Successful haploidentical BMT with post-transplant cyclophosphamide for refractory autoimmune pancytopenia after cord blood transplant in pediatric myelodysplastic syndrome

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).

Table 1a HLA and bloodtype of recipient and donors
Table 1b Change in anti-HLA antibodies detected in recipient
Figure 1
figure1

Clinical course of autoimmune cytopenia after cord blood transplantation for MDS, and recovery after HLA-haploidentical bone marrow transplantation. MMF=mycophenolate mofetil; haplo-BMT=haploidentical bone marrow transplantation; IVIG=intravenous immunoglobulin.

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.

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Correspondence to H Shima.

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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

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