4 Discussion
None of the optimal protocol is defined for treating extramedullary leukemia. Some patients still would experience multiple relapses even if they had received chemotherapy, allo-HSCT, and/or radiation16,17. Before the off-the-shelf of CAR-T therapy, blinatumomab already received regulatory approval and was widely available to treat with relapsed or refractory B-cell precursor ALL patients in clinical practice18,19. However, the presence of extramedullary relapse is associated with a lower CR rate of patients treated with blinatumomab, which is a CD19/CD3 bispecific T‐cell engager antibody (BiTE) inducing cell death of CD19+ leukemia cells by redirecting CD3+ T cells20. Furthermore, many patients with the failure of blinatumomab still had an expression of CD1921. Two studies have presented that CD19 CAR-T therapy can eradicate leukemic cells in B-ALL patients with extramedullary involvement. In a study of 7 boys with testicular relapse, 6 of them remained CR in a median of 14 months (5 to 23 months)22. The group from the Children’s Hospital of Philadelphia demonstrated that 6 in 10 patients with various extramedullary sites of relapse were without recurrence of disease for 6 to 13 months after CAR-T infusion23. A clinical remission in extramedullary B-ALL patients was also noted with anti-CD19 CAR-T therapy in this study.
Nevertheless, CD19+ relapse was still the most frequently occurred in the failures of 19CAR-T treatment. A trial is conducted with bispecific anti CD19/20 CAR-T as a second therapy to treat 5 anti-CD19 CAR exposed patients with B-cell lymphoma. Poor abilities of expansion in vitro and persistence were identified in their CAR-T cells and all patients were still under disease progression state24. However, both targeted does of CAR-T cells and 100% CR were achieved in 3 relapsed patients of our study, which indicates that retreatment with CAR-T cell infusion may offer an opportunity for B-ALL pediatric patients with extramedullary relapse to wait and look for a bridge to effective HSCT. This result also suggests that combined targeting CAR-T cells can be effective to deal with this kind of immune escape problem related to tumor cells with antigen switching.
This study reveals that CD19+ relapse remains the main problem of anti-CD19 CAR-T therapy treating patients with extramedullary relapses. We envisage a second CAR-T therapy as a means to create another surviving chance for these patients and combined targeting CD19 and CD22 CAR-T therapy could be a promising choice.