An 8-year-old girl was transferred to our hospital due to hyperleukocytosis, which was incidentally discovered as she did not exhibit any symptoms. Upon physical examination, we found severe hepatosplenomegaly, with her liver and spleen palpated at about 9cm and 7cm, respectively, below the costal margin. Initial peripheral blood counts showed the following results: white blood cells (WBCs) of 198 x 109/L (normal: 4-10 x 109/L) with 1% blast, hemoglobin of 10.0 g/dL (normal: 11.0-14.5 g/dL), and platelets of 352 x 109/L (normal: 150-450 x 109/L). The bone marrow aspirate smears revealed hypercellularity with a high myeloid: erythroid ratio (higher than 20:1), and approximately 5% of all nucleated cells were lymphoblasts. Karyotyping and fluorescence in situ hybridization (FISH) of a bone marrow sample were positive for t(9;22)(q34;q11), leading to a diagnosis of CML-CP. The patient's EUTOS Long-Term Survival score was 1.229, indicating that she belonged to the low-risk group. We started on dasatinib (60 mg/m2, once daily) for initial TKI therapy.
Three months after treatment, the patient exhibited both a complete hematologic response (CHR) and a complete cytogenetic response (CCyR). Quantitative polymerase chain reaction revealed a BCR::ABL1 transcript level of 2.55% on the international scale (IS) at 3 months, indicating an optimal response. However, the therapy did not yield the milestones of an optimal response thereafter: 1.6% IS at 6 months and 0.9% IS at 12 months. Although her TKI response was at the "warning" level, we decided to maintain her on dasatinib instead of changing the medication because the BCR::ABL1 transcript levels were constantly decreasing ( Table 1 ).
Fourteen months after treatment, the patient was admitted due to visual disturbance. Fundoscopy revealed bilateral optic disc edema with a macular star, and brain MRI revealed diffuse swelling of both optic nerves without clear leptomeningeal and parenchymal abnormalities ( Figure 1 ). Based on our initial assessment of dasatinib-induced optic neuropathy, we decided to discontinue dasatinib and start methylprednisolone pulse therapy. Within a month, her subjective symptoms and visual acuity improved. At 15 months from the start of treatment, the patient's BCR::ABL1 transcript level in the bone marrow remained at the warning level (0.3% IS) but had decreased from previous time points.
Two months later, the patient returned to our hospital due to severe and aggravated headaches that had persisted for two weeks. Upon examination, cerebrospinal fluid (CSF) immunophenotyping revealed a large proportion of abnormal cell populations, with approximately 89% lymphoblasts expressing CD20, TdT, and PAX-5 (negative for CD3 and MPO). The bone marrow was free of leukemic infiltration and the patient maintained a CHR and CCyR, indicating that she was experiencing an isolated CNS lymphoblastic crisis. At this time, the MRI showed an improvement in optic nerve swelling compared to the previous MRI.
She was begun triple intrathecal (ITT) chemotherapy (methotrexate, cytarabine, and hydrocortisone) and the lymphoblast was eliminated after single dose of ITT chemotherapy. Hence, she was administered an additional five doses of ITT chemotherapy and a subsequent allogeneic HSCT was planned ( Figure 2 ). Since she was still off dasatinib and had an isolated CNS relapse, we decided to resume dasatinib, which is known to penetrate the CNS, instead of switching to another TKI until allogeneic HSCT. The patient's BCR::ABL1 transcript level was 0.6% IS at the time of HSCT.
The patient underwent peripheral blood stem cell transplantation from a 1-allele-mismatched (HLA-A), unrelated donor. The preparative regimen consisted of myeloablative conditioning, with total body irradiation (TBI) of 1,320 cGy (from days -7 to -4), cyclophosphamide (120 mg/kg from days -3 to -2), and rabbit antithymocyte globulin (3.75 mg/kg from days -3 to -1). The infused CD34+-cell dose was 10.3 x 106 cells/recipient kg. She developed grade 2 graft-versus-host disease in the gut, which was well tolerated with a short course of steroid treatment. Full donor chimerism was detected on day 28 post transplantation, and the BCR::ABL1 transcript levels in the peripheral blood at 1, 3, and 6 months after transplantation were 0% IS without TKI therapy.