CASE HISTORY
A 17-year-old female presented with epistaxis and bleeding gums in February 2019. Complete blood cell count showed white blood cells 26.98×109/L, hemoglobin 79g/L and platelets 12×109/L. A differential count found 91% blasts. The diagnosis of B-ALL was confirmed by bone marrow morphology and flow cytometry (FCM). Cytogenetics was normal. No fusion genes or mutations were detected with polymerase chain reaction and targeted next-generation sequencing. Complete remission (CR) was not achieved after induction therapy with the Hyper-CVAD regimen [7] (11.5% blasts in morphology). After reinduction with idarubicin, pegasparagase and dexamethasone, she achieved CR but measurable residual disease (MRD, 1.6%) was detected by FCM. This was followed by consolidation therapy, including 1 cycle of high-dose methotrexate plus vincristine and dexamethasone, and 1 cycle of high-dose cytarabine. To prevent central nervous system infiltration, intrathecal chemotherapy with methotrexate was used. However, MRD was consistently detected in bone marrow specimens. Though she had no unfavorable genetic aberrations at diagnosis, the persistence of MRD supported the risk classification of high-risk group. As neither blinatumomab nor InO were approved for marketing in China in 2019, she underwent haploidentical hematopoietic stem cell transplantation (HSCT) from her father in August 2019 with a positive MRD (1.47% MRD before HSCT). She did not suffer from acute or chronic graft versus host disease (GVHD) and immunosupressors were tapered off and stopped in 6-months post transplantation. Unfortunately, a hematologic relapse was detected 23 months post-transplant (July 2021). She was then enrolled in a clinical trial (NCT04825496) and received autologous anti-CD19 CART therapy (dose: 1×106/kg). At the day 28 evaluation after CAR T-cell infusion, the patient achieved a MRD negative remission. She had grade 2 cytokine release syndrome and recovered with symptomatic treatment (Fig. 1A). The persistence of CAR T-cells was only detected within a month following CART therapy (Fig. 1B). At the regular follow-up in August 2022, MRD-positive relapse was detected (FCM of 2.9% blasts with CD10+CD19+CD20-CD22+CD38+ and morphology of 3% blasts). Expression of CD22 was detected in 63.74% of the blasts. InO was selected for the treatment of MRD. InO was applied 3 times: 0.8 mg/m2on day 1 and 0.5 mg/m2 on days 8 and 15. Ursodeoxycholic acid was administered to prevent the development of liver venoocclusive disease (VOD). She experienced only mild nausea. Grade 1 neutropenia and grade 4 thrombocytopenia were observed, which recovered with supportive care. At day 30 evaluation, no blasts were detected in the BM smear. Surprisingly, the MRD by FCM decreased to 2.68×10-5 and CD22 expression was negative (Fig. 1C, 1D, 1E). No sinusoidal obstruction syndrome or other adverse effects occurred. Currently, the patient is in remission until follow-up to September 2023. Timeline of the treatments and responses are shown in Fig. 1F.