Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape

Abstract

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.

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

“…The immune system is an essential player within the BMM, and expression of specific immune cells might dictate successful TKI responses [ 203 , 204 ]. At diagnosis, CML is characterized by immune dysfunction, with a reduction in the number and function of NK and dendritic cells as well as dysfunctional CD8+ cytotoxic T cells [ 203 , 205 ].…”

Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort?

“…A role for the immune control has indeed been suggested by several studies (recently reviewed by Hsieh et al [134]). If residual LSCs persist and the immune system is the key to keep them in check, efforts towards sensitive LSC identification and quantitation and/or LSC phenotypical and functional characterization might be useless.…”

Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients

“…This is due to the decreased NK cell cloning frequency in CP at diagnosis and worsening as the disease progresses to AP and BC, whereas successful TFR patients are recorded to have elevated NK cells at TKI discontinuation. 77 , 81 , 82 Conversely, immune suppressor cells such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) expand during disease progression or relapse and are reduced following TKI therapy. 77 , 80 Other immunological factors, such as dendritic cells (DCs), 83 plasmacytoid dendritic cells (pDCs), 84 CD8 + cytotoxic T-cells (CTLs), 85 leukemia-associated antigens (LAAs), 86 and B-cells, 87 also play a pivotal role in contributing to CML; however, further investigation should be launched to explore their impact on therapy responses.…”

“…PD-1 is positively correlated with the BCR-ABL gene; furthermore, PD-1 expression in CD4+ T cells in BP is higher than that in patients who achieve CHR, emphasizing the role of detecting PD-1 expression in CD8+ T cells in predicting disease recurrence or progression. 77 , 102 Thus, PD-LI inhibitors may be considered.…”

“…BCR-ABL monitoring should be performed monthly for the first 6 to 12 months during TKI discontinuation and may be tapered off after that to avoid recurrence. 4,6,69,[71][72][73][74][75][76][77] Finally, in the posttransplant population, persistently positive BCR-ABL levels after 6-12 months can be regarded as a precursor for disease relapse. The BCR-ABL transcripts also differed significantly between molecular and cytogenetic recurrence (0.004% VS 0.4%; P< 0.001), and the clinical significance is that unequivocal therapeutic decisions are allowed, such as the withdrawal of immunosuppressive agents to prevent and treat graftversus-host disease (GVHD), application of donor leukocyte infusion, or therapy with interferon (IFN)-a.…”