Case report
A 15-year-old female presented to our hospital for evaluation of dyspnea on effort and pancytopenia. Bone marrow aspiration (BMA) showed 76.6% blasts, which were negative for myeloperoxidase (MPO) and 2–3 times the size of small lymphocytes (Fig. 1A, 1B, and 1C). Flow cytometric analysis revealed that the blasts expressed surface cyCD22, cyCD79a, CD34, CD38, and HLA-DR, and partially expressed CD19, but lacked cyCD3, MPO, and specific features of other lineages, such as monocytes, megakaryocytes, or plasmacytoid dendritic cells. Karyotype analysis revealed 46, XX, add(2)(q31), add(6)(p21), add(16)(q22), del(20)(q11.2q13.3). No known chimeric transcripts (e.g., rearrangements of KMT2A , or BCR-ABL1 ) were detected. Immunophenotype analysis met the criteria of B-cell precursor ALL,4and she received ALL-oriented induction therapy;8however, BMA after induction chemotherapy showed > 90% blasts, which expressed only CD34, CD7, and CD13, and partially expressed cyCD79a and HLA-DR, but not CD19 or surface and cyCD22. Given the lack of expression of lineage-specific markers and the fact that less than two myeloid associated markers were detected,5 she was diagnosed with AUL and treated with AML-oriented chemotherapy.9 After re-induction therapy, partial remission was achieved, with approximately 10% blasts in the bone marrow (BM); however, she could not obtain morphological CR after two courses of consolidation therapy. She subsequently received a clofarabine-containing regimen (clofarabine 40 mg/m2, cyclophosphamide 400 mg/m2, and etoposide 150 mg/m2, daily for 5 consecutive days), which is used for relapsed/refractory ALL and AML;10,11 however, she achieved only partial remission (8.0% blasts in the BM). CD22 expression was transiently lost after induction therapy, but the blasts became positive for surface CD22 again and remained negative for CD19 after re-induction therapy (Figure. 1D, 1E, and 1F). Hence, based on the persistent expression of CD22 after re-induction therapy, she received InO (0.8 mg/m2 on day +1, and 0.5 mg/m2 on days +8 and +15) at 16 years of age, which has approval for use in young adults by the Patient Safety Unit, Kyoto University Hospital. She experienced an acute adverse effect of slight transient elevation of aspartate aminotransferase and alanine aminotransferase (grade I, National Cancer Institute Common Terminology Criteria for Adverse Events, version 5). Hematological toxicity was only thrombocytopenia, which recovered within approximately 3 weeks. After one course of InO, she attained MRD-negative CR, as determined by flow cytometry. Therefore, she proceeded to receive bone marrow transplantation (BMT) from an HLA-7/8 allele-matched unrelated donor, with a myeloablative conditioning regimen consisting of total body irradiation (12 Gy in 6 fractions) and melphalan (180 mg/m2). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (TAC) and short-course methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, and +11). She received low molecular-weight heparin, ursodeoxycholic acid, and antithrombin for veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) prophylaxis. She was infused with a cell dose of 2.4 × 108/kg body weight. From day +6, she had fever with fluid retention and a rash on her face and extremities, and received methylprednisolone for pre-engraftment immune reaction. Neutrophil engraftment was confirmed on day +19. From day +25, she became platelet transfusion-dependent, with elevated lactase dehydrogenase and undetectable serum haptoglobin. Although she did not have findings of increased schistocytes or renal dysfunction, we considered probable thrombotic microangiopathy. Approximately 3 weeks after reduction of TAC, she responded to platelet transfusion, with recovery of serum haptoglobin level. From day +35, she experienced abdominal swelling and her body weight increased by 5–6%. Abdominal ultrasonography revealed ascites and slight hepatomegaly, without diminished portal venous flow. She never exhibited elevated serum bilirubin or liver tenderness. She met the diagnostic criteria for pediatric VOD/SOS (grade II), suggested by the European Society for Blood and Marrow Transplantation (EBMT).12 She received recombinant human soluble thrombomodulin and coadministration of albumin and furosemide for 1 week, and the ascites and hepatomegaly resolved in a few weeks.13 She presented with grade II acute GVHD (stage 2 skin and stage 1 gastrointestinal) from around day +36 and was treated with prednisolone and short-course methotrexate (7.5 mg/m2 on days +70, +77, and +84). She responded well to prednisolone; however, there was repeated acute GVHD after weaning off prednisolone. At last follow up, she was 10 months post-BMT and received prednisolone and tacrolimus without GVHD. She was free from disease, with no other severe complications.