Combination Therapies in Chronic Myeloid Leukemia for Potential Treatment-Free Remission: Focus on Leukemia Stem Cells and Immune Modulation

Mu, Huiling; Zhu, Xiaojian; Jia, Hui; Zhou, Lu; Liu, Hong

doi:10.3389/fonc.2021.643382

Cited by 27 publications

(21 citation statements)

References 163 publications

(177 reference statements)

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“…Considering these causes of therapy failure, several strategies have been used to overcome drug resistance in CML: (I) the use of drugs targeting the allosteric site of BCR-ABL1 oncoprotein; (II) the use of drugs targeting the ATP site of BCR-ABL1 along with drugs that bind in a different way to Imatinib; (III) the use of drugs, like Asciminib, that target the myristoyl pocket of BCR-ABL1; (IV) the combined use of several TKIs; (V) the use of a TKI in combination with other drugs that target different objectives, such as TKI+IFNα, TKI+chemotherapy, TKI+immune-modulators, etc. [210]; (vi) the use of new TKIs designed to overcome ABL1 gatekeeper mutations (mainly T315I) that at present are only preclinically validated [248]. All these therapeutic approaches are taken in second and third line treatments when initial therapies are not efficient or faint over time due to the emergence of resistance.…”

Section: Discussionmentioning

confidence: 99%

“…This culminates into increased Treg levels, T-cell inhibition, and dysfunction of NK cells [202,209]. The relevance of BMM and immunological status in CML was highlighted in TFR studies, where specific immune cell types have been proposed as predictive biomarkers of successful TKI discontinuation [204,210,211].…”

Section: Microenvironment and Immunological Statusmentioning

confidence: 99%

“…Ruxolitinib, a JAK2 inhibitor currently approved for myelofibrosis and polycythemia vera, demonstrated promising results in combination with TKI in reducing LSC viability in CML [265]. Its mechanism of action is associated with direct inhibition of JAK signaling but is also linked with enhancing MHC molecules expression making CML cells more visible to the immune system [210]. The combination approach of Ruxolitinib with TKI is currently under investigation in different clinical trials (NCT03610971, NCT01702064).…”

Section: Non-bcr-abl1 Targeted Therapiesmentioning

confidence: 99%

“…Targeting signaling pathways essential to maintain and regulate key features of LSCs is a very promising strategy in different cancers [210]. Inhibition of sonic hedgehog pathway with Vismodegib (GDC-0449) or Sonidigib (LDE225) in preclinical studies showed a reduction in number and self-renewal capacity of CML-LSCs and a possible synergistic effect with TKI [280,281].…”

Section: Non-bcr-abl1 Targeted Therapiesmentioning

confidence: 99%

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

Alves

Gonçalves

Rutella

et al. 2021

Cancers

101

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Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Microenvironment and Immunological Statusmentioning

confidence: 99%

Section: Non-bcr-abl1 Targeted Therapiesmentioning

confidence: 99%

Section: Non-bcr-abl1 Targeted Therapiesmentioning

confidence: 99%

See 2 more Smart Citations

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

Alves

Gonçalves

Rutella

et al. 2021

Cancers

101

View full text Add to dashboard Cite

show abstract

“…Targeted agents targeting the above molecules or pathways have shown promising efficacy in eliminating LSCs by enhancing the killing effect of TKI on LSCs in vitro and vivo studies. Several promising strategies have also entered clinical trials, and some preliminary results showed that TKIs in combination with IFNa, JAK2 inhibitors, PPAR-g agonists, BCL-2 inhibitors, and lysosomotropic agents have the potential to improve treatment response in CML (169,170).…”

Section: Targeting Lscs Via Surface Markersmentioning

confidence: 99%

Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

et al. 2021

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The therapeutic landscape for chronic myeloid leukemia (CML) has improved significantly with the approval of tyrosine kinase inhibitors (TKIs) for therapeutic use. Most patients with optimal responses to TKIs can have a normal life expectancy. Treatment-free remission (TFR) after discontinuing TKI has increasingly become a new goal for CML treatment. However, TKI only “control“ CML, and relapse after discontinuation has become a key factor hindering patient access to attempt TFR. In this study, we reviewed studies on TKI discontinuation, including both first and second-generation TKI. We also reviewed predictors of relapse, new monitoring methods, and strategies targeting leukemic stem cells.

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Treatment‐free remission in patients with chronic myeloid leukemia following the discontinuation of tyrosine kinase inhibitors

et al. 2022

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Tyrosine kinase inhibitors (TKIs) discontinuation in patients with Philadelphia‐chromosome‐positive chronic myeloid leukemia (Ph‐positive CML) is increasingly considered. We aim to evaluate the outcome of patients with CML who discontinued TKIs, and determine the factors associated with differences in the success rates of treatment‐free remission (TFR). Patients with Ph‐positive CML treated between October 1999 and February 2017 who discontinued therapy were analyzed. A major molecular response (MMR) was defined as BCR‐ABL1/ABL1 ratio on the International Scale ≤0.1%. TFR failure was defined as the loss of MMR on any single test. We analyzed TFR rates according to duration and depth of response, and conducted a multivariate analysis for factors associated with loss of MMR. Two‐hundred and eighty‐four patients were analyzed; 199 patients (70%) electively discontinued TKIs. At a median follow‐up of 36 months (95% confidence interval, 32–40) after TKI discontinuation, 53 patients (19%) lost MMR. The estimated 5‐year TFR rate was 79%. All but one patient regained MMR after resuming therapy. The estimated 5‐year TFR rates were higher with MR4 and MR4.5 ≥5 years, compared with MR4 <5 years (87% vs. 92% vs. 64%; p < .0001). By multivariate analysis, only the duration of MR4 or MR4.5 ≥5 years before stopping treatment was associated with a lower risk of loss of MMR. In summary, TFR is safe and feasible in patients with Ph‐positive CML on TKI therapy. Achieving MR4 or MR4.5 for at least 5 years is correlated with a better outcome.

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Combination Therapies in Chronic Myeloid Leukemia for Potential Treatment-Free Remission: Focus on Leukemia Stem Cells and Immune Modulation

Cited by 27 publications

References 163 publications

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

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

Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

Treatment‐free remission in patients with chronic myeloid leukemia following the discontinuation of tyrosine kinase inhibitors

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