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TKIs in CML

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https://www.readbyqxmd.com/read/29032513/sudden-blast-phase-in-chronic-myeloid-leukemia-developed-during-nilotinib-therapy-after-major-molecular-response-was-achieved
#1
Yosuke Okada, Ken Sato, Shinichi Kobayashi, Shigeki Nagao, Kosuke Takano, Masahiro Teramoto, Noriaki Tachi, Toshikuni Kawamura, Toshikatsu Horiuchi, Shoichiro Kato, Reina Saga, Takaaki Maekawa, Takeshi Yamamura, Junichi Watanabe, Ayako Kobayashi, Fumihiko Kimura
Sudden blast phase (SBP) is a rare event in which patients with chronic myeloid leukemia (CML) in complete cytogenetic response (CCyR) rapidly progress to the blast phase. Few patients on second-generation tyrosine kinase inhibitors (2nd TKIs) have been reported to develop SBP. Here, we report a 45-year-old man diagnosed with CML in the chronic phase in April 2008 and immediately started on imatinib therapy. He achieved CCyR 12 months after starting imatinib therapy. Imatinib was followed by treatment with the 2nd TKIs nilotinib and dasatinib from January 2011 to yield a better response...
October 14, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/29032022/outcomes-of-newly-diagnosed-chronic-phase-chronic-myeloid-leukemia-following-an-elective-switch-from-second-generation-tyrosine-kinase-inhibitor-to-imatinib
#2
Vamsi K Kota, Jee Hyun Kong, Martha Arellano, Fuad El Rassi, Manila Gaddh, Leonard T Heffner, Elliott F Winton, Anand P Jillella, Morgan L McLemore, H Jean Khoury
The second-generation tyrosine kinase inhibitors (TKIs) (2G-TKIs) dasatinib (DAS) and nilotinib (NIL) yield faster responses in newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) as compared with imatinib (IM); however, long-term safety of these agents is a growing concern. We identified 20 patients with CP-CML diagnosed between August 2013 and October 2016 who initiated 2G-TKIs and were then switched after optimal response at 3 months to IM. Second-generation TKIs initiated were DAS (n = 15), NIL (n = 3), or both sequentially due to intolerance (n = 1)...
September 19, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29027647/dasatinib-associated-reversible-demyelinating-peripheral-polyneuropathy-in-a-case-of-chronic-myeloid-leukemia
#3
Takashi Ishida, Naoyuki Akagawa, Tomomi Miyata, Naomi Tominaga, Takahiro Iizuka, Masaaki Higashihara, Takahiro Suzuki, Koji Miyazaki
Tyrosine kinase inhibitors (TKIs) are essential for the treatment of chronic myeloid leukemia (CML). Adverse effects of dasatinib have been reported; however, few reports have highlighted the association between dasatinib and demyelinating peripheral neuropathy (DPN). We report a patient with CML who developed acute onset of DPN associated with dasatinib therapy. A 46-year-old Japanese woman was treated with dasatinib for 7 months after the diagnosis of CML and she achieved a major molecular response (MMR)...
October 13, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/29027641/cost-effectiveness-of-imatinib-dasatinib-and-nilotinib-as-first-line-treatment-for-chronic-phase-chronic-myeloid-leukemia-in-china
#4
Na Li, Bin Zheng, Hong-Fu Cai, Jing Yang, Xiao-Feng Luo, Li-Zhu Weng, Feng-Mei Zhan, Mao-Bai Liu
BACKGROUND AND OBJECTIVE: Tyrosine kinase inhibitors (TKIs) have obvious effects on chronic myeloid leukemia (CML), but they are expensive in China. Moreover, the overall cost of treatment of CML is high and the medical economic burden of patients with CML on the government is heavy. This study tested the cost effectiveness of imatinib, nilotinib, and dasatinib as first-line treatment in Chinese patients who were first diagnosed with chronic myeloid leukemia in the chronic phase (CML-CP)...
October 13, 2017: Clinical Drug Investigation
https://www.readbyqxmd.com/read/29027261/prognostic-significance-of-additional-chromosomal-abnormalities-at-the-time-of-diagnosis-in-patients-with-chronic-myeloid-leukemia-treated-with-frontline-tyrosine-kinase-inhibitors
#5
Ahmad Alhuraiji, Hagop Kantarjian, Prajwal Boddu, Farhad Ravandi, Gautam Borthakur, Courtney DiNardo, Naval Daver, Tapan Kadia, Naveen Pemmaraju, Sherry Pierce, Guillermo Garcia-Manero, William Wierda, Srdan Verstovsek, Elias Jabbour, Jorge Cortes
Additional cytogenetic abnormalities (ACA) are considered a high risk feature in chronic myeloid leukemia (CML). However, its prognostic significance at the time of diagnosis in the setting of new tyrosine kinase inhibitors (TKIs) is less well understood. Patients with CML in CP with or without ACA at diagnosis treated with frontline TKIs in prospective clinical trials were analyzed for outcomes. Among 603 patients treated, 29 (5%) had ACA. Patients with ACA included 2 of 72 (2.8%) treated with imatinib 400 mg, 9 of 207 (4...
October 13, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29022901/bcr-abl1-induced-downregulation-of-wasp-in-chronic-myeloid-leukemia-involves-epigenetic-modification-and-contributes-to-malignancy
#6
Welbert O Pereira, Daniel D De Carvalho, Maria Emilia Zenteno, Beatriz F Ribeiro, Jacqueline F Jacysyn, Luiz R Sardinha, Maria A Zanichelli, Nelson Hamerschlak, Gareth E Jones, Katia B Pagnano, Fabiola A Castro, Yolanda Calle, Gustavo P Amarante-Mendes
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the BCR-ABL1 tyrosine kinase (TK). The development of TK inhibitors (TKIs) revolutionized the treatment of CML patients. However, TKIs are not effective to those at advanced phases when amplified BCR-ABL1 levels and increased genomic instability lead to secondary oncogenic modifications. Wiskott-Aldrich syndrome protein (WASP) is an important regulator of signaling transduction in hematopoietic cells and was shown to be an endogenous inhibitor of the c-ABL TK...
October 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28990873/third-line-treatment-with-second-generation-tyrosine-kinase-inhibitors-dasatinib-or-nilotinib-in-patients-with-chronic-myeloid-leukemia-after-two-prior-tkis-real-life-data-on-a-single-center-experience-along-with-the-review-of-the-literature
#7
Seniz Ongoren, Ahmet Emre Eskazan, Veysel Suzan, Sercan Savci, Isil Erdogan Ozunal, Selin Berk, Fevzi Fırat Yalniz, Tugrul Elverdi, Ayse Salihoglu, Yucel Erbilgin, Sibel Aylin Iseri, Muhlis Cem Ar, Zafer Baslar, Yildiz Aydin, Nukhet Tuzuner, Ugur Ozbek, Teoman Soysal
OBJECTIVES: Newer tyrosine kinase inhibitors (TKIs) (bosutinib, ponatinib) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be utilized as a salvage therapy in patients with chronic myeloid leukemia (CML) who failed two lines (imatinib → nilotinib or imatinib → dasatinib) of TKI therapy. However, these TKIs are not available in many countries and not all patients can undergo allo-HSCT. METHODS: In this study, CML patients who received dasatinib or nilotinib as a third-line treatment were retrospectively evaluated...
October 9, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28990077/inhibitory-effect-of-the-anthelmintic-drug-pyrvinium-pamoate-on-t315i-bcr%C3%A2-abl%C3%A2-positive-cml-cells
#8
Jing Zhang, Yanli Jin, Jingxuan Pan
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a chromosome translocation that generates the BCR‑ABL oncogene, which encodes a constitutively activated tyrosine kinase. Despite progress in controlling CML at the chronic phase by first and second generations of BCR‑ABL tyrosine kinase inhibitors (TKIs), effective drugs with good safety are not available for CML patients harboring T315I BCR‑ABL and those in advanced stages of CML. Therefore, there is an urgent requirement for the development of effective therapies against T315I BCR‑ABL...
October 2, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28988389/treatment-free-remission-a-new-therapeutic-goal-in-chronic-myelogenous-leukemia
#9
REVIEW
Ahmed Gamal Elsayed, Roma Srivastava, Muhammad Omer Jamil
PURPOSE OF REVIEW: Chronic myelogenous leukemia (CML) is a chronic myeloproliferative neoplasm characterized by the presence of Philadelphia chromosome [t(9:22)] leading to the presence of pathognomonic fusion gene product, BCR-ABL1. This leads to constitutive activation of ABL1 kinase. CML was a difficult-to-treat illness until the advent of small molecule tyrosine kinase inhibitor (TKI), imatinib which revolutionized therapy of CML. Since then, multiple second- and third-generation TKIs have been formulated which have proven effective and has led to marked improvement in survival...
October 7, 2017: Current Oncology Reports
https://www.readbyqxmd.com/read/28978834/molecular-biology-and-treatment-of-cml
#10
Shinya Kimura
Since the development of imatinib mesylate, an ABL tyrosine kinase inhibitor (TKI), the treatment of chronic myeloid leukemia (CML) has made remarkable progress. Second and third generation TKIs have also become available for clinical use. Considering the improved treatment outcomes, chronic phase CML has become manageable, with a low mortality rate. Furthermore, clinical trials such as STIM and DADI have shown that TKI can be discontinued safely in certain CML patients. However, some CML patients, especially those in accelerated phase (AP) or blast phase (BP), require more aggressive forms of treatment such as allogenic hematopoietic stem cell transplantation...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28976559/adherence-to-tyrosine-kinase-inhibitors-among-medicare-part-d-beneficiaries-with-chronic-myeloid-leukemia
#11
Chan Shen, Bo Zhao, Lei Liu, Ya-Chen Tina Shih
BACKGROUND: Tyrosine kinase inhibitors (TKIs) improve the survival of patients with chronic myeloid leukemia (CML) dramatically; however, nonadherence to TKI therapy may lead to resistance to the therapy. TKIs are very expensive and are covered under Part D insurance for Medicare patients. To the authors' knowledge, the impact of low-income subsidy status and cost sharing on adherence among this group has not been well studied in the literature. METHODS: Surveillance, Epidemiology, and End Results (SEER) registry data linked with Medicare Part D data from the years 2007 through 2012 were used in the current study...
October 4, 2017: Cancer
https://www.readbyqxmd.com/read/28972430/life-after-ponatinib-failure-outcomes-of-chronic-and-accelerated-phase-cml-patients-who-discontinued-ponatinib-in-the-salvage-setting
#12
Prajwal Boddu, Abdul Rashid Shah, Gautam Borthakur, Srdan Verstovsek, Guillermo Garcia-Manero, Naval Daver, Tapan Kadia, Farhad Ravandi, Nitin Jain, Ahmad Alhuraiji, Jan Burger, Steven Kornblau, Sherry Pierce, Sara Dellasala, Elias Jabbour, Hagop Kantarjian, Jorge Cortes
Ponatinib is a pan-tyrosine kinase inhibitor (TKI) with efficacy in multirefractory CML patients who have failed other TKIs. Despite excellent response rates, resistance or intolerance may develop. We conducted a retrospective review of the outcome of patients with chronic (CP) and accelerated (AP) phase CML refractory to prior TKI who discontinued ponatinib for resistance or intolerance. Nineteen CP patients, discontinued due to resistance (n = 13), toxicity (n = 5) and to pursue stem cell transplantation (n = 1)...
October 3, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28972424/first-line-therapy-for-chronic-phase-cml-selecting-the-optimal-bcr-abl1-targeted-tki
#13
Giuseppe Saglio, Elias Jabbour
Patients diagnosed with chronic myeloid leukemia (CML) and treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs) have long life spans. Selection of an appropriate first-line therapy can be difficult as both the unique characteristics of each TKI and patient need to be taken into account to find the optimal match. Patient characteristics include comorbidities, concomitant medications, lifestyle, risk factors, BCR-ABL1 transcript type (e.g. b2a2 or b3a2) and additional chromosomal abnormalities. Just as patients differ, side effects, drug-drug interactions, administration plans, dosing schedules and treatment-related expenses across TKIs also vary...
October 3, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28969255/alterations-in-the-reactive-oxygen-species-in-peripheral-blood-of-chronic-myeloid-leukaemia-patients-from-northern-india
#14
Sunita Jetly, Neha Verma, Kumar Naidu, Muneeb Ahmad Faiq, Tulika Seth, Daman Saluja
INTRODUCTION: There is a significant difference in the Reactive Oxygen Species (ROS) levels of Chronic Myeloid Leukaemia (CML) patients before and during treatment with Tyrosine Kinase Inhibitors (TKIs). This is because high ROS levels support oncogenic phenotype of CML by inducing proliferation pathway and accumulation of further genetic mutations. Often the measurement is done on WBC or serum for ascertaining one type of ROS species, but measurement of global ROS in fresh whole blood will give more accurate estimation of ROS...
August 2017: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28962554/propofol-enhances-bcr-abl-tkis-inhibitory-effects-in-chronic-myeloid-leukemia-through-akt-mtor-suppression
#15
Zhimin Tan, Aixia Peng, Jingwen Xu, Mingwen Ouyang
BACKGROUND: The anti-cancer activities of intravenous anesthetic drug propofol have been demonstrated in various types of cancers but not in chronic myeloid leukemia (CML). METHODS: We systematically examined the effect of propofol and its combination with BCR-ABL tyrosine kinase inhibitors (TKIs) in CML cell lines, patient progenitor cells and mouse xenograft model. We analyzed propofol's underlying mechanism focusing on survival pathway in CML cells. RESULTS: We show that propofol alone is active in inhibiting proliferation and inducing apoptosis in KBM-7, KU812 and K562 cells, and acts synergistically with imatinib or dasatinib, in in vitro cell culture system and in vivo xenograft model...
September 29, 2017: BMC Anesthesiology
https://www.readbyqxmd.com/read/28944397/chronic-myeloid-leukemia-the-promise-of-tyrosine-kinase-inhibitor-discontinuation
#16
REVIEW
Ravi Kishore Narra, Kathryn E Flynn, Ehab Atallah
Some believe that tyrosine kinase inhibitor (TKI) therapy is as close to perfect as it gets in oncologic therapy. Patients diagnosed with chronic myeloid leukemia (CML) are treated with a daily oral therapy, through which most achieve remission. TKI therapy is not associated with classic chemotherapy side effects, and most patients are able to resume their normal activities of daily living. Moreover, recent data has demonstrated that CML does not affect the life expectancy of patients whose disease is well controlled with a TKI...
September 25, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28942039/comparative-effect-of-imatinib-and-ponatinib-on-autophagy-and-mirnome-in-chronic-myeloid-leukemia
#17
Cagla Kayabasi, Tugce Balci Okcanoglu, Besra Ozmen Yelken, Aycan Asik, Sunde Yilmaz Susluer, Cigir Biray Avci, Guray Saydam, Cumhur Gunduz
BCR-ABL tyrosine kinase inhibitors (TKIs) are selective therapies for the patients with Chronic Myeloid Leukemia (CML). Imatinib and ponatinib have remarkable long-term efficacy on a major molecular response. Although TKI related induction of cytotoxicity and apoptosis have been clearly investigated in molecular levels, their comparative effect on autophagy and miRNome are largely unknown. This study aimed to investigate the involvement of alterations of miRNA expressions in CML progression, and how imatinib and ponatinib affect this process, by comparing CML, imatinib-resistant CML and leukemia stem cells (LSC)...
December 30, 2017: Gene
https://www.readbyqxmd.com/read/28939746/phase-iii-clinical-trial-rerise-study-results-of-efficacy-and-safety-of-radotinib-compared-with-imatinib-in-newly-diagnosed-chronic-phase-chronic-myeloid-leukemia
#18
Jae Yong Kwak, Sung-Hyun Kim, Suk Joong Oh, Dae Young Zang, Hawk Kim, Jeong-A Kim, Young Rok Do, Hyeoung-Joon Kim, Joon Seong Park, Chul Won Choi, Won-Sik Lee, Yeung-Chul Mun, Jee Hyun Kong, Joo-Seop Chung, Ho Jin Shin, Dae-Young Kim, Jinny Park, Chul Won Jung, Udomask Bunworasate, Narcisa Sonia Comia, Saengsuree Jootar, Harryanto Reksodiputro, Priscilla B Caguioa, Sung-Eun Lee, Dong-Wook Kim
PURPOSE: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for CML-CP in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. METHODS: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily (bid) radotinib doses, or imatinib daily (qd). The primary endpoint was major molecular response (MMR) by 12 months...
September 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28936999/non-adherence-to-cml-therapy-and-its-clinical-implications-in-india
#19
REVIEW
Hari Menon
Clinical trials have shown that early and deeper cytogenetic/ molecular responses to tyrosine kinase inhibitors (TKIs) help in achieving improved long-term outcomes including lower rates of disease progression in chronic myeloid leukaemia (CML). However, the level of molecular responses achieved with TKI therapy in patients with CML is variable and this could be explained by differences in adherence to CML therapy. A systematic literature review of CML studies reporting adherence to BCR-ABL inhibitors from the USA, Asia and Europe (19 articles: 9 retrospective, 4 prospective, rest cross-sectional) showed that average adherence varies from 19% to 100% of the proportion of prescribed drug taken...
May 2017: National Medical Journal of India
https://www.readbyqxmd.com/read/28930482/diagnostic-and-prognostic-cytogenetics-of-chronic-myeloid-leukaemia-an-update
#20
Matteo Molica, Fulvio Massaro, Massimo Breccia
Despite the advent of molecular assessment, banding cytogenetics and fluorescence in situ hybridization (FISH) still have a significant role in diagnostic and prognostic approaches to chronic myeloid leukaemia (CML). Area covered: At diagnosis and during treatment with tyrosine kinase inhibitors (TKIs), cytogenetics is used to detect the Philadelphia chromosome, with its typical translocation t(9;22)(q34;q11.2), and any additional or other chromosomal aberrations (ACAs and OCAs) that may arise in 5-10% of cases, the latter associated to transformation of the disease in blast phases...
September 26, 2017: Expert Review of Molecular Diagnostics
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