Successful treatment‐free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells

Irani, Yazad; Hughes, Amy; Clarson, Jade; Kok, Chung Hoow; Shanmuganathan, Naranie; White, Deborah L.; Yeung, David T.; Ross, David M.; Hughes, Timothy P.; Yong, Agnes S. M.

doi:10.1111/bjh.16718

Cited by 55 publications

(49 citation statements)

References 38 publications

(54 reference statements)

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“…Additionally, approximately half of the patients who have achieved an optimal therapy response can discontinue their treatment without relapse, partly because of the immunological changes observed during TKI treatment. 80 The immune system, notably natural killer (NK) cell-mediated immune surveillance, is now the most consistently identified predictor of TFR success following TKI cessation. 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.…”

Section: What Is a Better Methods Of Management?mentioning

confidence: 99%

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

Wang¹,

Li²,

Chen³

et al. 2021

CMAR

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Chronic myeloid leukemia (CML) is triggered primarily by the t(9;22) (q34.13; q11.23) translocation. This reciprocal chromosomal translocation leads to the formation of the BCR-ABL fusion gene. Patients in the chronic phase (CP) experience a good curative effect with tyrosine kinase inhibitors. However, cases are treatment refractory, with a dismal prognosis, when the disease has progressed to the accelerated phase (AP) or blast phase (BP). Until now, few reports have provided a comprehensive description of the mechanisms involved at different molecular levels. Indeed, the underlying pathogenesis of CML evolution comprises genetic aberrations, chromosomal translocations (except for the Philadelphia chromosome), telomere biology, and epigenetic anomalies. Herein, we provide knowledge of the biology responsible for blast transformation of CML at several levels, such as genetics, telomere biology, and epigenetic anomalies. Because of the limited treatment options available and poor outcomes, only the therapeutic response is monitored regularly, which involves BCR-ABL transcript level assessment and immunologic surveillance, with the optimal treatment strategy for patients in CP adapted to evaluate disease recurrence or progression. Overall, selecting optimal treatment endpoints to predict survival and successful TFR improves the quality of life of patients. Thus, identifying risk factors and developing risk-adapted therapeutic options may contribute to a better outcome for advanced-phase patients.

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Section: What Is a Better Methods Of Management?mentioning

confidence: 99%

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

Wang¹,

Li²,

Chen³

et al. 2021

CMAR

View full text Add to dashboard Cite

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“…DMR is associated with increased NK and CD8+ T-cell numbers, and decreased MDSCs in the peripheral blood of CML patients [ 14 ]. Likewise, successful TFR has been linked to increased NK/CD8 T-cells, and decreased Tregs/MDSCs [ 3 , 22 , 27 , 28 ], and low mature (CD86+) pDC frequencies [ 4 ]. In addition, the combination of IFN-α with imatinib has been demonstrated to improve outcomes [ 29 , 30 ], with several clinical studies indicating that IFN-α in combination with TKI elicits a sustained DMR enabling possible TKI cessation [ 31 – 33 ].…”

Section: An Overview Of Immunological Profile In CML and Effects Of Tki Treatmentmentioning

confidence: 99%

Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape

2021

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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.

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“…28 Defective immunological control in an experimental mouse model of CML results in shortened survival, 29 and several studies have reported changes in immunological cell populations to be associated with TFR outcome in patients. 30,31,32 Adding a factor for immunological control to a kinetic model improved its goodness of fit with observed data. 28 Interestingly, TKI treatment duration has also been shown to be associated with changes in the immune landscape.…”

Section: Sir Ronald Fishermentioning

confidence: 99%

Counterpoint: There is a best duration of deep molecular response for treatment‐free remission, but it is patient‐specific, and that is the challenge

Ross

Hughes

2020

Br J Haematol

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There is considerable clinical and scientific interest in identifying reliable predictors of treatment-free remission in chronic myeloid leukaemia. Most predictors have been identified from non-randomized clinical trials or retrospective cohorts that could be subject to bias. The validity of predictive factors, such as duration of treatment or of deep molecular response, has been questioned. We briefly review the relevant data and the potential for bias, arguing that the risk of bias may be overstated, and that accumulating data strongly suggest that depth and duration of molecular response are critical factors to enable us to predict the probability of treatment-free remission.

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Successful treatment‐free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells

Cited by 55 publications

References 38 publications

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

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

Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape

Counterpoint: There is a best duration of deep molecular response for treatment‐free remission, but it is patient‐specific, and that is the challenge

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