A recent approach to HLA-haploidentical donor transplantation with post-transplant cyclophosphamide (PTCy) has extended the availability of hematopoietic stem cell transplantation (HSCT) for patients who lack an HLA-matched donor. By selectively depleting the proliferating alloreactive T cells that are responsible for GvHD and graft rejection while preserving the resting memory T cells that are essential for post-transplant immunologic recovery, PTCy contributes to a low rate of both post-transplant infections and treatment-related toxicities.1 In adults, some physicians have adopted the HLA-haploidentical BMT with PTCy strategy for non-malignant diseases such as severe aplastic anemia.2 However, only limited evidence for this strategy is available in children. In this report, we present the case of a girl with myelodysplastic syndrome, who developed autoimmune pancytopenia after a cord blood transplantation (CBT) from her brother. Because conventional therapies, including steroids, intravenous immunoglobulin, rituximab and even bortezomib were not fully effective, we successfully retransplanted her from her HLA-haploidentical father with reduced intensity conditioning and PTCy. We also discuss the feasibility of HLA-haploidentical HSCT in children.
A 3-year-old girl was admitted to our hospital because of thrombocytopenia (24 × 109/L). A bone marrow (BM) biopsy revealed myelodysplastic syndrome (refractory cytopenia with unilineage dysplasia) and a normal karyotype. At this time, she had no sibling and no matched unrelated donor; therefore, she was treated with cyclosporine A (CsA). However, this treatment resulted in progression toward severe neutropenia and thrombocytopenia. At the age of 5, her mother gave birth to a son, and subsequently, cord blood with a 7/8 HLA allelic match was available (Table 1a). Thus, she underwent CBT, 20 months after diagnosis. She was conditioned with fludarabine 25 mg/m2 on days −7 to −3 (total dose, 125 mg/m2), melphalan 70 mg/m2 on days −3 and −2 (total dose, 140 mg/m2) and 3 Gy total body irradiation (TBI) with ovary shielding on day −1. GvHD prophylaxis was performed with short-term methotrexate (10 mg/m2 on day +1, 7 mg/m2 on day +3 and +6) and CsA. The cord blood nucleated cell count was 4.5 × 107/kg, and the CD34-positive cell count was 0.99 × 105/kg. The donor was blood type B Rh-positive and the recipient was blood type O Rh-positive. Anti-HLA antibodies were checked by panel-reactive antibody beads before CBT, and antibodies for DQA1*05 and DQA1*06 were detected. From strong linkage disequilibrium between HLA-DR and DQ, these antibodies were determined not to be donor-specific (Table 1b). During the conditioning phase, she developed recurrent anaphylactic reactions to platelet transfusion. She was treated with 1 mg/kg methylprednisolone (mPSL) infusion and plasma removal from the transfused platelets. Her post-transplantation course was complicated with a delayed neutrophil recovery, thrombocytopenia that was refractory to platelet transfusion, and hemolytic anemia. Although a BM aspirate showed hypoplastic marrow with few erythroid cells and megakaryocytes, a BM XY-FISH revealed 90% donor chimerism on day +28 and complete donor chimerism on day +55. ANC was below 0.5 × 109/L, while monocytes were maintained at around 0.5 × 109/L from day +42. We detected anti-HLA antibodies, which were different from those before CBT, anti-HPA antibodies, anti-neutrophil antibodies and irregular erythrocyte antibodies, and her direct anti-globulin test was positive on day +42, suggesting autoimmune pancytopenia. Chronological changes in anti-HLA antibodies are shown in Table 1b. Anti-HLA antibodies for A*30 and A*31 were newly detected. She also developed grade II stage 3 skin acute GvHD on day +55. Mycophenolate mofetil (45 mg/kg per day, orally) was initiated in addition to mPSL, which was already used for allergic reaction to platelet transfusions. CsA was discontinued at this time; mPSL was tapered from day +66 because skin GvHD had resolved and was then continued at a dose of 0.4 mg/kg per day from day +101. No anaphylactic reaction to platelet transfusions was observed after tapering mPSL. HLA-matched platelet transfusions were transiently useful for refractoriness to platelet transfusion, and rituximab could eliminate circulating CD20+ B cells. However, she remained transfusion dependent with severe neutropenia. Recently, several case reports have suggested that bortezomib, a 26 S proteasome inhibitor that eliminates plasma cells and decreases the production of IgG antibodies, was safe and effective for autoimmune cytopenia after HSCT in both adults and children.3, 4, 5 From day +255, 1.3 mg/m2 of bortezomib was intravenously administered per week for 4 weeks in combination with rituximab. A continuous ANC of >0.5 × 109/L was observed from day +300. We also could avoid transfusion for 3 months from day +330. Despite the successful elimination of the anti-HLA antibodies and negative conversion of direct anti-globulin test on day +404, and a stable neutrophil recovery, the patient became dependent on both platelet and RBC transfusions again from day +432. A BM aspirate showed hypocellular marrow with decreased megakaryocytes and erythroid cells, whereas a BM XY-FISH continued to display full donor chimerism. On day +457, she underwent a BMT from her 5/8 HLA allelic-matched, ABO-matched haploidentical father. BM was T-cell repleted and nuclear cell count was 3.5 × 108/kg. She was conditioned with fludarabine 30 mg/m2 on days −6 to −2 (total dose, 150 mg/m2), Cy 14.5 mg/kg on days -6 and −5 (total dose, 29 mg/kg), and 3 Gy of TBI with ovary shielding on day 0. She underwent GvHD prophylaxis with Cy 50 mg/kg on day +3 and with tacrolimus 0.02 mg/kg per day through continuous intravenous infusion and mycophenolate mofetil 45 mg/kg per day orally from day +5.6 She made good progress after the second transplantation with an ANC of >0.5 × 109/L on day +14 (+471 from CBT), a reticulocyte count of >20 × 109/L on day +19 and platelet counts of >20 × 109/L on day +28. There were no episodes of infection. Full donor chimerism was identified on day +28. She became transfusion independent with a hemoglobin level of >10 g/dL and a platelet count of >100 × 109/L from day +80 and day +143, respectively. Mycophenolate mofetil was discontinued on day +55, and the tacrolimus was gradually tapered. Grade I stage 2 skin GvHD was observed on day +96; however, it resolved without additional immunosuppressants. Thirteen months have passed without any further evidence of GvHD (Figure 1).
Due to the allowance of more HLA disparities compared with that of BM or PBSC, CB has become an important alternative source for patients lacking a suitable donor, particularly in children. Furthermore, its prompt availability establishes CBT as a therapeutic rescue option for graft failure after a previous HSCT. When there is an immediate requirement, HSCT from an HLA-haploidentical relative is another option. However, a T-cell-depleted HLA-haploidentical HSCT has a high incidence of engraftment failure mainly because the remaining host alloreactive T cells may escape the conditioning procedure, whereas a T-cell-repleted HLA-haploidentical HSCT has great concerns for severe GvHD.7
Recently, the feasibility of PTCy-based haploidentical HSCT was demonstrated in children with advanced leukemia; these patients displayed excellent engraftment along with acceptable rates of treatment-related toxicities and GvHD.8 That report encouraged us to take a step forward by performing a retransplantation from the patient’s HLA-haploidentical father as a curative therapy for donor-type BM hypoplasia. While early HSCT is recommended as a cure for pediatric MDS, immunosuppressive therapy remains an option for low-risk patients without a suitable related or unrelated donor.9, 10 Regarding alternative donors for immunosuppressive-therapy-resistant MDS or severe aplastic anemia, patients who received CBT may be at higher risk of infections or relapse compared with patients transplanted with other sources.11, 12 Furthermore, although infrequent, a CBT may be a risk factor for autoimmune cytopenia.4, 13, 14 Because a 7/8 HLA allelic-matched sibling was born, CBT emerged as a therapeutic option for the cure of immunosuppressive-therapy-resistant MDS in our case. However, if we consider the risk of relapse, infection or autoimmune cytopenia, HLA-haploidentical BM may become a higher priority source compared with CB in the treatment of pediatric MDS patients without siblings or HLA-matched unrelated donors. Our patient underwent PTCy-based haploidentical HSCT at the age of 5. Although she experienced no severe GvHD, young children <10 years of age may be at high risk of GvHD and hemophagocytic syndrome due to significant variability of Cy metabolism.8, 15 Further studies to determine the safety and feasibility of reduced intensity conditioning and PTCy-based HLA-haploidentical HSCT in children are warranted.
Bashey A, Solomon SR . T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor. Bone Marrow Transplant 2014; 49: 999–1008.
Esteves I, Bonfim C, Pasquini R, Funke V, Pereira NF, Rocha V et al. Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study. Bone Marrow Transplant 2015; 50: 685–689.
Mehta B, Mahadeo K, Zaw R, Tang S, Kapoor N, Abdel-Azim H . Bortezomib for effective treatment of a child with refractory autoimmune hemolytic anemia post allogeneic hematopoietic stem cell transplant. Pediatr Blood Cancer 2014; 61: 2324–2325.
Waespe N, Zeilhofer U, Güngör T . Treatment-refractory multi-lineage autoimmune cytopenia after unrelated cord blood transplantation: remission after combined bortezomib and vincristine treatment. Pediatr BloodCancer 2014; 61: 2112–2114.
Hosoba S, Jaye DL, Cohen C, Roback JD, Waller EK . Successful treatment of severe immune hemolytic anemia after allogeneic stem cell transplantation with bortezomib: report of a case and review of literature. Transfusion 2015; 55: 259–264.
Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641–650.
Ball LM, Bernardo ME, Roelofs H, Lankester A, Cometa A, Egeler RM et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 2007; 110: 2764–2767.
Jaiswal SR, Chakrabarti A, Chatterjee S, Bhargava S, Ray K, O'Donnell P et al. Haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide in children with advanced acute leukemia with fludarabine-, busulfan-, and melphalan-based conditioning. Biol Blood Marrow Transplant 2016; 22: 499–504.
Niemeyer CM, Baumann I . Myelodysplastic syndrome in children and adolescents. Semin Hematol 2008; 45: 60–70.
Smith AR, Christiansen EC, Wagner JE, Cao Q, MacMillan ML, Stefanski HE et al. Early hematopoietic stem cell transplant is associated with favorable outcomes in children with MDS. Pediatr Blood Cancer 2013; 60: 705–710.
Basquiera AL, Pizzi S, Correas AG, Longo PG, Goldman WC, Prates MV et al. Allogeneic hematopoietic stem cell transplantation in pediatric myelodysplastic syndromes: a multicenter experience from Argentina. Pediatr Blood Cancer 2015; 62: 153–157.
Kosaka Y, Yagasaki H, Sano K, Kobayashi R, Ayukawa H, Kaneko T et al. Prospective multicenter trial comparing repeated immunosuppressive therapy with stem-cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia. Blood 2008; 111: 1054–1059.
Daikeler T, Labopin M, Ruggeri A, Crotta A, Abinun M, Hussein AA et al. New autoimmune diseases after cord blood transplantation: a retrospective study of EUROCORD and the Autoimmune Disease Working Party of the European Group for Blood and Marrow Transplantation. Blood 2013; 121: 1059–1064.
Faraci M, Zecca M, Pillon M, Rovelli A, Menconi MC, Ripaldi M et al. Autoimmune hematological diseases after allogeneic hematopoietic stem cell transplantation in children: an Italian multicenter experience. Biol Blood Marrow Transplant 2014; 20: 272–278.
Jaiswal SR, Chakrabarti A . Haploidentical transplantation in children with acute leukemia: the unresolved issues. Adv Hematol 2016; 2016: 3467672.
The authors declare no conflict of interest.
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Shima, H., Isshiki, K., Yamada, Y. et al. Successful haploidentical BMT with post-transplant cyclophosphamide for refractory autoimmune pancytopenia after cord blood transplant in pediatric myelodysplastic syndrome. Bone Marrow Transplant 52, 653–655 (2017). https://doi.org/10.1038/bmt.2016.341