Why chronic myeloid leukaemia cannot be cured by tyrosine kinase-inhibitors

Baccarani, Michele; Gale, Robert Peter

doi:10.1038/s41375-021-01272-8

Cited by 14 publications

(17 citation statements)

References 70 publications

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“…The optimal goal of CML therapy is cure resulting in normal sex- and age-adjusted survival with a normal quality-of-life (QoL) [ 1 – 3 ]. Unfortunately, cure is achieved in few people with CML [ 4 , 5 ]. An intermediate goal is achieving near normal age- and sex-matched adjusted survival off tyrosine kinase inhibitor (TKIs)-therapy referred to as therapy-free remission (TFR) [ 2 – 10 ].…”

Section: What Is the Appropriate Goal Of CML Therapy?mentioning

confidence: 99%

“…But there is another important consideration. TKI-therapy rarely cures CML, as we discussed elsewhere [ 5 ]. If so, should the only therapy of CML be TKIs?…”

Section: Are Current Recommendations For Tki-therapy Appropriate?mentioning

confidence: 99%

“…Also older persons receiving TKI therapy are less likely to be therapy compliant, achieve TFR and remain on lifelong TKI therapy with attendant impacts on QoL. This is especially true for 2G-TKIs [ 2 , 5 – 8 ].…”

Section: Do We Need To Reconsider Use Of Transplant In Chronic Phase ...mentioning

confidence: 99%

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Questions concerning tyrosine kinase-inhibitor therapy and transplants in chronic phase chronic myeloid leukaemia

et al. 2022

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In this provocative commentary, we consider several questions posed by the late chronic myeloid leukaemia (CML) expert Prof. Michele Baccarani, which he challenged us to address after his death. He noted only a small proportion of people with chronic phase CML receiving tyrosine kinase-inhibitor (TKI)-therapy are likely to achieve sustained therapy-free remission (TFR) and even fewer are likely to be cured. Persons most likely to fail TKItherapy can be identified at diagnosis or soon after starting TKI-therapy. These persons are likely to need lifetime TKI-therapy with attendant risks of adverse events, cost and psychological consequences. Allogeneic transplants achieve much higher rates of leukaemia-free survival compared with TKI-therapy but are associated with transplant-related adverse events including an almost 20 percent risk of transplant-related deaths within 1 year post-transplant and a compromised quality-of-life because of complications such as chronic graft-versus-host disease. Subject-, disease- and transplant-related co-variates associated with transplant outcomes are known with reasonable accuracy. Not everyone likely to fail TKI-therapy is a transplant candidate. However, in those who candidates are physicians and patients need to weigh benefits and risks of TKI-therapy versus a transplant. We suggest transplants should be more often considered in the metric when counseling people with chronic phase CML unlikely to achieve TFR with TKI-therapy. We question whether we are discounting a possible important therapy intervention; we think so.

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Section: What Is the Appropriate Goal Of CML Therapy?mentioning

confidence: 99%

“…But there is another important consideration. TKI-therapy rarely cures CML, as we discussed elsewhere [ 5 ]. If so, should the only therapy of CML be TKIs?…”

Section: Are Current Recommendations For Tki-therapy Appropriate?mentioning

confidence: 99%

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Questions concerning tyrosine kinase-inhibitor therapy and transplants in chronic phase chronic myeloid leukaemia

et al. 2022

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“…The Failure of TKIs to eliminate the LSCs, plus the development of drug resistance and transformation to a more fatal disease make CML an exemplar of cancer stem cell research highlighting the difficulties encountered in precision medicine as applied to cancer treatment. It has been argued that CML cannot be cured by TKIs alone but what is needed are new drugs exploiting differences between CML and normal haematopoietic stem cells [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Combination of curaxin and tyrosine kinase inhibitors display enhanced killing of primitive Chronic Myeloid Leukaemia cells

2022

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Despite the big increase in precision medicine targeted therapies developing curative treatments for many cancers is still a major challenge due mainly to the development of drug resistance in cancer stem cells. The cancer stem cells are constantly evolving to survive and targeted drug treatment often increases the selective pressure on these cells from which the disease develops. Chronic myeloid leukaemia is a paradigm of cancer stem cell research. Targeted therapies to the causative oncogene, BCR/ABL, have been developed but drug resistance remains a problem. The introduction of tyrosine kinase inhibitors targeting BCR/ABL were transformative in the management of CML. However, patients are rarely cured as the tyrosine kinase inhibitors fail to eradicate the leukaemic stem cell which often leads to loss of response to therapy as drug resistance develops and progression to more fatal forms of acute leukaemia occurs. New treatment strategies targeting other entities within the leukemic stem cell either alone or in combination with tyrosine kinase are therefore required. Drawing on our previous published work on the development of potential novel targets in CML and other myeloproliferative diseases along with analysis of the facilitates chromatin transcription (FACT) complex in CML we hypothesised that curaxin, a drug that targets the FACT complex and is in clinical trial for the treatment of other cancers, could be of use in the treatment of CML. We therefore assessed the curaxin CBL0137 as a new agent to extinguish CML primitive cells and show its ability to preferentially target CML cells compared to healthy control cells, especially in combination with clinically relevant tyrosine kinase inhibitors.

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“…CML LSCs are a population of rare cells with high BCR-ABL1-independent survival skills that initiate leukemia and contribute to its progression and drug resistance. In result, CML may not be curable with TKIs [ 30 ]. Therefore, targeting LSCs has become the main aim in therapeutic approaches to CML, and several strategies have been proposed and explored for achieving TFR [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Dicarboximide BK124.1 Breaks Multidrug Resistance and Shows Anticancer Efficacy in Chronic Myeloid Leukemia Preclinical Models and Patients’ CD34+/CD38− Leukemia Stem Cells

Stukan

Gryzik

Hoser

et al. 2022

Cancers

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The search is ongoing for new anticancer therapeutics that would overcome resistance to chemotherapy. This includes chronic myeloid leukemia, particularly suitable for the studies of novel anticancer compounds due to its homogenous and well-known genetic background. Here we show anticancer efficacy of novel dicarboximide denoted BK124.1 (C31H37ClN2O4) in a mouse CML xenograft model and in vitro in two types of chemoresistant CML cells: MDR1 blasts and in CD34+ patients’ stem cells (N = 8) using immunoblotting and flow cytometry. Intraperitoneal administration of BK124.1 showed anti-CML efficacy in the xenograft mouse model (N = 6) comparable to the commonly used imatinib and hydroxyurea. In K562 blasts, BK124.1 decreased the protein levels of BCR-ABL1 kinase and its downstream effectors, resulting in G2/M cell cycle arrest and apoptosis associated with FOXO3a/p21waf1/cip1 upregulation in the nucleus. Additionally, BK124.1 evoked massive apoptosis in multidrug resistant K562-MDR1 cells (IC50 = 2.16 μM), in CD34+ cells from CML patients (IC50 = 1.5 µM), and in the CD34+/CD38− subpopulation consisting of rare, drug-resistant cancer initiating stem cells. Given the advantages of BK124.1 as a potential chemotherapeutic and its unique ability to overcome BCR-ABL1 dependent and independent multidrug resistance mechanisms, future development of BK124.1 could offer a cure for CML and other cancers resistant to present drugs.

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Why chronic myeloid leukaemia cannot be cured by tyrosine kinase-inhibitors

Cited by 14 publications

References 70 publications

Questions concerning tyrosine kinase-inhibitor therapy and transplants in chronic phase chronic myeloid leukaemia

Questions concerning tyrosine kinase-inhibitor therapy and transplants in chronic phase chronic myeloid leukaemia

Combination of curaxin and tyrosine kinase inhibitors display enhanced killing of primitive Chronic Myeloid Leukaemia cells

Novel Dicarboximide BK124.1 Breaks Multidrug Resistance and Shows Anticancer Efficacy in Chronic Myeloid Leukemia Preclinical Models and Patients’ CD34+/CD38− Leukemia Stem Cells

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