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TKIs in CML

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https://www.readbyqxmd.com/read/28543934/clinical-impact-of-pre-transplant-use-of-multiple-tyrosine-kinase-inhibitors-on-the-outcome-of-allo-hsct-for-cml
#1
Takeshi Kondo, Tokiko Nagamura-Inoue, Arinobu Tojo, Fumitaka Nagamura, Naoyuki Uchida, Hirohisa Nakamae, Takahiro Fukuda, Takehiko Mori, Shingo Yano, Mineo Kurokawa, Hironori Ueno, Heiwa Kanamori, Hisako Hashimoto, Makoto Onizuka, Minoko Takanashi, Tatsuo Ichinohe, Yoshiko Atsuta, Kazuteru Ohashi
Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with chronic myelogenous leukemia in the chronic phase (CML-CP), and outcomes of TKI treatment for patients with CML-CP have been excellent. Since multiple TKIs are currently available, second-line or third-line TKI therapy is considered for patients who are intolerant of or resistant to the previous TKI treatment. Therefore, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered only for patients with disease progression or for patients after treatment failure with multiple TKIs...
May 20, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28534184/evaluation-of-cardiovascular-ischemic-event-rates-in-dasatinib-treated-patients-using-standardized-incidence-ratios
#2
Giuseppe Saglio, Philipp le Coutre, Jorge Cortes, Jiří Mayer, Philip Rowlings, François-Xavier Mahon, Glenn Kroog, Kyna Gooden, Milayna Subar, Neil P Shah
With high survival rates for chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs), emerging consequences, such as arterial ischemic events, require consideration when evaluating treatment options. Cardiovascular ischemic event incidence in clinical trials was evaluated in 2712 dasatinib-treated patients with Philadelphia chromosome-positive (Ph+) leukemias from 11 first- and second-line trials (pooled), newly diagnosed CML patients treated with dasatinib or imatinib (DASISION), and prostate cancer patients treated with dasatinib or placebo plus docetaxel/prednisone (READY)...
May 22, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28533818/a-novel-bcr-abl1-fusion-gene-with-genetic-heterogeneity-indicates-a-good-prognosis-in-a-chronic-myeloid-leukemia-case
#3
Fen Zhou, Runming Jin, Yu Hu, Heng Mei
BACKGROUND: Chronic myelogenous leukemia (CML) is a pluripotent hematopoietic stem cell disorder caused by the fusion of the BCR and ABL1 genes. Quantitative RT-PCR (qRT-PCR) is a routinely performed screening technique to identify BCR-ABL1 fusion genes, but a limitation of this method is its inability to recognize novel fusions that have not been previously characterized. Next-generation sequencing (NGS) is an effective and sensitive detection method for the determination of novel BCR-ABL1 fusion genes as well as previously characterized ones...
2017: Molecular Cytogenetics
https://www.readbyqxmd.com/read/28511567/treating-the-chronic-phase-chronic-myeloid-leukemia-patient-which-tki-when-to-switch-and-when-to-stop
#4
Ami B Patel, Brandon W Wilds, Michael W Deininger
With the discovery of imatinib mesylate nearly 20 years ago, tyrosine kinase inhibitors (TKIs) were found to be effective in chronic myeloid leukemia (CML). TKI therapy has since revolutionized the treatment of CML and has served as a paradigm of success for targeted drug therapy in cancer. Several new TKIs for CML have been approved over the last two decades that exhibit improved potency over imatinib and have different off-target profiles, providing options for individualized therapy selection. Areas covered: Current management of chronic phase CML, including guidance on the sequential use of imatinib and newer-generation TKIs and evolving treatment strategies such as TKI discontinuation...
May 22, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28501913/chronic-myeloid-leukemia-immunobiology-and-novel-immunotherapeutic-approaches
#5
Emilie Cayssials, Francois Guilhot
Imatinib has revolutionized the treatment and prognosis of chronic myeloid leukemia (CML) with survival rates now approaching those of the age-matched healthy population. To be able to discontinue tyrosine kinase inhibitor (TKI) treatment, it is necessary to develop complementary therapies to target minimal residual disease. Recent findings by a number of investigators in both CML mouse models and CML patients offer evidence that many factors in the leukemic microenvironment can collectively contribute to immune escape, including expansion of myeloid-derived suppressor cells, programmed death-1/programmed death-1 ligand interactions resulting in T-cell impairment, expression of soluble suppressive factors such as soluble CD25, and down-regulation of MHC molecules by CML cells...
May 13, 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/28501737/the-bcr-abl-tyrosine-kinase-inhibitor-nilotinib-stimulates-expression-of-il-1%C3%AE-in-vascular-endothelium-in-association-with-downregulation-of-mir-3p
#6
Masumi Sukegawa, Xiangmin Wang, Chie Nishioka, Bin Pan, Kailin Xu, Hiroshi Ohkawara, Yoichi Hamasaki, Masayuki Mita, Kenichi Nakamura, Masatoshi Okamoto, Hiromi Shimura, Masatsugu Ohta, Takayuki Ikezoe
BCR/ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis for in dividuals with chronic myeloid leukemia (CML). However, many patients treated with TKIs suffer from TKI-related complications. In particular, vascular events such as peripheral artery occlusive disease have become aserious clinical problem for patients who receive the TKI, nilotinib. At present, the molecular mechanisms by which TKIs cause vascular endothelial cell insults remain unknown.This study explored the effects of the TKIs, imatinib, nilotinib and dasatinib, on vascular endothelial cells in vitro, and found that only nilotinib induced expression of interleukin-1β (IL-1β) by vascular endothelial cells...
May 5, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28484463/immune-effector-recovery-in-chronic-myeloid-leukemia-and-treatment-free-remission
#7
REVIEW
Amy Hughes, Agnes S M Yong
Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28484170/chronic-myeloid-leukemia-and-nk-cell-immunity
#8
Hiroshi Ureshino, Takero Shindo, Hidenori Tanaka, Shinaya Kimura
BCR-ABL1 tyrosine kinase inhibitors (TKIs) have dramatically improved the long-term outcomes of patients with chronic myelogenous leukemia (CML). Notably, approximately half of patients with a sustained deep molecular response experienced treatment free remission (TFR) even after discontinuation of TKI. Although antitumor immunity by natural killer (NK) cells might contribute to the effects of TKI and TFR in CML, the details of their actions have not as yet been elucidated. Recently, several reports have raised the possibility that the killer immunoglobulin-like receptor (KIR), a highly polymorphic NK cell receptor, may play important roles, because polymorphic patterns of KIR were shown to be associated with the intensity of clinical responses and outcomes in TKI-treated CML patients...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28482729/treatment-of-chronic-myeloid-leukemia-assessing-risk-monitoring-response-and-optimizing-outcome
#9
Naranie Shanmuganathan, Devendra Keshaorao Hiwase, David Morrall Ross
Over the past two decades, tyrosine kinase inhibitors have become the foundation of chronic myeloid leukemia (CML) treatment. The choice between imatinib and newer tyrosine kinase inhibitors (TKIs) needs to be balanced against the known toxicity and efficacy data for each drug, the therapeutic goal being to maximize molecular response assessed by BCR-ABL RQ-PCR assay. There is accumulating evidence that the early achievement of molecular targets is a strong predictor of superior long-term outcomes. Early response assessment provides the opportunity to intervene early with the aim of ensuring an optimal response...
May 9, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28452984/frequent-somatic-mutations-in-epigenetic-regulators-in-newly-diagnosed-chronic-myeloid-leukemia
#10
E Togasaki, J Takeda, K Yoshida, Y Shiozawa, M Takeuchi, M Oshima, A Saraya, A Iwama, K Yokote, E Sakaida, C Hirase, A Takeshita, K Imai, H Okumura, Y Morishita, N Usui, N Takahashi, S Fujisawa, Y Shiraishi, K Chiba, H Tanaka, H Kiyoi, K Ohnishi, S Ohtake, N Asou, Y Kobayashi, Y Miyazaki, S Miyano, S Ogawa, I Matsumura, C Nakaseko, T Naoe
Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17)...
April 28, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28431398/decreased-calpain-activity-in-chronic-myeloid-leukemia-impairs-apoptosis-by-increasing-survivin-in-myeloid-progenitors-and-xiap1-in-differentiating-granulocytes
#11
Weiqi Huang, Ling Bei, Elizabeth E Hjort, Elizabeth A Eklund
Chronic Myeloid Leukemia (CML) is characterized by translocations between chromosomes 9 and 22, resulting in expression of Bcr-abl oncogenes. Although the clinical course of CML was revolutionized by development of Bcr-abl-directed tyrosine kinase inhibitors (TKIs), CML is not cured by these agents. Specifically, the majority of subjects relapsed in clinical trials attempting TKI discontinuation, suggesting persistence of leukemia stem cells (LSCs) even in molecular remission. Identifying mechanisms of CML-LSC persistence may suggest rationale therapeutic targets to augment TKI efficacy and lead to cure...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28424749/development-of-asymmetric-facial-depigmentation-in-a-patient-treated-with-dasatinib-with-new-onset-hypovitaminosis-d-case-report-and-review-of-the-literature
#12
Kirsten C Webb, Magdalena Harasimowicz, Monica Janeczek, Jodi Speiser, James Swan, Rebecca Tung
Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) used to treat imatinib-resistant chronic myelogenous leukemia (CML), as well as other Philadelphia chromosome-positive lymphoproliferative disorders. While the most commonly reported cutaneous side effects with this therapy include a morbilliform eruption, skin exfoliation, and skin irritation, pigmentary abnormalities have also been observed, albeit much more rarely. We present the case of a 72-year-old South Asian male with CML who presented with new-onset hypopigmentation of his face and scalp three years after a dose increase of dasatinib therapy, in the setting of newly discovered borderline hypovitaminosis D...
2017: Case Reports in Dermatological Medicine
https://www.readbyqxmd.com/read/28418880/contributions-of-met-activation-to-bcr-abl1-tyrosine-kinase-inhibitor-resistance-in-chronic-myeloid-leukemia-cells
#13
Masanobu Tsubaki, Tomoya Takeda, Toshiki Kino, Kazuko Sakai, Tatsuki Itoh, Motohiro Imano, Takashi Nakayama, Kazuto Nishio, Takao Satou, Shozo Nishida
Resistance to the breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitor (TKI) imatinib poses a major problem when treating chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, in the absence of a mutation in BCR-ABL1, the basis of BCR-ABL1-independent resistance must be elucidated. To gain insight into the mechanisms of BCR-ABL1-independent imatinib resistance, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, and focused on MET...
March 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28405921/the-role-of-early-molecular-response-in-the-management-of-chronic-phase-cml
#14
REVIEW
Patrick Harrington, Aytug Kizilors, Hugues de Lavallade
PURPOSE OF REVIEW: Although tyrosine kinase inhibitors (TKIs) spectacularly improve the disease burden and the overall survival of chronic myeloid leukemia patients, early identification of a subset of poor TKI responders has been recognized as a critical goal to prevent disease progression in these patients. We herein review the past and recent evidence on the impact of early response. RECENT FINDINGS: In the recent years, the achievement of an early molecular response (EMR, defined as 3-month BCR-ABL1 transcript <10% IS) has emerged as a useful tool to identify poor-risk patients...
April 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28404889/cryptic-bcr-abl-fusion-gene-as-variant-rearrangement-in-chronic-myeloid-leukemia-molecular-cytogenetic-characterization-and-influence-on-tkis-therapy
#15
Simona Luatti, Carmen Baldazzi, Giulia Marzocchi, Gaia Ameli, Maria Teresa Bochicchio, Simona Soverini, Fausto Castagnetti, Mario Tiribelli, Gabriele Gugliotta, Giovanni Martinelli, Michele Baccarani, Michele Cavo, Gianantonio Rosti, Nicoletta Testoni
At diagnosis, about 5% of Chronic Myeloid Leukemia (CML) patients lacks Philadelphia chromosome (Ph), despite the presence of the BCR/ABL rearrangement. Two mechanisms have been proposed about the occurrence of this rearrangement: the first one is a cryptic insertion between chromosomes 9 and 22; the second one involves two sequential translocations: a classic t(9;22) followed by a reverse translocation, which reconstitutes the normal morphology of the partner chromosomes. Out of 398 newly diagnosed CML patients, we selected 12 Ph-negative cases...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28378056/analysis-of-adverse-events-associated-with-dasatinib-and-nilotinib-treatments-in-chronic-phase-chronic-myeloid-leukemia-patients-outside-clinical-trials
#16
Koung Jin Suh, Ji Yun Lee, Dong-Yeop Shin, Youngil Koh, Soo-Mee Bang, Sung-Soo Yoon, Seonyang Park, Inho Kim, Jeong-Ok Lee
We analyzed adverse events (AEs) in 201 chronic phase CML patients treated with nilotinib (n = 120) or dasatinib (n = 81) as first- or second-line therapy. The dasatinib group had significantly higher grade 3-4 AEs compared to the nilotinib group (22 vs. 54%, p < 0.001), and had more frequent dose reduction, interruption, and discontinuation (p < 0.001, p = 0.004, and p = 0.006, respectively). Of 59 patients who discontinued treatment, 47 (80%) discontinued treatment due to AEs; 50% of the AEs causing drug discontinuation were of grade 2 severity...
April 4, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28368400/interferon-%C3%AE-is-a-stat1-dependent-direct-inducer-of-bcl6-expression-in-imatinib-treated-chronic-myeloid-leukemia-cells
#17
H S Madapura, N Nagy, D Ujvari, T Kallas, M C L Kröhnke, S Amu, M Björkholm, L Stenke, P K Mandal, J S McMurray, M Keszei, L S Westerberg, H Cheng, F Xue, G Klein, E Klein, D Salamon
B-cell CLL/lymphoma 6 (BCL6) exerts oncogenic effects in several human hematopoietic malignancies including chronic myeloid leukemia (CML), where BCL6 expression was shown to be essential for CML stem cell survival and self-renewal during imatinib mesylate (IM) treatment. As several lines of evidence suggest that interferon γ (IFNγ) production in CML patients might have a central role in the response to tyrosine kinase inhibitor (TKI) therapy, we analyzed if IFNγ modulates BCL6 expression in CML cells. Although separate IFNγ or IM treatment only slightly upregulated BCL6 expression, combined treatment induced remarkable BCL6 upregulation in CML lines and primary human CD34+ CML stem cells...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28366933/a-novel-ahi-1-bcr-abl-dnm2-complex-regulates-leukemic-properties-of-primitive-cml-cells-through-enhanced-cellular-endocytosis-and-ros-mediated-autophagy
#18
X Liu, K Rothe, R Yen, C Fruhstorfer, T Maetzig, M Chen, D L Forrest, K Humphries, X Jiang
Tyrosine kinase inhibitor (TKI) therapies induce clinical remission with remarkable effects on chronic myeloid leukemia (CML). However, very few TKIs completely eradicate the leukemic clone and persistence of leukemic stem cells (LSCs) remains challenging, warranting new, distinct targets for improved treatments. We demonstrated that the scaffold protein AHI-1 is highly deregulated in LSCs and interacts with multiple proteins, including Dynamin-2 (DNM2), to mediate TKI-resistance of LSCs. We have now demonstrated that the SH3 domain of AHI-1 and the proline rich domain of DNM2 are mainly responsible for this interaction...
April 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28365527/imatinib-discontinuation-in-chronic-myeloid-leukaemia-patients-with-undetectable-bcr-abl-transcript-level-a%C3%A2-systematic-review-and-a-meta-analysis
#19
REVIEW
Leonardo Campiotti, Matteo Basilio Suter, Luigina Guasti, Rocco Piazza, Carlo Gambacorti-Passerini, Anna Maria Grandi, Alessandro Squizzato
PURPOSE: Tyrosine kinase inhibitors (TKIs) are the cornerstones of treatment for patients with chronic myeloid leukaemia (CML). In recent years, several studies were conducted to evaluate the safety of TKIs discontinuation. We performed a systematic review of the literature to determine the incidence of CML relapse, to identify possible factors relapse rates and to evaluate the long-term safety in CML patients with stable undetectable BCR-ABL transcript level who discontinued TKIs. DESIGN: Studies evaluating TKIs discontinuation in CML patients with undetectable BCR-ABL transcript level were identified by electronic search of MEDLINE and EMBASE database until May 2015...
March 30, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28340283/comparative-analysis-of-pulmonary-hypertension-in-patients-treated-with-imatinib-nilotinib-and-dasatinib
#20
Mariko Minami, Takeshi Arita, Hiromi Iwasaki, Tsuyoshi Muta, Takatoshi Aoki, Kenichi Aoki, Satoshi Yamasaki, Takamitsu Matsushima, Koji Kato, Katsuto Takenaka, Kazuki Tanimoto, Tomohiko Kamimura, Ryosuke Ogawa, Koichi Akashi, Toshihiro Miyamoto
Pulmonary hypertension (PH) is a rare, but life-threatening, adverse event in patients treated with tyrosine kinase inhibitors (TKIs), such as dasatinib, but has not been fully evaluated in patients treated with imatinib or nilotinib. We used echocardiography to noninvasively assess the incidence of PH in 105 patients with chronic myeloid leukaemia (CML) treated with imatinib (n = 37), nilotinib (n = 30) or dasatinib (n = 38). The mean triscupid regurgitation peak gradient (TRPG), which reflects pulmonary arterial pressure, was 22·7 mmHg in the imatinib group, 23·1 mmHg in the nilotinib group and 23·4 mmHg for dasatinib group...
March 24, 2017: British Journal of Haematology
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