Strategic therapeutic approaches to overcome emerging dual SRC/ABL kinase inhibitors resistances in chronic phase Ph positive chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a haematopoietic neoplasm with clinically distinct phases and BCR⁄ABL1 oncogene. Imatinib mesylate, a potent inhibitor of BCR-ABL was highly effective in CML but later in-vitro derived cell line with resistance namely BCR-ABL duplication point mutation, P loop mutation, T315I mutation, C helix, SH2 domain, activation loop, C terminal lobe, SRC family kinase activation led to development of Nilotinib. Although it has potential drug targets as BCR-ABL kinase, KIT, PDGFR but has no role in overcoming in Src family kinase. It prompted strategic rational drug design of Dual Src Family Kinase/Abl Inhibitor Dasatinib, active against 15 clinically significant Imatinib resistant BCR-ABL mutations but inactive against T315I mutation. The propensity of Ph+ CML to develop novel mechanism of resistance led designing of rational therapeutic approaches to eradicate minutest residual diseases along with long term resistance risk. DOI: http://dx.doi.org/10.3126/ajms.v6i1.10454 Asian Journal of Medical Sciences Vol.6(1) 2015 8-15

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Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations

Blood ◽

10.1182/blood-2009-01-197715 ◽

2009 ◽

Vol 114 (10) ◽

pp. 2037-2043 ◽

Cited By ~ 88

Author(s):

Elias Jabbour ◽

Daniel Jones ◽

Hagop M. Kantarjian ◽

Susan O'Brien ◽

Constantine Tam ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Inhibitory Concentration ◽

Chronic Phase ◽

Kinase Domain ◽

Abl Kinase

AbstractSecondary imatinib resistance in chronic myeloid leukemia (CML) is associated in approximately 50% of cases with mutations in the BCR-ABL kinase domain, necessitating switch to one of several new tyrosine kinase inhibitors (TKIs) that act differentially on mutated BCR-ABL. We assess here whether scoring mutation based on in vitro inhibitory concentration of each TKI-mutation pair can predict long-term clinical outcome. Among 169 patients with CML after imatinib failure, mutations were detected before TKI switch in 41 (48%) treated with dasatinib and 45 (52%) treated with nilotinib. Inhibitory concentration values for each TKI-mutation pair were stratified into high (n = 42), intermediate (n = 25), low (T315I, n = 9), or unknown sensitivity (n = 10). Hematologic and cytogenetic response rates were similar for patients with or without mutations. For patients in chronic phase, hematologic and cytogenetic responses correlated with mutation score; tumors with low and intermediate scores had lower response rates than those with highly sensitive mutations, and worse event-free and overall survival. These correlations with overall survival were not seen for advanced phases. Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TKIs and can help in therapy selection. More complex prognostic models will be required for advanced stages of disease.

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BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet

Blood ◽

10.1182/blood-2010-12-326405 ◽

2011 ◽

Vol 118 (5) ◽

pp. 1208-1215 ◽

Cited By ~ 332

Author(s):

Simona Soverini ◽

Andreas Hochhaus ◽

Franck E. Nicolini ◽

Franz Gruber ◽

Thoralf Lange ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Mutation Analysis ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Direct Sequencing ◽

Chronic Phase ◽

Kinase Domain ◽

Abl Kinase

AbstractMutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists' experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection.

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Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation

Case Reports in Hematology ◽

10.1155/2011/263725 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4

Author(s):

B. Uz ◽

O. Bektas ◽

E. Eliacik ◽

H. Goker ◽

Y. Erbilgin ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Kinase Domain ◽

Current Treatment ◽

Hematopoietic Stem ◽

Abl Kinase ◽

Kinase Domain Mutation ◽

Kinase Mutation

The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a “difficult-to-manage” state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the hope and progress in CML in the TKI era.

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T315I mutation with lymphoblasts in a newly diagnosed patient with chronic-phase chronic myeloid leukemia

Leukemia & Lymphoma ◽

10.1080/10428194.2018.1548704 ◽

2019 ◽

Vol 60 (6) ◽

pp. 1591-1594

Author(s):

Kenji Kimura ◽

Shokichi Tsukamoto ◽

Koji Takaishi ◽

Yusuke Isshiki ◽

Kensuke Kayamori ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Newly Diagnosed ◽

T315i Mutation

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C/EBPβ is a critical mediator of IFN-α–induced exhaustion of chronic myeloid leukemia stem cells

Blood Advances ◽

10.1182/bloodadvances.2018020503 ◽

2019 ◽

Vol 3 (3) ◽

pp. 476-488 ◽

Cited By ~ 3

Author(s):

Asumi Yokota ◽

Hideyo Hirai ◽

Ryuichi Sato ◽

Hiroko Adachi ◽

Fumiko Sato ◽

...

Keyword(s):

Stem Cells ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Interferon Α ◽

Dependent Manner ◽

Distal Enhancer ◽

Induced Differentiation ◽

Ifn Γ

Abstract Even in the era of ABL tyrosine kinase inhibitors, eradication of chronic myeloid leukemia (CML) stem cells is necessary for complete cure of the disease. Interferon-α (IFN-α) has long been used for the treatment of chronic-phase CML, but its mechanisms of action against CML stem cells remain unclear. We found that IFN-α upregulated CCAAT/enhancer binding protein β (C/EBPβ) in BCR-ABL–expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 3′ distal enhancer of Cebpb that contains tandemly aligned IFN-γ–activated site elements. Suppression or deletion of the IFN-γ–activated site elements abrogated IFN-α–dependent upregulation of C/EBPβ. IFN-α induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBPβ-dependent manner. In addition, IFN-α upregulated C/EBPβ and induced exhaustion of lineage− CD34+ cells from CML patients. Collectively, these results clearly indicate that C/EBPβ is a critical mediator of IFN-α–induced differentiation and exhaustion of CML stem cells.

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Autografting with cultured marrow in chronic myeloid leukemia: results of a pilot study [see comments]

Blood ◽

10.1182/blood.v84.3.724.724 ◽

1994 ◽

Vol 84 (3) ◽

pp. 724-732 ◽

Cited By ~ 108

Author(s):

MJ Barnett ◽

CJ Eaves ◽

GL Phillips ◽

RD Gascoyne ◽

DE Hogge ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Intensive Therapy ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Phase Group ◽

Cytogenetic Remission ◽

Group 2 ◽

Group 1

Abstract Incubation of chronic myeloid leukemia (CML) marrow for 10 days in vitro causes a marked and selective loss of very primitive Philadelphia chromosome (Ph)+ as compared with Ph- progenitors. We have autografted 22 patients with CML (16 in first chronic phase [group 1] and 6 with more advanced disease [group 2]) with marrow treated in this way to facilitate restoration of Ph- hematopoiesis after intensive therapy. Hematologic recovery to greater than 0.5 x 10(9)/L neutrophils occurred in 16 patients, and to greater than 20 x 10(9)/L platelets in 15 of 21 evaluable patients at a median of 29 and 48 days postautograft, respectively. Regenerating marrow cells were 100% Ph- in 13 patients and 75% to 94% Ph- in 3. Between 4 and 36 months (median 12) postautograft, Ph+ cells became detectable in all but 1 (who died in remission) of the 13 patients who achieved complete cytogenetic remission. Four of 7 evaluable patients treated with low-dose interferon alpha were returned to complete cytogenetic remission. Thirteen group 1 patients (81%) are alive 1.0 to 5.7 years (median 2.6) after autografting: 4 in complete cytogenetic remission, 2 in hematologic remission, 6 in chronic phase, and 1 in myeloid blast phase. Three group 2 patients (50%) are alive at 2.6, 3.8, and 4.3 years after autografting: 1 in partial cytogenetic remission, 1 in chronic phase, and 1 in accelerated phase. Thus, autografts of cultured marrow can result in prolonged restoration of Ph- hematopoiesis for some patients with CML.

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Phenotypic heterogeneity of primitive leukemic hematopoietic cells in patients with chronic myeloid leukemia

Blood ◽

10.1182/blood.v80.10.2522.2522 ◽

1992 ◽

Vol 80 (10) ◽

pp. 2522-2530 ◽

Cited By ~ 38

Author(s):

C Udomsakdi ◽

CJ Eaves ◽

PM Lansdorp ◽

AC Eaves

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Philadelphia Chromosome ◽

Significant Proportion ◽

Hematopoietic Cells ◽

Chronic Phase ◽

Leukemic Cells ◽

Clonogenic Cell ◽

Clonogenic Cells

Abstract The peripheral blood of chronic myeloid leukemia (CML) patients with chronic-phase disease and elevated white blood cell (WBC) counts typically contains markedly increased numbers of a variety of neoplastic pluripotent and lineage-restricted hematopoietic progenitors. These include cells detected in standard colony assays as well as their more primitive precursors. The latter are referred to as long-term culture-initiating cells (LTC-IC) because of their ability to generate clonogenic cell progeny detectable after a minimum of 5 weeks incubation on competent fibroblast feeder layers. In this study, we have investigated a number of the properties of the LTC-IC and clonogenic cells present in the blood of such CML patients with high WBC counts. This included an analysis of the light scattering properties of these progenitors, as well as their expression of CD34 and HLA-DR, Rhodamine-123 staining, and in vitro sensitivity to 4- hydroperoxycyclophosphamide. In the case of LTC-IC, the production of different types of lineage-restricted and multipotent progeny was also analyzed. Most of the circulating LTC-IC and clonogenic cells in the CML patients studied (on average approximately 70% and approximately 90%, respectively) showed features of proliferating or activated cells. This is in marked contrast to the majority of progenitors in the blood of normal individuals and most of the LTC-IC in normal marrow, all of which exhibit a phenotype expected of quiescent cells. Interestingly, a significant proportion of the circulating clonogenic cells and LTC-IC in the CML samples studied (on average approximately 10% and approximately 30%, respectively) appeared to be phenotypically similar to normal circulating progenitors, although their absolute numbers were indicative of a neoplastic origin. Both phenotypes of circulating CML clonogenic cells and LTC-IC could be obtained at approximately 10% to 20% purity by differential multiparameter sorting. These findings suggest that expansion of the Philadelphia chromosome-positive clone at the level of the earliest types of hematopoietic cells results from the activation of mechanisms that enable some, but not all, signals that block the cycling of normal stem cells to be bypassed or overcome. In addition, they provide strategies for purifying these primitive leukemic cells that should facilitate further analysis of the mechanisms underlying their abnormal proliferative behavior.

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In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML

Blood ◽

10.1182/blood-2005-03-1103 ◽

2005 ◽

Vol 106 (7) ◽

pp. 2520-2526 ◽

Cited By ~ 104

Author(s):

Deborah White ◽

Verity Saunders ◽

A. Bruce Lyons ◽

Susan Branford ◽

Andrew Grigg ◽

...

Keyword(s):

Myeloid Leukemia ◽

De Novo ◽

Chronic Phase ◽

Adaptor Protein ◽

Prognostic Indicator ◽

Molecular Response ◽

Log Reduction ◽

Abl Kinase ◽

Marked Variability

AbstractMost patients with de novo chronic myeloid leukemia (CML) achieve good responses to imatinib, but the rate and degree of molecular response is variable. We assessed the inhibitory concentration 50% for imatinib (IC50imatinib) in 62 patients with de novo chronic-phase CML as a predictor of molecular response. IC50imatinib was determined in pretherapy blood samples by measuring the in vitro imatinib-induced reduction of the phosphorylated form of the adaptor protein Crkl (CT10 regulator of kinase like). There was marked variability between patients, with IC50imatinib ranging from 0.375 to 1.8 μM (median, 0.6 μM). Patients with low IC50imatinib (IC50 ≤ 0.6 μM; n = 36) had a 36% probability of achieving 2-log reduction in BCR-ABL (breakpoint cluster region-abelson) by 3 months compared with 8% in patients with high IC50imatinib (n = 26) (P = .01). The IC50imatinib was also predictive of molecular response at 12 months, with 47% of patients in the low IC50imatinib group achieving 3-log reduction and 23% in the high IC50imatinib group (P = .03). The predictive power of IC50imatinib was particularly strong in patients with low Sokal scores. These data provide strong evidence that intrinsic sensitivity to imatinib is variable in previously untreated patients with CML, and the actual level of BCR-ABL kinase inhibition achieved is critical to imatinib response. The IC50imatinib potentially provides a new prognostic indicator for molecular response in patients treated with imatinib. (Blood. 2005; 106:2520-2526)

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Therapeutic Immune Monitoring of Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors: Focus on CD4+ CD25+ t Cells

Blood ◽

10.1182/blood.v126.23.4036.4036 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4036-4036

Author(s):

Ziyuan Lu ◽

Na Xu ◽

Xuan Zhou ◽

Guanlun Gao ◽

Lin Li ◽

...

Keyword(s):

T Cells ◽

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Conflicts Of Interest ◽

Chronic Phase ◽

Similar Proportion

Abstract Background and Objectives: In clinical, conventional Tyrosine Kinase Inhibitors (TKIs) including imatinib, dasatinib, and nilotinib are remarkably effective forms of therapy for certain types of solid cancers as well as Ph+ leukemias. In addition to the BCR-ABL target oncoprotein, they also inhibit certain off-target kinases (Eph, c-KIT, TEC, SRC). Some TKIs affect immune reconstitution as well as the proliferation, function, and activation of T cells. Certain TKIs have been known to have an especially strong effect on CD4+CD25+ T cells, also known as regulatory T Cells (Tregs). There is currently a gap in the clinical data available about on this area of study. Patients and methods: In this study, we collected 108 Peripheral Blood (PB) samples from patients in the Chronic Phase (CP) of Chronic Myeloid Leukemia (CML) at the time of diagnosis (n=31) and also the TKIs treatment. Groups consisted of individuals treated with TKIs like imatinib (n=12), dasatinib (n=11) and nilotinib (n=8), as well as healthy controls (n=15). We evaluated the quantity and function of Tregs from patients in the CML-CP at the time of diagnosis and during treatment with TKIs. Results: It was found that at diagnosis, patients with CML had a similar proportion and absolute number of lymphocytes compared to healthy donors. After TKIs treatment, proportions and absolute numbers of total T cellsACD4+ T cells and Tregs decreased at different degree. Moreover, thedecrease would be more and more significant as time goes on.Our results indicated that although these three TKIs show similar inhibitory effects in the proportion and number of Tregs in vivo, they have differential effects on the functions of Tregs in vitro. The proliferation, suppression, and expression of suppressive cytokines (IL-4,IL-10 and TGF-β) as well as suppression-associated molecules (FoxP3, GITR, and CTLA-4) of Tregs decreased in groups treated with imatinib and dasatinib. The decrease was not significant in the nilotinib-treated group. Conclusions: The results showed that imatinib and dasatinib have stronger inhibitory roles than nilotinib when it comes to regulating the number and functions of Tregs. These findings can be used to argue in favor of calls for personalized treatment and follow-up of CML patients during TKIs treatment, particularly for those patients who received combination therapy with allo-transplantation and post-transplant TKIs. Disclosures No relevant conflicts of interest to declare.

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