Share:

Top

Clinical Case of the Month – Desensitization Therapy with Daratumumab for Donor Specific Antibodies (DSA) in Mismatched Unrelated HCT

by
Training/Education
Clinical Case

Title: Desensitization Therapy with Daratumumab for Donor Specific Antibodies (DSA) in Mismatched Unrelated HCT

Submitted by Alexander Kulagin and Alexandra Laberko, RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russia

Physicians expert perspective: Alexander Kulagin and Alexandra Laberko

A 17-year-old male of Avar nationality with ADA2 deficiency presented with transfusion-dependent pure red cell aplasia, progressing to pancytopenia. Immunosuppressive therapies yielded only transient responses, necessitating allogeneic HCT. Potential donors included two 10/12 HLA-matched unrelated donors and haploidentical parents. 

Q1. DSA testing is currently recommended for:

  1. Any transplants
  2. HLA-mismatched unrelated and haploidentical donor transplants
  3. HLA-mismatched unrelated donor transplants
  4. Haploidentical donor transplants

Pre-transplant assessment revealed positive anti-HLA class I and II antibodies, including donor-specific antibodies (DSA) to unrelated donors and father. The mother was pregnant at the time of scheduled HCT. A B- and DPB1-mismatched unrelated donor was selected with anti-class II antibodies against DPB1 with 8864 MFI. 

Q2. What strategy is currently recommended in DSA-positive patients?

  1. If DSA>1,000 MFI use alternative donor or perform desensitization
  2. If DSA 1,000-5,000 MFI use alternative donor or wait until DSA clearance
  3. If DSA >5,000 MFI use alternative donor or perform desensitization

Q3. What methods of desensitization therapy may be used?

  1. Antibody removal
  2. Antibody removal and inhibition of antibody production
  3. Antibody removal, inhibition of antibody production and antibody neutralization
  4. Antibody removal, inhibition of antibody production, antibody neutralization and inhibition of complement cascade

A desensitization protocol was initiated, comprising two cycles of daratumumab 16 mg/kg (day -24 and -14 before HCT) interspersed with three sessions of plasmapheresis from day -17 to -15 and intravenous immunoglobulin (IVIG) infusion of 1g/kg. Following the first daratumumab, plasmapheresis and IVIG, the DSA titer decreased to 4909 MFI, and, upon completion of desensitization, to 239 MFI.

The patient received conditioning with fludarabine, treosulfan, thiotepa and thymoglobulin, with posttransplant cyclophosphamide/ ruxolitinib for GVHD prophylaxis. Engraftment occurred at day +21. The post-transplant course was complicated by prolonged poor graft function (grade 2 anemia, grade 4 thrombocytopenia). Serial monitoring showed DSA titers of 240 and 440 MFI in two and six months post-HCT, respectively. At one-year follow-up, the patient maintains full donor chimerism with satisfactory graft function.

Expert Perspective

Since the crucial role of DSA was demonstrated for rejection of solid organs, their emerging significance has been demonstrated in the setting of HLA-mismatched HCT. Many studies showed increased risks of graft failure and decreased survival for those patients having DSA for haploidentical and HLA-mismatched unrelated donors.

Several studies demonstrate that the highest risk of developing anti-HLA antibodies is seen in women (especially those having pregnancies) and recipients of multiple blood transfusions (1). Our patient with ADA2 deficiency developed pure red cell aplasia of the age of 13 and required regular red blood cell (RBC) transfusions for about 2 years before HCT. Importantly, repeated RBC transfusions may also lead to iron overload, which is an additional risk factor of graft failure and poor graft function after HCT. Of note, pure red cell aplasia is one of the most common indications for HCT in ADA2 deficiency, due to very poor response to immunosuppressive therapy (2), which was also seen in our patient. The patient had four potential donors with DSA to three of them, including two 10/12 HLA mismatched unrelated and haploidentical father, and the mother was pregnant. As the patient had no life-threating conditions, the potential option was to postpone HCT until the mother would become available. Nevertheless, the decision was made to proceed to HCT, because of risks of further DSA production, more organ damage with iron overload upon continued RBC transfusions, and additional risks of development of other ADA2 deficiency related complications. 

A 10/12 HLA mismatched unrelated donor was chosen with anti-DPB1 DSA. Importantly, DPB1 is appraised as less significant for immune-mediated post-HCT complications, and is not considered by many transplant centres during a donor search (3). However, anti-DPB1 DSA have been shown to increase risks of graft failure after HCT (4).

Both European and American recommendations suggest treatment of DSA in mismatched donor setting with DSA cut off of 1000-2000 MFI (5), (6). Multiple options or their combinations can be used to treat DSA, including antibody removal with plasmapheresis or immunoabsorption, inhibition of antibody production with anti-B-cell therapy, antibody neutralization with IVIG or platelet and white blood cell transfusions and inhibition of complement cascade. Complement mediated cytotoxicity is thought to be the main mechanism of graft failure, and testing for complement-binding DSA (C1q) is recommended for HCT recipients with DSA, especially in those with higher MFI (>5000). However, it is unclear if complement inhibition itself would be enough to prevent graft failure. No standardized treatment for DSA is elaborated, and the current guidelines propose usage of local institutional protocols. It is also of question if lower DSA levels may require less intensive antibody eliminating regimens. Some centers implement protocols of desensitization based on DSA MFI levels and presence of additional risks (7).

The options of B-cell depletion usually include monoclonal anti-CD20 antibodies - rituximab and the proteasome inhibitor – bortezomib. However, monoclonal anti-CD38 antibodies – daratumumab is successfully used for plasma-cell depletion in different antibody-mediated conditions. Daratumumab is increasingly used to treat anti-HLA antibodies in solid organ transplantation, and few reports demonstrate efficacy of daratumumab for DSA treatment before allogeneic HCT, however no optimal doses and timing are established.

After HCT, the patient experienced long-term (up to 6 months post-HCT) poor graft function with profound thrombocytopenia requiring multiple platelet transfusions and thrombopoetin agonists with very limited effect. Although the role of DSA in persistence of poor graft function remains less clear, the DSA were tested twice more after HCT. No significant increase in DSA level was seen and graft function improved after HSV infection clearance and antiviral therapy weaned.

To conclude, high titers of anti-HLA antibodies may significantly increase risks of graft failure after HLA-mismatched allogeneic HCT. Desensitization with a combination of anti-CD38 monoclonal antibodies - daratumumab, plasmapheresis and IVIG can successfully eliminate DSA and prevent graft loss after HCT.

Correct Answers: Q1 – B, Q2 – A, Q3 – D 

References:

  1. La Rocca U, Ricci R, Piciocchi A, Barberi W, Oldani E, Dominietto A, et al. Donor-specific anti-HLA antibodies (DSAs) in patients undergoing allogeneic hematopoietic stem cell transplantation from mismatched donors on behalf of GITMO and AIBT. Blood Transfus. 2025 Mar;23(2):176–85.
  2. Hashem H, Bucciol G, Ozen S, Unal S, Bozkaya IO, Akarsu N, et al. Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients. J Clin Immunol. 2021 Oct;41(7):1633–47.
  3. Spierings E, Madrigal A, Fleischhauer K. Histocompatibility. 2024 Apr 11. In: Sureda A, Corbacioglu S, Greco R, et al., editors. The EBMT Handbook: Hematopoietic Cell Transplantation and Cellular Therapies [Internet]. 8th edition. Cham (CH): Springer; 2024. Chapter 9. Available from: https://www.ncbi.nlm.nih.gov/books/NBK608307/ doi: 10.1007/978-3-031-44080-9_9. In.
  4. Ciurea SO, Thall PF, Wang X, Wang SA, Hu Y, Cano P, et al. Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation. Blood. 2011 Nov 24;118(22):5957–64.
  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. Transplant Cell Ther. 2024 Dec;30(12):1139–54. 

  7. Gocke CB, Zahurak M, Sinanidis I, Berger SA, Bolaños-Meade J, Fuchs EJ, et al. Personalized  Desensitization for DSAs in Allogeneic Blood or Marrow  Transplantation: Impact on Graft Outcomes and Access to Transplant. Blood. 67th ASH Annual Meeting Abstracts. 2025 Nov 3; 146 (Supplement 1): 510–511

Future Clinical Case of the Month

If you have a suggestion for future clinical case to feature, please contact Anna Sureda.

View past Clinical Cases