Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape

The quest for treatment-free remission (TFR) and deep molecular response (DMR) in chronic myeloid leukemia (CML) has been profoundly impacted by tyrosine kinase inhibitors (TKIs). Immunologic surveillance of residual leukemic cells is hypothesized to be one of the critical factors in successful TFR, with self-renewing leukemic stem cells implicated in relapse. Immunological characterization in CML may help to develop novel immunotherapies that specifically target residual leukemic cells upon TKI discontinuation to improve TFR rates. This review focuses on immune dysfunction in newly diagnosed CML patients, and the role that TKIs and other therapies have in restoring immune surveillance. Immune dysfunction and immunosurveillance in CML points towards several emerging areas in the key goals of DMR and TFR, including: (1) Aspects of innate immune system, in particular natural killer cells and the newly emerging target plasmacytoid dendritic cells. (2) The adaptive immune system, with promise shown in regard to leukemia-associated antigen vaccine-induced CD8 cytotoxic T-cells (CTL) responses, increased CTL expansion, and immune checkpoint inhibitors. (3) Immune suppressive myeloid-derived suppressor cells and T regulatory cells that are reduced in DMR and TFR. (4) Immunomodulator mesenchymal stromal cells that critically contribute to leukomogenesis through immunosuppressive properties and TKI- resistance. Therapeutic strategies that leverage existing immunological approaches include donor lymphocyte infusions, that continue to be used, often in combination with TKIs, in patients relapsing following allogeneic stem cell transplant. Furthermore, previous standards-of-care, including interferon-α, hold promise in attaining TFR in the post-TKI era. A deeper understanding of the immunological landscape in CML is therefore vital for both the development of novel and the repurposing of older therapies to improve TFR outcomes