Successful Allogeneic Hematopoietic Stem Cell Transplantation from A 5/10 Mismatched Unrelated Donor in A Patient with Donor-Specific Anti-HLA Antibodies.

Currently, for patients requiring hematopoietic stem cell transplantation (HSCT) but lacking a matched related or a matched unrelated donor (MUD) (20%) an HSTC from a mismatched unrelated donor (mMUD), a cord blood unit (CBU) or an HLA-haploidentical HSCT (haplo-HSCT) represent a widely available approach.

Several studies show that high dose cyclophosphamide administered after HCT (PTCy) is a feasible option for haploidentical and mismatched in terms of safety profile and low rates of graft versus host disease (GVHD) and transplant non-related mortality (NRM) ¹,²

HLA antibodies should be examined as part of the pre-transplant work-up, especially in transplants with HLA-mismatches planned for parous women and multi-transfused receptors. Furthermore, donors who have HLA antigens that correspond to high levels of donor-specific anti-HLA antibodies (DSAs) in the patient should be avoided. DSAs are considered positive when median fluorescence intensity (MFI) is > 3000 -5000 and > 10.000 as very high levels corresponding to the mismatched donor HLA antigen³,⁴

Thus, if the patient has donor-specific anti-HLA antibodies against antigens present in the mismatched donor or CBU, this option should be disregarded due to the high risk of graft failure (GF)³,⁵,⁶.

The risk of GF in the presence of DSAs is approximately 70% after T-cell replete and T-cell deplete haplo-HSCT and after CBU transplants. Similarly, after mMUD transplant the risk is between 11 to 22% ³_,⁵,⁶,⁷

In an attempt to reduce DSAs, desensitization can be used but if levels of DSAs are high, this technique has limited results ⁴,³_,⁸

A 62-year-old woman with a high-risk acute myeloid leukemia (high ratio FLT-ITD mutation and NPM1 mutation) was diagnosed on December 2016. The patient weighed 58 Kg and had a history of one pregnancy. After induction chemotherapy that included idarubicin, cytarabine and midostaurine, she achieved a complete response. She then received three consolidation cycles with high dose cytarabine.

Because of the poor prognosis and high risk of relapse⁸,⁹an allogeneic HCT was planned. The patient had no HLA identical sibling nor 9/10-10/10 unrelated donor. A search for CBU was also performed but all units were discharged because of low cellularity. Two familiar haploidentical donors (sister and son) were identified but the patient had high titters of DSAs (16616 MFI against B*49:01, 18464 MFI against DQB*03:01/DQ DRB1*11:01, and 20810 MFI against DRB1*11:01). Before the transplant, during the aplasia after chemotherapy, she had received transfusions with 19 RBC units and 29 pools of platelets.

At this stage, a desensitization treatment including plasma exchange, rituximab and immunoglobulins as a new treatment strategy for severe HLA alloimmune platelet refractoriness¹¹ was administered without success.

For this reason, a directed search for mMUD for which the patient did not have DSAs, was performed through the Spanish Marrow Donor Registry (REDMO).

A 30 year-old-female donor weighing 68 Kg, with intermediate CMV risk (patient + /donor +) and major bidirectional ABO incompatibility (patient A +/donor B +) was found. Between donor and patient there were 5 out of 10 HLA-mismatches, 3 at antigen level (loci A, C, and DRB1) and 2 at allele level (loci B and DQ).

In Table 1 appear the HLA genotype of the patient and the donor.

Although the patient was extensively alloimmunized, she had no DSAs against the donor mismatches.Figure 1

Figure 1.DSAs against HLA antigens of sister and son pre and after desensitization.

The patient received our standard conditioning regimen for haploidentical transplantation for patients older than 50 years, with fludarabine 30 mg/sqm (days -6 to -2) and busulfan 3.2 mg/sqm(days -7 to -5) and 2Gy TBI (day -1), followed by the infusion of 8 x 10^6 CD34+/kg, 603·106 /CD3+/kg on day 0 (12/05/2017). She did not receive stimulants of the granulocyte colonies (GCSF).

A panel of selected platelet donors where identified before transplantation to ensure adequate platelet transfusions during aplasia. The patient did not present any bleeding problems.

GVHD prophylaxis was done with high dose PTCy (+3 and +4), tacrolimus and mycophenolate. The patient achieved neutrophils ≥500/µL on day +23 and platelets ≥20.000/µL on day +25. At + 30, full donor chimerism on neutrophils and T lymphocytes was achieved.

There were no severe complications except a grade IV mucositis, cervical edema without any radiological findings that was resolved with antibiotic and antifungal therapy, a CMV reactivation that was treated with valganciclovir and a biological TMA at +35 which was resolved by withdrawing tacrolimus and adding rapamycin.

After 9 months, the patient continues in CR, with full donor chimerism, and no GVHD has occurred.

This is a successful HLA- 5/10 mMUD-HSCT in a woman that without this strategy wouldn´t have been transplanted. Taking into account the list of the DSAs, REDMO did a manual selection of the possible donors, selecting those that for which the patient didn´t have DSAs.

With the classical conditioning and GVHD proplylaxis with PTCy used in the haploidentical transplants, the patient engrafted, faster full chimerism was achieved and she didn´t present GVHD.

This case highlights that almost every patient that needs an allogeneic transplantation can have a donor. In such difficult cases of patients who lack of HLA matched related or unrelated donors, and who have DSAs that rules out the possibility of an haploidentical related or a mismatched unrelated transplantation, an individualized strategy together with the registry should be taken to select mMUD to which a patient has no DSAs.

1. 1.Kasamon Y, Ambinder R, Fuchs E, Zahurak M, Rosner G et al. (2017) Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide. , Blood Advances 1(4), 288-292.
   PubMed·Search at Google Scholar

1. 2.Kanakry C, Bolaños-Meade J, Kasamon Y, Zahurak M, Durakovic N et al. (2017) Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide. , Blood 129(10), 1389-1393.
   Search at Google Scholar

1. 3.oshihara S, Taniguchi K, Ogawa H, Saji H. (2012) The role of HLA antibodies in allogeneic SCT: is the ‘type-and-screen’ strategy necessary not only for blood type but also for HLA?. , Bone Marrow Transplantation 47(12), 1499-1506.
   Search at Google Scholar

1. 4.Gladstone D, Zachary A, Fuchs E, Luznik L, Kasamon Y et al. (2013) Partially Mismatched Transplantation and Human Leukocyte Antigen Donor-Specific Antibodies. , Biology of Blood and Marrow Transplantation 19(4), 647-652.
   Search at Google Scholar

1. 5.Ciurea S, M de Lima, Cano P, Korbling M, Giralt S et al. (2009) High Risk of Graft Failure in Patients With Anti-HLA Antibodies Undergoing Haploidentical Stem-Cell Transplantation. , Transplantation 88(8), 1019-1024.
   Search at Google Scholar

1. 6.Spellman S, Bray R, Rosen-Bronson S, Haagenson M, Klein J et al. (2010) The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure. , Blood 115(13), 2704-2708.
   Search at Google Scholar

1. 7.Taylor P, Ehrhardt M, Roforth M, Swedin J, Panoskaltsis-Mortari A et al. (2006) Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients. , Blood 109(3), 1307-1315.
   Search at Google Scholar

1. 8.Bramanti S, Nocco A, Mauro E, Milone G, Morabito L et al. (2016) Desensitization with plasma exchange in a patient with human leukocyte antigen donor-specific antibodies before T-cell-replete haploidentical transplantation. , Transfusion 56(5), 1096-1100.
   Search at Google Scholar

1. 9.Pratcorona M, Brunet S, Nomdedeu J, Ribera J, Tormo M et al. (2013) Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. , Blood 121(14), 2734-2738.
   Search at Google Scholar

1. 10.Schnittger S, Bacher U, Kern W, Alpermann T, Haferlach C et al. (2011) Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia. , Leukemia 25(8), 1297-1304.
   Search at Google Scholar

1. 11.Cid J, Magnano L, Acosta M, Alba C, Esteve J et al. (2014) Rituximab, plasma exchange and intravenous immunoglobulins as a new treatment strategy for severe HLA alloimmune platelet refractoriness. , Platelets 26(2), 190-194.
   Search at Google Scholar

1. 1.Bailén Rebeca, Vicario José Luis, Solán Laura, Sánchez-Vadillo Irene, Herrera Pilar, et al, 2021, Management of Donor-Specific Antibodies in Haploidentical Transplant: Multicenter Experience From the Madrid Group of Hematopoietic Transplant, Frontiers in Immunology, 12(), 10.3389/fimmu.2021.674658

1. 2.Bailén Rebeca, Alenda Raquel, Herruzo-Delgado Beatriz, Acosta-Fleitas Cynthia, Vallés Ana, et al, 2023, Results of haploidentical transplant in patients with donor-specific antibodies: a survey on behalf of the Spanish Group of Hematopoietic Transplant and Cell Therapy, Frontiers in Immunology, 14(), 10.3389/fimmu.2023.1165759