Rapid Donor-Specific Antibodies Clearance with Short-Course Blinatumomab Prior to Haploidentical HSCT: A Case of Successful Engraftment

Rapid Donor-Specific Antibodies Clearance with Short-Course Blinatumomab Prior to Haploidentical HSCT: A Case of Successful Engraftment | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Blood & Cancer This is a preprint and has not been peer reviewed. Data may be preliminary. 1 August 2025 V1 Latest version Share on Rapid Donor-Specific Antibodies Clearance with Short-Course Blinatumomab Prior to Haploidentical HSCT: A Case of Successful Engraftment Authors : Zebin Luo 0009-0009-6487-0834 , Miner Gu , Xiaoping Guo , Fenying Zhao , and Xiao-Jun Xu 0000-0003-1388-2535 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175403194.41174748/v1 Published Pediatric Blood & Cancer Version of record Peer review timeline 246 views 204 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract This report describes the first successful use of blinatumomab for desensitization against donor-specific antibodies (DSAs) prior to haploidentical hematopoietic stem cell transplantation (haplo-HSCT). A 16-year-old male with aplastic anemia(AA) and high-titer DSA (MFI 5,155) contraindicated conventional plasma exchange due to anaphylaxis history. A reduced-dose blinatumomab regimen (8 μg/day × 8 days) achieved rapid DSA reduction to subthreshold levels (MFI 701) within two weeks. Subsequent paternal haplo-HSCT resulted in neutrophil/platelet engraftment by days +18/+28, with 98.41% donor chimerism. This novel approach demonstrates blinatumomab’s potential as an effective desensitization strategy for highly sensitized haplo-HSCT recipients. Introduction Haploidentical donors are increasingly utilized for hematopoietic stem cell transplantation (HSCT) when HLA-matched donors are unavailable or urgent transplantation is required 1 . Donor-specific antibodies (DSAs)—recipient antibodies against donor HLA antigens—frequently arise from HLA mismatches, with prior transfusions, pregnancies, or transplants being key risks 2 . Crucially, DSAs prevalence is significantly elevated in haploidentical HSCT (haplo-HSCT). Substantial clinical evidence confirms that preformed DSAs significantly correlate with primary graft failure (GF) in haplo-HSCT recipients 3,4 . Consensus guidelines consequently recommend desensitization therapy for patients with DSA mean fluorescence intensity (MFI) >2,000 in the absence of alternative suitable donors, with particularly strong indication at high-titer levels (MFI >5,000) 5,6 . Blinatumomab—a bispecific T-cell engager antibody targeting CD19 and CD3—induces immunologic synapse formation between cytotoxic T lymphocytes and CD19+ B cells, resulting in targeted B-cell lysis 7 . Beyond its established role in B-cell malignancies, emerging evidence supports blinatumomab’s efficacy in B-cell-mediated autoimmune disorders, where it significantly reduces pathogenic autoantibody titers 8 . Prior report has documented profound DSA attenuation following blinatumomab therapy in acute lymphoblastic leukemia (ALL) patients 9 . These findings provide a compelling mechanistic foundation for investigating blinatumomab as a novel desensitization strategy in haplo-HSCT recipients with preformed DSAs. This case represents the first documented application of blinatumomab for DSA desensitization in a patient undergoing hapol-HSCT. We describe a high-risk pediatric patient (DSA MFI >5,000) undergoing paternal haplo-HSCT who achieved successful DSA reduction following a truncated, low-dose blinatumomab protocol. The resultant engraftment with complete donor chimerism establishes a novel therapeutic paradigm for high-risk sensitized transplant recipients. Case presentation A 16-year-old male patient, weighing 80 kg, was admitted to our hospital on January 1, 2025, with a one-year history of pancytopenia. One year earlier, he had presented to another hospital for evaluation of an upper respiratory tract infection. Routine blood tests revealed leukopenia (white blood cell count: 2.10 × 10⁹/L), an absolute neutrophil count of 1.04 × 10⁹/L, anemia (hemoglobin: 78 g/L), and thrombocytopenia (platelets: 35 × 10⁹/L). He was afebrile and exhibited no rash. Physical examination was unremarkable, with no palpable lymphadenopathy or hepatosplenomegaly. Subsequent diagnostic evaluations—including bone marrow biopsy, flow cytometric immunophenotyping, cytogenetic testing, and genetic sequencing—confirmed the diagnosis of aplastic anemia (AA). Initial treatment included eltrombopag and adjunctive traditional Chinese hematopoietic stimulants; however, the pancytopenia remained refractory, necessitating frequent transfusions of packed red blood cells and platelets. He was therefore referred to our center for HSCT. Human leukocyte antigen (HLA) typing and donor screening were performed. Given the absence of matched siblings or unrelated donors in registries, paternal haplo-HSCT was planned. Pre-transplant anti-HLA antibody profiling using Luminex-based multiplex bead immunoassay revealed strong positivity for HLA class I antibodies (MFI 10,516), with a donor-specific anti-HLA-B*46:01 antibody (DSA MFI 5,155). Additional HLA-B loci with MFI >5,000 are detailed in Figure 1 B. Following informed consent from the patient and parents, blinatumomab desensitization was initiated at a reduced-dose regimen: 8 μg daily for consecutive 8 days. On Day 1, transient pyrexia (38.5°C) resolved with oral acetaminophen and empiric piperacillin-tazobactam, with no subsequent adverse events. Post-therapeutic evaluation at two weeks demonstrated significant improvement: composite HLA class I antibody MFI declined to 5,449 (48.2% reduction), anti-HLA-B*46:01 DSA decreased to subthreshold levels (MFI 701), and all previously sensitized loci exhibited MFI reduction (Figure 1B). One month later, the patient underwent HSCT (Figure 1A). The conditioning regimen included fludarabine (30 mg/m²/day for 5 days), busulfan (3.2 mg/kg/day for 2 days), cyclophosphamide (50 mg/kg/day for 2 days), and rabbit anti-thymocyte globulin (2.5 mg/kg/day for 4 days). Stem cell infusion was performed over three days, with bone marrow–derived hematopoietic stem cells administered on day 1, followed by peripheral blood stem cells on days 2 and 3. The total nucleated cell dose was 7.65 × 10⁸/kg, and the CD34⁺ cell dose was 1.60 × 10⁶/kg. Acute GVHD prophylaxis consisted of mycophenolate mofetil, cyclosporine A and short-course methotrexate. Neutrophil and platelet engraftment were achieved on days +18 and +28, respectively. Short tandem repeat (STR) analysis on day +28 demonstrated 98.41% donor chimerism. The patient remains under regular outpatient follow-up. Peripheral blood counts have normalized, and there are no signs of GVHD. Discussion To our knowledge, this is the first report describing the use of blinatumomab as a desensitization approach in a patient with high-risk DSA prior to allo-HSCT. Our patient presented with a strong DSA, which precluded immediate transplantation. Instead, we employed a truncated, low-dose blinatumomab regimen, achieving substantial reductions in DSA level within two weeks. In allo-HSCT, pre-existing DSAs constitute a critical immunologic barrier that substantially elevates the risk of primary GF 4 . Current guidelines recommend desensitization therapy for patients exhibiting DSAs exceeding 2,000 MFI when alternative donors are unavailable 6 . Conventional desensitization strategies include antibody depletion via plasma exchange or immunoadsorption, suppression of antibody production using B-cell-targeting agents (e.g., rituximab) or proteasome inhibitors (e.g., bortezomib), antibody neutralization with high-dose intravenous immunoglobulin (IVIG), and complement cascade inhibition—with plasma exchange combined with rituximab representing the most frequently employed regimen. However, this conventional approach proved clinically contraindicated in our 80-kg adolescent patient due to dual constraints: theoretically requiring approximately 4,000 mL of plasma exchange per procedure (presenting significant logistical challenges), alongside a documented history of severe anaphylactic reactions to blood products constituting an absolute contraindication. While rituximab monotherapy demonstrates partial efficacy against DSAs in moderate-titer primary poor graft function (primary PGF) (2000–5000 MFI), its suboptimal performance in high-titer cohorts (5000–10,000 MFI) fails to eliminate residual primary PGF risk 10 . Consequently, blinatumomab was investigated as a novel desensitization strategy for this pediatric case. To the best of our knowledge, only one report has documented a decrease in DSAs in patients with ALL following blinatumomab treatment⁹. In that study, patients received blinatumomab as a 28-day continuous intravenous infusion for one to two cycles, with six of seven treated patients achieving substantial DSA attenuation. Crucially, effective antibody clearance does not require malignancy-targeting dosing regimens. In refractory autoimmune disorders—including rituximab-resistant cases—a truncated low-dose protocol (9 μg/day × 5 days, repeated after 1 week) induced marked autoantibody reduction and clinical improvement, high-dimensional flow cytometry revealed profound B-cell reconstitution: activated memory B-cell depletion with concomitant expansion of non-class-switched naïve B cells 8 . Mechanistically, sustained CD19 expression across B-cell ontogeny—including memory B cells and plasma cell subsets—enables comprehensive elimination of antibody-producing lineages. This contrasts fundamentally with rituximab’s limitation: its inability to target plasma cells accounts for its suboptimal antibody clearance compared to blinatumomab’s CD19-directed approach. In our case, a truncated low-dose blinatumomab regimen (total dose: 64 μg over 8 days) achieved sustained DSA abrogation (MFI reduction from 5,155 to 701 within two weeks), supporting its potential as a novel desensitization agent in haplo-HSCT. This report presents the first clinical evidence supporting the feasibility and efficacy of blinatumomab as a desensitization agent in the setting of haplo-HSCT involving DSAs. The rapid and significant reduction in DSA levels, combined with successful engraftment and the absence of major toxicities, underscores a novel immunotherapeutic strategy that merits prospective validation. Future studies should focus on defining the optimal application of blinatumomab—whether used as monotherapy or in combination regimens—for DSA-positive transplant candidates. Reference 1. Zhang X hui, Chen J, Han MZ, Huang H, Jiang E lie, Jiang M, et al. The consensus from the chinese society of hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update. J Hematol Oncol [Internet]. 2021 Sep 15 [cited 2025 Jul 10];14(1). 2. Zhou Y, Chen YL, Huang XY, Chang YJ. Desensitization strategies for donor-specific antibodies in HLA-mismatched stem cell transplantation recipients: what we know and what we do not know. Oncol Ther. 2024 Sep;12(3):375–94. 3. Ciurea SO, de Lima M, Cano P, Korbling M, Giralt S, Shpall EJ, et al. High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation. Transplantation. 2009 Oct 27;88(8):1019–24. 4. Chang YJ, Zhao XY, Xu LP, Zhang XH, Wang Y, Han W, et al. Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets. J Hematol Oncol [Internet]. 2015 Dec [cited 2025 Jul 10];8(1). 5. Ciurea SO, Cao K, Fernandez-Vina M, Kongtim P, Malki MA, Fuchs E, et al. The european society for blood and marrow transplantation (EBMT) consensus guidelines for the detection and treatment of donor-specific anti-HLA antibodies (DSA) in haploidentical hematopoietic cell transplantation. Bone Marrow Transplant. 2018 May;53(5):521–34. 6. Kongtim P, Vittayawacharin P, Zou J, Srour S, Shaffer B, Shapiro RM, et al. ASTCT consensus recommendations on testing and treatment of patients with donor-specific anti-HLA antibodies. Transplantation and Cellular Therapy. 2024 Dec;30(12):1139–54. 7. Kantarjian H, Jabbour E, Topp MS. Blinatumomab for acute lymphoblastic leukemia. N Engl J Med. 2017 Jun 8;376(23):e49. 8. Bucci L, Melanie Hagen, Rothe T, Raimondo MG, Fagni F, Tur C, et al. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat Med. 2024 Jun;30(6):1593–601. 9. Zhang X. Reduction of HLA antibodies by bi-specific antibody blinatumomab. Hum Immunol. 2024 Nov;85(6):111163. 10. Chang YJ, Xu LP, Wang Y, Zhang XH, Chen H, Chen YH, et al. Rituximab for desensitization during HLA-mismatched stem cell transplantation in patients with a positive donor-specific anti-HLA antibody. Bone Marrow Transplant. 2020 Jul;55(7):1326–36. Funding The authors received no financial support for this article’s research, authorship or publication. Conflict-of-interest statement: All authors declare no competing financial interests or personal relationships that could influence the work reported in this paper. Patient consent statement Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Author contributions Xu XJ are responsible for the study design. LUO ZB, GU ME, ZHAO FY, GUO XP are responsible for patient care and data collection. LUO ZB is responsible for data analyses. Luo ZB drafted the manuscript; Xu XJ revised the manuscript; All authors approved the final version to be published. Figure legend Figure 1. Treatment Timeline and Anti-HLA Antibody Response (A) Treatment timeline: Blinatumomab desensitization (8 μg/day for 8 consecutive days), conditioning regimen (fludarabine: 30 mg/m²/day × 5 days, busulfan: 3.2 mg/kg/day × 2 days, cyclophosphamide: 50 mg/kg/day × 2 days, rabbit anti-thymocyte globulin [rATG]: 2.5 mg/kg/day × 4 days), and time to engraftment. (B) MFI values of HLA class I antibodies and HLA-B locus with MFI Information & Authors Information Version history V1 Version 1 01 August 2025 Peer review timeline Published Pediatric Blood & Cancer Version of Record 29 Aug 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Blood & Cancer Keywords anemia aplastic immunotherapy stem cell transplantation Authors Affiliations Zebin Luo 0009-0009-6487-0834 Zhejiang University School of Medicine Children's Hospital View all articles by this author Miner Gu Zhejiang University School of Medicine Children's Hospital View all articles by this author Xiaoping Guo Zhejiang University School of Medicine Children's Hospital View all articles by this author Fenying Zhao Zhejiang University School of Medicine Children's Hospital View all articles by this author Xiao-Jun Xu 0000-0003-1388-2535 [email protected] Zhejiang University School of Medicine Children's Hospital View all articles by this author Metrics & Citations Metrics Article Usage 246 views 204 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Zebin Luo, Miner Gu, Xiaoping Guo, et al. Rapid Donor-Specific Antibodies Clearance with Short-Course Blinatumomab Prior to Haploidentical HSCT: A Case of Successful Engraftment. Authorea . 01 August 2025. DOI: https://doi.org/10.22541/au.175403194.41174748/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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