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The results of treatment of recurrent/refractory acute lymphoblastic leukemia (ALL) with both standard and high-dose chemotherapy are unsatisfactory and require the development of new therapeutic options. The use of immunotherapy approaches opens up new perspectives for patients whose cytotoxic chemotherapy was ineffctive or intolerable. This article describes the experience of using CD19 CAR-T cells manufactured at the Republican Scientifi and Practical Center for Pediatric Oncology, Hematology and Immunology after lymphodepletion with fldarabine and cyclophosphamide in two patients over 18 years of age with refractory relapse of ALL. Other possibilities of conservative treatment for these patients have been exhausted. The study was approved by the Independent Ethics Committee and the Scientifi Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (Republic of Belarus). The chimeric 2nd generation receptor was constructed from the anti-CD19 scFv antibody fragment, the CD28 transmembrane domain, signaling domains of the 4-1BB and CD3z proteins, and transduced into T-lymphocytes as part of the pWPXL lentiviral vector. The cell product was obtained by separation and separate processing of CD4 and CD8 lymphocytes in the presence of IL-7 and IL-15. The subpopulation composition of the resulting CAR-T cell product and the expression of immune checkpoints were assessed. The results obtained indicate a high antileukemic activity of the obtained CAR-T cells. Monitoring of CAR-T cells' persistence, the level of minimal residual disease, and the spectrum of inflmmatory cytokines in the blood was performed. Both patients responded to CAR-T therapy by lowering their blast cell levels. Treatment was accompanied by a cytokine release syndrome controlled by a recombinant monoclonal antibody to the human IL-6 receptor, tocilizumab. The developed and replicated laboratory-derived CAR-T cell technology can be used to treat patients with severe relapsed/refractory B-line ALL as rescue therapy and provide additional chances for their cure.

Minimal residual disease (MRD) is the most significant predictor of the relapse in patients with acute lymphoblastic leukemia (ALL). MRD evaluation is necessary not only for the prediction of the relapse, but for additional stratification of patients by the risk groups in order to address the issue of the therapy individualization and to evaluate the therapy quality. This study analyzes the MRD parameters in patients with ALL at the stage of induction therapy and evaluates the effect of the value of the minimum residual disease on survival rates and the risk of relapse in patients with ALL treated according to protocol ALL-MB 2008.