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TKIs in CML

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https://www.readbyqxmd.com/read/29222245/novel-approaches-to-therapy-in-cml
#1
REVIEW
Ravi Bhatia
Treatment with tyrosine kinase inhibitors (TKIs) results in remission and prolongation of survival in most chronic myeloid leukemia (CML) patients but fails to eliminate the leukemia stem cells (LSCs) responsible for disease development and propagation. This accounts for the clinical observation that TKI discontinuation leads to rapid leukemia relapse. Most patients require continued treatment to prevent relapse, with associated risk of relapse, toxicity, teratogenic effects, financial burden, and noncompliance...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29222244/cardiovascular-care-of-patients-with-chronic-myeloid-leukemia-cml-on-tyrosine-kinase-inhibitor-tki-therapy
#2
REVIEW
Mary C Barber, Michael J Mauro, Javid Moslehi
Cardiovascular (CV) health has emerged as an important consideration in patients with chronic myeloid leukemia (CML) because of improved prognosis. Indeed, the success of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has increased the focus on survivorship and late toxicity in oncological care. Survivorship issues in this population include CV disease prevention, given its prevalence in the general population. The introduction of BCR-ABL1 TKIs represented a unique concept of indefinite cancer therapy, only recently evolving to include "treatment-free remission...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29222243/treatment-free-remission-in-cml-who-how-and-why
#3
REVIEW
Francois-Xavier Mahon
Chronic myeloid leukemia (CML) is the best example of successful targeted therapy. Today, the overall survival of patients with CML treated by using tyrosine kinase inhibitors (TKIs) is very close to that of the healthy population. The current question is: how can we further ameliorate the clinical outcome of patients with CML? Clinical trials have shown that some patients with CML in the chronic phase who achieve sustained deep molecular responses on TKI therapy can safely suspend therapy with no evidence of relapse...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29212733/successful-ovarian-stimulation-for-fertility-preservation-in-a-patient-with-chronic-myeloid-leukemia-switch-from-nilotinib-to-interferon-%C3%AE
#4
Smaranda Gazdaru, Lucien Perey, Anne Rosselet, Patrice Mathevet, Yves Chalandon, Nicolas Vulliemoz
The development of tyrosine-kinase inhibitors (TKIs) has improved survival of patients with chronic myeloid leukemia (CML). Some patients may become resistant to TKIs and require hematopoietic stem cell transplant (HSCT) that is highly gonadotoxic. Fertility preservation with ovarian stimulation might be indicated but is challenging if patients need to remain on TKIs until HSCT because TKIs may compromise follicular development and response to ovarian stimulation. We report the case of a patient with CML resistant to TKI and planned for an HSCT, in which treatment by TKI was replaced by interferon-α before and during ovarian stimulation for fertility preservation...
December 6, 2017: Oncologist
https://www.readbyqxmd.com/read/29198338/ponatinib-in-chronic-myeloid-leukemia-cml-consensus-on-patient-treatment-and-management-from-a-european-expert-panel
#5
REVIEW
Martin C Müller, Francisco Cervantes, Henrik Hjorth-Hansen, Jeroen J W M Janssen, Dragana Milojkovic, Delphine Rea, Gianantonio Rosti
Five tyrosine kinase inhibitors (TKIs) are currently approved in the European Union for treatment of chronic myeloid leukemia (CML) and all have considerable overlap in their indications. While disease-specific factors such as CML phase, mutational status, and line of treatment are key to TKI selection, other important features must be considered, such as patient-specific comorbidities and TKI safety profiles. Ponatinib, the TKI most recently approved, has demonstrated efficacy in patients with refractory CML, but is associated with an increased risk of arterial hypertension, sometimes severe, and serious arterial occlusive and venous thromboembolic events...
December 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29185155/successful-treatment-of-follicular-lymphoma-with-second-generation-tyrosine-kinase-inhibitors-administered-for-coexisting-chronic-myeloid-leukemia
#6
Shin-Ichiro Fujiwara, Yuya Shirato, Takashi Ikeda, Shin-Ichiro Kawaguchi, Yumiko Toda, Shoko Ito, Shin-Ichi Ochi, Takashi Nagayama, Kiyomi Mashima, Kento Umino, Daisuke Minakata, Hirofumi Nakano, Kaoru Morita, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Masahiro Ashizawa, Chihiro Yamamoto, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Kazuo Muroi, Yoshinobu Kanda
Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic myeloid leukemia (CML). However, the effects of these agents on mature B cell lymphoma are not well known. We describe a 50-year-old man who was diagnosed with CML in the chronic phase and treated with imatinib. After 3 years of imatinib therapy that achieved a complete cytogenetic response of CML, he developed Philadelphia-negative follicular lymphoma (FL). Rituximab monotherapy induced a partial response of FL, and he subsequently achieved a major molecular response (MMR) of CML...
November 28, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/29165716/targeting-bcr-abl-independent-tki-resistance-in-chronic-myeloid-leukemia-by-mtor-and-autophagy-inhibition
#7
Rebecca Mitchell, Lisa E M Hopcroft, Pablo Baquero, Elaine K Allan, Kay Hewit, Daniel James, Graham Hamilton, Arunima Mukhopadhyay, Jim O'Prey, Alan Hair, Junia V Melo, Edmond Chan, Kevin M Ryan, Véronique Maguer-Satta, Brian J Druker, Richard E Clark, Subir Mitra, Pawel Herzyk, Franck E Nicolini, Paolo Salomoni, G Vignir Helgason
Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment...
November 20, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29149649/chk1-inhibitors-overcome-imatinib-resistance-in-chronic-myeloid-leukemia-cells
#8
Hu Lei, Jin Jin, Meng Liu, Xiangyun Li, Hao Luo, Li Yang, Hanzhang Xu, Yingli Wu
Drug resistance to tyrosine kinase inhibitors (TKIs) is currently a clinical problem of chronic myelogenous leukemia (CML). Bcr-Abl protein depletion is considered as a way to overcome drug resistance to TKIs. In our study, Chk1 inhibitors, AZD7762 and MK-8776, had strong antitumor effects on CML cell line KBM5 and imatinib-resistant form KBM5T315I. Moreover, Chk1 inhibitors showed a strong cytotoxic effect on leukemia cells from primary CML and imatinib-resistance CML patients, but low cytotoxic effect on normal human mononuclear cells...
November 11, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29137227/re-balance-of-memory-t-cell-subsets-in-peripheral-blood-from-patients-with-cml-after-tki-treatment
#9
Danlin Yao, Ling Xu, Jiaxiong Tan, Yikai Zhang, Shuai Lu, Mingde Li, Sichun Lu, Lijian Yang, Shaohua Chen, Jie Chen, Jing Lai, Yuhong Lu, Xiuli Wu, Xianfeng Zha, Yangqiu Li
T cell immune surveillance is considered an important host protection process for inhibiting carcinogenesis. The full capacity of T cell immune surveillance is dependent on T cell homeostasis, particularly for central memory T (TCM) cells and stem cell memory T (TSCM) cells. In this study, distribution of T cell subsets in peripheral blood from 12 patients with chronic myeloid leukemia (CML) and 12 cases with CML in complete remission (CR) was analyzed using a multicolor flow cytometer, and 16 samples from healthy individuals (HIs) served as control...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29121435/altered-intracellular-signaling-by-imatinib-increases-the-anti-cancer-effects-of-tyrosine-kinase-inhibitors-in-cml-cells
#10
Takuya Hirao, Masashi Yamaguchi, Megumi Kikuya, Hiroji Chibana, Kousei Ito, Shigeki Aoki
Tyrosine kinase inhibitors (TKIs), including imatinib (IM), improve the outcome of chronic myelogenous leukemia (CML) therapy. However, TKI treatment is long-term and can induce resistance to TKIs, which often leads to a poor clinical outcome in CML patients. Here, we examined the effect of continuous IM exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome-positive CML cell line, and its subsequent sensitivity to anti-cancer agents. Contrary to our expectations, we found that continuous IM exposure increased sensitivity to TKIs...
November 9, 2017: Cancer Science
https://www.readbyqxmd.com/read/29100409/overcoming-imatinib-resistance-conferred-by-the-bim-deletion-polymorphism-in-chronic-myeloid-leukemia-with-splice-switching-antisense-oligonucleotides
#11
Jun Liu, Malini Bhadra, Joanna Rajeswary Sinnakannu, Wan Lin Yue, Cheryl Weiqi Tan, Frank Rigo, S Tiong Ong, Xavier Roca
Many tyrosine kinase-driven cancers, including chronic myeloid leukemia (CML), are characterized by high response rates to specific tyrosine kinase inhibitors (TKIs) like imatinib. In East Asians, primary imatinib resistance is caused by a deletion polymorphism in Intron 2 of the BIM gene, whose product is required for TKI-induced apoptosis. The deletion biases BIM splicing from exon 4 to exon 3, generating splice isoforms lacking the exon 4-encoded pro-apoptotic BH3 domain, which impairs the ability of TKIs to induce apoptosis...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29058817/dasatinib-cessation-after-deep-molecular-response-exceeding-2-years-and-nk-cell-transition-during-dasatinib-consolidation
#12
Takashi Kumagai, Chiaki Nakaseko, Kaichi Nishiwaki, Chikashi Yoshida, Kazuteru Ohashi, Naoki Takezako, Hina Takano, Yasuji Kouzai, Tadashi Murase, Kosei Matsue, Satoshi Morita, Junichi Sakamoto, Hisashi Wakita, Hisashi Sakamaki, Koiti Inokuchi
Tyrosine kinase inhibitors (TKIs) improve the prognosis of patients with chronic myelogenous leukemia (CML) by inducing substantial deep molecular responses (DMRs); some patients could successfully discontinue TKI therapy after maintaining DMR for ≥1 year. In this cessation study, we investigated the optimal conditions for dasatinib discontinuation in patients who maintained DMR for ≥2 years. This study included 54 patients with CML who were enrolled in D-STOP multicenter prospective trial, had achieved DMR, and had discontinued dasatinib after 2-year consolidation...
October 23, 2017: Cancer Science
https://www.readbyqxmd.com/read/29052661/adherence-and-coping-strategies-in-outpatients-with-chronic-myeloid-leukemia-receiving-oral-tyrosine-kinase-inhibitors
#13
Jochen Hefner, Eva-Johanna Csef, Volker Kunzmann
PURPOSE/OBJECTIVES: To assess adherence and coping strategies in outpatients with chronic myeloid leukemia (CML) on oral tyrosine kinase inhibitors (TKIs).
. DESIGN: Prospective, descriptive.
. SETTING: An interdisciplinary oncology outpatient clinic in Germany.
. SAMPLE: 35 outpatients with CML on oral TKIs.
. METHODS: Adherence and coping strategies were assessed with questionnaires. Clinical data were extracted from medical charts...
November 1, 2017: Oncology Nursing Forum
https://www.readbyqxmd.com/read/29051802/radotinib-and-its-clinical-potential-in-chronic-phase-chronic-myeloid-leukemia-patients-an-update
#14
REVIEW
Ahmet Emre Eskazan, Dilek Keskin
Although imatinib has dramatically improved major outcomes in patients with chronic myeloid leukemia (CML), there are newer tyrosine kinase inhibitors (TKIs) approved worldwide for the treatment of resistant cases, and two second-generation TKIs (dasatinib, nilotinib) are approved in some nations for treating patients in the upfront setting. Radotinib (IY5511HCL, Supect®) is a novel and selective second-generation BCR-ABL1 TKI, which is currently approved in Korea for the treatment of patients with CML both in the upfront and salvage settings...
September 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/29032513/sudden-blast-phase-in-chronic-myeloid-leukemia-developed-during-nilotinib-therapy-after-major-molecular-response-was-achieved
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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