventional approaches—including corticosteroids, intravenous immunoglobulin (IVIG), therapeutic plasma exchange (TPE), and rituximab—often yield transient or incomplete responses, in part because they do not eradicate long-lived plasma cells responsible for sustained antibody production [ 12 , 13 ].

Here, we report two SAA patients who developed refractory IMCs after allo-HSCT in association with high-titer de novo HLA antibodies and preserved full donor chimerism, and in whom durable hematologic recovery was achieved only after plasma cell-directed antibody eradication with daratumumab. By demonstrating concordant patterns of antibody class, lineage-specific or multilineage hematopoietic injury, and lineage-matched recovery after antibody clearance, these cases provide initial hypothesis-generating observations for a functional immunophenotype-hematopoietic phenotype coupling and suggest that de novo HLA antibodies are associated with posttransplant bone marrow failure.

Case presentation

Case 1

A 45-year-old woman presented on October 4, 2024 with petechiae, ecchymoses, and fever. Laboratory testing showed severe pancytopenia, and bone marrow aspiration/biopsy confirmed SAA. Whole-exome sequencing identified a FANCE variant (c.1111 C > T; p.Arg371Trp) of uncertain significance. Owing to persistent profound neutropenia complicated by pneumonia and bacteremia, she proceeded to allo-HSCT after adequate infection control.

The donor was her 40-year-old sister (6/12 HLA match) with minor ABO incompatibility (recipient B⁺, donor O⁺). Pretransplant HLA antibody screening was negative. A non-myeloablative conditioning regimen consisted of fludarabine (30 mg/m²/day for 5 days), cyclophosphamide (60 mg/kg/day for 2 days), and thymoglobulin (2.5 mg/kg/day for 4 days). GVHD prophylaxis included cyclosporine A (CsA) and short-course mycophenolate mofetil (MMF). Peripheral blood stem cells were infused on December 5–6 with a CD34⁺ cell dose of 2.9 × 10⁶/kg.

Neutrophil engraftment occurred on day + 13, but platelet engraftment failed (Fig. 1 A). Bone marrow aspirate on day + 28 showed marked megakaryocyte depletion; peripheral blood chimerism demonstrated 99.51% donor cells (full donor chimerism rules out graft failure but does not exclude IMCs). Workup excluded acute GVHD, transplant-associated thrombotic microangiopathy, viral infections (cytomegalovirus, Epstein–Barr virus, parvovirus B19), and common autoimmune causes of cytopenia. Anti-HLA antibody testing revealed high-titer de novo antibodies: a mean fluorescence intensity (MFI) of 7,648 for class I and 1,673 for class II, including anti–DQB1 DSAs (maximum MFI 10,820) (See Table 1 for details). She received eltrombopag (75 mg/d) and rituximab (100 mg weekly ×3) [ 14 – 16 ], with delayed platelet recovery by day + 43 (20–30 × 10⁹/L). Subsequently, she developed persistent anemia (hemoglobin 60–70 g/L, erythropoietin-refractory) and granulocyte colony-stimulating factor–dependent neutropenia (Fig. 1 A). Repeat antibody testing showed increased class I and II MFI (8,491 and 2,112), while anti-DQB1 DSAs decreased to 7,539 (Fig. 1 B). Corticosteroids plus two TPE sessions produced transient improvement with platelet normalization and hemoglobin rise to ~ 100 g/L. By day + 80, class II antibodies (including anti-DQB1 DSAs) became negative (below the 500 cutoff), but class I antibodies remained strongly positive (MFI 5,767) (Fig. 1 B). Cytopenia relapsed promptly with steroid taper, resulted in only a transient and incomplete response (Fig. 1 A).

Fig. 1 Results of treatment with daratumumab for IMCs mediated by de novo HLA antibodies in case 1. Trends in neutrophil, hemoglobin, and platelet count ( A ), and MFI of the de novo HLA class I and II antibodies (including DSAs against HLA-DQB1) ( B ) before and after treatment with daratumumab following allo-HSCT. R: Rituximab; TPE: Therapeutic plasma exchange; IVIG: Intravenous immunoglobulin; Dara: Daratumumab; DSA: Donor-specific antibody

Table 1 Detailed epitope information of the de novo HLA antibodies in the patients after transplantation Patient ID Posttransplant Post-daratumumab HLA class I (MFI) HLA class II HLA class I HLA class II Mixed antibodies （MFI） Single antibody (MFI range) Mixed antibodies (MFI) Single antibody （MFI range） Mixed antibodies （MFI） Single antibody （MFI range） Mixed antibodies （MFI） Single antibody （MFI range） Case 1 7647.97 B*13:01, B*13:02, B*15:01, B*15:12, B*15:02, B*67:01, B*15:13, B*15:11, B*15:16, B*07:02, B*57:01, B*54:01, B*42:01, B*27:08, B*57:03 (528–18803) 1673.33 DQA1*05:05 DQB1*03:19, DQA1*00:01 DQB1*03:01 # , DQA1*05:03 DQB1*03:01 # , DRB1*12:02, DRB3*03:01, DQA1*03:01 DQB1*03:01 # , DQA1*02:01DQB1*03:01 # , DRB1*12:01, DRB1*08:01, DRB1*15:01, DRB1*15:03, DRB1*15:02, DRB3*01:01, DRB1*07:01, DRB5*01:01, DRB5*02:02, DRB1*10:01 (842–11557) 126.4 0.4 Case2 75.04 1817.88 DRB1*11:04, DRB1*14:54, DRB1*13:03, DRB1*13:01, DRB1*11:01, DRB1*14:01, DRB1*03:01, DRB1*14:02, DRB1*03:02, DRB1*01:02, DRB1*04:04, DRB1*15:01, DRB1*12:01 (534–3554) 45 10.02 HLA antibody testing was performed on the Luminex 200 platform. “Mixed antibodies” refer to the positive result obtained with the LABScreen Mixed assay (screening test), which indicates the presence of HLA antibodies but does not identify specificities. “Single antibody” refers to the specific HLA epitope identified by the LABScreen Single Antigen assay (confirmatory test), including DSAs and NDSAs # DSAs positive Criteria for Interpreting Positive Results in Mixed Antibody Testing: Weak positive: 500 ≤ MFI < 1000; Positive: 1000 ≤ MFI ≤ 2000; Strong positive: MFI > 2000 Criteria for Interpreting Positive Results in Single Antibody Testing: Weak positive: 500 ≤ MFI < 5000; Positive: 5000 ≤ MFI ≤ 10,000; Strong positive: MFI > 10,000; HLA human leukocyte antigen, MFI mean fluorescence intensity, DSAs donor-specific antibodies, NDSAs non-donor-specific antibodies

Repeat marrow demonstrated active erythropoiesis but marked megakaryocyte maturation arrest with only granular-stage megakaryocytes. By day + 123, class I antibodies remained positive (MFI 2,914) following IVIG treatment. Given persistent high-titer HLA class I antibodies despite rituximab, corticosteroids, TPE, and IVIG, IMCs was considered and plasma cell–directed therapy with daratumumab (8 mg/kg weekly×4) was started on day + 164. Prophylactic antivirals (acyclovir), antifungals (posaconazole), and intravenous immunoglobulin were administered to prevent infectious complications. After four doses, HLA class I antibody MFI declined to 742 and became negative by day 300 (MFI 126) (Fig. 1 B). Platelets, hemoglobin, and neutrophils increased rapidly within 10 days, and returned to normal levels at 37, 77, and 39 days after daratumumab treatment, respectively, and have remained within normal ranges to date (Fig. 1 A). The course was complicated by febrile neutropenia responsive to supportive care, without other significant adverse events.

Case 2

A 47-year-old woman presented with petechiae and ecchymoses and was diagnosed with non-severe aplastic anemia (NSAA) based on pancytopenia and marrow findings. After six months of immunosuppressive therapy with CsA and thrombopoietin receptor agonists plus androgen stimulation, she remained transfusion dependent. Repeat marrow confirmed persistent NSAA. Targeted next-generation sequencing identified a likely pathogenic PIGA mutation (c.635del) and variants of uncertain significance in KIT (c.2234–3 C > T) and RECQL4 (c.3526G > A). Flow cytometry showed a paroxysmal nocturnal hemoglobinuria clone in 13.68% of monocytes without clinical or laboratory hemolysis. Given refractoriness to immunosuppressive therapy, she proceeded to allo-HSCT.

An unrelated male donor (Chinese Marrow Donor Program) was selected with a 9/10 HLA match and a single HLA-B allele mismatch; major ABO incompatibility was present (donor AB⁺ to recipient B⁺). Pretransplant HLA antibody screening was negative. Myeloablative conditioning included fludarabine (30 mg/m²/day for 5 days), busulfan (3.2 mg/kg/day for 1 day), cyclophosphamide (25 mg/kg/day for 2 days), thiotepa (5 mg/kg/day for 1 day), and thymoglobulin (2 mg/kg/day for 3 days). GVHD prophylaxis comprised posttransplant cyclophosphamide (50 mg/kg/day on days + 3 and + 4), CsA, and short-course MMF. The infused peripheral blood CD34⁺ cell dose was 19.4 × 10⁶/kg.

Neutrophil and platelet engraftment occurred by day + 12 with rapid hematologic recovery. Whole-blood chimerism remained stable at full donor levels (99.78%) from day + 28 onward. On day + 100, she developed recurrent petechiae and isolated thrombocytopenia with platelet count 13 × 10⁹/L (Fig. 2 A), while hemoglobin and neutrophil counts stayed normal. Bone marrow aspirate showed impaired megakaryocyte maturation; platelet-associated antibodies (including platelet glycoprotein antibodies) were negative. Posttransplant IMCs was suspected. High-dose dexamethasone (40 mg/day for 4 days) produced a transient platelet rise to 126 × 10⁹/L, followed by decline to 15 × 10⁹/L within one week. Rituximab (375 mg/m² weekly×2) plus romiplostim (3 µg/kg subcutaneously weekly, titrated to maintain platelet count > 50 × 10⁹/L, maximum 10 µg/kg) resulted in only an unsustained response (peak 45 × 10⁹/L) (Fig. 2 A).

Fig. 2 Results of treatment with daratumumab for IMCs mediated by de novo HLA antibodies in case 2. Trends in platelet count ( A ) and MFI of the de novo HLA class II antibodies before and after treatment with daratumumab following allo-HSCT. R: Rituximab; Dara: Daratumumab

Anti-HLA antibody screening revealed isolated high-titer de novo HLA class II antibodies against HLA-DRB1 (maximum MFI 3,554) without detectable DSAs (See Table 1 ). With alternative causes excluded and refractoriness to standard therapies, the de novo class II antibodies were considered a plausible pathogenic factor. Daratumumab (8 mg/kg weekly × 3) was initiated on day + 173, following a 2-month wait (~ 2 rituximab half-lives of 27 days) [ 17 ]. This patient also received acyclovir, posaconazole, and intravenous immunoglobulin for infection prophylaxis. Platelets increased within one week, and normalized after three doses (Fig. 2 A). One month after daratumumab initiation, class II antibodies were undetectable (MFI 10), and platelet counts have remained normal (Fig. 2 B). Hemoglobin and neutrophils remained stable throughout. The patient developed an upper respiratory tract infection after receiving three doses of daratumumab, with no other adverse reactions observed.

Discussion

To our knowledge, this is the first report describing eradication of de novo HLA antibodies by plasma cell–directed therapy with daratumumab in association with reversal of refractory IMCs after allo-HSCT. In both cases, daratumumab achieved definitive antibody clearance after failure of standard immunosuppressive/desensitization therapies and was followed by sustained hematologic recovery. Beyond clinical response, the temporal and biologic concordance supports the hypothesis that de novo HLA antibodies are associated with and may contribute to posttransplant cytopenia, though causality cannot be established from two cases.

The adverse impact of preexisting HLA antibodies—particularly DSAs—on graft outcomes is well established [ 5 , 12 ]. By contrast, the relevance of posttransplant de novo HLA antibodies is incompletely defined. While such antibodies are associated with inferior outcomes in solid organ transplantation [ 18 – 20 ], data in HSCT are emerging. A prospective unrelated-donor allo-HSCT study identified de novo HLA antibodies in 12.1% of recipients and linked them to severe acute GVHD [ 8 ]. A retrospective haploidentical transplant cohort reported a high incidence (75.9%) of de novo HLA antibodies, with persistent positivity independently predicting inferior survival [ 9 ]. These studies support clinical association but do not resolve whether de novo antibodies can act as effectors of hematopoietic injury.

In our two patients with IMCs, preserved full donor chimerism, and exclusion of alternative etiologies, the shared feature was concurrent high-titer de novo HLA antibodies. Importantly, the cases exhibited coherent coupling between antibody immunophenotype and hematopoietic phenotype: (1) distinct HLA antibody class profiles, (2) corresponding lineage-specific or multilineage hematopoietic injury, and (3) lineage-matched recovery after antibody eradication. In case 1, combined class I and II antibodies coincided with trilineage cytopenia; class II antibodies cleared with conventional therapies, yet persistent class I antibodies paralleled ongoing pancytopenia and megakaryocyte maturation arrest until daratumumab achieved clearance, after which coordinated trilineage recovery followed. In case 2, isolated class II antibodies coincided with isolated thrombocytopenia and impaired megakaryocyte maturation, with platelet recovery occurring only after daratumumab-induced antibody clearance. Together, these aligned patterns support a functional immunophenotype–hematopoietic phenotype coupling, wherein the antibody class profile corresponds to the pattern and severity of hematopoietic failure.

Mechanistically, this pattern is distinct from classic autoimmune cytopenias in which lineage-restricted autoantibodies (e.g., platelet glycoprotein antibodies) primarily drive peripheral destruction [ 21 ]. HLA class I antigens are broadly expressed on nucleated hematopoietic cells and marrow elements, providing a substrate for wide antibody binding and potential effector mechanisms such as complement activation and antibody-dependent cytotoxicity [ 22 ]. High-titer class I antibodies could therefore plausibly contribute to multilineage suppression and impaired megakaryopoiesis, consistent with the phenotype in case 1. By contrast, HLA class II antigens are not constitutively expressed on progenitors or platelets but may be induced on megakaryocytes/platelets under inflammatory conditions, including interferon-γ signaling [ 23 ]. Aberrant HLA-DR expression on platelets has been reported in immune thrombocytopenia (ITP) [ 24 ], offering a biologic basis for preferential platelet-directed injury in the presence of class II antibodies. The selective thrombocytopenia and isolated megakaryocyte maturation defect in case 2, together with lineage-restricted recovery after antibody clearance, are consistent with this class II–linked phenotype. The two cases also constitute a quasi-experimental internal contrast that strengthens inference: the antibody spectrum differed (class I + II vs. class II only), the injury spectrum differed (multilineage vs. platelet-restricted), and the recovery spectrum after daratumumab differed accordingly (global vs. platelet-selective). This three-dimensional concordance—immunophenotype, injury phenotype, recovery phenotype—argues against coincidence and supports a potential association between de novo HLA antibodies and refractory posttransplant IMCs. We recognize that definitive causality cannot be established from two cases, and alternative interpretations—including alloimmunization from transfusions or antibodies as markers of global immune dysregulation—remain plausible [ 10 , 15 ]. Nonetheless, the temporal, phenotypic, and therapeutic-response specificity observed in our patients positions these antibodies as likely contributors rather than mere epiphenomena. Prospective studies incorporating functional assays are warranted to confirm this mechanism.

Posttransplant IMCs are associated with high morbidity and mortality and pose significant therapeutic challenges [ 10 , 25 ]. First-line therapies, such as corticosteroids and rituximab, achieve response rates of only 30%–50%, underscoring the need for more effective treatments [ 10 ]. Our experience supports daratumumab as a rational intervention because it targets the cellular source of sustained antibody production. While daratumumab has been reported for posttransplant IMCs such as ITP, autoimmune hemolytic anemia, pure red cell aplasia [ 26 – 29 ], our cases are notable for demonstrating antibody eradication as a measurable immunologic endpoint linked to durable hematologic recovery. This shifts daratumumab from nonspecific immunosuppression toward mechanism-based therapy for antibody-associated posttransplant marrow failure. The failure of corticosteroids, rituximab, IVIG, and TPE in our patients is biologically plausible, given the relative resistance of long-lived, CD38-positive plasma cells to CD20-directed or short-lived immunosuppression [ 30 ].

Dose and safety considerations are important in this vulnerable population. Instead of the 16 mg/kg weekly dose commonly used in multiple myeloma and reported in some desensitization or refractory IMCs protocols [ 26 – 29 , 31 , 32 ], we employed 8 mg/kg weekly to balance efficacy with infection risk. The rationale for this low-dose, non-fixed regimen rests on four points: (1) non-malignant HLA antibody-producing plasma cells may be more sensitive to daratumumab; (2) daratumumab can cause prolonged hypogammaglobulinemia, which—especially in patients previously exposed to rituximab, corticosteroids, or other immunosuppressants—significantly increases infection risk [ 15 , 33 ]; (3) an 8 mg/kg dose has been shown to clear preexisting HLA antibodies [ 34 ]; and (4) a flexible schedule allows real-time adjustment based on treatment response (via HLA antibody monitoring) and complications such as infection. Both patients achieved antibody clearance and durable recovery, suggesting that lower-dose regimens may be sufficient, though this requires prospective validation. Toxicities were manageable, consisting mainly of transient cytopenias and mild infections responsive to supportive care [ 35 ], supporting the importance of vigilant monitoring and prophylactic strategies such as IVIG to mitigate humoral immunodeficiency.

Several alternative explanations warrant consideration. First, heavily transfused patients with aplastic anemia frequently develop alloimmunization from blood product exposure, and transfusion-related antibodies may coexist with or mimic de novo HLA antibodies. Second, de novo antibodies could be markers of global immune dysregulation after transplantation rather than direct effectors of hematopoietic injury. Third, daratumumab may exert immunomodulatory effects beyond plasma cell depletion, including effects on regulatory T cells or myeloid-derived suppressor cells, that could contribute to hematologic recovery independently of antibody clearance. These possibilities remain plausible and cannot be excluded by the present data. Additionally, both patients received multiple prior interventions (corticosteroids, rituximab, plasma exchange, IVIG); although the rapid recovery within 10 days of daratumumab initiation and after failure of prior agents argues against a delayed or cumulative effect, such contributions cannot be fully excluded.

This report is limited by its retrospective nature and two-patient design, which precludes definitive causal proof and broad generalization. The absence of functional validation (e.g., complement-binding assays, IgG subclass characterization, in vitro progenitor suppression) limits mechanistic inference, and the semi-quantitative nature of MFI values does not directly equate to pathogenic potential. The short follow-up limits conclusions on durable HLA antibody clearance and hematologic recovery. Extended follow-up with monitoring of blood counts, HLA antibody, chimerism, immune reconstitution, and adverse effects at predefined intervals (e.g., 6, 12, and 24 months post-treatment) is needed. In case of recurrence, daratumumab could be re-administered. Prospective and controls studies incorporating systematic antibody surveillance, longitudinal immune profiling, and predefined daratumumab intervention criteria are warranted. Additionally, the CD34⁺ cell dose was markedly lower in Case 1 (2.9 × 10⁶/kg) than in Case 2 (19.4 × 10⁶/kg), which could have contributed to delayed hematopoietic recovery. Although neutrophil engraftment, full donor chimerism, and trilineage recovery after daratumumab argue against this as the primary cause, we cannot definitively exclude a contribution of cell dose—a limitation for interpreting the association between de novo HLA antibodies and hematopoietic failure.

Conclusions

In conclusion, these cases provide initial hypothesis-generating evidence that de novo HLA antibodies are associated with and may contribute to refractory IMCs after allo-HSCT. The concordance across antibody immunophenotype, lineage-specific or multilineage hematopoietic injury, and lineage-matched recovery following daratumumab-induced antibody clearance supports a functional immunophenotype–hematopoietic phenotype coupling and suggests a mechanism-based diagnostic and therapeutic framework for this challenging complication.

Publisher’s note

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Tonglin Hu contributed equally to this work

Acknowledgements

We thank the patients who accepted to participate in this study.

Author contributions

S-XF and H-TL collected the data, created the charts, and wrote the manuscript; G-HP verified the data and reviewed the manuscript; H-HJ and H-LL checked the charts and reviewed the manuscript; Y-BD and Z-Y designed the article, verified the data, reviewed and revised the manuscript, and assumed overall responsibility for the manuscript.

Funding

This work was supported by the Special Project for the Modernization of Traditional Chinese Medicine in Zhejiang Province (No. 2020ZX007); National Major and Difficult Diseases (Lymphoma) Clinical Collaboration Project of Traditional Chinese and Western Medicine (No. ZDYN-2024-A-024); Zhejiang Provincial Natural Science Foundation (No. LY19H270004, LQ24H290001).

Data availability

The original data is available upon special request to Yu Zhang, E-mail: zhang-821121@163.com.

Declarations

Ethics approval

This study was approved by the Institutional Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University. Written informed consent was obtained from the patients for the publication of any potentially identifiable images or data included in this article.

Competing interests

The authors declare no competing interests.

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