Pediatr Transplantation 2014: 18: 896–898

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric Transplantation DOI: 10.1111/petr.12371

Letter to the Editor Successful engraftment of third allogeneic hematopoietic stem cell transplantation after two graft failures and treatment for anti-HLA antibody in a pediatric acquired aplastic anemia patient Preexisting anti-HLA antibodies have recently been reported to be associated with unsatisfactory outcome of hematopoietic stem cell transplantation (HSCT). Several studies demonstrated that donor-specific anti-HLA antibodies (DSHA) increased the risk of graft failure (1–5), and some researchers indicated that anti-HLA antibodies had a negative impact on the outcome of HSCT (6–8). Therapeutic strategies directed at anti-HLA antibodies are being investigated currently; however, consensus has not yet been reached on clinical practice guidelines. This report describes a pediatric aplastic anemia patient with anti-HLA antibodies who experienced graft failure twice and achieved successful engraftment with her third HSCT after treatment for anti-HLA antibodies. Case report

A two-yr-old Chinese girl was referred to our center due to severe pallor. She was diagnosed with acquired severe aplastic anemia and immediately received immunosuppressive therapy (IST) with antithymocyte globulin (ATG, Fresenius) (5 mg/ kg/day for five days) and cyclosporine A (100– 130 mg/day, maintaining serum concentration at 100–150 lg/L), because there was no HLA identical sibling donor for first-line HSCT. The patient persisted with anemia after four months of IST, without response according to the worldwide acknowledged criteria (9). Therefore, preparation of alternative donor HSCT was started. First allogeneic HSCT

The patient received first allogeneic HSCT five months after diagnosis from a matched unrelated 896

donor from the China Marrow Donor Program (HLA 10/10, HLA-A, B, Cw, DRB1, DQB1 loci by high-resolution typing methods), which provided peripheral blood stem cells. The conditioning regimen included total body irradiation (TBI, 300 cGy), fludarabine (Fluda, 40 mg/m2/day for five days), cyclophosphamide (Cy, 60 mg/kg/day for two days), and ATG (Thymoglobulin, 10 mg/kg) (FCA-TBI). The patient was transfused mononuclear cells 17.7*108/kg in which CD34+ cells were 3.5*106/kg. Neutrophil count in peripheral blood remained 0 after the first allo-HSCT, which was diagnosed as a primary graft failure at Day 20. Second allogeneic HSCT

A second allo-HSCT was carried out 23 days after the first one. The patient received peripheral blood hematopoietic stem cells from the same donor as the first HSCT (HLA 10/10-matched unrelated donor). Conditioning regimen included Fluda (40 mg/m2/day for three days), Cy (60 mg/kg/day for two days), and 6 mg/kg ATG (Thymoglobulin). The number of infused mononuclear cells was 24.8*108/kg, including 4.9*106/ kg CD34+ cells. The second allo-HSCT ended in primary graft failure 20 days afterwards. Third allogeneic HSCT and outcome

After anti-HLA antibody detection and treatment, the patient underwent a third allo-HSCT 23 days after the second one. She received peripheral blood hematopoietic stem cells from her mother (HLA 9/10 by high-resolution typing methods with one HLA-Cw locus antigen mismatched). The conditioning regimen included TBI (250 cGy) and Fluda (40 mg/m2/day for

Letter to the Editor

three days). Moreover, anti-CD20 monoclonal antibody (200 mg), plasma exchange (2.5 times blood volume), and intravenous immunoglobulin (IVIG, 7.5 g, equivalent to 0.6 g/kg) were given prior to HSCT. The patient achieved neutrophil recovery (absolute neutrophil count >0.5*109/L) by day 15, and the donor chimerism detection subsequently indicated the percentage of donor cells in her peripheral blood was 100% (by short tandem repeat PCR). Platelet recovery was reached at day 30. Grade II acute graft versus host disease (aGVHD) occurred at day 15 (skin), which resolved around day 33 after methylprednisolone therapy. The patient left hospital and started outpatient follow-up on day 38. Donor cells remained 100% by donor chimerism detection three and six months after the third allo-HSCT. She is now living well and independent from transfusion with recent follow-up time 190 days after the third HSCT. Anti-HLA antibody detection and treatment

After the patient developed graft failure twice, a serum sample was examined for anti-HLA antibodies and was found to have as follows: HLA-Cw17 antibody (MFI 2764), HLA-DR52 antibody (MFI 2406), HLA-A68 antibody (MFI 1567), HLA-B37 antibody (MFI 1521), and HLA-DR18 antibody (MFI 1144) positive, which were non-donor-specific anti-HLA antibody (NDSHA). Anti-HLA antibodies detection was retrospectively conducted on a preserved serum sample collected before the first alloHSCT, which indicated the patient had preexisting anti-class I and II HLA antibodies before the first transplantation. Prior to the third transplantation, combined application of anti-CD20 monoclonal antibody, immunoglobulin and plasma exchange was adopted for the treatment of anti-HLA antibodies. Rituximab (200 mg) was used two days before HSCT. On day 0, the patient underwent plasma exchange (2.5 times of blood volume), followed by IVIG (7.5 g, equivalent to 0.6 g/kg). Afterwards, peripheral blood hematopoietic stem cells were transfused. Anti-HLA antibodies were not detected on day 1 and day 15 detection after the third HSCT. Discussion

Graft failure occurs as the result of several factors, including HLA matching, cell dose infused, and conditioning regimen. Anti-HLA antibody has currently been found to associate with graft failure (1–8). In the present case, the patient

developed primary graft failure in her first HSCT, even though she received abundant hematopoietic stem cells from an HLA 10/10matched unrelated donor with irradiation containing conditioning (FCA-TBI), and her second HSCT failed again with stem cells from the same donor, which indicated that there may be some immunological factors directed at the donor cells participating in the mechanism of two graft failure. This speculation was also confirmed by the following facts: The patients had preexisting anti-HLA antibodies (although NDSHA) and the third HSCT achieved engraftment after treatment for antibody and donor alteration. Similarly, Costa et al. reported a patient with DSHA who developed primary graft failure. They reduced intensity of DSHA by plasma exchange and IVIG before the second HSCT instead of changing donor. The patient reached engraftment from the same unrelated donor with his second HSCT (10). Hoshino et al. applied plasma exchange, CD20 monoclonal antibody and IVIG to a patient with DSHA and NDSHA; however, the level of anti-HLA antibodies remained very high and she failed the first HSCT afterwards (11). Therefore, the existence of anti-HLA antibodies may be the barriers to engraftment. Treatment options for anti-HLA antibodies include removing the existing antibodies (plasma exchange/ platelet transfusion), inhibiting activity of antibody (immunoglobin/eculizumab), and blocking B cells or plasma cells (rituximab/bortezomib) (12), some of which have been reported with certain clinical effect. Ishiyama et al. used only IVIG for a patient with high level of DSHA, who achieved hematopoietic reconstitution in an unmanipulated haploidentical transplantation (13). In the report by Shiratori, CD 20 monoclonal antibody, plasma exchange, and IVIG were used in combination to a patient with strong positive DSHA, who had DSHA reduce gradually and achieved engraftment (14). Ciurea et al. treated four patients with DSHA by plasmapheresis and rituximab and two of them reached engraftment in the following HSCT. In the present case, the patient was also treated by rituximab, plasma exchange, and IVIG in combination, whose NDSHA turned negative immediately and finally achieved engraftment in her third HSCT. Due to the impact of anti-HLA antibodies, the monitoring and treatment of the antibodies may become an indispensable part of HSCT. However, should NDSHA be taken into consideration when treating anti-HLA antibodies? What is the threshold of antibody level for antibody treatment? How to make a decision 897

Letter to the Editor

between antibody treatment and changing donor with existence of DSHA? Problems remain to be solved and clinical practice guidelines are needed.

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Acknowledgment

This work was supported by the National Natural Science Foundation of China (No. 81273266), the Outstanding Medical Academic Leader Program of Jiangsu Province (No. LJ 201138), and the Science and Technology Key Project on Clinical Medicine of Jiangsu Province No. SBL201320030, BL2014038)

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Hua Zhu *, Changying Luo *, Jun He , Lixia Ding , Jianmin Wang2, Chengjuan Luo2 and Jing Chen1 1 Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Pediatric Hematology and Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 2Department of Pediatric Hematology and Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 3 Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China E-mail: [email protected]

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*These authors contributed equally to this work. References 1. CIUREA SO, THALL PF, WANG X, et al. Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation. Blood 2011: 118: 5957–5964. 2. CUTLER C, KIM HT, SUN L, et al. Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation. Blood 2011: 118: 6691–6697. 3. RUGGERI A, ROCHA V, MASSON E, et al. Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: A Eurocord, Societe Francophone d’Histocompatibilite

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Successful engraftment of third allogeneic hematopoietic stem cell transplantation after two graft failures and treatment for anti-HLA antibody in a pediatric acquired aplastic anemia patient.

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