children Case Report Successful Hematopoietic Stem Cell Transplantation from a Matched Related Donor with Beta- Thalassemia Minor for Severe Aplastic Anemia Mi Young Jung 1, Young Tae Lim 1, Hyunji Lim 1, Jeong Ok Hah 2 and Jae Min Lee 1,* 1 Department of Pediatrics, Yeungnam University College of Medicine, Daegu 42415, Korea; [email protected] (M.Y.J.); [email protected] (Y.T.L.); [email protected] (H.L.) 2 Department of Pediatrics, Daegu Fatima Hospital, Daegu 41199, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-53-620-3536 Received: 7 September 2020; Accepted: 30 September 2020; Published: 4 October 2020 Abstract: The first-line treatment for severe aplastic anemia (SAA) patients is hematopoietic stem cell transplantation (HSCT), with full-matched related donors considered the most suitable. We report a case of SAA in which the patient successfully underwent HSCT from a donor with β-thalassemia minor. The patient in this case underwent HSCT from a human leukocyte antigen (HLA)-matched younger brother with β-thalassemia minor. A 7-year-old girl was referred to our facility following a 6-month history of easy bruising and pallor. Laboratory examinations showed pancytopenia and hypocellular bone marrow with cellularity of <5%. She was diagnosed with acquired SAA, and HLA typing of her family members was performed. Her younger brother was an HLA-matched sibling but had β-thalassemia minor. Since his hemoglobin levels were maintained at 10–11 d/dL, he was considered a suitable HSCT donor. The conditioning regimen included fludarabine, cyclophosphamide, and anti-thymocyte globulin. The CD34+ and CD3+ cell counts were 6.6 106/kg and 0.48 108/kg, × × respectively. White blood cell engraftment was evident on day +11. Regimen-associated toxicities, such as anorexia and enteritis, were mild; no infections occurred, and no symptoms of acute graft-versus-host disease (GVHD) were observed. The 30-day follow-up bone marrow examination revealed normocellular marrow with 80%–90% cellularity. Acute or chronic GVHD has not been reported, and good performance status has been observed throughout the 5 years after HSCT. β-thalassemia minor patients can be considered as bone marrow donors for SAA patients. Keywords: aplastic anemia; beta-thalassemia; thalassemia minor; hematopoietic stem cell transplantation 1. Introduction Aplastic anemia is a rare disorder characterized by pancytopenia and a hypocellular bone marrow [1]. The pathogenesis of aplastic anemia includes the number of hemopoietic progenitor cells, an increased number of suppressor T-cells releasing IFN-γ, and abnormalities in mesenchymal stem cells with a reduced ability to inhibit T-cell function [2]. According to the treatment guidelines from the Bone Marrow Committee of the Korean Society of Pediatric Hematology-Oncology, the treatment of choice for severe aplastic anemia (SAA) in children is hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched family donor (HLA-MFD). For children without an MFD, HSCT from a matched unrelated donor (MUD) or immunosuppressive therapy (IST) in combination with anti-thymocyte globulin (ATG) and cyclosporine (CSA) has been a therapeutic option [3]. Alternative donor transplantations for patients non-responsive to IST include mismatched unrelated donor HSCT, umbilical cord blood HSCT, and haploidentical HSCT [4]. Until now, there have been no reports on HSCT from an MFD with Children 2020, 7, 162; doi:10.3390/children7100162 www.mdpi.com/journal/children Children 2020, 7, x FOR PEER REVIEW 2 of 5 patients non-responsive to IST include mismatched unrelated donor HSCT, umbilical cord blood HSCT, and haploidentical HSCT [4]. Until now, there have been no reports on HSCT from an MFD withChildren β-thalassemia2020, 7, 162 as an alternative donor following IST failure. We hereby report a case2 ofof 5 successful HSCT from a hematologically stable MFD with β-thalassemia as an alternative donor in a patientβ-thalassemia without asan anMFD alternative who had donor failed followingto respond IST to IST. failure. We hereby report a case of successful HSCT from a hematologically stable MFD with β-thalassemia as an alternative donor in a patient 2. Case Report without an MFD who had failed to respond to IST. A 7-year-old girl was referred to Yeungnam University Hospital following a 6-month history of easy2. Case bruising Report and pallor. Physical examination revealed multiple ecchymoses on her extremities. The patientA was 7-year-old the first girl child was of referred a non-consanguineous, to Yeungnam University native Korean Hospital couple. following She was a pale 6-month but had history no palpableof easy bruising lymphadenopathy and pallor. or Physical hepatosplenomegaly. examination revealed Her neurological multiple ecchymoses examination on herfindings extremities. were normal.The patient The wasinitial the complete first child blood of a non-consanguineous,count revealed a leukocyte native count Korean of 3.1 couple. × 109/L, She hemoglobin was pale but (Hb) had levelno palpable of 7.3 g/dL, lymphadenopathy platelet count of or 16 hepatosplenomegaly. × 109/L, absolute neutrophil Her neurological count of 0.899 examination × 109/L, and findings corrected were reticulocytenormal. The count initial of complete 0.59%. The blood initial count bone revealed marrow a biopsy leukocyte showed count a hypocellular of 3.1 109/L, marrow hemoglobin with 40% (Hb) × cellularitylevel of 7.3 that g/dL, did platelet not fit count the diagnosis of 16 10 of9/ L,SAA. absolute Other neutrophil laboratory count findings of 0.899 were:10 C-reactive9/L, and corrected protein × × level,reticulocyte 0.092 mg/dL count (normal of 0.59%. range, The initial<0.5 mg/dL), bone marrow erythrocyte biopsy sedimentation showed a hypocellular rate, 42 mm/h marrow (normal with range,40% cellularity 0–20 mm/h); that C3 did level, not 89 fit mg/dL the diagnosis (normal of ra SAA.nge, 83–177 Other laboratorymg/dL); C4 findings level, 23 were: mg/dL C-reactive (normal range,protein 15–45 level, mg/dL); 0.092 mgdirect/dL and (normal indirect range, Coombs<0.5 te mgst, /negative;dL), erythrocyte antinuclear sedimentation antibody, negative; rate, 42 blood mm/h cytomegalovirus(normal range, 0–20 polymerase mm/h); C3chain level, reaction 89 mg/ dLtest, (normal negative; range, anti-E 83–177pstein–Barr mg/dL); virus C4 level, viral 23 capsid mg/dL antigen(normal immunoglobulin range, 15–45 mg/ dL);M (IgM), direct andnegative; indirect anti-hep Coombsatitis test, A negative; virus IgM, antinuclear negative; antibody, anti-hepatitis negative; C virusblood antibody, cytomegalovirus negative; polymerase hepatitis B chainsurface reaction antige test,n, negative; negative; and anti-Epstein–Barr anti-mycoplasma virus IgM, viral positive. capsid Despiteantigen positivity immunoglobulin for anti-mycoplasma M (IgM), negative; IgM, anti-hepatitisshe had no respiratory A virus IgM, symptoms negative; or anti-hepatitis any signs of C infection;virus antibody, therefore, negative; antibiotic hepatitis administration B surface was antigen, not indicated. negative; She and had anti-mycoplasma no dysmorphic IgM,features positive. and noDespite cutaneous positivity pigmentation, for anti-mycoplasma nail dystrophy, IgM, sheleukopla had nokia, respiratory or skeletal symptoms anomaly or was any found. signs of Inherited infection; bonetherefore, marrow antibiotic failure administrationsyndrome was wasnot notsuspected, indicated. and Shethe chromosomal had no dysmorphic breakage features test showed and no normalcutaneous results. pigmentation, The telomere nail length dystrophy, test was leukoplakia, not available or skeletal at that anomalytime. A diagnosis was found. of non-SAA Inherited bonewas assignedmarrow to failure the patient, syndrome and wastreatment not suspected, was not indicated and the chromosomalat this stage. breakage test showed normal results.A repeat The telomere bone marrow length test examination was not available was performe at that time.d 10 Amonths diagnosis later of non-SAAbecause of was persistent assigned pancytopenia.to the patient, Her and bone treatment marrow was was not hypocellular indicated at thiswith stage. less than 5% cellularity, and complete blood countA showed repeat a bone white marrow blood cell examination (WBC) count was of performed3.43 × 109/L, 10 Hb months level of later 7.7 g/dL, because platelet of persistent count of 13pancytopenia. × 109/L, absolute Her boneneutrophil marrow count was hypocellularof 0.871 × 10 with9/L, and less thancorrected 5% cellularity, reticulocyte and count complete of 0.76%. blood Therefore,count showed she was a white diagnosed blood with cell (WBC)SAA at countthat time. of 3.43 109/L, Hb level of 7.7 g/dL, platelet count × of 13We 10considered9/L, absolute HSCT neutrophil for this patient count ofand 0.871 perfor10med9/L, HLA and correctedtyping and reticulocyte blood tests count of her of family 0.76%. × × membersTherefore, to she find was a suitable diagnosed donor. with Her SAA younger at that time.brother was an HLA-matched sibling but had mild anemiaWe with considered Hb levels HSCT maintained for this patientat approximat and performedely 10–11 HLA g/dL. typing The whole-exome and blood tests sequencing of her family test revealedmembers a heterozygous to find a suitable frameshift donor. variant Her younger of Hemoglobin brother was Subunit an HLA-matched Beta (c.27dupG, sibling p.Ser10Valfs*14), but had mild aanemia mutation with that Hb has levels previously maintained been atreported approximately in patients 10–11 with g /βdL.-thalassemia The whole-exome (Figure 1) sequencing [5]. test revealed a heterozygous frameshift variant of Hemoglobin Subunit Beta (c.27dupG, p.Ser10Valfs*14), a mutation that has previously been reported in patients with β-thalassemia (Figure1)[5]. Figure 1. Pedigree of proband (black arrowhead) with aplastic anemia and β-thalassemia minor. NoFigure HLA-identical 1. Pedigree of matched proband related(black arrowh donorsead) other with than aplastic her anemia brother and were β-thalassemia identified. minor. HSCT from an HLA-identical donor with β-thalassemia minor has raised skepticism regarding its therapeutic outcome.