Case: A 46-year-old woman with fever and petechiae visited her family doctor, and was transferred to our hospital because of anemia and thrombocytopenia. Laboratory findings included a hemoglobin concentration of 4.9 g/dL, platelet count of 19 x 10^9/L, and white blood cell count of 3.81 x 10^9/L with 4% blasts. In addition, bone marrow examination demonstrated the proliferation of abnormal lymphoid blasts (91%) with a phenotype of CD19+, CD10+, HLA-DR+, CD24+, cyCD79a+, cyCD22+, CD15+, CD65+, CD13-, CD33-, and myeloperoxidase (MPO)-. Chromosomal analysis by G-banding revealed a normal karyotype without the Philadelphia chromosome. Other molecular analyses revealed negative findings regarding PML-RARA, AML1-MTG8, CBFB-MYH11, NUP98-HoxA, ETV 6-AML 1, E2A-HLF, SIL-TAL-1, MLL-AF4, MLL-AF6, MLL-AF9, and MLL-EML. No extramedullary mass lesions were found on whole-body CT. Based on these findings, the patient was finally diagnosed with Philadelphia chromosome-negative B-ALL. At the initial diagnosis, the extramedullary lesion was not present on CT examination. The patient was treated by the protocol of MRD 2008 and achieved complete remission (CR).
However, after 18 months, the patient developed the first relapse in the bone marrow (41% abnormal lymphoid blasts). No extramedullary lesion was observed at that time. The patient received two courses of hyper-CVAD/MA therapy and achieved second CR. As the patient had no HLA-identical donor among related or unrelated individuals, she received allogeneic CBT from a two HLA loci-mismatched cord blood (NCC 2.96 x 10^7 cells/kg and 1.07 x10^5 CD34+ cells/kg), with a conditioning regimen consisting of cyclophosphamide (120 mg/kg) and total-body irradiation (TBI, 12 Gy). Engraftment was achieved at day 17. The main complications were pre-engraftment immune reaction (PIR), human herpesvirus 6 (HHV-6) DNAemia, cytomegalovirus (CMV) antigenemia, and acute graft-versus-host disease (GVHD) (grade 2 by skin biopsy). Thus, the patient achieved second CR, and by controlling transplantation-related complications, she was discharged from the hospital on day 90.
Six months later, the patient suddenly presented with abnormal vaginal/uterine bleeding. CT revealed a large mass in the uterine region (Figure 1A, B), but no masses were found in other regions of the body. Furthermore, MRI revealed a heterogeneous high-intensity mass (T2-WI/D-WI) with a diameter of 6.8 cm, a notable decrease in the apparent diffusion coefficient (ADC) (0.4 x 10(-3) mm2/s), and mild enhancement by contrast enhancement study (Figure 1C-F). Biopsy of the uterine cervix revealed small aggregates of atypical lymphoid cells with round nuclei, some distinct nucleoli, and scant cytoplasm in the hemorrhagic and edematous background (Figure 2A). Immunohistochemically, these lymphoid cells were positive for CD79a and TdT (Figure 2B, C), but negative for CD20, cCD3, CD5, CD34, and MPO. Reactive T cells (cCD3+/CD5+) were intermingled in the background. Bone marrow examination demonstrated 81% blasts. Based on these findings, the patient was judged to have secondary relapse involving the bone marrow and uterus. Subsequently, two courses of hyper-CVAD/MA therapy were performed, which led to the third CR according to the response criteria of the International Working Group of Acute Leukemia (2003). Furthermore, extramedullary uterine lesions of ALL were not detected by CT or MRI. However, the third relapse was observed five months later. Bone marrow examination demonstrated 40% blasts and PET/CT revealed a mass in the uterus. Thus, she underwent the second transplantation from an HLA-haploidentical donor (her daughter) with a conditioning regimen consisting of fludarabine (Flu) (150 mg/mm2), busulfan (Bu) (12.8 mg/kg), melphalan (MEL) (100 mg/mm2), anti-thymocyte globulin (ATG) (5 mg/kg), and TBI (2 Gy). The second transplantation led to the fourth CR without extramedullary uterus lesions by PET/CT, but she died on day 166 because of severe hemorrhagic cystitis (BK) (grade 3) and sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) (grade 4). Permission for autopsy was not granted.