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Nasir, Tajwar, Claudia Lee, Alexandra SC Lawrence, and Jeremy S. Brown. "Invasive aspergillosis complicating treatment with tyrosine kinase inhibitors." BMJ Case Reports 12, no. 1 (2019): e226121. http://dx.doi.org/10.1136/bcr-2018-226121.
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We describe three cases of pulmonary aspergillosis (PA) in three patients without traditional risk factors for invasive aspergillosis infection, such as prolonged neutropenia or high dose systemic corticosteroid therapy. All three patients developed PA while taking tyrosine kinase inhibitors (TKI) and sustained greater clinical improvement once TKI were withdrawn. Our case series supports the theory TKI treatment can increase susceptibility to PA without causing neutropenia. Recognition that TKI treatment may predispose to invasive aspergillosis will allow for rapid recognition of affected patients and more effective management of future cases.
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Cher, Chae Yin, Cheuk Him Man, Stephen S. Y. Lam, et al. "Targeting Polo-like Kinase in Acute Myeloid Leukemia." Blood 124, no. 21 (2014): 2234. http://dx.doi.org/10.1182/blood.v124.21.2234.2234.
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Abstract Acute myeloid leukemia (AML) carrying fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) is associated with poor prognosis when treated with conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Despite much interest in tyrosine kinase inhibitor (TKI) targeting FLT3 activation, drug resistance is invariable and acquisition of secondary point mutation in the tyrosine kinase domain (TKD) of FLT3 was frequently reported. We have shown that genes encoding cell cycle regulators including polo-like kinase 1 (PLK1), cell division cycle 25 homolog A (CDC25A), cyclin B2 (CCNB2), and cyclin E1 (CCNE1) were up-regulated in sorafenib-resistant primary AML samples. In particular, PLK1, a member of the polo-like kinase family, has been found to express at several checkpoints critical for cell cycle progression. PLK1 inhibitors have recently been exploited for the treatment of both solid organ and haematological cancers. We hypothesized that aberrant cell cycle progression mediated by increased PLK1 expression might confer survival advantage to drug resistant AML cells and be targetable by PLK1 inhibition. In vitro treatment with PLK1 inhibitors volasertib and BI 2536 significantly inhibited the growth of 8 AML cell lines (KG-1, ML2, MOLM-13, MV4-11, Kasumi-1, NB4, THP-1 and OCI-AML3) with IC50 (all in nM) ranging from 48.7 - 98.4 (volasertib) and 35.1 - 81.6 (BI 2536). The growth inhibitory effects of PLK1 inhibition on two FLT3-ITD+ cell lines, MOLM-13 and MV411, correlated with induction of apoptosis and cell cycle arrest at G2/M phase. Moreover, both PLK1 inhibitors significantly suppressed the growth of a sorafenib resistant MOLM-13R cell line and sorafenib naïve MOLM-13N cell line. Introduction of FLT3-ITD alone or FLT3-ITD and TKD double mutations into Ba/F3 cell lines sensitized them to the growth inhibitory effects of PLK1 inhibitors. Primary FLT3-ITD+ AML cells obtained from patients at TKI resistance were shown to be more sensitive to PLK1 inhibitors than those obtained before treatment. The results suggested that the TKI resistant clones could be effectively targeted by PLK1 inhibition, providing an insight to the design of combination treatment with FLT3 inhibitors in FLT3-ITD+ AML. Disclosures No relevant conflicts of interest to declare.
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Illouz, Frédéric, Sandrine Laboureau-Soares, Séverine Dubois, Vincent Rohmer, and Patrice Rodien. "Tyrosine kinase inhibitors and modifications of thyroid function tests: a review." European Journal of Endocrinology 160, no. 3 (2009): 331–36. http://dx.doi.org/10.1530/eje-08-0648.
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Tyrosine kinase inhibitors (TKI) belong to new molecular multi-targeted therapies that are approved for the treatment of haematological and solid tumours. They interact with a large variety of protein tyrosine kinases involved in oncogenesis. In 2005, the first case of hypothyroidism was described and since then, some data have been published and have confirmed that TKI can affect the thyroid function tests (TFT). This review analyses the present clinical and fundamental findings about the effects of TKI on the thyroid function. Various hypotheses have been proposed to explain the effect of TKI on the thyroid function but those are mainly based on clinical observations. Moreover, it appears that TKI could alter the thyroid hormone regulation by mechanisms that are specific to each molecule. The present propositions for the management of TKI-induced hypothyroidism suggest that we assess the TFT of the patients regularly before and during the treatment by TKI. Thus, a better approach of patients with TKI-induced hypothyroidism could improve their quality of life.
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Agrawal, Vineet, Eric S. Christenson, and Margaret M. Showel. "Tyrosine Kinase Inhibitor Induced Isolated Pericardial Effusion." Case Reports in Oncology 8, no. 1 (2015): 88–93. http://dx.doi.org/10.1159/000375484.
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Long-term therapy with tyrosine kinase inhibitors (TKI) has resulted in improved outcomes for patients suffering from Bcr-Abl fusion protein-harboring leukemias. As a result, a growing population of patients on TKI therapy present to their primary care providers. In this case, we report on the case of a 62-year-old male who presented with a symptomatic pericardial effusion. After pericardiocentesis, malignancy and infectious etiologies were excluded. The pericardial effusion was attributed to his TKI, with a transition of this medication to a different TKI. A repeat evaluation 1 month following the withdrawal of the offending agent showed no recurrence of his pericardial effusion on echocardiogram. In this report, we will highlight a rare but important side effect of TKI therapy before discussing its purported mechanisms and differing incidence rates. Early recognition of serosal inflammation related to long-term TKI therapy by primary care providers is important in preventing patient morbidity and mortality.
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Dimou, Maria, and Panagiotis Panagiotidis. "TYROSINE KINASE INHIBITORS AND INTERFERON." Mediterranean Journal of Hematology and Infectious Diseases 6, no. 1 (2014): e2014006. http://dx.doi.org/10.4084/mjhid.2014.006.
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The use of interferon-a (INF) in chronic myeloid leukemia, when it started in the 80s, was considered as a breakthrough in the therapy of this disease; INF administered alone or in combination with aracytine was the standard choice for treatment for Chronic Myeloid Leukemia (CML) patients unfit for bone marrow transplantation. With the appearance of the first Tyrosine Kinase Inhibitor (TKI) (imatinib) and based on the results of the pivotal IRIS trial, imatinib monotherapy was the new treatment of choice for CML, according to the ELN recommendations. The possibility of combining INF with imatinib, for obtaining better therapeutic responses in CML patients has been already tested and reported. The current challenge is the combined use of second generation TKIs with pegylated –IFN, in order to minimize failures to therapy and increase the number of CML patients with deep molecular responses, who may be able to discontinue lifelong treatment.
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Preda, Mariana, Andrei Seferian, Etienne-Marie Jutant, et al. "Tyrosine Kinase Inhibitor–Induced Pulmonary Arterial Hypertension." Advances in Pulmonary Hypertension 17, no. 2 (2018): 69–74. http://dx.doi.org/10.21693/1933-088x-17.2.69.
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The treatment of the malignant hematological diseases has been revolutionized by the use of tyrosine kinase inhibitors (TKI): for example, imatinib in patients with chronic myeloid leukemia. Dasatinib, a second-generation TKI, has been reported to induce severe pulmonary arterial hypertension (PAH). The mechanism of PAH development is presumed to be endothelial cell toxicity through the production of mitochondrial reactive oxygen species. There are other TKIs that are reported to cause PAH, such as: ponatinib, bosutinib, lapatinib, and lorlatinib. The management of PAH due to TKIs primarily involves stopping the TKI treatment, which can lead to clinical and hemodynamic normalization. A third of the patients who develop PAH can have persistent symptoms of dyspnea and right heart failure even after the interruption of the TKIs. For these patients, use of specific PAH treatment is indicated along with close follow-up. In rare cases, TKI-induced PAH can be fatal. Thus, early screening for PAH diagnosis and proper management is required.
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Heidari, Alireza, Angela Caissutti, Maria Henderson, et al. "Recent New Results and Achievements of California South University (CSU) BioSpectroscopy Core Research Laboratory for COVID-19 or 2019-nCoV Treatment: Diagnosis and Treatment Methodologies of “Coronavirus”." Journal of Current Viruses and Treatment Methodologies 1, no. 1 (2020): 3–41. http://dx.doi.org/10.14302/issn.2691-8862.jvat-20-3275.
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Coronavirus nanoparticles show a strong peak of Plasmon absorption in ultraviolet–visible zone. A strong interaction exists between the surface of Coronavirus nanoparticles and Bcr–Abl tyrosine–kinase inhibitors (TKI) such as Imatinib (STI571), Nilotinib (AMN107), Dasatinib (BMS–345825), Bosutinib (SKI–606), Ponatinib (AP–24534) and Bafetinib (INNO–406). Bcr–Abl tyrosine–kinase inhibitors (TKI) such as Imatinib (STI571), Nilotinib (AMN107), Dasatinib (BMS–345825), Bosutinib (SKI–606), Ponatinib (AP–24534) and Bafetinib (INNO–406) cause to aggregation of Coronavirus nanoparticles linked to DNA/RNA and hence, lead to widening of peak Plasmon of Coronavirus nanoparticles surface at 550 (nm) and emerging a new peak at higher wavelength. In the current project, this optical characteristic of Coronavirus nanoparticles is used to time investigate of interaction between different Bcr–Abl tyrosine–kinase inhibitors (TKI) such as Imatinib (STI571), Nilotinib (AMN107), Dasatinib (BMS–345825), Bosutinib (SKI–606), Ponatinib (AP–24534) and Bafetinib (INNO–406) and Coronavirus nanoparticles. The results were shown that Bcr–Abl tyrosine–kinase inhibitors (TKI) such as Imatinib (STI571), Nilotinib (AMN107), Dasatinib (BMS–345825), Bosutinib (SKI–606), Ponatinib (AP–24534) and Bafetinib (INNO–406) with shorter chain length interact faster with Coronavirus nanoparticles. Therefore, a simple and fast method for identification of Bcr–Abl tyrosine–kinase inhibitors (TKI) such as Imatinib (STI571), Nilotinib (AMN107), Dasatinib (BMS–345825), Bosutinib (SKI–606), Ponatinib (AP–24534) and Bafetinib (INNO–406) with various chain length using red shift in surficial Plasmon absorption is presented.
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Lovly, Christine M. "Combating Acquired Resistance to Tyrosine Kinase Inhibitors in Lung Cancer." American Society of Clinical Oncology Educational Book, no. 35 (May 2015): e165-e173. http://dx.doi.org/10.14694/edbook_am.2015.35.e165.
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The prospective identification and therapeutic targeting of oncogenic tyrosine kinases with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment for patients with non–small cell lung cancer (NSCLC). TKI therapy frequently induces dramatic clinical responses in molecularly defined cohorts of patients with lung cancer, paving the way for the implementation of precision medicine. Unfortunately, acquired resistance, defined as tumor progression after initial response, seems to be an inevitable consequence of this treatment approach. This brief review will provide an overview of the complex and heterogeneous problem of acquired resistance to TKI therapy in NSCLC, with a focus on EGFR-mutant and ALK-rearranged NSCLC. In vitro models of TKI resistance and analysis of tumor biopsy samples at the time of disease progression have generated breakthroughs in our understanding of the spectrum of mechanisms by which a tumor can thwart TKI therapy and have provided an important rationale for the development of novel approaches to delay or overcome resistance. Numerous ongoing clinical trials implement strategies, including novel, more potent TKIs and rational combinations of targeted therapies, some of which have already proven effective in surmounting therapeutic resistance.
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Ozdemir, N., S. Toptas, M. A. N. Sendur, et al. "Tyrosine kinase inhibitors (TKI): Awareness of drug-drug interaction." Annals of Oncology 28 (September 2017): v399. http://dx.doi.org/10.1093/annonc/mdx375.014.
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Albiges, Laurence, Stéphane Oudard, Sylvie Negrier, et al. "Complete Remission With Tyrosine Kinase Inhibitors in Renal Cell Carcinoma." Journal of Clinical Oncology 30, no. 5 (2012): 482–87. http://dx.doi.org/10.1200/jco.2011.37.2516.
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Purpose Complete remission (CR) is uncommon during treatment for metastatic renal cell carcinoma (mRCC) with tyrosine kinase inhibitors (TKIs), but it may occur in some patients. It remains a matter of debate whether therapy should be continued after CR. Methods A multicenter, retrospective analysis of a series of patients with mRCC who obtained CR during treatment with TKIs (sunitinib or sorafenib), either alone or with local treatment (surgery, radiotherapy, or radiofrequency ablation), was performed. Results CR was identified in 64 patients; 36 patients had received TKI treatment alone and 28 had also received local treatment. Most patients had clear cell histology (60 of 64 patients), and all had undergone previous nephrectomy. The majority of patients were favorable or intermediate risk; however, three patients were poor risk. Most patients developed CR during sunitinib treatment (59 of 64 patients). Among the 36 patients who achieved CR with TKI alone, eight continued TKI treatment after CR, whereas 28 stopped treatment. Seventeen patients who stopped treatment (61%) are still in CR, with a median follow-up of 255 days. Among the 28 patients in CR after TKI plus local treatment, 25 patients stopped treatment, and 12 of these patients (48%) are still in CR, with a median follow-up of 322 days. Conclusion CR can occur after TKI treatment alone or when combined with local treatment. CR was observed at every metastatic site and in every prognostic group.
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Ahmadieh, Hala, and Ibrahim Salti. "Tyrosine Kinase Inhibitors Induced Thyroid Dysfunction: A Review of Its Incidence, Pathophysiology, Clinical Relevance, and Treatment." BioMed Research International 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/725410.
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Tyrosine kinase inhibitors (TKI) belong to a new class of molecular multitargeted anticancer therapy which targets different growth factor receptors and hence attenuates cancer cell survival and growth. Since their introduction as adjunct treatment for renal cell carcinoma and gastrointestinal stromal tumors (GIST), a number of reports have demonstrated that TKI can induce thyroid dysfunction which was especially more common with sunitinib maleate. Many mechanisms with respect to this adverse effect of tyrosine kinase inhibitors have been proposed including their induction of thyroiditis, capillary regression in the thyroid gland, antithyroid peroxidase antibody production, and their ability to decrease iodine uptake by the thyroid gland. Of interest is the observation that TKI-induced thyroid dysfunction may actually be protective as it was shown to improve overall survival, and it was suggested that it may have a prognostic value. Followup on thyroid function tests while patients are maintained on tyrosine kinase inhibitor is strongly recommended. When thyroid dysfunction occurs, appropriate treatment should be individualized depending on patients symptoms and thyroid stimulating hormone level.
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Young, David J., Jun O. Liu, and Donald Small. "Combinatorial Approaches to Overcome Plasma Protein Inhibition of FLT3 Tyrosine Kinase Inhibitors." Blood 132, Supplement 1 (2018): 1362. http://dx.doi.org/10.1182/blood-2018-99-118820.
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Abstract Background: The FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML) and also results in poor prognosis for adult and pediatric patients, and thus represents an attractive target for tyrosine kinase inhibitors (TKI). The activity of FLT3-targeted TKI is inhibited to varying extents by plasma protein binding. Staurosporine (STS)-derived TKI are inhibited almost exclusively by the plasma protein alpha-1 acid glycoprotein (AGP), an acute-phase reactant. We studied the impact of AGP binding on the other STS-derivatives and report the development of a novel method to overcome this binding. Methods: We assayed the impact of human AGP upon the activity of the STS-derived TKI (midostaurin, lestaurtinib, TTT-3002) against proliferation of the FLT3-ITD dependent cell line MOLM-14 and upon the parent compound (staurosporine) against the non-FLT3-dependent cell line HL-60. These experiments were repeated, co-incubating with drugs that competitively bind AGP to identify those that may restore TKI activity. Results: The TKI are inhibited in a linear AGP-dependent manner (fold change increase of IC50 per mg/dL AGP: midostaurin 3.00-fold, lestaurtinib 11.73-fold, TTT-3002 0.33-fold) across the range of AGP concentrations observed in human plasma. These results correspond to the drug-protein binding constants for the TKI: midostaurin 12.6 µM-1, lestaurtinib 49.2 µM-1, TTT-3002 1.41 µM-1, all validated by competitive fluorescence displacement of the AGP-binding dye, 1-anilino-8-naphthalenesulfonate. These results predict that in vivo IC50 values for these FLT3 TKI will be significantly higher than those measured under typical (10% FCS) in vitro culture conditions: midostaurin 4.7 µM, lestaurtinib 4.8 µM, TTT-3002 34 nM. By comparison, activity of the parent compound, staurosporine, against HL60 is completely inhibited by AGP. Assays using bovine plasma, serum or purified AGP do not demonstrate similar inhibition of FLT3 TKI. We are developing a murine model to overcome this experimental limitation. We have developed a mathematical model describing the interactions of AGP with FLT3 TKI using classical mass action relationships that match experimental results and furthermore describe the effects of competitive plasma protein binding by unrelated agents. These models predict that disinhibition of TKI may be achievable in vivo, and define the properties of such "rescue" agents. Mifepristone binds AGP (2-10 fold greater than STS-derived TKI) and has no independent effect upon FLT3-dependent cell growth. Co-treatment with mifepristone restores the IC50 of TTT-3002 from 12 nM with AGP to < 0.1 nM. Disinhibition is seen for lestaurtinib (IC50 shift reduced from >1000-fold to 50-fold) and midostaurin (300-fold reduced to 80-fold). This results in predicted in vivo IC50 that are clinically relevant, and serve as a proof-of-principle for this method. Using this principle we have screened a library of FDA-approved compounds for the ability to rescue TKI activity despite the presence of potentially inhibitory plasma proteins. This screen has identified 40 potential agents that may displace STS-derived TKI from AGP, and an additional 90 agents that may restore TKI activity through off-target effects. Several agents have already been validated in vitro, and found to decrease the IC50 of midostaurin and other TKI to clinically achievable ranges despite the presence of inhibiting proteins. Conclusions: The failure of FLT3 TKI in previous clinical trials has been linked to a lack of plasma drug activity. This work provides biochemical confirmation of this effect. Furthermore, these results indicate that this is a property of the class as a whole, including midostaurin. Indeed, for midostaurin, the predicted in vivo IC50 is higher than steady state levels suggesting that in clinical trials it likely acts through non-FLT3 mechanisms. Disinhibition of TKIs by mifepristone suggests a novel combinatorial approach restore TKI activity using unrelated compounds. We are currently examining other agents for similar synergy. By improving TKI potency in the face of inhibitory plasma protein binding, such combinations would be expected to improve their clinical efficacy by reducing the dosages necessary to thoroughly inhibit FLT3. Finally, this report provides a method for predicting at least one factor that affects the success or failure of FLT3 TKI in clinical trials. Disclosures No relevant conflicts of interest to declare.
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Gameiro, Andreia, Filipe Almeida, Catarina Nascimento, Jorge Correia, and Fernando Ferreira. "Tyrosine Kinase Inhibitors Are Promising Therapeutic Tools for Cats with HER2-Positive Mammary Carcinoma." Pharmaceutics 13, no. 3 (2021): 346. http://dx.doi.org/10.3390/pharmaceutics13030346.
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Feline mammary carcinoma (FMC) is a common neoplasia in cat, being HER2-positive the most prevalent subtype. In woman’s breast cancer, tyrosine kinase inhibitors (TKi) are used as a therapeutic option, by blocking the phosphorylation of the HER2 tyrosine kinase domain. Moreover, clinical trials demonstrated that TKi produce synergistic antiproliferative effects in combination with mTOR inhibitors, overcoming resistance to therapy. Thus, to uncover new chemotherapeutic strategies for cats, the antiproliferative effects of two TKi (lapatinib and neratinib), and their combination with a mTOR inhibitor (rapamycin), were evaluated in FMC cell lines (CAT-M, FMCp and FMCm) and compared with a human breast cancer cell line (SkBR-3). Results revealed that both TKi induced antiproliferative effects in all feline cell lines, by blocking the phosphorylation of EGFR members and its downstream effectors. Furthermore, combined treatments with rapamycin presented synergetic antiproliferative effects. Additionally, the DNA sequence of the her2 TK domain (exons 18 to 20) was determined in 40 FMC tissue samples, and despite several mutations were found none of them were described as inducing resistance to therapy. Altogether, our results demonstrated that TKi and combined protocols may be useful in the treatment of cats with mammary carcinomas, and that TKi-resistant FMC are rare.
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Yau, Thomas Cheung, Vikki Tang, Jess Chan, et al. "Outcomes of tyrosine kinase inhibitors (TKI) after immunotherapy in unresectable or advanced hepatocellular carcinoma (HCC) patients." Journal of Clinical Oncology 37, no. 4_suppl (2019): 361. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.361.
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361 Background: The outcomes of tyrosine kinase inhibitor(TKI) treatment after immune checkpoint inhibitors (PD-1i, PD-L1i, CTLA-4i) in unresectable/advanced HCC population is largely unknown. Methods: Retrospective analysis of advanced HCC patients treated with immune checkpoint inhibitors followed by TKI therapy at Queen Mary Hospital, Hong Kong were reviewed for the outcomes. Patients received locoregional therapy immediately after immunotherapy were excluded. Results: From January 2016 to July 2018, 30 HCC patients (83% of HBV, 80% of Child Pugh A, 83% of EHS/ MVI, median AFP=1,353ng/mL) who received TKI (11 lenvatinib, 10 sorafenib, 6 regorafenib, 3 axitinib) after immunotherapy were identified. TKI post-immunotherapy ("index TKI") was administered as third-line or beyond in 70% of patients. At the time of analysis (September 2018), median duration of index TKI was 72 days (IQR 36- 119∗) (∗3 patients were still receiving TKI). AFP declined in 53% of patients and the median change from baseline to nadir was -25% (IQR -65% to +6%). 40% of patients received subsequent systemic therapy. Median OS from index TKI was 602 days (95%CI 124-not reached; death event rate: 47%). 3 patients achieved partial response to TKI and they had at least stable disease with the previous immunotherapy. No unexpected safety issues of TKI and death related to adverse events were noted (table). Conclusions: TKI is active with good tolerabilty following immunotherapy in advanced HCC patients.[Table: see text]
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Thomas, Rintu, Shivangi Srivastava, Rajasekhara Reddy Katreddy, Jason Sobieski, and Zhang Weihua. "Kinase-Inactivated EGFR Is Required for the Survival of Wild-Type EGFR-Expressing Cancer Cells Treated with Tyrosine Kinase Inhibitors." International Journal of Molecular Sciences 20, no. 10 (2019): 2515. http://dx.doi.org/10.3390/ijms20102515.
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Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small molecule tyrosine kinase inhibitors (TKIs) is often ineffective in treating cancers harboring wild-type EGFR (wt-EGFR). TKIs are known to cause dimerization of EGFR without altering its expression level. Given the fact that EGFR possesses kinase-independent pro-survival function, the role of TKI-inactivated EGFR in cancer cell survival needs to be addressed. In this study, using wt-EGFR-expressing cancer cells A549 (lung), DU145 (prostate), PC3 (prostate), and MDA-MB-231 (breast), we characterized the TKI-induced dimerization status of EGFR and determined the dependency of cells on kinase-inactivated EGFR for survival. We report that TKI-induced EGFR dimerization is dependent on palmitoylation and independent of its kinase activity, and that mutations of the cysteine residues known to be critical for EGFR’s palmitoylation abolished TKI-induced EGFR dimerization. Furthermore, TKI-induced EGFR dimerization is persistent in TKI-resistant cells, and inhibition of palmitoylation by 2-bromopalmitate, or targeted reduction of the kinase-inactivated EGFR by siRNA or by an EGFR-downregulating peptide, are lethal to TKI-resistant cancer cells. This study suggests that kinase-inactivated EGFR remains to be a viable therapeutic target for wt-EGFR cancers and that inhibiting palmitoylation or downregulating EGFR may overcome TKI resistance.
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Vladimirova, Liubov Yu, Oleg Ivanovich Kit, Irina L. Popova, and Natalya A. Abramova. "Tyrosine-kinase inhibitors (TKI) in metastatic kidney cancer (mKC) treatment." Journal of Clinical Oncology 32, no. 15_suppl (2014): e15546-e15546. http://dx.doi.org/10.1200/jco.2014.32.15_suppl.e15546.
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Slobbe, Paul, Alex J. Poot, Albert D. Windhorst, and Guus A. M. S. van Dongen. "PET imaging with small-molecule tyrosine kinase inhibitors: TKI-PET." Drug Discovery Today 17, no. 21-22 (2012): 1175–87. http://dx.doi.org/10.1016/j.drudis.2012.06.016.
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Kampa, Kerstin M., Tanja Grandl, Sandra Mueller, et al. "KIT Inhibition Affects Heat Shock Protein (HSP) Activity: A Potential Rescue Mechanism towards KIT Tyrosine Kinase Inhibition and a Rationale for Dual KIT/HSP Inhibition." Blood 114, no. 22 (2009): 2753. http://dx.doi.org/10.1182/blood.v114.22.2753.2753.
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Abstract Abstract 2753 Poster Board II-729 Activating mutations of the KIT class III receptor tyrosine kinases are associated with core binding factor leukemias (CBF AML), systemic mastocytosis (SM), gastrointestinal stromal tumors (GIST), melanomas, seminoma/dysgerminoma and sinonasal natural killer/T-cell non-Hodgkin lymphoma. Despite the encouraging therapeutic potential of KIT-tyrosine kinase inhibitors (TKI), resistance leading to disease progression occurs in many patients, specifically after TKI monotherapy. We hypothesized that resistance to therapy is promoted by activation of alternative signaling pathways which override TKI inhibition. To explore the downstream signaling pathways of class III receptor tyrosine kinases, we performed unbiased phoshoproteomic analyses of mutant FLT3 or KIT leukemia and mastocytosis cell lines before and after TKI treatment. Tantalizingly, immunoaffinity purification of phosphopeptides followed by tandem mass spectrometry following KIT-inhibition with Imatinib at IC90 (100nM) revealed a significant upregulation of phosphorylation levels of peptides identified as members of the heat shock protein (HSP) family. Of interest, mRNA GeneChip® Array analysis of hematopoietic Ba/F3 cells transfected with either a mutant KIT isoform (D816V) or a mutant FLT3 isoform (ITD) and treated with TKI revealed significant downregulation of HSP family members in the FLT3 model – but stable mRNA levels in the KIT model. Taken together, our phosphoproteome and mRNA data suggest a protective function of HSP in mutant-KIT tumors treated with TKI. Next we studied the antiproliferative and proapoptotic effects of the HSP90 inhibitor IPI-504, a 17-AGG-derivative, in mutant-KIT cell models. IPI-504 potently inhibited proliferation and induced apoptosis with an IC50 of 0.5 up to 5μM depending on the KIT isoform. Importantly, combination of IPI-504 with TKIs resulted in potentiation of the antiproliferative and proapoptotic effects achieved by either drug alone. Antitumor efficacy in combination therapy was observed even at HSP90 inhibitor concentrations that did not display antitumor activity if administered alone. In conclusion, our model suggests that inhibition of KIT affects heat shock protein activity serving to stabilize the functionality of targeted autoactivated receptor tyrosine kinases, which provides a potential mechanism for resistance to TKI therapy. Importantly, we provide a rationale to combine TKI with (low-dose) HSP-inhibitors such as IPI-504 to optimize TKI therapy. Disclosures: Normant: Infinity: Employment.
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Kumar, Suresh, and Ritesh Agrawal. "Next Generation Tyrosine Kinase Inhibitor (TKI): Afatinib." Recent Patents on Anti-Cancer Drug Discovery 9, no. 3 (2014): 382–93. http://dx.doi.org/10.2174/1574892809666140520114928.
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Schallier, D., F. Trullemans, C. Fontaine, L. Decoster, and J. DeGreve. "1253 Tyrosine kinase inhibitor (TKI)-induced macrocytosis." European Journal of Cancer Supplements 7, no. 2 (2009): 136. http://dx.doi.org/10.1016/s1359-6349(09)70465-3.
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Yen, Hsin-Yung, Ying-Chih Liu, Nai-Yu Chen, et al. "Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition." Proceedings of the National Academy of Sciences 112, no. 22 (2015): 6955–60. http://dx.doi.org/10.1073/pnas.1507329112.
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Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR undergoes conformational changes to dimerize, resulting in kinase activation and autophosphorylation and downstream signaling. Tyrosine kinase inhibitors (TKIs) have been used to treat lung cancer by inhibiting EGFR phosphorylation. Previously, we demonstrated that EGFR sialylation suppresses its dimerization and phosphorylation. In this report, we further investigated the effect of sialylation on the phosphorylation profile of EGFR in TKI-sensitive and TKI-resistant cells. Sialylation was induced in cancer progression to inhibit the association of EGFR with EGF and the subsequent autophosphorylation. In the absence of EGF the TKI-resistant EGFR mutant (L858R/T790M) had a higher degree of sialylation and phosphorylation at Y1068, Y1086, and Y1173 than the TKI-sensitive EGFR. In addition, although sialylation in the TKI-resistant mutants suppresses EGFR tyrosine phosphorylation, with the most significant effect on the Y1173 site, the sialylation effect is not strong enough to stop cancer progression by inhibiting the phosphorylation of these three sites. These findings were supported further by the observation that the L858R/T790M EGFR mutant, when treated with sialidase or sialyltransferase inhibitor, showed an increase in tyrosine phosphorylation, and the sensitivity of the corresponding resistant lung cancer cells to gefitinib was reduced by desialylation and was enhanced by sialylation.
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Fatima, Kaynat, Syed Tasleem Raza, Ale Eba, Sanchita Srivastava, and Farzana Mahdi. "A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA." Era's Journal of Medical Research 7, no. 2 (2020): 205–11. http://dx.doi.org/10.24041/ejmr2020.34.
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The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.
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Piloto, Obdulio, Melissa Wright, Patrick Brown, Kyu-Tae Kim, Mark Levis, and Donald Small. "Prolonged Exposure to FLT3 Inhibitors Leads to Resistance Via Activation of Parallel Signaling Pathways." Blood 108, no. 11 (2006): 1380. http://dx.doi.org/10.1182/blood.v108.11.1380.1380.
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Abstract A number of tyrosine kinase inhibitors (TKI) have been developed to treat a variety of malignancies. However, continuous treatment with TKIs may select for resistant clones as has been seen with Gleevec treatment of CML. To study resistance to TKIs targeting FLT3, a receptor tyrosine kinase that is frequently mutated in AML, we developed resistant human cell lines through prolonged co-culture with FLT3 TKIs. Both FLT3 TKI sensitive and resistant cell lines exhibit inhibition of FLT3 phosphorylation upon FLT3 TKI treatment. However, FLT3 TKI resistant cell lines and primary samples often show continued activation of downstream PI3K/Akt and/or Ras/MEK/MAPK signaling pathways as well as continued expression of genes involved in FLT3-mediated cellular transformation. Inhibition of these pathways restores partial sensitivity to FLT3 TKIs. Mutational screening of FLT3 TKI resistant cell lines and primary samples failed to reveal any mutations in FLT3 or in 100 kinases/phosphatases tested but did reveal activating N-Ras mutations that were not present in the parental FLT3 TKI sensitive cell line. Taken together, these data indicate that FLT3 TKI resistant cells most frequently become FLT3 independent due to activation of parallel signaling pathways that provide compensatory survival / proliferation signals when FLT3 is inhibited. IMC-EB10, an unconjugated monoclonal antibody against FLT3, is still cytotoxic to FLT3 TKI resistant clones in vivo. An approach combining FLT3 TKIs with anti-FLT3 antibodies may prove superior and result in reduced chances of developing resistance.
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Kyle, Rachel MA, Alejandro Lazo-Langner, Anargyros Xenocostas, et al. "Patient Preferences for Stopping Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia." Blood 120, no. 21 (2012): 4274. http://dx.doi.org/10.1182/blood.v120.21.4274.4274.
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Abstract Abstract 4274 Introduction: After the introduction of tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) became the first cancer with a medical treatment that affords patients a normal lifespan. First-line treatment includes one of the three approved TKIs with regular molecular monitoring. Several reports have described individuals stopping imatinib and remaining in complete molecular response (CMR). There are currently several ongoing randomized clinical trials evaluating the safety of stopping TKI treatment in patients with a sustained CMR. In 2010 the preliminary results from the STIM (STop IMatinib) trial (Mahon, Lancet Oncology), were published. Results showed that 38% of patients had a sustained CMR after 2 years off TKI treatment and the remaining 62% who relapsed responded to restarting their previous TKI treatment. As this research will potentially influence clinical practice in the near future, we aimed to explore patient reactions, preferences and risk acceptability of stopping TKI treatment. With that in mind we conducted an interview-assisted survey of CML patients seen at a single tertiary care centre. Methods: We included CML patients with cytogenetic and molecular Ph+ chromosome confirmation currently being treated with a TKI. Patients were approached during regular follow-up appointments. A survey was conducted through structured interviews using a standard form. Patients' preferences were explored through a case-based scenario using Visual Analog Scales ranging from 0 to 100% or 5-point Likert scales ranging from “absolutely stop” (1) to “absolutely not stop” (5). A trained interviewer asked the survey questions and was able to clarify questions that were unclear to the participant. Data was analyzed using proportions for dichotomous variables and medians and interquartile ranges for continuous variables. 95% confidence intervals for the proportions were calculated using the normal approximation interval. Results: Interviews were conducted between June and August 2012 at the London Regional Cancer Program (LRCP) in London, Ontario. 38 out of 40 (95%) CML patients approached completed the survey. Mean age of participants was 51 years old and 47% were male. 37% of participants had not finished high school and another 37% had completed college/university/trade school. Participants had a diagnosis of CML for an average of 50 months prior to enrollment. The majority (21/38 participants, 55%) were taking imatinib, with 11 (29%) on nilotinib and 6 (16%) on dasatinib. 71% (95% CI ± 14%) of the participants said that taking their medications daily was “simple and easy and they were able to remember 100% of the time.” 26% reported daily side effects while 24% reported never experiencing side effects from their TKI. 79% (95% CI ± 13%) of the participants said that they have never considered stopping the drug based on the side effects that they experience. 61% of participants responded that fear of the disease going out of control keeps them taking their TKI (95% CI ± 16%), whereas 34% responded that it is their doctor's strong recommendation that motivates them (95% CI ± 15%). When asked what risk of relapse after stopping the TKI they would be willing to accept the median response was a 25% relapse rate (interquartile range 20–50). When responding to the same question after informing the participant that all patients have responded to restarting TKIs the median response increased to a 35% relapse rate (interquartile range 20–60). When given a relapse rate of 20% and a likert scale ranging from “absolutely stop” to “absolutely not stop,” the median response was “likely stop” with the 25th and 75th interquartile ranges being “absolutely stop” and “likely not stop” respectively. When the published relapse rate of 60% was given, however, the median was “likely not stop” with the 25th interquartile range at “neutral to stopping” and 75thinterquartile range at “absolutely not stop.” Discussion: This data suggests that the majority of participants perceive little difficulty with taking their TKI regularly and have never considered stopping it. Two major determinants on participant's decisions are fear of the disease going out of control and their physician's influence. Further, with the published rate of relapse after stopping TKI treatment the majority of individuals would choose to continue taking their medications for CML. Disclosures: Lazo-Langner: LeoPharma: Honoraria; Pfizer: Honoraria. Hsia:Novartis: Participant in Advisory Board Other.
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Tarver, Theodore C., Jason E. Hill, Leena Rahmat, et al. "Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations." Blood Advances 4, no. 3 (2020): 514–24. http://dx.doi.org/10.1182/bloodadvances.2019000919.
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Abstract Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at &lt;200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.
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Deininger, Michael. "Targeting Tyrosine Kinase Receptors." Blood 122, no. 21 (2013): SCI—25—SCI—25. http://dx.doi.org/10.1182/blood.v122.21.sci-25.sci-25.
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Abstract Protein tyrosine kinases (PTKs) regulate cell growth and other key functions. Constitutive PTK activation by somatic mutations, overexpression, or abnormal upstream signaling is characteristic of many cancers, including hematologic malignancies, providing a rationale for therapeutically targeting PTKs with small molecules. Imatinib, an ATP-competitive inhibitor of BCR-ABL1, the PTK causal to chronic myeloid leukemia (CML), established a paradigm for tyrosine kinase inhibitors (TKIs) as cancer therapeutics. Although a relatively weak inhibitor, imatinib is effective in most patients with chronic phase CML (CML-CP), while responses are transient in blastic phase (CML-BP). Point mutations in the BCR-ABL1 kinase domain have emerged as a major mechanism of drug resistance. The more potent second-generation TKIs – dasatinib, nilotinib, and bosutinib – induce deeper and faster responses and are active against many imatinib-resistant mutants, with the exception of T315I in the gatekeeper position of the catalytic site. This problem was addressed with ponatinib, a third-generation TKI covering all single BCR-ABL1 mutants, including T315I. Ponatinib has excellent clinical activity in CML-CP patients who failed other TKIs, while responses in CML-BP are short-lived. Some patients fail ponatinib due to BCR-ABL1 compound mutations, suggesting even third-generation TKIs cannot completely prevent mutational escape by the disease-initiating kinase. Another unsolved problem is that TKIs fail to efficiently target CML stem cells, leading to recurrence of active leukemia upon discontinuation. Despite these shortcomings, TKIs have completely changed the face of CML. Unfortunately, repeating this success in other hematologic malignancies has been challenging, likely reflecting differences in disease biology as much as suboptimal design of early compounds. CML-CP represents one extreme of the spectrum, where a single genetic lesion is sufficient to produce the phenotype and the hierarchy of hematopoietic differentiation is maintained. The situation is different in acute myeloid leukemia (AML) with activating FLT3 mutations. Not only these AML cases have mutations in other genes, they typically acquire FLT3 mutations late during disease evolution, implying that the disease-initiating clone will be impervious to FLT3 inhibition. Progress has been made through successive development of more potent TKIs with improved pharmacology, leading to quizartinib. It is clear, however, that FLT3 inhibitors cannot be used as single agents if there is a curative intent and the same may be true for JAK2 inhibitors in myelofibrosis. The first approved JAK2 inhibitor, ruxolitinib, dramatically improves symptoms, but has yet to demonstrate a significant impact on the malignant clone and is certainly not curative. It remains to be seen whether this reflects the fact that JAK2 activation is not the disease–initiating event, lack of inhibitor specificity towards the mutant JAK2 kinase, or other undesirable off-target effects that may be overcome with improved drugs. A completely new chapter was opened with ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), for the treatment of chronic lymphocytic leukemia (CLL). BTK is essential for signal transduction from the B-cell receptor (BCR). No activating mutations in BTK have been identified in lymphoma or CLL, but constitutive BCR signaling is critical to CLL cell survival in the microenvironment. Early studies show excellent clinical activity in patients with advanced CLL, although many responses are incomplete; much like the imatinib responses in late CML-CP. Ibrutinib may have a similarly profound effect upon CLL as imatinib on CML, but perhaps also similar limitations, such as the inability to eradicate residual leukemia; this of course needs to be tested in frontline studies. TKIs have had a significant albeit uneven impact upon treatment paradigms in hematologic malignancies. Future progress will involve optimizing compounds in terms of potency, selectivity, and pharmacokinetics. Allosteric inhibitors may add to the armamentarium. From the target perspective, it is likely that most activated kinase alleles have been discovered and the focus should shift to identification of disease-critical unmutated kinases. Lastly, identifying synthetically lethal inhibitor combinations will be critical to fully exploit the potential of TKI therapy. Disclosures: Deininger: BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; ARIAD: Consultancy, Membership on an entity’s Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CELGENE: Research Funding; GENZYME: Research Funding; INCYTE: Consultancy, Membership on an entity’s Board of Directors or advisory committees; GILEAD: Research Funding.
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Shojaee, Seyedmehdi, Maike Buchner, Srividya Swaminathan, et al. "Negative Feedback Signaling Enables Leukemic Transformation by Oncogenic Tyrosine Kinases." Blood 120, no. 21 (2012): 1352. http://dx.doi.org/10.1182/blood.v120.21.1352.1352.
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Abstract Abstract 1352 Background: Oncogenic tyrosine kinases drive malignant transformation in large subsets of hematological malignancies (e.g. BCR-ABL1, FLT3ITD) and are often associated with poor clinical outcome. Current efforts to improve therapeutic options for the treatment of tyrosine kinase-driven (TKD-) leukemia are almost entirely focused on the development of more potent tyrosine kinase inhibitors (TKI) with the goal to reduce oncogenic signaling below a minimum threshold that is required for the survival of TKD-tumor cells. Here we report the surprising finding that hyperactivation of oncogenic tyrosine kinase signaling is likewise toxic when it surpasses a previously unrecognized upper threshold of maximum tolerable signaling strength. Negative feedback signaling molecules have been shown to limit tyrosine kinase signaling strength. For instance, DUSP6 and SPRY2 attenuate signaling from surface receptors and thereby function as tumor suppressors. Here we studied mechanisms of negative feedback signaling in tyrosine kinase-driven (TKD) malignancies. Results: We identified the sprouty family inhibitor of Ras signaling Spry2, the dual-specificity phosphatase Dusp6 and the Ets transcription factor Etv5 as central components of a common negative feedback signaling module that is required to calibrate signaling strength downstream of oncogenic tyrosine kinases in ALL and CML. In genetic experiments, we demonstrated that negative feedback to oncogenic tyrosine kinase signaling is required for malignant transformation and the ability of leukemia cells to form colonies. In the absence of adequate negative feedback, hyperactive tyrosine kinase signaling leads to accumulation of ROS, activation of p53/DNA damage response, cellular senescence and massive activation of the pro-apoptotic MAP kinases JNK and p38a. Studying gene expression changes by microarray analysis, RT-PCR and Western blot, we found that the DUSP6, SPRY2 and ETV5 negative feedback regulator molecules are highly expressed in a wide array of myeloid and B cell lineage leukemia. In contrast to TKD leukemia, Non-TKD leukemias lack expression of these genes and DUSP6 and SPRY2 promoters are hypermethylated. To study the function of Dusp6, Spry2 and Etv5 in a genetic mouse model of TKD-leukemia, we transduced bone marrow pre-B cells from Dusp6−/−, Spry2fl/fland Etv5−/−mice and respective wildtype controls with retroviral BCR-ABL1. Defects in one of these negative feedback mediators caused profound signaling imbalances in TKD leukemia cells. For instance, Dusp6-deficient TKD-leukemia cells rapidly underwent cellular senescence. Lack of Dusp6 and Spry2 dramatically increased cellular ROS. Owing to excessively high levels of ROS, TKD-leukemia cells lacking one of these negative feedback mediators failed to initiate colonies in semisolid agar and failed to initiate leukemia in transplant recipient mice. Inducible activation of Cre-mediated deletion of Spry2 in leukemia cells resulted in rapid cell death. Clinical relevance: To test whether negative feedback signaling molecules represent a potential target for pharmacological inhibition in the treatment of TKD-leukemia, we tested the Dusp6 small molecule inhibitor 2-benzylidene-3-(cyclohexylamino)-1-Indanone hydrochloride (BCI). At 3mmol/l, BCI induces massive accumulation of ROS and subsequent cell death in 5 patient-derived cases of Ph+ ALL including two cases with T315I mutation. To test in vivo efficacy of BCI, patient-derived Ph+ ALL cells with T315I were xenografted into NOD/SCID recipient mice. Mice were treated ten times with either vehicle or 25 mg/kg BCI (i.p.). In agreement with in vitro results, treatment with BCI resulted in significant prolongation of overall survival compared to standard TKI-treatment (BCI vs TKI Nilotinib p=0.008). Conclusion: Our studies identify negative feedback mediators including DUSP6, Spry2 and ETV5 as a novel therapeutic targets in TKD-leukemia, e.g. Ph+ ALL. Pharmacological inhibition of negative feedback signaling represents a fundamentally novel and powerful approach to increase oncogenic signaling beyond a tolerable threshold, thus causing excessive accumulation of ROS and subsequent cell death. Normal cells lacking oncogenic tyrosine kinase signaling are spared in this approach since they do not harbor an oncogenic tyrosine kinase and are not prone to excessive signaling strength. Disclosures: No relevant conflicts of interest to declare.
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Cortes, Jorge, Elias Jabbour, Hagop Kantarjian, et al. "Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors." Blood 110, no. 12 (2007): 4005–11. http://dx.doi.org/10.1182/blood-2007-03-080838.
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AbstractDasatinib and nilotinib are potent tyrosine kinase inhibitors (TKIs) with activity against many imatinib-resistant chronic myeloid leukemia (CML) clones with BCR-ABL kinase domain (KD) mutations, except T315I. We assessed for changes in the BCR-ABL KD mutation status in 112 patients with persistent CML who received a second-generation TKI after imatinib failure. Sixty-seven different KD mutations were detected before the start of therapy with a second TKI, with T315I seen in 15%. Equal numbers of patients received nilotinib or dasatinib following imatinib, and 18 received 3 TKIs. Response rates were similar for patients with and without mutations, regardless of mutation site except for T315I. Overall, 29 patients (26%) developed new KD mutations after therapy with a second (n = 24) or third (n = 5) TKI, but only 4 (4%) developed T315I. In 73% of cases, the KD mutations that persisted or developed following switch to new TKI were at sites also found in prior in vitro TKI mutagenesis assays. Although there is only a mild increase in mutation frequency with sequential TKI treatment, novel mutations do occur and mutation regression/acquisition/persistence generally reflects the in vitro differential sensitivity predicted for each TKI. In this study, there was no marked increase in development of T315I.
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Britt, Christopher J., and Jonathon O. Russell. "Tyrosine Kinase Inhibitor Use and Wound Healing in Tracheoesophageal Punctures." Ear, Nose & Throat Journal 98, no. 8 (2019): 510–12. http://dx.doi.org/10.1177/0145561319839805.
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Tyrosine kinase inhibitors (TKIs) aid in prolonging life in patients with advanced locoregional thyroid malignancy. Such patients may undergo total laryngectomy for local disease control and tracheoesophageal puncture (TEP) for speech rehabilitation. Enlargement of TEP fistulas is usually attributed to wound healing issues and leads to major complications. Four laryngectomies with TEP were performed between 2015 and 2016 and subsequently placed on a TKI. Three patients developed a complication after TKI treatment, and 2 patients had a tracheoesophageal fistula. Patients should be counseled about possible wound healing risks associated with TKIs.
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Mohanavelu, Prahathishree, Mira Mutnick, Nidhi Mehra, et al. "Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia." Cancers 13, no. 7 (2021): 1643. http://dx.doi.org/10.3390/cancers13071643.
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Tyrosine kinase inhibitors (TKIs) are the frontline therapy for BCR-ABL (Ph+) chronic myeloid leukemia (CML). A systematic meta-analysis of 43 peer-reviewed studies with 10,769 CML patients compared the incidence of gastrointestinal adverse events (GI AEs) in a large heterogeneous CML population as a function of TKI type. Incidence and severity of nausea, vomiting, and diarrhea were assessed for imatinib, dasatinib, bosutinib, and nilotinib. Examination of combined TKI average GI AE incidence found diarrhea most prevalent (22.5%), followed by nausea (20.6%), and vomiting (12.9%). Other TKI GI AEs included constipation (9.2%), abdominal pain (7.6%), gastrointestinal hemorrhage (3.5%), and pancreatitis (2.2%). Mean GI AE incidence was significantly different between TKIs (p < 0.001): bosutinib (52.9%), imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). Diarrhea was the most prevalent GI AE with bosutinib (79.2%) and dasatinib (28.1%), whereas nausea was most prevalent with imatinib (33.0%) and nilotinib (13.2%). Incidence of grade 3 or 4 severe GI AEs was ≤3% except severe diarrhea with bosutinib (9.5%). Unsupervised clustering revealed treatment efficacy measured by the complete cytogenetic response, major molecular response, and overall survival is driven most by disease severity, not TKI type. For patients with chronic phase CML without resistance, optimal TKI selection should consider TKI AE profile, comorbidities, and lifestyle.
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Williams, Allen, Li Li, Bao Nguyen, Patrick Brown, Mark J. Levis, and Donald Small. "Statin Treatment Prevents FLT3 Glycosylation and Overcomes Resistance to FLT3 Tyrosine Kinase Inhibitors." Blood 118, no. 21 (2011): 1421. http://dx.doi.org/10.1182/blood.v118.21.1421.1421.
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Abstract Abstract 1421 FLT3 is a receptor tyrosine kinase that is expressed on hematopoietic stem and progenitor cells where it functions in cell differentiation, survival and proliferation. It is also one of the most frequently mutated genes in acute myeloid leukemia (AML), and has thus become a target for modulation by the use of FLT3 tyrosine kinase inhibitors (TKI). Unfortunately, clinical resistance emanating via several different mechanisms has limited the potential benefit of FLT3 TKI. Some of these include FLT3 mutations that reduce drug binding, elevated FLT3 ligand (FL) levels that shift the dose-response curve and activation of parallel signaling pathways. These all pose major challenges to TKI effectiveness that must be overcome to improve patient outcomes. Since FLT3 is dependent upon N-linked glycosylation for its maturation and surface localization, we sought to determine whether statins might disrupt FLT3 signaling. Statins inhibit the mevalonate pathway and reduce levels of all ensuing end-products including dolichol, which transfers preassembled oligosaccharides onto nascent polypeptides. Here, we demonstrate by Western blotting that statins can indeed prevent complex FLT3 glycosylation, thus leading to loss of surface receptor expression. Immunofluorescence microscopy confirms a reduction in surface localization and a concomitant increase in intracellular FLT3/ITD accumulation. Interestingly, this aberrant localization was associated with increased STAT5 activation while inhibiting both MAP kinase and AKT phosphorylation. We have extended our previous findings that statins are cytotoxic to mutant FLT3 expressing cell lines to examine whether they are also able to overcome the resistance mechanisms discussed above. We show that the following mechanisms of resistance could be circumvented by fluvastatin. First, stimulation of BaF3 FLT3/ITD cells with exogenous FL at physiologic concentrations induces a three-fold increase in the IC50 for inhibition of phosphorylated FLT3/ITD by the FLT3 TKI lestaurtinib. Pretreatment with fluvastatin for 24 h eliminated surface FLT3/ITD: FL interactions and restored the potency of lestaurtinib. Secondly, resistance to another clinical FLT3 TKI, sorafenib, caused by the FLT3/ITD N676K or D835Y mutations increased the IC50 from 5 nM for BaF3/ITD cells to 30 nM and >50 nM, respectively. In contrast, both of these mutants remained just as sensitive to treatment with fluvastatin as were the BaF3/ITD cells (approx. IC50 of 0.2 μM). A third mechanism of resistance that can be circumvented by fluvastatin is the over expression and/or activation of alternative pathways that can compensate for inhibited FLT3. A model of this is rescue of BaF3 FLT3/ITD cell lines from FLT3 TKI-mediated cytotoxicity by stimulation with IL-3. When this cell line is stimulated with IL-3, fluvastatin is able to inhibit activation of STAT5, AKT and MAP kinase caused by the IL-3 receptor, as well as FLT3/ITD signaling, leading to cell death. Fluvastatin was also effective in other cell lines expressing constitutively activated FLT3 (Molm-14, MV4;11, HB1119 and SEM-K2 cells) and in other cell lines in which glycosylated transmembrane receptors drive proliferation (mutant c-Kit in Kasumi cells) but not in cells that rely upon intracellular kinases (BCR-ABL in K562 cells). Importantly, fluvastatin also reduced FLT3 glycosylation in and was cytotoxic to primary AML patient samples harboring FLT3/ITD mutations at therapeutically achievable concentrations (1 μM). Finally, fluvastatin reduced engraftment of BaF3 FLT3/ITD cells transplanted in syngeneic Balb/c mice and prolonged their survival. These results demonstrate that statins, a class of drugs already FDA approved, might be useful, either alone or in combination with a FLT3 TKI, in the management of FLT3 AML cases including those resistant to FLT3 TKI. Disclosures: Levis: Ambit Biosciences, Inc: Consultancy.
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Hardwick, Rhiannon N., Marina Snellings, Brian C. Ferslew, Yang Lu, and Kim L. R. Browuer. "Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)." ADMET and DMPK 4, no. 4 (2016): 302. http://dx.doi.org/10.5599/admet.4.4.322.
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<p class="PaperKeywordTitle">Tyrosine and aurora kinases are important effectors in signal transduction pathways that are often involved in aberrant cancer cell growth. Tyrosine (TKI) and aurora (AKI) kinase inhibitors are anti-cancer agents specifically designed to target such signaling pathways through TKI/AKI binding to the ATP-binding pocket of kinases thereby leading to diminished kinase activity. Some TKIs have been identified as inhibitors of ATP-binding cassette (ABC) transporters such as P-glycoprotein and breast cancer resistance protein (BCRP), which are commonly upregulated in malignant cells. TKI/AKIs have been investigated as ABC transporter inhibitors in order to facilitate the accumulation of concomitantly administered chemo-therapeutics within cancer cells. However, ABC transporters are prominently expressed in the liver and other eliminating organs, and their inhibition has been linked to intracellular accumulation of drugs, altered disposition, and toxicity. The potential for TKIs/AKIs to inhibit other important hepatic efflux transporters, particularly multidrug resistance-associated proteins (MRPs), remains unknown. The aim of the current study was to compare the inhibitory potency of 20 selected TKI/AKIs against MRP4 and BCRP through the use of inverted membrane vesicle assays. Relative IC<sub>50 </sub>values were estimated by determining TKI/AKI inhibition of MRP4-mediated [<sup>3</sup>H]-dehydroepiandrosterone sulfate uptake and BCRP-mediated [<sup>3</sup>H]-estrone sulfate uptake. To provide insight to the clinical relevance of TKI/AKI inhibition of ABC efflux transporters, the ratio of the steady-state maximum total plasma concentration (C<sub>ss</sub>) to the IC<sub>50</sub> for each compound was calculated with C<sub>ss</sub>/IC<sub>50</sub> ratio &gt;0.1 deemed potentially clinically relevant. Such analysis identified several potentially clinically relevant inhibitors of MRP4: alisertib, danusertib, erlotinib, lapatinib, neratinib, nilotinib, pazopanib, sorafenib, and tozasertib. The potentially clinically relevant inhibition of BCRP was much more extensive and included alisertib, barasertib, danusertib, enzastaurin, erlotinib, gefitinib, imatinib, neratinib, nilotinib, pazopanib, selumetinib, sorafenib, sunitinib, tozasertib, and vandetanib. These findings indicate the significant potential for TKI/AKIs to inhibit multiple ABC efflux transporters. The resulting inhibition data could provide insight regarding the clinical interpretation of pharmacokinetic/pharmacodynamic outcomes when TKI/AKIs are administered concomitantly with additional chemotherapeutic agents.</p>
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Naglieri, Emanuele. "Management of toxicity in patients treated with tyrosine kinase inhibitors (TKI)." European Journal of Cancer Supplements 6, no. 14 (2008): 42–45. http://dx.doi.org/10.1016/j.ejcsup.2008.06.012.
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George, Tiffany L., Sandip H. Patel, Tzu-Fei Wang, Sherry Mori-Vogt, Edmund Folefac, and Ming Yin. "Analysis of bleeding risk with concurrent treatment of VEGFR tyrosine kinase inhibitors (TKIs) and factor Xa inhibitors." Journal of Clinical Oncology 38, no. 15_suppl (2020): e19305-e19305. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e19305.
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e19305 Background: Tyrosine kinase inhibitors (TKIs) of vascular endothelial growth factor receptor (VEGFR) may interfere with the coagulation system making patients susceptible to both hemorrhage and thromboembolism. Some cancer patients require dual treatment with VEGFR TKIs and factor Xa inhibitors. However, the safety of such combination treatment (e.g. bleeding risk) has not been well characterized in the literature. Methods: This retrospective study identified metastatic cancer patients who received VEGFR TKIs (pazopanib, sunitinib, sorafenib, axitinib, regorafenib, vandetanib, lenvatinib, cabozantinib, tivozanib) and Xa inhibitors (low-molecular weight heparin [LMWH] or direct oral anticoagulants [DOACs]- rivaroxaban or apixaban) from 2001 to 2018 at the Ohio State University. We assessed bleeding risks of dual therapy vs factor Xa inhibitors alone, using the same patients as self-controls. We defined bleeding based on criteria from the International Society on Thrombosis and Haemostasis. Fisher’s exact test was used to compare distribution of bleeding severities and the Cox model was used to analyze bleeding risk. Results: A total of 86 patients were included for analysis, with a median age of 56 (range, 34-88). The patient population was predominantly of male gender (69.7%), Caucasian race (89.3%) and renal cell cancer type (48.9%). As some patients had been on both LMWH and DOAC at different time periods, we found that 81 patients received concurrent TKI and LMWH; 19 patients had concurrent TKI and DOAC. Overall, 25 patients developed 29 clinically significant bleeding events (including 8 major bleeding) during concurrent treatment, and 15 patients developed 17 clinically significant bleeding events (4 major bleeding) during factor Xa inhibitor alone over a median follow up of 63 days. We found a statistically higher bleeding risk with concurrent treatment (HR = 2.23, 95% CI, 1.13–4.42, p = 0.02) compared with Xa inhibitor alone. In a stratified analysis, concurrent VEGFR TKI plus LMWH or DOAC both showed a strong trend for elevated bleeding risk. Although there were increased bleeding events with concurrent treatment, there was no significant difference in the proportion of major bleeding (27.6% vs 23.5%, p = 0.76). Median time to first bleeding event was 56 days for concurrent therapy and 72 days for Xa inhibitor alone. Conclusions: Concurrent treatment of VEGFR TKI and factor Xa inhibitors is associated with significantly increased bleeding risk when compared with factor Xa inhibitors alone in metastatic cancer patients.
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Mallampati, Saradhi, Xiaohong Leng, Haiqing Ma, et al. "Tyrosine kinase inhibitors induce mesenchymal stem cell–mediated resistance in BCR-ABL+ acute lymphoblastic leukemia." Blood 125, no. 19 (2015): 2968–73. http://dx.doi.org/10.1182/blood-2014-05-576421.
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Kindler, Thomas, Daniel B. Lipka, and Thomas Fischer. "FLT3 as a therapeutic target in AML: still challenging after all these years." Blood 116, no. 24 (2010): 5089–102. http://dx.doi.org/10.1182/blood-2010-04-261867.
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Abstract Mutations within the FMS-like tyrosine kinase 3 (FLT3) gene on chromosome 13q12 have been detected in up to 35% of acute myeloid leukemia (AML) patients and represent one of the most frequently identified genetic alterations in AML. Over the last years, FLT3 has emerged as a promising molecular target in therapy of AML. Here, we review results of clinical trials and of correlative laboratory studies using small molecule FLT3 tyrosine kinase inhibitors (TKIs) in AML patients. We also review mechanisms of primary and secondary drug resistance to FLT3-TKI, and from the data currently available we summarize lessons learned from FLT3-TKI monotherapy. Finally, for using FLT3 as a molecular target, we discuss novel strategies to overcome treatment failure and to improve FLT3 inhibitor therapy.
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Long, Jun, Ming-Yuan Jia, Wei-Yue Fang, et al. "FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia." Blood 135, no. 17 (2020): 1472–83. http://dx.doi.org/10.1182/blood.2019003538.
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Abstract Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient–derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase–activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation–harboring leukemias.
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Garmezy, Benjamin, Tian Zhang, Andrew Leonard Laccetti, et al. "Combination therapy with nivolumab and tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma." Journal of Clinical Oncology 38, no. 15_suppl (2020): e17090-e17090. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e17090.
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e17090 Background: Two immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations are FDA-approved for patients (pts) with metastatic renal cell carcinoma (mRCC). Here we present a multicenter off-protocol experience with IO/TKI combinations after progression on monotherapy. Methods: We performed a retrospective analysis of pts with mRCC who received combination non-FDA approved off-protocol IO/TKI combination therapy from 11/2015 – 1/2019 at MD Anderson Cancer Center and Duke Cancer Institute. Results: 48 pts met criteria for study inclusion. At therapy start: median (med) age 65 years; 75% clear cell histology; 68.8% IMDC intermediate risk (20.8% favorable, 10.4% poor); 81.3% prior nephrectomy; med metastatic sites: 2; med prior systemic treatments: 2; most common metastatic sites: lung (58.3%), lymph node (52.1%), and bone (43.8%). Pts received nivolumab (nivo) in combination with the following: cabozantinib (n = 24, 50%), pazopanib (13, 27.1%), axitinib (6, 12.5%), lenvatinib (2, 4.2%), ipilimumab/cabozantinib (3, 6.3%). Med PFS was 13.7 months and med OS was not reached. The two largest cohorts received nivo + cabozantinib (N+C; med dose 40 mg daily) or nivo + pazopanib (N+P; med dose 400 mg daily). The N+C cohort had higher med metastatic sites (3 vs 2) and was more pretreated with agents unique to their IO/TKI combination (med 2 vs 0). In the N+P group, more pts had started on TKI prior to addition of nivo at progression (69.2% vs 45.8%), and fewer had IO monotherapy with TKI addition (30.8% vs 50%). With a med follow up of 14.0 months after combination start, the N+C cohort had a med PFS of 7.3 months (initiated TKI first: 4.8, IO first: 8.2) and med OS of 18.2 months (TKI first: 11.8, IO first: 24.3). The N+P cohort had med follow up of 20.5 months after combination, med PFS of 21.3 months (TKI first: 16.5, IO first: 21.8), and med OS was not reached. In the N+C group, 87.5% experienced any grade adverse event (AE), most common included fatigue (79.2%), diarrhea (42.7%), nausea (29.2%), hypertension (29.2%), and weight loss (25.0%). In the N+P group, 92.3% experienced any grade AE, including fatigue (76.9%), hypertension (38.5%), diarrhea (30.8%), nausea (30.8%), and weight loss (30.8%). There were no grade ≥3 AEs. Conclusions: Slow disease progression on nivo or TKI may be safely controlled with addition of IO/TKI therapy. Med PFS after addition of nivo to TKI appears similar (N+C) and improved (N+P) compared to nivo monotherapy (Checkmate-025). Med PFS after addition of TKI to IO was also similar (N+C) and improved (N+P) compared to historical controls.
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Carofiglio, Francesca, Antonio Lopalco, Angela Lopedota, et al. "Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML." International Journal of Molecular Sciences 21, no. 12 (2020): 4469. http://dx.doi.org/10.3390/ijms21124469.
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The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy.
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Miller, Jacob A., Ehsan H. Balagamwala, Lilyana Angelov, et al. "Spine stereotactic radiosurgery with concurrent tyrosine kinase inhibitors for metastatic renal cell carcinoma." Journal of Neurosurgery: Spine 25, no. 6 (2016): 766–74. http://dx.doi.org/10.3171/2016.4.spine16229.
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OBJECT Systemic control of metastatic renal cell carcinoma (mRCC) has substantially improved with the development of VEGF, mTOR, and checkpoint inhibitors. The current first-line standard of care is a VEGF tyrosine kinase inhibitor (TKI). In preclinical models, TKIs potentiate the response to radiotherapy. Such improved efficacy may prolong the time to salvage therapies, including whole-brain radiotherapy or second-line systemic therapy. As the prevalence of mRCC has increased, the utilization of spine stereotactic radiosurgery (SRS) has also increased. However, clinical outcomes following concurrent treatment with SRS and TKIs remain largely undefined. The purpose of this investigation was to determine the safety and efficacy of TKIs when delivered concurrently with SRS. The authors hypothesized that first-line TKIs delivered concurrently with SRS significantly increase local control compared with SRS alone or TKIs alone, without increased toxicity. METHODS A retrospective cohort study of patients undergoing spine SRS for mRCC was conducted. Patients undergoing SRS were divided into 4 cohorts: those receiving concurrent first-line TKI therapy (A), systemic therapy–naïve patients (B), and patients who were undergoing SRS with (C) or without (D) concurrent TKI treatment after failure of first-line therapy. A negative control cohort (E) was also included, consisting of patients with spinal metastases managed with TKIs alone. The primary outcome was 12-month local failure, defined as any in-field radiographic progression. Multivariate competing risks regression was used to determine the independent effect of concurrent first-line TKI therapy upon local failure. RESULTS One hundred patients who underwent 151 spine SRS treatments (232 vertebral levels) were included. At the time of SRS, 46% were receiving concurrent TKI therapy. In each SRS cohort, the median prescription dose was 16 Gy in 1 fraction. Patients in Cohort A had the highest burden of epidural disease (96%, p < 0.01). At 12 months, the cumulative incidence of local failure was 4% in Cohort A, compared with 19%–27% in Cohorts B–D and 57% in Cohort E (p < 0.01). Multivariate competing risks regression demonstrated that concurrent first-line TKI treatment (Cohort A) was independently associated with a local control benefit (HR 0.21, p = 0.04). In contrast, patients treated with TKIs alone (Cohort E) experienced an increased rate of local failure (HR 2.43, p = 0.03). No toxicities of Grade 3 or greater occurred following SRS with concurrent TKI treatment, and the incidence of post-SRS vertebral fracture (overall 21%) and pain flare (overall 17%) were similar across cohorts. CONCLUSIONS The prognosis for patients with mRCC has significantly improved with TKIs. The present investigation suggests a local control benefit with the addition of concurrent first-line TKI therapy to spine SRS. These results have implications in the oligometastatic setting and support a body of preclinical radiobiological research.
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Burchert, Andreas. "Maintenance therapy for FLT3-ITD-mutated acute myeloid leukemia." Haematologica 106, no. 3 (2021): 664–70. http://dx.doi.org/10.3324/haematol.2019.240747.
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FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. Its expression in acute myeloid leukemia (AML) is associated with a poor prognosis. Due to this, the development of tyrosine kinase inhibitors (TKI) blocking FLT3-ITD became a rational therapeutic concept. This review describes key milestones in the clinical development of different FLT3-specific TKI with a particular focus on FLT3-TKI maintenance therapy in remission after allogeneic hematopoietic stem cell transplantation (HCT). Recent evidence from randomized trials using sorafenib in FLT3-ITD mutated AML provided a proof of concept that targeted post-HCT maintenance therapy could become a new treatment paradigm in AML.
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Ergün Barış, Kaya, and Şener Yusuf Ziya. "Hypertensive toxicity of thyrosine kinase inhibitors; Friend or Foe?" Annals of Clinical Hypertension 5, no. 1 (2021): 001–2. http://dx.doi.org/10.29328/journal.ach.1001025.
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Tyrosine kinase inhibitors (TKIs) are widely used in Oncology practice. Hypertension may develop during cancer treatment and TKIs are well known drugs that are associated with drug related hypertensive toxicity. TKI related hypertensive toxicity is not always the indicator of worse clinical outcomes and it may be the sign of treatment efficacy.
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Smith, Stephanie M., Himalee S. Sabnis, Rebecca Williamson Lewis, et al. "Screening practices for late effects in pediatric patients on tyrosine kinase inhibitors." Journal of Clinical Oncology 38, no. 15_suppl (2020): e22527-e22527. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e22527.
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e22527 Background: BCR-ABL tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) and chronic myeloid leukemia (CML). The off-target effects of long-term TKI use in children are poorly understood. We evaluated institutional screening practices for cardiac and endocrine late effects in those who had received TKIs at two large pediatric cancer centers. Methods: This retrospective cohort included patients diagnosed with Ph+ALL (post completion of frontline therapy) or CML at age < 21 years with ≥1 years of follow-up. Patients were censored at stem cell transplant, blast crisis, secondary neoplasm, death, or last contact. Demographics, clinical features, and incidence of screening echocardiogram (ECHO), electrocardiogram (EKG), dual-energy x-ray absorptiometry (DXA), bone age, and thyroid function (TSH) were abstracted. Descriptive statistics and incidence of screening are presented by diagnosis. Results: The cohort (n = 68) was 50% female, 28% non-Hispanic white, 24% non-Hispanic black, 24% Asian, and 19% Hispanic. CML: Patients were diagnosed at 12.9±4.6 years of age and had 6.3 (0.9-15.6) years of TKI exposure and 6.3 (0.9-15.6) years of follow-up. Imatinib was most commonly used (80%) followed by dasatinib (59%); 48% were exposed to > 1 TKI. Excluding tests at diagnosis, 48% had an ECHO and 48% had an EKG during the follow-up period. TSH, DXA and bone age were measured in 50%, 9% and 11% patients, respectively. Ph+ALL: Patients were diagnosed at 10.8±5.1 years of age and had 2.8 (0.6-11.6) years of TKI exposure and 5.7 (2.1-11.8) years of follow-up. Dasatinib was most commonly used (73%) followed by imatinib (64%); 36% were exposed to > 1 TKI. All received anthracyclines and steroids. Excluding tests at diagnosis, 91% had an ECHO and 77% had an EKG. TSH, DXA and bone age were measured in 82%, 68% and 36% patients, respectively. Conclusions: We note inconsistent cardiac and endocrine screening in patients receiving TKIs for CML and Ph+ALL. Evidence-based guidelines for long-term follow-up and structured monitoring for potential off-target effects are needed. A prospective screening study is in progress and may enhance our understanding of the prevalence of late effects of TKIs. [Table: see text]
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Breccia, Massimo, and Giuliana Alimena. "SECOND-GENERATION TYROSINE KINASE INHIBITORS (TKI) AS SALVAGE THERAPY FOR RESISTANT OR INTOLERANT PATIENTS TO PRIOR TKIs." Mediterranean Journal of Hematology and Infectious Diseases 6, no. 1 (2014): e2014003. http://dx.doi.org/10.4084/mjhid.2014.003.
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With the advent of target therapies, imatinib became the mainstay for treatment of chronic myeloid leukemia. However, despite the brilliant results obtained with this drug, more than 30% of patients discontinue therapy in long-term due to several reasons, including failure and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) are more potent drugs and have expanded inhibition against a broad spectrum of mutations resistant to imatinib. Both nilotinib and dasatinib have demonstrated in vitro and in vivo clinical activity against different types of mutations and various forms of resistance. However, patients with T315I mutation do not obtain an advantage from these drugs and a third generation inhibitor ponatinib, a pan-BCR drug, was tested with significant results. In this review, we report the results of second- and third-generation TKIs tested as second or third line therapy in patients resistant and/or intolerant to previous inhibitors.
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Patel, Sandip, Tiffany George, Tzu-Fei Wang, Sherry Mori Vogt, Edmund Folefac, and Ming Yin. "Concurrent Treatment of VEGFR Tyrosine Kinase Inhibitors (TKIs) and Factor Xa Inhibitors Is Associated with Increased Bleeding Risks." Blood 134, Supplement_1 (2019): 3681. http://dx.doi.org/10.1182/blood-2019-130465.
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ABSTRACT Background: Some cancer patients with thromboembolism require dual treatment of VEGFR TKIs and factor Xa inhibitors (direct or indirect), which may contribute to increased bleeding risks. However, the safety of such combination treatment has not been well characterized in the literature or national guidelines. Methods: This is a single center retrospective study, where we identified metastatic cancer patients (renal cancer, colorectal cancer, sarcoma, etc) who received concurrent VEGFR TKIs (pazopanib, sunitinib, sorafenib, axitinib, regorafenib, vandetanib, lenvatinib or cabozantinib) and Xa inhibitors (low-molecular weight heparin [LMWH] or direct oral anticoagulants [DOACs] including rivaroxaban or apixaban) at the Ohio State University Medical Center. We assessed bleeding risks of dual therapies vs. factor Xa inhibitors alone, using the same patients as self controls. We reviewed medical charts of all identified patients for clinically significant bleeding events (defined as combined major bleeding and clinically relevant non-major bleeding by the International Society of Thrombosis and Haemostasis criteria). The Cox proportional hazard model was used to compare the differences of time to first clinically significant bleeding event between the groups of concurrent use and anticoagulant use only. Results: A total of 86 patients (26 females and 60 males) were included: 78 Caucasians, 6 African Americans, and 2 others. 81 patients had concurrent TKI and LMWH treatment; 20 patients had concurrent TKI and DOACs; and 85 patients have had been on factor Xa inhibitor alone (LMWH or DOACs) at some point. Some patients had been on both LMWH and DOACs at different time periods. Overall, there were 29 clinically significant bleeding events (including 8 major bleeding) during concurrent treatment and 17 events (4 major bleeding) during factor Xa inhibitor alone over a median follow up of 63 days (52 days for concurrent treatment and 99 days for Xa inhibitor alone). In this self-control study, concurrent treatment was associated with a statistically higher risk of clinically significant bleeding events (HR, 2.84; 95% CI, 1.43-5.64, P &lt; 0.01), which reached 37% patient population in the first 3 months, while the bleeding associated with factor Xa inhibitor alone seemed spaced out at the entire length of anticoagulation (8% by 6 months). Similar trend was found in the analysis of patient group of concurrent TKI and LMWH vs. LMWH alone (HR, 1.96; 95% CI, 0.95-4.02, P = 0.067), although significance was not reached likely due to insufficient power. Sample size was inadequate for meaningful comparison between concurrent VEGFR TKI and DOAC vs. DOAC alone. Conclusions: Concurrent treatment of VEGFR TKI and factor Xa inhibitors is associated with a significantly increased bleeding risks when compared with factor Xa inhibitors alone in patients with metastatic cancer. Disclosures No relevant conflicts of interest to declare.
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Piloto, Obdulio, Melissa Wright, Patrick Brown, Kyu-Tae Kim, Mark Levis, and Donald Small. "Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways." Blood 109, no. 4 (2006): 1643–52. http://dx.doi.org/10.1182/blood-2006-05-023804.
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Abstract Continuous treatment of malignancies with tyrosine kinase inhibitors (TKIs) may select for resistant clones (ie, imatinib mesylate). To study resistance to TKIs targeting FLT3, a receptor tyrosine kinase that is frequently mutated in acute myelogenous leukemia (AML), we developed resistant human cell lines through prolonged coculture with FLT3 TKIs. FLT3 TKI-resistant cell lines and primary samples still exhibit inhibition of FLT3 phosphorylation on FLT3 TKI treatment. However, FLT3 TKI-resistant cell lines and primary samples often show continued activation of downstream PI3K/Akt and/or Ras/MEK/MAPK signaling pathways as well as continued expression of genes involved in FLT3-mediated cellular transformation. Inhibition of these signaling pathways restores partial sensitivity to FLT3 TKIs. Mutational screening of FLT3 TKI-resistant cell lines revealed activating N-Ras mutations in 2 cell lines that were not present in the parental FLT3 TKI-sensitive cell line. Taken together, these data indicate that FLT3 TKI-resistant cells most frequently become FLT3 independent because of activation of parallel signaling pathways that provide compensatory survival/proliferation signals when FLT3 is inhibited. Anti-FLT3 mAb treatment was still cytotoxic to FLT3 TKI-resistant clones. An approach combining FLT3 TKIs with anti-FLT3 antibodies and/or inhibitors of important pathways downstream of FLT3 may reduce the chances of developing resistance.
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Radich, Jerald P., and Vivian Oehler. "Monitoring Chronic Myelogenous Leukemia in the Age of Tyrosine Kinase Inhibitors." Journal of the National Comprehensive Cancer Network 5, no. 5 (2007): 497–504. http://dx.doi.org/10.6004/jnccn.2007.0044.
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Tyrosine kinase inhibitors (TKIs) are now standard up-front therapy for chronic myeloid leukemia (CML). Patients with newly diagnosed chronic-phase CML treated with the TKI imatinib mesylate typically experience a complete cytogenetic remission. Outcomes for patients with advanced-phase disease are distinctly worse. Unfortunately, a small proportion of chronic-phase patients experience relapse during this therapy, and most with advanced-phase disease develop resistance to imatinib mesylate after months of therapy. Hematopoietic cell transplantation remains the only curative approach for CML and can salvage patients with advanced-phase disease. Therefore, physicians must carefully monitor patients with chronic-phase CML treated with TKIs so that they can undergo hematopoietic cell transplant (or treatment with another TKI or experimental therapy) before frank progression occurs. Fortunately, monitoring CML using cytogenetic and molecular methods (i.e., quantitative polymerase chain reaction) effectively defines end points that correlate highly with outcome.
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Rummelt, Christoph, Sivahari P. Gorantla, Michael Sigl та ін. "FLT3-ITD Interacts with and Phosphorylates IL-3β, and JAK1/2 Dependent IL-3β Activation Bypasses FLT3-ITD in FLT3 Kinase Independent Inhibitor Resistance in Vitro: Evidence for the Significance of IL-3β for FLT3-ITD Dependent Oncogeneic Signaling in AML." Blood 120, № 21 (2012): 2423. http://dx.doi.org/10.1182/blood.v120.21.2423.2423.
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Abstract Abstract 2423 Activating FLT3 mutations are found in 30% of AML patients. Internal tandem duplication (ITD) mutations are most common, and are associated with poor prognosis. FLT3 tyrosine kinase inhibitors (TKI) display limited activity in FLT3 mutant AML. Most patients experience primary or secondary TKI resistance. Only single cases of FLT3 kinase-dependent TKI resistance by secondary FLT3-ITD kinase domain mutations were reported. We therefore examined the mechanism of FLT3-ITD kinase-independent TKI resistance using an in vitro model. FLT3-ITD cell lines resistant to PKC412 or Sorafenib in 50% of the cases did not harbor secondary FLT3-ITD kinase domain mutations. However, 30% of these lines displayed a persistent phosphorylation of JAK2, IL-3βc and STAT5, while FLT3 phosphorylation was suppressed, indicating that these cell lines bypassed FLT3-ITD by activation of IL-3β by JAK2. Strikingly, TKI sensitive FLT3-ITD cells also displayed IL-3β phosphorylation, which in contrast to TKI resistant cells was JAK2 independent and was suppressed upon FLT3 TKI treatment. Expression of FLT3-ITD in IL-3β and JAK2 deficient g2A cells was sufficient for IL-3β phosphorylation. Co-IP experiments indicated a direct interaction of IL-3β and FLT3-ITD in TKI-sensitive and -resistant cells, which did not require interaction of IL-3β with IL-3a. This indicates that FLT3-ITD “physiologically” uses IL-3β as signaling intermediate. Mapping experiments showed that FLT3-ITD binding occurs in the membrane proximal region of IL-3β, independent of 8 tyrosines present in the cytoplasmic part. In search of the kinase bypassing FLT3-ITD in TKI-resistant cell lines, we identified an activating JAK1 mutation V658F in all TKI resistant FLT3-ITD cell lines displaying phosphorylation of JAK2, IL-3β and STAT5. JAK1 V658F is homologous to JAK2 V617F present in PV, phosphorylates IL-3β and STAT5, and confers TKI resistance in FLT3-ITD positive cells, which could be overcome by the JAK1/2 inhibitor Ruxolitinib. In summary, these data indicate that IL-3β not only mediates “physiological” FLT3-ITD dependent STAT5 activation, but also serves as a signaling module mediating JAK1/2-dependent TKI resistance. Thus, JAK inhibitors might represent an attractive therapeutic option in addition to FLT3 inhibitors in FLT3-ITD positive AML. Disclosures: Duyster: Novartis: Honoraria, Speakers Bureau. von Bubnoff:Novartis: Honoraria, Research Funding, Speakers Bureau.
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Kong, Jee Hyun, Hanna Jean Khoury, Elliott F. Winton, et al. "Outcomes of Chronic Phase Chronic Myeloid Leukemia Patients Following Tyrosine Kinase Inhibitors Dose-Reductions." Blood 128, no. 22 (2016): 3093. http://dx.doi.org/10.1182/blood.v128.22.3093.3093.
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Abstract Introduction: Tyrosine kinase inhibitors (TKI) are overall well tolerated in chronic myeloid leukemia (CML) s, but more than 30% require dose reduction or change to another TKIs due to intolerance. Impact of TKI dose-reduction on outcomes in a "real world" setting is unknown, thus, we evaluated the characteristics and outcomes of chronic phase (CP)-CML patients who received doses of TKI lower than the label/FDA recommendation. Method: CP-CML with at least 12 months of follow-up, with ISBCR/ABL1 available after dose reduction were selected. Last TKI was defined as TKI which were taken at the last follow up visit or before disease progression to accelerated (AP) or blast phase (BP). FDA approved doses of imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) were 400mg, 100mg, 600mg (300mg BID), 500mg, and 45mg, respectively . Results: Between January 2005 and April 2016, 173 CP-CML patients, started IM (75%), DAS (18%) NIL (5%) and PON, BOS on clinical trial in 2%. Overall Fifty-eight (33.5%) patients had TKI dose reduction. IM (n=15) dose was reduced to 75% (range, 25-75), DAS (n=15) to 50% (range, 20-80), NIL (n=15) to 50% (range, 13-67), BOS (n=15) to 80% (range, 40-80) and PON (n=15) to 33% (range, 33-67). Median age for patients that received dose-reduced TKI was 55 (range, 18-88), and 27% received > 3 prior TKIs. With a median follow up of 53.6 (range 13.4-183.7) months, only 1 progressed to AP, and none to BP. Overall 60% achieved MMR. Among 35 patients who achieved MMR before dose reduction, MMR was maintained in 25 (71.4%) for a median of 17.2 (2-97.9) months from dose-reduction. CMR was achieved in patients on a maintenance dose of IM, 100mg QD (n=8); DAS, 20mg QD (n=4); NIL 300mg QD (n=3) and BOS, 200mg QD (n=3). Conclusion: Similar to data reported from clinical trials, TKI dose reduction appears to be safe and associated with high response rates. This data confirms that the minimal effective dose for each TKI remains to be defined. Disclosures Heffner: Pharmacyclics: Research Funding; AbbVie: Research Funding; Millennium: Research Funding; Celgene: Research Funding. Jillella:Leukemia Lymphoma Society: Research Funding. Kota:Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.
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Iurlo, Alessandra, Daniele Cattaneo, Cristina Bucelli, and Massimo Breccia. "Dose Optimization of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A New Therapeutic Challenge." Journal of Clinical Medicine 10, no. 3 (2021): 515. http://dx.doi.org/10.3390/jcm10030515.
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The chronic myeloid leukemia (CML) therapeutic landscape has dramatically changed with tyrosine kinase inhibitor (TKI) development, which allows a near-normal life expectancy. However, long-term TKI exposure has been associated with persistent adverse events (AEs) which negatively impact on quality of life (QoL) and have the potential to cause significant morbidity and mortality. In clinical practice, TKI dose reduction is usually considered to reduce AEs and improve QoL, but dose optimization could have also another aim, i.e., the achievement and maintenance of cytogenetic and molecular responses. While therapy cessation appeared as a safe option for about half of the patients achieving an optimal response, no systematic assessment of long-term TKI dose de-escalation has been made. The present review is focused on the most recent evidences for TKIs dose modifications in CML clinical studies and in the real-life setting. It will consider TKI dose modifications in newly diagnosed patients, dose reduction for AEs, or in deep molecular response, either as a prelude to treatment-free remission (TFR) or as continuous maintenance therapy in those patients not wishing to attempt TFR. In addition, it will focus on patients not achieving a molecular response deep enough to go to TFR, and for whom dose reduction could be an option to avoid AEs.