2 CASE DESCRIPTION
A 3-year-old male presented at the referred hospital with chief complaints of fever and subcutaneous bleeding. Blood tests showed bicytopenia, with a white blood cell count of 7.34 × 109/L (blasts 42%, neutrophils 22%), hemoglobin 7.3 g/dL, and platelet count of 57 × 109/L. He was diagnosed with ALL, with no abnormal karyotype, based on findings of 94.8% CD19+ cyCD79a+HLA-DR+ CD38+ blasts on BM examination. KMT2A rearrangement was detected by fluorescence in situ hybridization (FISH) analysis, but no partner genes were identified.
He received induction therapy, including vincristine, L-asparaginase, prednisolone, and doxorubicin, and achieved first complete remission (CR) at the molecular level; however, a very early relapse occurred, with 30% BM blast cells. After admission to our hospital, he received reinduction therapy using the ALL-REZ BFM 90 protocol9, leading to achievement of second CR, negative for minimal residual disease (MRD) by KMT2A FISH analysis. He underwent unrelated CBT from a human leukocyte antigen 6/8 allele-matched male donor, containing 4.9 × 107/kg total nucleated cells and 1.7 × 105/kg CD34+ cells, following a MAC regimen consisting of TBI (total dose, 12 Gy at 2 Gy/fraction) twice daily from day –3 to –1, 60 mg/kg/day of cyclophosphamide on days –5 and –4, and 60 mg/kg/day of etoposide on day –7 (Fig. 1). As prophylaxis for graft versus host disease (GVHD), tacrolimus was continuously administered from day –1, with short-term methotrexate at 10 mg/m2/day on day 1 and 7 mg/m2/day on days 3 and 6. He had fever on day 9 and a rash, expanding to his whole body on days 9–11. We diagnosed engraftment syndrome and started 2 mg/kg/day methylprednisolone twice daily. Neutrophil engraftment was achieved on day 20, as the first of 3 consecutive days of neutrophil count >0.5 x 109/L; however, his absolute neutrophil count (ANC) gradually decreased shortly after the engraftment and reached a nadir on day 26. BM examination on day 27 showed apparent hypocellularity with no myeloblasts but macrophages, a proportion of which exhibited hemophagocytosis (Fig. 2), suggesting secondary engraftment failure, despite 49–62% recipient-derived cells on chimerism analysis of short tandem repeat (STR) sequences. We planned a salvage transplantation, but white blood cells and neutrophils showed upward trends on days 33 and 39, respectively. BM chimerism analysis on day 41 revealed that recipient-derived cells accounted for more than 95%, suggesting autologous hematopoietic recovery. His BM achieved CR at MRD levels byKMT2A FISH and showed a complex karyotype of 46,XY,t(7;8)(q11.2;q11.2) in five cells; 46,XY,t(1;4)(p32;q21),t(5;10)(p15;p11.2) in five cells; 46,XY,t(9;19;12)(p24;p13;q13) in two cells; 46,XYadd(1)(p34),add(3)(p21),add(5)(q31) in one cell; 46,XY,-1,-2,+add(3)(q11.1),-7,der(8)t(7;8)(q11.2;p23),-11,-12,+4mar in one cell; and 46,XY in six cells at cytogenetic examination.
Neutrophil count exceeded 0.5 x 109/L again on day 51, reticulocyte count exceeded 1% on day 63, and platelet count exceeded 50 x 109/L on day 105, independent of transfusion. After careful discussion of the treatment plan with his parents, we decided to observe with caution, without another HSCT. Although BM examinations continued to reveal different chromosomal abnormalities, he remains alive 12 months after CBT without any relapse of primary disease or secondary malignant disease.