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.