Cases
Case 1 is a 10-year-old girl who was born to non-consanguineous healthy
Japanese parents. As we previously reported, she had severe macrocytic
anemia without reticulocytopenia (red blood cells [RBCs] 0.95 ×
1012/L, hemoglobin level 43 g/L, mean corpuscular
volume [MCV] 123 fL, reticulocytes 158 × 109/L,
white blood cells [WBCs] 2.3 × 109/L, and
platelets 396 × 109/L) from birth. Anemia did not
improve with oral iron supplements or erythropoietin administration, and
she had to undergo recurring RBC transfusions. The first bone marrow
examination was performed when she was 6 months old, showing normal
cellularity and marked dysplasia only in the erythroid lineage.
G-banding karyotyping of the bone marrow aspirate showed a normal female
karyotype (46, XX). She also developed chronic bloody diarrhea at the
age of 2 months. Inflammatory bowel disease (IBD), unclassified type,
was diagnosed based on endoscopic and pathological findings at the age
of 8 months. She became corticosteroid dependent and required
intravenous hyperalimentation to treat malnutrition. A follow-up bone
marrow examination at the age of 17 months revealed hypercellularity and
dysplasia of trilineage cells without excess blasts. However, bone
marrow examination before HCT showed multilineage dysplasia and 7.5%
blastic cells, reminiscent of progression to MDS with excess blast-1. As
she remained transfusion dependent, HCT was performed at the age of 1
year and 10 months from an unrelated human leukocyte antigen
(HLA)–matched donor (8/8 allele matched). She received myeloablative
conditioning (MAC) composed of busulfan (1.2 mg/kg) four times daily on
days −9 to −6 (total dose, 19.2 mg/kg) and cyclophosphamide (50 mg/kg)
once daily from days −5 to −2 (total dose, 200 mg/kg). The infused bone
marrow cells contained 3.0 × 106/kg of CD34-positive
cells. Graft-versus-host disease (GVHD) prophylaxis was performed with
tacrolimus and short-term methotrexate (15 mg/m2 on
day +1 and 10 mg/m2 on days +3, +6, and +11).
Engraftment was achieved on day +22 with full donor chimerism. She
developed grade II acute skin GVHD on day +94 which resolved immediately
after initiating corticosteroid treatment. However, she developed grade
III gastrointestinal GVHD after discontinuing corticosteroid on day
+140. The effect of reinitiated corticosteroid was insufficient, and
infliximab was added. Her bloody stool and diarrhea gradually resolved,
and corticosteroid was stopped approximately 1 year and 4 months after
developing gastrointestinal GVHD. Infliximab was discontinued 3 years
after discontinuing corticosteroid. Approximately ten years have passed
since HCT, and she is doing well without active complications or
transfusion demand and all her immunosuppressants have been
discontinued. However, due to prolonged tube feeding associated with
inflammation of the gastrointestinal tract, she is unable to ingest
orally. After HCT, a novel compound heterozygous variant in POLE(p.[D1131fs];[T1891del]) was found by genetic analysis using her
dermal fibroblasts.
Case 2 is a 3-year-old girl, a younger sister of Case 1. She also had
severe macrocytic anemia without reticulocytopenia (RBCs 1.71 ×
1012/L, hemoglobin level 54 g/L, MCV 117 fL,
reticulocytes 30 × 109/L, WBCs 12.8 ×
109/L, and platelets 306 × 109/L)
from birth and became transfusion-dependent. Genetic analysis of her
peripheral blood cells revealed the same variant of POLE as in
Case 1. Bone marrow findings at 3 months of age were similar to those in
Case 1, with dysplasia only in the erythroid without hypoplasia.
Dysplasia of all three lineages was seen at 13 months of age (G-banding
karyotyping showed a normal female karyotype (46, XX), with 8% blastic
cells. These findings indicated MDS with excess blast-1. However,
blastic cells decreased to 4.2% at 16 months of age. Unlike Case 1 she
did not develop IBD. She remained transfusion dependent and there were
fluctuations in the proportion of blasts. HCT was performed at the age
of 1 year and 5 months from an unrelated HLA one allele mis-matched
donor. She received conditioning composed of fludarabine (25
mg/m2) on days −8 to −4 (total dose, 125
mg/m2), melphalan (90 mg/m2) once
daily from days −4 to −3 (total dose, 180 mg/ m2),
anti-thymocyte globulin (2.5 mg/kg) once daily from days −7 to −6 (total
dose, 5.0 mg/kg) and total body irradiation of 3 Gray on day 0. The
infused bone marrow cells contained 6.3 × 106/kg of
CD34-positive cells. GVHD prophylaxis was the same as in Case 1.
Engraftment was achieved on day +16 with full donor chimerism. She
developed grade III acute gastrointestinal GVHD on day +24 and was
treated with immunosuppressive agents including corticosteroid,
mycophenolate mofetil, and additional methotrexate. However, her
symptoms were refractory and required addition of mesenchymal stem cell
therapy. Meanwhile, pathological findings of her gastrointestinal biopsy
revealed intestinal thrombotic microangiopathy and recombinant human
soluble thrombomodulin was also administered. Her gastrointestinal
symptoms gradually resolved, and each treatment was able to be tapered
off without recurrence. Two years have passed since HCT, and she is
doing well without active complications or transfusion demand and all
her immunosuppressants have been discontinued.