Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia

Abstract

Despite the rapid development of medicine, even nowadays, acute lymphoblastic leukemia (ALL) is still a problem for pediatric clinicians. Modern medicine has reached a limit of curability even though the recovery rate exceeds 90%. Relapse occurs in around 20% of treated patients and, regrettably, 10% of diagnosed ALL patients are still incurable. In this article, we would like to focus on the treatment resistance and disease relapse of patients with B-cell leukemia in the context of prognostic factors of ALL. We demonstrate the mechanisms of the resistance to steroid therapy and Tyrosine Kinase Inhibitors and assess the impact of genetic factors on the treatment resistance, especially TCF3::HLF translocation. We compare therapeutic protocols and decipher how cancer cells become resistant to innovative treatments-including CAR-T-cell therapies and monoclonal antibodies. The comparisons made in our article help to bring closer the main factors of resistance in hematologic malignancies in the context of ALL.

Keywords: acute lymphoblastic leukemia; resistance; treatment resistance.

Figure 1

Effect of Blinatumomab and Inotuzumab ozogamicin (InO) on a cancer cell and the mechanism of tumor cell escape. (a) Blinatumomab in therapeutic context. Blinatumomab is a mediator between CD19 antigen on T lymphocytes and CD19 antigen localized on cancer cells. Effect of connection is cancer cell death, caused by cytotoxic activity of T lymphocyte; (b) Resistance to Blinatumomab. No CD19 antigen on cancer cells leads to no connection between T lymphocyte and cancer cell, where there is no cell death; (c) Inotuzumab ozogamicin (InO) in therapeutic context. When CD22 antigens are found on cancer cells, InO binds, and it causes the production of intracellularly unconjugated calicheamicin, which causes blast cell death. (d) Resistance to InO. InO has no effect when CD22 antigens are not present on cancer cells. Image created with BioRender.com, accessed on 29 January 2022.

Figure 2

Response to B-ALL treatment. (a) Effective influence of therapeutic protocols. Patients are curable in 90% of cases, which still leaves 10% og patients resistant to therapeutic protocols; (b) Overcoming treatment. Cancer cells gain resistance by multiple changes in construction and activeness, such as activation of new transcripts, silencing genes, gene aberration, gene impact for expression of genes—changes observable in metabolic cell’s proteins; (c) Resistance to treatment. Treatment is overcome by cancer cells through genetic modifications, which protect it from the typical protocol treatment.