scholarly journals Antimetabolic cooperativity with the clinically approved kidrolase and tyrosine kinase inhibitors to eradicate cml stem cells

2020 ◽  
Author(s):  
Anne Trinh ◽  
Raeeka Khamari ◽  
Quentin Fovez ◽  
François-Xavier Mahon ◽  
Béatrice Turcq ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Atp Synthesis ◽  
Term Treatment ◽  
Glutamine Metabolism ◽  
Apoptotic Pathway ◽  
Long Term Treatment

AbstractLong-term treatment with tyrosine kinase inhibitors (TKI) represents an effective treatment for chronic myeloid leukemia (CML) and discontinuation of TKI therapy is now proposed to patient with deep molecular responses. However, evidence demonstrating that TKI are unable to fully eradicate dormant leukemic stem cells indicate that new therapeutic strategies are needed to prevent molecular relapses. We investigated the metabolic pathways responsible for CML surviving to Imatinib exposure and its potential therapeutic utility to improve the efficiency of TKI against CML stem cells. Using complementary cell-based techniques, we demonstrated that TKI suppressed glycolysis in a large panel of BCR-ABL1 + cell lines as well as in primary CD34+ stem-like cells from CML patients. However, compensatory glutamine-dependent mitochondrial oxidation supported ATP synthesis and CML cell survival. Glutamine metabolism was inhibited by L-asparaginases such as Kidrolase without inducing predominant CML cell death. Clinically relevant concentrations of TKI render CML progenitors and stem cells susceptible to Kidrolase. The combination of TKI with L-asparaginase reactivated the intinsic apoptotic pathway leading to efficient CML cell death. Thus, targeting glutamine metabolism with the clinically-approved drug Kidrolase, in combination with TKI that suppress glycolysis represents an effective and widely applicable therapeutic strategy for eradicating CML stem cells.

scholarly journals BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia

2017 ◽  
Vol 24 (6) ◽  
pp. 433-452 ◽  
Author(s):  
Sandra Cuellar ◽  
Michael Vozniak ◽  
Jill Rhodes ◽  
Nicholas Forcello ◽  
Daniel Olszta
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Drug Interactions ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Term Treatment ◽  
Patient Centered ◽  
Long Term Treatment

The management of chronic myeloid leukemia with BCR-ABL1 tyrosine kinase inhibitors has evolved chronic myeloid leukemia into a chronic, manageable disease. A patient-centered approach is important for the appropriate management of chronic myeloid leukemia and optimization of long-term treatment outcomes. The pharmacist plays a key role in treatment selection, monitoring drug–drug interactions, identification and management of adverse events, and educating patients on adherence. The combination of tyrosine kinase inhibitors with unique safety profiles and individual patients with unique medical histories can make managing treatment difficult. This review will provide up-to-date information regarding tyrosine kinase inhibitor-based treatment of patients with chronic myeloid leukemia. Management strategies for adverse events and considerations for drug–drug interactions will not only vary among patients but also across tyrosine kinase inhibitors. Drug–drug interactions can be mild to severe. In instances where co-administration of concomitant medications cannot be avoided, it is critical to understand how drug levels are impacted and how subsequent dose modifications ensure therapeutic drug levels are maintained. An important component of patient-centered management of chronic myeloid leukemia also includes educating patients on the significance of early and regular monitoring of therapeutic milestones, emphasizing the importance of adhering to treatment in achieving these targets, and appropriately modifying treatment if these clinical goals are not being met. Overall, staying apprised of current research, utilizing the close pharmacist–patient relationship, and having regular interactions with patients, will help achieve successful long-term treatment of chronic myeloid leukemia in the age of BCR-ABL1 tyrosine kinase inhibitors.

scholarly journals Handling challenging questions in the management of chronic myeloid leukemia: when is it safe to stop tyrosine kinase inhibitors?

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 243-247
Author(s):  
Delphine Rea
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Term Treatment ◽  
Long Term Treatment ◽  
Treatment Free Remission

Abstract The paradigm for managing patients with chronic myeloid leukemia is evolving. In the recent past, restoring a normal life expectancy while patients are receiving never-ending targeted therapy with BCR–ABL1 tyrosine kinase inhibitors through prevention of progression to blast phase and mitigation of iatrogenic risks was considered the best achievable outcome. Now, long-term treatment-free remission with continued response off tyrosine kinase inhibitor therapy is recognized as the most optimal benefit of treatment. Indeed, numerous independent clinical trials provided solid proof that tyrosine kinase inhibitor discontinuation was feasible in patients with deep and sustained molecular responses. This article discusses when tyrosine kinase inhibitors may be safely stopped in clinical practice on the basis of the best and latest available evidence.

scholarly journals Handling challenging questions in the management of chronic myeloid leukemia: when is it safe to stop tyrosine kinase inhibitors?

2020 ◽  
Vol 4 (21) ◽  
pp. 5589-5594
Author(s):  
Delphine Rea
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Term Treatment ◽  
Long Term Treatment ◽  
Treatment Free Remission

Abstract The paradigm for managing patients with chronic myeloid leukemia is evolving. In the recent past, restoring a normal life expectancy while patients are receiving never-ending targeted therapy with BCR–ABL1 tyrosine kinase inhibitors through prevention of progression to blast phase and mitigation of iatrogenic risks was considered the best achievable outcome. Now, long-term treatment-free remission with continued response off tyrosine kinase inhibitor therapy is recognized as the most optimal benefit of treatment. Indeed, numerous independent clinical trials provided solid proof that tyrosine kinase inhibitor discontinuation was feasible in patients with deep and sustained molecular responses. This article discusses when tyrosine kinase inhibitors may be safely stopped in clinical practice on the basis of the best and latest available evidence.

Successful use of long-term follow-up in patients with chronic myeloid leukemia with a deep molecular response at reduced doses of 2nd generation tyrosine kinase inhibitors: clinical cases and literature review

2020 ◽  
Vol 92 (7) ◽  
pp. 90-94
Author(s):  
M. A. Gurianova ◽  
E. Yu. Chelysheva ◽  
O. A. Shukhov ◽  
A. G. Turkina
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Term Treatment ◽  
Molecular Response ◽  
Long Term Treatment ◽  
Deep Molecular Response

Therapy with tyrosine kinase inhibitors (TKI) allows to achieve a deep molecular response in 6070% of patients with chronic myeloid leukemia (CML). According to the current guidelines CML patients receive a long-term treatment with TKI in standard dose. The frequently observed adverse effects (AE) of TKI therapy are mostly dose-dependent. A new treatment approach with TKI use in reduced dose is desirable for the CML patients with existing AE or with a high risk of AE occurrence. We report the two cases of successful long-term treatment of CML patients with reduced doses of second generation TKIs. The aim of the TKI dose reduction was to reduce the clinical manifestations of drug toxicities and to prevent the AE.

Growth Factor Independent 1b (Gfi1b) Is Highly Expressed in Human CML and Accelerates p210BCR-ABL Induced Leukemia in Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1023-1023
Author(s):  
Lothar Vassen ◽  
Daniel G. Tenen ◽  
Bert A. van der Reijden ◽  
Ulrich Duehrsen ◽  
Tarik Moroy ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Human Leukemia ◽  
Hematopoietic Stem ◽  
Long Term Treatment

Abstract Chronic myeloid leukemia (CML) is one of the most frequent leukemic diseases and invariably associated with a reciprocal t(9;22) translocation which creates a juxtaposition of the BCR and ABL genes to form the p230-, p190- or p210BCR-ABL constitutively active tyrosine kinases. This constitutive tyrosine kinase activity is the cause of CML and other leukemic diseases. CML is very efficiently treated with small molecule tyrosine kinase inhibitors, but CML is a stem cell initiated disease and surprisingly the leukemic stem cells cannot be eradicated by tyrosine kinase inhibitor treatment, resulting in a high risk of the development of therapy resistance. To design more successful therapies, it is primordial to understand the molecular mechanisms underlying this disease. Here we show that growth factor independent 1b (Gfi1b), also translocated in CML, is strongly induced in peripheral blood mononuclear cells (PBMCs) in patients with chronic- or acute myeloid leukemia (AML) as well as in patients suffering from myeloprolifarative syndrome (MPS) or B-lymphoblastic leukemia (B-ALL). Gfi1b is a transcriptional repressor essential for erythroid- and megacaryocytic cells, but also expressed in hematopoietic stem cells, early myeloid precursors and mature myeloid cells in peripheral blood. Interestingly, the expression of Gfi1b is further induced by long term treatment with tyrosine kinase inhibitors like Glivec, although the patients are phenotypically in remission. Additionally we describe a new splice variant of Gfi1b which is overrepresented in CML, AML and B-ALL, but not in MPS. Using a mouse model system we demonstrate, that Gfi1b strongly accelerates p210BCR-ABL induced leukemogenesis. We further show that Gfi1b inhibits the activity of PU.1, a key molecule in hematopoiesis and repressor of leukemogenesis. Our findings bear considerable significance with regard to the role of Gfi1b as an oncogene in human leukemia and to its possible value as a new target for leukemia therapy.

scholarly journals FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3/ITD acute leukemia cells through BIM activation

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ruiqi Zhu ◽  
Li Li ◽  
Bao Nguyen ◽  
Jaesung Seo ◽  
Min Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Selective Inhibitor ◽  
Leukemia Cells ◽  
Sorafenib Treatment ◽  
Limited Success ◽  
Pathway Inhibition

AbstractTyrosine kinase inhibitors (TKIs) targeting FLT3 have shown activity but when used alone have achieved limited success in clinical trials, suggesting the need for combination with other drugs. We investigated the combination of FLT3 TKIs (Gilteritinib or Sorafenib), with Venetoclax, a BCL-2 selective inhibitor (BCL-2i), on FLT3/ITD leukemia cells. The combination of a FLT3 TKI and a BCL-2i synergistically reduced cell proliferation and enhanced apoptosis/cell death in FLT3/ITD cell lines and primary AML samples. Venetoclax also re-sensitized FLT3 TKI-resistant cells to Gilteritinib or Sorafenib treatment, mediated through MAPK pathway inhibition. Gilteritinib treatment alone dissociated BIM from MCL-1 but increased the binding of BIM to BCL-2. Venetoclax treatment enhanced the binding of BIM to MCL-1 but dissociated BIM from BCL-2. Treatment with the drugs together resulted in dissociation of BIM from both BCL-2 and MCL-1, with an increased binding of BIM to the cell death mediator BAX, leading to increased apoptosis. These findings suggest that Venetoclax mitigates the unintended pro-survival effects of FLT3 TKI mainly through the dissociation of BIM and BCL-2 and also decreased BIM expression. This study provides evidence that the addition of BCL-2i enhances the effect of FLT3 TKI therapy in FLT3/ITD AML treatment.

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