艾曲波帕成功治疗ABO血型不合的异基因造血干细胞移植后难治性纯红细胞再生障碍性贫血

Successful treatment of refractory pure red cell aplasia with eltrombopag after ABO-incompatible allogeneic hematopoietic stem cell transplantation 艾曲波帕成功治疗ABO血型不合的异基因造血干细胞移植后难治性纯红细胞再生障碍性贫血 1 2 3 first-author 1 2 3 1 2 3 1 2 3 1 2 3 corresp He HUANG, huanghe@zju.edu.cn He HUANG, huanghe@zju.edu.cn huanghe@zju.edu.cn https://orcid.org/0000-0002-2723-1621 1 2 3 corresp Yanmin ZHAO, yanminzhao@zju.edu.cn Yanmin ZHAO, yanminzhao@zju.edu.cn yanminzhao@zju.edu.cn https://orcid.org/0000-0003-3857-5574 Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou310003, China Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou310003, China Institute of Hematology, Zhejiang University, Hangzhou310058, China Institute of Hematology, Zhejiang University, Hangzhou310058, China Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou310058, China Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou310058, China 纯红细胞再生障碍性贫血是ABO血型不合的异基因造血干细胞移植后常见的并发症。治疗该并发症有多种方法可供选择，包括大剂量激素、促红细胞生成素、血浆置换、免疫吸附、供者淋巴细胞输注、利妥昔单抗、硼替佐米、达雷木单抗以及减停免疫抑制剂等。在本文中，我们呈现了一个ABO血型不合的异基因造血干细胞移植后出现纯红细胞再生障碍性贫血的病例。重组人促红细胞生成素、糖皮质激素、供着淋巴细胞输注、血浆置换以及减停免疫抑制剂等方法均对其无明显疗效，最终在足剂量长疗程的艾曲波帕治疗下，患者得以康复。通过对艾曲波帕在治疗纯红细胞再生障碍性贫血中的机制的推测，我们发现艾曲波帕可能对单系造血有效，并且可被用于ABO不合的异基因造血干细胞移植后纯红细胞再生障碍性贫血的治疗。 纯红细胞再生障碍性贫血 异基因造血干细胞移植 艾曲波帕 Pure red cell aplasia (PRCA) is a well-recognized complication of ABO major mismatched allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a reported incidence of 10%–20% ( Zhidong et al., 2012 Zhidong et al., 2012 ; Busca et al., 2018 Busca et al., 2018 ). It is clinically characterized by anemia, reticulocytopenia, and the absence of erythroblasts in a normal-appearing bone marrow biopsy ( Shahan and Hildebrandt, 2015 Shahan and Hildebrandt, 2015 ). The mechanism for PRCA has been presumed to be persistence of recipient isoagglutinins, produced by residual host B lymphocytes or plasma cells, which can interfere with the engraftment of donor erythroid cells ( Zhidong et al., 2012 Zhidong et al., 2012 ). Several risk factors of PRCA at presentation are known, such as presence of anti-A isoagglutinins before transplantation, reduced intensity conditioning, absence of acute graft-versus-host disease (GVHD), sibling donors, and cyclosporin A (CsA) as GVHD prophylaxis ( Hirokawa et al., 2013 Hirokawa et al., 2013 ). PRCA is not considered to be a barrier to HSCT, as some patients can recover spontaneously or benefit from various approaches including high-dose steroids, erythropoietin (EPO), plasma exchange, immunoadsorption, donor lymphocyte infusion (DLI), treatment with rituximab, bortezomib, or daratumumab, and tapering or discontinuation of immunosuppression ( Hirokawa et al., 2013 Hirokawa et al., 2013 ; Bathini et al., 2019 Bathini et al., 2019 ). However, there are still some patients who fail to respond even to aggressive treatment; they become red cell transfusion-dependent and iron-overloaded, and their life quality is impaired. Eltrombopag (EPAG; Revolade, Novartis, Switzerland), a novel oral thrombopoietin receptor agonist (TPO-RA), acts on the thrombopoietin receptor (TpoR; c-myeloproliferative leukemia (c-MPL)) on hematopoietic stem cells (HSCs) and megakaryocytes, showing encouraging efficacy in patients with chronic immune thrombocytopenic purpura (ITP) and refractory severe aplastic anemia (rSAA). Additionally, these investigations reported that red blood cell counts were increased ( Olnes et al., 2012 Olnes et al., 2012 ; Desmond et al., 2014 Desmond et al., 2014 ). However, whether EPAG will improve unilineage erythroid hematopoiesis for PRCA after HSCT is still unknown. Until now, only one case report has been published ( Busca et al., 2018 Busca et al., 2018 ). Herein, we describe a patient with refractory PRCA following major ABO-mismatched HSCT from a matched related donor, who eventually responded well to long-course EPAG at a sufficient dosage. Our case might add useful knowledge on the effectiveness, optimal dosage, and ideal treatment duration of EPAG. A 27-year-old female weighing 45 kg was diagnosed with common B cell-acute lymphoblastic leukemia (ALL) with mixed-lineage leukemia-AF4 ( MLL-AF4 ) fusion gene expression. In October 2018, she underwent peripheral blood stem cell transplantation (PBSCT) from her human leukocyte antigen (HLA)‍-matched sibling brother in first complete remission (CR1) status. The patient did not have any donor-specific antibodies (DSAs) in her plasma. There was a major ABO mismatch between the recipient (O) and the donor (A). The conditioning regimen consisted of cytarabine (2 g/(m 2‍ ∙‍d) intravenously (IV) on Days -8 to -7), etoposide (VP16, 100 mg/d IV on Days -8 to -6), busulfan (3.2 mg/(kg‍∙‍d) IV on Days -6 to -4), cyclophosphamide (1.8 g/(m 2‍ ∙‍d) IV on Days -3 to -‍2), and methyl- N -‍(2-chloroethyl)‍- N -cyclohexyl- N -nitrosourea (Me-CCNU) (250 mg/m 2 orally on Day -‍1). CsA and a short course of methotrexate and mycophenolate mofetil were given for GVHD prophylaxis. A total of 1.10×10 9 mononuclear cells per kilogram of patient weight, including 7.41×10 6 CD34 + cells, were transplanted on Day 0. Granulocyte and platelet engraftment were achieved on Day +12. On Day +34, the patient's hemoglobin (Hb) was 69 g/L, with a normal leukocyte and platelet count. Reticulocytes accounted for approximately 0.2% and the absolute value was 1.00×10 10 cells/L. Bone marrow smear showed hyperplasia of the megakaryocytic/granulocytic lineages with hypoplasia of erythroid cells (accounting for 5%). Minimal residual disease (MRD) was negative, with less than 0.01% abnormal cells by six-color flow cytometry (FC), and MLL-AF4 fusion gene was absent. Chimerism was tested by short tandem repeat (STR) analyses every month for the first five months, at the ninth month, and at the first year post-transplantation (Fig. 1). Coombs testing and parvovirus B19 were negative. Levels of folic acid and vitamin B 12 were in normal ranges. Anti-A isoagglutinin titers were 1:‍32 (immunoglobulin M (IgM)) and 1:128 (immunoglobulin G (IgG)) on Day +41. According to the above analysis, the patient was diagnosed as PRCA. On Day +34, she was treated with testosterone undecanoate 40 mg bis in die (BID) and recombinant human erythropoietin (rhEPO) 6000 IU once a week. The dose of CsA was tapered rapidly to 50 mg/d per os (PO) and prednisone was given at a dose of 0.5 mg/(kg‍∙‍d). The patient received red blood cell transfusions on Days +42, +63, +119, and +132. On Days +43, +69, +71, and +79, a series of plasma exchanges were performed, but she remained reticulocytopenic and anemic. DLI was performed twice on Days +77 and +112. The volume of each infusion was 17 mL (8.47×10 7 mononuclear cells/kg, 4.52×10 5 CD34 + cells/kg, 1.27×10 7 CD 3+ cells/kg). However, there was not a significant increase in Hb level with the value of 49 g/L on Day +119. The patient's anti-A titers had dropped to 1:64 for IgG and 1:2 for IgM on Day +90. Bone marrow smear showed 5%, 2%, 1%, and 1% erythroid cells on Days +31, +64, +94, and +127, respectively. Due to the absence of GVHD, CsA was discontinued within four months. RhEPO and prednisone were withdrawn because of a lack of efficacy. The duration of prednisone was approximately 130 d, and the total dose was 1925 mg. EPAG was initiated on Day +111 at an initial dose of 50 mg/d. After four weeks of treatment with EPAG, it was increased to 75 mg/d without any adverse side effects. On Day +160, after seven weeks of treatment with EPAG, the patient's Hb recovered to 57 g/L. Bone marrow smear also revealed that erythroid cells were at a level of 5.5%. Almost three months after treatment with EPAG, Hb grew to 89 g/L. Moreover, the proportion of reticulocytes rose to 5.9%. EPAG was tapered gradually and eventually discontinued. The patient had a progressive improvement of Hb values; she had taken EPAG 98 d, totaling 258 tablets (6450 mg). On Day +217, bone marrow smear showed an active proliferation of erythroid cells, accounting for 21.5%. One year after the transplant, Hb rose to a normal level and currently was maintained at around 130 g/L. At 9 and 12 months post-HSCT, bone marrow smear showed 16%–20% erythroid cells, indicating complete recovery of normal hematopoiesis in the erythroid lineage. At an 18-month follow-up evaluation after PBSCT, the patient was in excellent physical condition with a normal level of Hb value. The time course of the patient is summarized in Fig. 2 Fig. 2 . 1;2; Some stem cell transplantation is performed between ABO-mismatched donors and recipients due to the limitations of donor selection. There is no clear evidence that ABO-incompatibility will influence the outcome of HSCT in the aspects of incidence and severity of graft rejection or GVHD, the engraftment of myeloid and megakaryocytic lineages, the relapse rate of disease, the non-relapse mortality rate, or overall survival, whereas the probability of PRCA will increase ( Yang and Levis, 2014 Yang and Levis, 2014 ). PRCA following ABO-incompatible allo-HSCT may resolve spontaneously, but some patients still need various treatments. There is no standard treatment modality for PRCA at the moment, and we summarize some studies on successful treatment in Table 1 Table 1 . The number in the brackets is the number of patients. AML: acute myeloid leukemia; AL: acute leukemia; CML-CP: chronic myeloid leukemia-chronic phase; MDS-RAEB-2: myelodysplastic syndrome with refractory anemia with excess blasts 2; HLA: human leukocyte antigen; PBSC: peripheral blood stem cell; BM: bone marrow; ATG: anti-human thymocyte globulin; CSA: cyclosporine A; MTX: methotrexate; MMF: mycophenolate mofetil; FK506: tacrolimus; EPO: erythropoietin; PEX: plasma exchange; ICT: iron chelation therapy; DFX: deferasirox; DFO: deferoxamine; EPAG: eltrombopag; IVIG: intravenous immunoglobulin; HSC: hematopoietic stem cell; D/R: donor/recipient; PRCA: pure red cell aplasia, GVHD: graft-versus-host disease. Reference Patient number Diagnosis Donor type HSC source D/R blood type Isoagglutinin titer pre-transplant Preconditioning GVHD prophylaxis Treatment Busca et al., 2018 Busca et al., 2018 2 AML (1); biphenotypic AL (1) HLA-matched unrelated (2) PBSC (2) A/O (2) 1:512 (1); 1:256 (1) Myeloablative (1); total body irradiation+cyclophosphamide (1) ATG+CsA+MTX (2) θ-EPO, PEX, ICT (DFX, DFO), rituximab, EPAG (1); θ-EPO, PEX, ICT (DFX, DFO), rituximab, bortezomib, EPAG (1) Zhidong et al., 2012 Zhidong et al., 2012 2 CML-CP (2) HLA-matched sibling (1); HLA-matched unrelated (1) PBSC (2) AB/O (1); A/O (1) Busulfan+cyclophosphamide (1); busulfan+cytarabine+cyclophosphamide+ATG (1) CsA+MTX (1); CsA+MTX+MMF (1) Taper CsA, EPO, rituximab (2) Shahan and Hildebrandt, 2015 Shahan and Hildebrandt, 2015 1 α-β subcutaneous panniculitis-like T cell lymphoma HLA-matched sibling PBSC A/B Negative Fludarabine+melphalan CsA+MTX Taper CsA, rituximab, pulse-dose dexamethasone, bortezomib Bathini et al., 2019 Bathini et al., 2019 1 MDS-RAEB-2 HLA-matched unrelated PBSC A/O Busulfan+fludarabine+ total body irradiation ATG+FK506+MTX Taper FK506, high-dose corticosteroid, rituximab, bortezomib, daratumumab Yang and Levis, 2014 Yang and Levis, 2014 1 AML HLA-matched PBSC A/O Busulfan+cyclophosphamide FK506+MMF Taper FK506, IVIG, four pulses of high-dose steroid Sackett et al., 2018 Sackett et al., 2018 1 Severe congenital neutropenia HLA-matched unrelated BM A/O Busulfan+fludarabine+alemtuzumab CsA+MMF Taper CsA, rituximab, bortezomib, PEX EPAG is a synthetic, orally bioavailable, small molecule; it is a nonpeptide agonist of the TpoR which is approved by the US Food and Drug Administration for treatment of immune thrombocytopenia (ITP) and severe aplastic anemia (SAA) ( Busca et al., 2018 Busca et al., 2018 ; Alvarado et al., 2019 Alvarado et al., 2019 ). Olnes et al. (2012) Olnes et al. (2012) showed that EPAG gave rise to multilineage clinical responses in some patients with rSAA. Some of the treated patients experienced improved Hb levels and no longer needed red cell transfusions. Therefore, we speculate that EPAG may obtain a therapeutic effect in PRCA after ABO-incompatible allo-HSCT. Previously, only one study from Busca et al. (2018) Busca et al. (2018) has reported the application of EPAG in treatment of PRCA after transplant. They observed that two patients with PRCA after major ABO-incompatible HSCT achieved complete remission upon treatment with EPAG after failing to respond to many other treatments. During treatment, EPAG was well tolerated by their patients, with only one patient experiencing transient platelet elevation and recovering after dose adjustment. In addition, they speculated that there might be a potential synergy between iron chelation therapy (ICT) and EPAG. The combination of EPAG with other therapeutic approaches for PRCA is worth discussing for its potential to accelerate recovery and reduce iron overload. The underlying mechanism of EPAG in erythroid reconstitution remains unclear; however, our speculations are as follows. Firstly, interferon-‍γ (IFN-‍γ), a pro-inflammatory cytokine that often increases after HSCT, prevents full engagement of thrombopoietin to its receptor c-MPL via steric occlusion of the low-affinity binding site, contributing to perturbation of thrombopoietin-induced signaling pathways and decreasing survival of human hematopoietic stem and progenitor cells (HSPCs). EPAG interacts selectively with c-MPL at a position distinct from the extracellular binding site of thrombopoietin, bypasses the inhibition of IFN-γ, and activates the the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, which can induce the proliferation and differentiation of HSPCs ( Alvarado et al., 2019 Alvarado et al., 2019 ; Gao et al., 2020 Gao et al., 2020 ). Secondly, EPAG enhances HSPC genome stability and improves HSPC survival and function by promoting DNA repair in human HSPCs ( Guenther et al., 2019 Guenther et al., 2019 ). Also, Bao et al. (2010) Bao et al. (2010) found an improvement in regulatory T cell (Treg) activity and a decrease in proinflammatory soluble CD40 ligand (sCD40L) with a concomitant increase in circulatory transforming growth factor-1 (TGF-1) in patients who received treatment with thrombopoietic agents. The treatment improved peripheral Treg function and had an accompanying decrease in inflammatory state. Finally, EPAG mobilizes intracellular iron via direct chelation, so that the negative effect of excess iron on normal hematopoiesis can be lessened. EPAG can decrease reactive oxygen species (ROS)‍-mediated cellular damage ( Vlachodimitropoulou et al., 2017 Vlachodimitropoulou et al., 2017 ; Zhao et al., 2018 Zhao et al., 2018 ). To sum up, EPAG may be of great help for erythroid reconstitution by activating proliferation and differentiation of HSPCs, improving their survival and function, decreasing the inflammatory state, and reducing cellular damage ( Fig. 3 Fig. 3 ). In conclusion, we reported a case of refractory PRCA after allo-HSCT, in which the patient had good recovery of erythropoiesis following treatment with EPAG. Although the possibility of spontaneous recovery cannot be ruled out, we still are of the opinion that EPAG played a key role in this case because spontaneous remission becomes less frequent and treatment is advised when PRCA continues beyond 60 d after HSCT ( Bathini et al., 2019 Bathini et al., 2019 ). There is little literature on the successful treatment of PRCA with DLI after allo-HSCT. Selleri et al. (1998) Selleri et al. (1998) showed a case of PRCA after major ABO-incompatible bone marrow transplantation, which achieved full engraftment after two dose-escalating CD34 + -enriched DLI. The patient's Hb level, reticulocyte count, and marrow erythropoiesis markedly improved within two months after the second DLI. We cannot completely rule out the role of DLI in our case. However, the patient's Hb increased significantly nearly three months after the last DLI. With this in view, we believe that EPAG played a most important role in our patient's hematopoietic recovery. In the course of treatment, no obvious side effects were noted (such as thrombocytosis, thrombosis, or liver function test abnormalities). EPAG may be effective and safe for unilineage hematopoiesis and can be used for the treatment of PRCA that develops following ABO-incompatible allo-HSCT. Further research is needed to confirm the effect of this medication. The Clinical Trials website ( https://www.clinicaltrials. https://www.clinicaltrials. ‍gov) has not recorded clinical trials of EPAG for PRCA because of the difficulty of multifactorial etiologies, rarity of cases, and the low interest of the pharmaceutical industry in a trial for such a low-volume disease. More clinical trials aim at investigating the treatment of aplastic anemia with EPAG. Hence, the optimal dosage, the time to start and end treatment, and the effectiveness of EPAG for PRCA still need to be refined by accumulated clinical experience. References Alvarado LJ , Huntsman HD , Cheng H , et al. , 2019 . Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ . Blood , 133 ( 19 ): 2043 - 2055 . https://doi.org/10.1182/blood-2018-11-884486 https://doi.org/10.1182/blood-2018-11-884486 Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ Bao WL , Bussel JB , Heck S , et al. , 2010 . Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents . Blood , 116 ( 22 ): 4639 - 4645 . https://doi.org/10.1182/blood-2010-04-281717 https://doi.org/10.1182/blood-2010-04-281717 Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents Bathini S , Holtzman NG , Koka R , et al. , 2019 . Refractory postallogeneic stem cell transplant pure red cell aplasia in remission after treatment with daratumumab . Am J Hematol , 94 ( 8 ): E216 - E219 . https://doi.org/10.1002/ajh.25515 https://doi.org/10.1002/ajh.25515 Refractory postallogeneic stem cell transplant pure red cell aplasia in remission after treatment with daratumumab Busca A , Dellacasa C , Giaccone L , et al. , 2018 . Eltrombopag for the treatment of refractory pure RBC aplasia after major ABO incompatible hematopoietic stem cell transplantation . Biol Blood Marrow Transplant , 24 ( 8 ): 1765 - 1770 . https://doi.org/10.1016/j.bbmt.2018.04.022 https://doi.org/10.1016/j.bbmt.2018.04.022 Eltrombopag for the treatment of refractory pure RBC aplasia after major ABO incompatible hematopoietic stem cell transplantation Desmond R , Townsley DM , Dumitriu B , et al. , 2014 . Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug . Blood , 123 ( 12 ): 1818 - 1825 . https://doi.org/10.1182/blood-2013-10-534743 https://doi.org/10.1182/blood-2013-10-534743 Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug Gao F , Zhou XY , Shi JM , et al. , 2020 . Eltrombopag treatment promotes platelet recovery and reduces platelet transfusion for patients with post-transplantation thrombocytopenia . Ann Hematol , 99 ( 11 ): 2679 - 2687 . https://doi.org/10.1007/s00277-020-04106-2 https://doi.org/10.1007/s00277-020-04106-2 Eltrombopag treatment promotes platelet recovery and reduces platelet transfusion for patients with post-transplantation thrombocytopenia Guenther KL , Cheruku PS , Cash A , et al. , 2019 . Eltrombopag promotes DNA repair in human hematopoietic stem and progenitor cells . Exp Hematol , 73 : 1 - 6.e6 . https://doi.org/10.1016/j.exphem.2019.03.002 https://doi.org/10.1016/j.exphem.2019.03.002 Eltrombopag promotes DNA repair in human hematopoietic stem and progenitor cells Hirokawa M , Fukuda T , Ohashi K , et al. , 2013 . Efficacy and long-term outcome of treatment for pure red cell aplasia after allogeneic stem cell transplantation from major ABO-incompatible donors . Biol Blood Marrow Transplant , 19 ( 7 ): 1026 - 1032 . https://doi.org/10.1016/j.bbmt.2013.04.004 https://doi.org/10.1016/j.bbmt.2013.04.004 Efficacy and long-term outcome of treatment for pure red cell aplasia after allogeneic stem cell transplantation from major ABO-incompatible donors Olnes MJ , Scheinberg P , Calvo KR , et al. , 2012 . Eltrombopag and improved hematopoiesis in refractory aplastic anemia . N Engl J Med , 367 ( 1 ): 11 - 19 . https://doi.org/10.1056/NEJMoa1200931 https://doi.org/10.1056/NEJMoa1200931 Eltrombopag and improved hematopoiesis in refractory aplastic anemia Sackett K , Cohn CS , Fahey-Ahrndt K , et al. , 2018 . Successful treatment of pure red cell aplasia because of ABO major mismatched stem cell transplant . J Clin Apher , 33 ( 1 ): 108 - 112 . https://doi.org/10.1002/jca.21553 https://doi.org/10.1002/jca.21553 Successful treatment of pure red cell aplasia because of ABO major mismatched stem cell transplant Selleri C , Raiola A , de Rosa G , et al. , 1998 . CD34 + -enriched donor lymphocyte infusions in a case of pure red cell aplasia and late graft failure after major ABO-incompatible bone marrow transplantation . Bone Marrow Transplant , 22 ( 6 ): 605 - 607 . https://doi.org/10.1038/sj.bmt.1701384 https://doi.org/10.1038/sj.bmt.1701384 CD34+-enriched donor lymphocyte infusions in a case of pure red cell aplasia and late graft failure after major ABO-incompatible bone marrow transplantation Shahan JL , Hildebrandt GC , 2015 . Successful treatment of refractory pure red cell aplasia with bortezomib after allogeneic haematopoietic cell transplantation in a patient with alpha-beta subcutaneous panniculitis-like T cell lymphoma . Transfus Med , 25 ( 5 ): 342 - 344 . https://doi.org/10.1111/tme.12216 https://doi.org/10.1111/tme.12216 Successful treatment of refractory pure red cell aplasia with bortezomib after allogeneic haematopoietic cell transplantation in a patient with alpha-beta subcutaneous panniculitis-like T cell lymphoma Vlachodimitropoulou E , Chen YL , Garbowski M , et al. , 2017 . Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator . Blood , 130 ( 17 ): 1923 - 1933 . https://doi.org/10.1182/blood-2016-10-740241 https://doi.org/10.1182/blood-2016-10-740241 Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator Yang X , Levis M , 2014 . Pulsed-high-dose dexamethasone as a treatment for pure red cell aplasia following ABO-incompatible allogeneic stem cell transplantation . Transfus Med , 24 ( 4 ): 246 - 248 . https://doi.org/10.1111/tme.12143 https://doi.org/10.1111/tme.12143 Pulsed-high-dose dexamethasone as a treatment for pure red cell aplasia following ABO-incompatible allogeneic stem cell transplantation Zhao Z , Sun Q , Sokoll LJ , et al. , 2018 . Eltrombopag mobilizes iron in patients with aplastic anemia . Blood , 131 ( 21 ): 2399 - 2402 . https://doi.org/10.1182/blood-2018-01-826784 https://doi.org/10.1182/blood-2018-01-826784 Eltrombopag mobilizes iron in patients with aplastic anemia Zhidong W , Hongmin Y , Hengxiang W , 2012 . Successful treatment of pure red cell aplasia with a single low dose of rituximab in two patients after major ABO incompatible peripheral blood allogeneic stem cell transplantation . Transfus Med , 22 ( 4 ): 302 - 304 . https://doi.org/10.1111/j.1365-3148.2012.01156.x https://doi.org/10.1111/j.1365-3148.2012.01156.x Successful treatment of pure red cell aplasia with a single low dose of rituximab in two patients after major ABO incompatible peripheral blood allogeneic stem cell transplantation Yang GAO contributed to reviewing the patient and writing the manuscript. Fei GAO wrote part of the manuscript and reviewed the literature. Jimin SHI and Huarui FU supported the treatment course of the patient, and provided their comments on this manuscript. He HUANG and Yanmin ZHAO were mainly in charge of the patient, and critically reviewed the patient and the manuscript. All authors have read and approved the final manuscript and, therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. This work was supported by the National Natural Science Foundation of China (No. 81670148) and the Health Science and Technology Project of Zhejiang Province (No. 2012KYB079), China. 10.1631/jzus.B2000532 1673-1581（2021）08-0695-06 2020-09-12 2020-12-23 2021-08-15 2022-05-09 2021-06-15 © Zhejiang University Press 2021 Yang GAO, Fei GAO, Jimin SHI, Huarui FU, He HUANG, and Yanmin ZHAO declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from the patient for being included in the report. Compliance with ethics guidelines 浙江大学学报（英文版）（B辑：生物医学和生物技术） 8 22