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Pediatric acute lymphoblastic leukemia
Figure 4. Immunotherapy in acute lymphoblastic leukemia. CAR T cells: chimeric antigen receptor T cells; ALL: acute lymphoblastic leukemia; TSLPR: thymic stromal lymphopoietin receptor.
receptor consisting of a single-chain variant fragment (scFv) domain directed against a B-lineage–associated anti- gen (e.g., CD19 and CD22) and intracellular signaling domains such as 4-1BB or CD28 with CD3ζ.144 A study of CD19 CAR T cells in children and young adults with relapsed/refractory B-ALL showed a complete remission rate of 81% with 12-month EFS and OS of 50% and 76%, respectively.144 CAR T cells can migrate to extramedullary sites such as the CNS and testes; therefore, they can be considered not only for patients with isolated bone mar- row relapses but also for those with isolated or combined extramedullary relapses.145 The persistence of CAR T cells and B-cell aplasia are important factors in long-term remis- sion unless there is loss of the target antigen.145,146 Therefore, CAR T cells have been developed that can tar- get other antigens (e.g., CD22 or the thymic stromal lym- phopoietin receptor) or simultaneously target dual anti- gens (e.g., CD19/CD22).146 As with blinatumomab, cytokine release syndrome and neurotoxicity are major adverse effects. Tocilizumab (an anti-IL-6 receptor anti- body) and/or steroid have been used to ameliorate these effects, and early intervention in patients who are devel- oping signs of cytokine release syndrome is effective with- out compromising the anti-leukemia potency of CAR T cells.147 Although CAR T cells can be curative by them- selves, some consider them as a bridging therapy to sub- sequent HCT.148
To monitor MRD and antigen escape, the leukemia pop- ulation should be characterized by multiparametric flow cytometry without using the targeted antigen prior to
immunotherapy.146 Alternatively, PCR or next-generation sequencing methods can be used.
Future perspectives
Comprehensive sequencing and integrative genome- wide analyses have profoundly refined the taxonomy of ALL, resulting in the identification of new entities with prognostic and therapeutic significance. There are dis- tinct gene expression patterns in ALL caused by a wide range of genetic alterations that converge on specific pathways. Identifying these pathways is crucial for ther- apeutic targeting and demands the incorporation of gene expression approaches into the clinical diagnostic work- up of ALL. Mutation-agnostic approaches, such as drug sensitivity testing of panels of chemotherapeutic agents ex vivo and functional genomic screens, also offer the promise of identifying new therapeutic vulnerabilities and efficacious combinations.149 Such intervention would lead to new therapeutic strategies incorporating individ- ualized mutation-directed targeted therapy, immunotherapy, and reduced-intensity conventional chemotherapy or a chemotherapy-free regimen, which would ultimately improve patient survival and reduce adverse effects.
Acknowledgments
The authors thank colleagues at St. Jude Children’s Research Hospital, the Children's Oncology Group, and multiple centers
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