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Liu SV, Nagasaka M, Atz J, Solca F, Müllauer L. Oncogenic gene fusions in cancer: from biology to therapy. Signal Transduct Target Ther 2025; 10:111. [PMID: 40223139 PMCID: PMC11994825 DOI: 10.1038/s41392-025-02161-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 12/06/2024] [Accepted: 01/16/2025] [Indexed: 04/15/2025] Open
Abstract
Oncogenic gene fusions occur across a broad range of cancers and are a defining feature of some cancer types. Cancers driven by gene fusion products tend to respond well to targeted therapies, where available; thus, detection of potentially targetable oncogenic fusions is necessary to select optimal treatment. Detection methods include non-sequencing methods, such as fluorescence in situ hybridization and immunohistochemistry, and sequencing methods, such as DNA- and RNA-based next-generation sequencing (NGS). While NGS is an efficient way to analyze multiple genes of interest at once, economic and technical factors may preclude its use in routine care globally, despite several guideline recommendations. The aim of this review is to present a summary of oncogenic gene fusions, with a focus on fusions that affect tyrosine kinase signaling, and to highlight the importance of testing for oncogenic fusions. We present an overview of the identification of oncogenic gene fusions and therapies approved for the treatment of cancers harboring gene fusions, and summarize data regarding treating fusion-positive cancers with no current targeted therapies and clinical studies of fusion-positive cancers. Although treatment options may be limited for patients with rare alterations, healthcare professionals should identify patients most likely to benefit from oncogenic gene fusion testing and initiate the appropriate targeted therapy to achieve optimal treatment outcomes.
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Affiliation(s)
- Stephen V Liu
- Division of Hematology and Oncology, Georgetown University, Washington, DC, USA.
| | - Misako Nagasaka
- Division of Hematology Oncology, Department of Medicine, University of California Irvine School of Medicine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, Orange, CA, USA
| | - Judith Atz
- Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
| | - Flavio Solca
- Boehringer Ingelheim RCV GmbH & Co.KG, Vienna, Austria
| | - Leonhard Müllauer
- Department of Pathology, Medical University of Vienna, 1090, Vienna, Austria
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Nikolova-Mladenova B, Mihaylova R, Atanasova M, Zhivkova Z, Doytchinova I. Salicylaldehyde Benzoylhydrazones with Anticancer Activity and Selectivity: Design, Synthesis, and In Vitro Evaluation. Molecules 2025; 30:1015. [PMID: 40076242 PMCID: PMC11901818 DOI: 10.3390/molecules30051015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/19/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Dimethoxy derivatives of salicylaldehyde benzoylhydrazone containing a methoxy group on both aromatic rings were designed and synthesized. The compounds were obtained in high yields, and their structures were confirmed by elemental analysis and various spectral techniques. In vitro evaluation of dimethoxy hydrazones demonstrated potent activity against the leukemic cell lines at low micro- and nanomolar concentrations. Remarkably, two dimethoxy analogs showed exceptional antileukemic selectivity, with no toxicity observed in normal human embryonic kidney HEK-293 cells. In silico modeling identified likely interactions with the target, human cAbl kinase, and suggested a possible mechanism for their antileukemic activity.
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Affiliation(s)
- Boryana Nikolova-Mladenova
- Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria; (M.A.); (Z.Z.); (I.D.)
| | - Rositsa Mihaylova
- Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria;
| | - Mariyana Atanasova
- Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria; (M.A.); (Z.Z.); (I.D.)
| | - Zvetanka Zhivkova
- Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria; (M.A.); (Z.Z.); (I.D.)
| | - Irini Doytchinova
- Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria; (M.A.); (Z.Z.); (I.D.)
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Phan TAT, Ngo KKH, Nguyen TCT, Mai TT, Nguyen HD, Duong TT, Tran LP, Duong TT, Huynh TKC, Koroleva EV, Ignatovich ZV, Ermolinskaya AL, Nguyen HP, Nguyen THA, Ton AK, Do TH, Hoang TKD. 2-Amino-4,6-diarylpyrimidines as potential chronic myeloid leukemia cell inhibitors targeting anti-ABL1 kinase: microwave-assisted synthesis, biological evaluation, molecular docking, and dynamics studies. RSC Adv 2025; 15:4458-4471. [PMID: 39931407 PMCID: PMC11808659 DOI: 10.1039/d4ra08330j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 01/27/2025] [Indexed: 02/13/2025] Open
Abstract
In this work, a simple and mild process was used to synthesize a series of 2-amino-4,6-diarylpyrimidine derivatives, 1a-1q, whose structures were verified by FTIR, 1D- and 2D-NMR, and HRMS techniques, to investigate and develop anticancer agents. Under microwave irradiation, a two-step process was carried out, consisting of aldol condensation of benzaldehydes and acetophenones to produce intermediate chalcones and ring closure condensation of chalcones and guanidine hydrochloride. Each generated compound's anticancer activity against the human chronic myelocytic leukemia K562 cancer cell line was investigated in vitro to determine the active compounds, which were subsequently evaluated for inhibiting the ABL1 tyrosine kinase. According to these findings, compound 1e demonstrated considerable inhibition against K562 cancer cells and ABL1 tyrosine kinase at IC50 values of 8.77 ± 0.55 μM and 3.35 ± 0.58 μM, respectively. The molecular docking on wild-type and mutant type ABL1 (PDB ID 2HYY and 5MO4) investigation indicated that 1e and 1g interacted with amino acids. It formed stable hydrogen bonds and π-π linkages with crucial residues in the active site of the enzyme. Moreover, the stability of these enzyme-ligand complexes was confirmed using molecular dynamics simulations. These findings suggested that compounds 1e and 1g can be considered promising cancer treatment agents.
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Affiliation(s)
- Thi-Anh-Truc Phan
- Institute of Chemical Technology, Vietnam Academy of Science and Technology No. 1A, TL29 St., Thanh Loc Ward, Dist. 12 Ho Chi Minh City 70000 Vietnam
- Ton Duc Thang University No. 19, Nguyen Huu Tho St., Tan Hung Ward, Dist. 7 Ho Chi Minh City 70000 Vietnam
| | - Kim-Khanh-Huy Ngo
- Institute of Chemical Technology, Vietnam Academy of Science and Technology No. 1A, TL29 St., Thanh Loc Ward, Dist. 12 Ho Chi Minh City 70000 Vietnam
| | - Thi-Cam-Thu Nguyen
- Institute of Chemical Technology, Vietnam Academy of Science and Technology No. 1A, TL29 St., Thanh Loc Ward, Dist. 12 Ho Chi Minh City 70000 Vietnam
| | - Thanh-Tan Mai
- University of Medicine and Pharmacy at Ho Chi Minh City No. 41, Dinh Tien Hoang St., Ben Nghe Ward, Dist. 1 Ho Chi Minh City 70000 Vietnam
| | - Hai-Dang Nguyen
- University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology No. 18, Hoang Quoc Viet St., Nghia Do Ward, Cau Giay District Ha Noi City 100000 Vietnam
| | - Thu-Trang Duong
- University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology No. 18, Hoang Quoc Viet St., Nghia Do Ward, Cau Giay District Ha Noi City 100000 Vietnam
| | - Le-Phu Tran
- Institute of Chemical Technology, Vietnam Academy of Science and Technology No. 1A, TL29 St., Thanh Loc Ward, Dist. 12 Ho Chi Minh City 70000 Vietnam
- Ton Duc Thang University No. 19, Nguyen Huu Tho St., Tan Hung Ward, Dist. 7 Ho Chi Minh City 70000 Vietnam
| | - Thanh-Tuyen Duong
- Institute of Chemical Technology, Vietnam Academy of Science and Technology No. 1A, TL29 St., Thanh Loc Ward, Dist. 12 Ho Chi Minh City 70000 Vietnam
- Ton Duc Thang University No. 19, Nguyen Huu Tho St., Tan Hung Ward, Dist. 7 Ho Chi Minh City 70000 Vietnam
| | - Thi-Kim-Chi Huynh
- Institute of Chemical Technology, Vietnam Academy of Science and Technology No. 1A, TL29 St., Thanh Loc Ward, Dist. 12 Ho Chi Minh City 70000 Vietnam
| | - Elena V Koroleva
- Institute of Chemistry of New Materials, National Academy of Sciences of Belarus 36, F. Skorina St. Minsk 220141 Republic of Belarus
| | - Zhanna V Ignatovich
- Institute of Chemistry of New Materials, National Academy of Sciences of Belarus 36, F. Skorina St. Minsk 220141 Republic of Belarus
| | - Anastasiya L Ermolinskaya
- Institute of Chemistry of New Materials, National Academy of Sciences of Belarus 36, F. Skorina St. Minsk 220141 Republic of Belarus
| | - Hoang-Phuc Nguyen
- Institute of Chemical Technology, Vietnam Academy of Science and Technology No. 1A, TL29 St., Thanh Loc Ward, Dist. 12 Ho Chi Minh City 70000 Vietnam
| | - Thi-Hong-An Nguyen
- Institute of Chemical Technology, Vietnam Academy of Science and Technology No. 1A, TL29 St., Thanh Loc Ward, Dist. 12 Ho Chi Minh City 70000 Vietnam
| | - Anh-Khoa Ton
- Institute of Chemical Technology, Vietnam Academy of Science and Technology No. 1A, TL29 St., Thanh Loc Ward, Dist. 12 Ho Chi Minh City 70000 Vietnam
| | - Tuong-Ha Do
- Ton Duc Thang University No. 19, Nguyen Huu Tho St., Tan Hung Ward, Dist. 7 Ho Chi Minh City 70000 Vietnam
| | - Thi-Kim-Dung Hoang
- Institute of Chemical Technology, Vietnam Academy of Science and Technology No. 1A, TL29 St., Thanh Loc Ward, Dist. 12 Ho Chi Minh City 70000 Vietnam
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Bhattacharjee U, Singh C, Jandial A, Lekshmon KS, Mishra K, Sandal R, Nampoothiri R, Naseem S, Suri V, Jain A, Lad DP, Prakash G, Khadwal A, Malhotra P. Maternal and Foetal Outcomes of Newly Diagnosed Chronic Myeloid Leukemia During Pregnancy and its Long-Term Impact. Indian J Hematol Blood Transfus 2024; 40:687-693. [PMID: 39469160 PMCID: PMC11512983 DOI: 10.1007/s12288-024-01743-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 02/24/2024] [Indexed: 10/30/2024] Open
Abstract
Diagnosing Chronic Myeloid Leukemia (CML) during pregnancy presents challenges for both haematologists and obstetricians. Limited data exists regarding the management of pregnancy-associated CML in low- and middle-income countries (LMICs). This study aimed to assess pregnancy, foetal, and long-term disease outcomes in female patients newly diagnosed with CML in the chronic phase (CML-CP) during pregnancy. A retrospective analysis was conducted on female CML-CP patients presenting between January 2002 and December 2022 at our institution. Inclusion criteria encompassed patients newly diagnosed with CML-CP during pregnancy. Data pertaining to pregnancy outcomes, foetal development, and disease progression were analysed through a comprehensive review of medical records. Among the female CML patients, thirteen were diagnosed with CML-CP during pregnancy. The median patient age was 24 years (range: 20-35). Diagnoses occurred in the first trimester for six patients, the second trimester for three, and the third trimester for four. Outcomes included five elective terminations (38.5%), five pre-term deliveries (38.5%), and three full-term deliveries (23.1%). Management included observation in 6 (46.3%), hydroxyurea in 3 (23.1%), imatinib in 3 (23.1%) and Interferon-α (IFN-α) in 1 (7.7%) patients. Noteworthy obstetric complications encompassed threatened abortion with intrauterine foetal death (IUFD) (1 patient), intrauterine growth retardation (IUGR) (3 patients), oligohydramnios (2 patients), antepartum haemorrhage (1 patient), placental abruption (1 patient), and postpartum haemorrhage (3 patients). At a median follow-up duration of 10.7 years, 11 patients were at a major molecular remission (including 2 patients with deep molecular remission) and two patients progressed to the accelerated phase. The diagnosis and management of CML during pregnancy is a complex and challenging task that requires collaboration between haematologists and obstetricians. Effective management of newly diagnosed CML-CP during pregnancy is contingent on the trimester of presentation. Further research and collaboration are warranted to develop standardised guidelines for managing pregnancy-associated CML, particularly in LMICs.
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Affiliation(s)
- Urmimala Bhattacharjee
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Charanpreet Singh
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Aditya Jandial
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - K. S. Lekshmon
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Kundan Mishra
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Rajeev Sandal
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Ram Nampoothiri
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Shano Naseem
- Department of Haematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vanita Suri
- Department of Obstetrics and Gynaecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Arihant Jain
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Deepesh P. Lad
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Gaurav Prakash
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Alka Khadwal
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Pankaj Malhotra
- Department of Clinical Haematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
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Hollenbach L, Rogahn J, le Coutre P, Schulze S, Muegge LO, Geissler J, Gruen J, Junghanss C, Felser S. Physical exercise recommendations for patients with chronic myeloid leukemia based on individual preferences identified in a large international patient survey study of the East German Study Group for Hematology and Oncology (OSHO #97). Front Oncol 2024; 14:1345050. [PMID: 38450192 PMCID: PMC10915004 DOI: 10.3389/fonc.2024.1345050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 02/06/2024] [Indexed: 03/08/2024] Open
Abstract
Background Tyrosine kinase inhibitors (TKIs) have significantly lowered mortality of chronic myeloid leukemia (CML) patients adjusting life expectancy to that of the standard population. However, CML and its treatment with TKIs causes a high disease burden. Physical exercise (PE) could be a non-pharmacological approach to reducing these and improving quality of life. Purpose The aim of this study was to determine the individual disease burden as well as PE preferences of CML patients and to deduce thereof specific PE recommendations. Methods This multicenter survey was conducted in cooperation with the LeukaNET/Leukemia-patient network including CML patients aged ≥18 years (German Registry of Clinical Trials, DRKS00023698). The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1-30 (mild), 31-70 (moderate), or 71-100 (severe). Information about patients' PE needs and preferences depending on their motivation was recorded. Results A total of 212 questionnaires were analyzed (52% female, median age 54 years). The prevalence of moderate-to-severe symptoms was 49% for fatigue, 40% for musculoskeletal pain, and 37% for concentration problems. Other commonly reported symptoms included skin reactions (42%) and weight gain (24%). The proportion of overweight/obese patients was 52%. Half of all respondents requested more information regarding PE. Patients with CML preferred individual training (82%), located outdoors (71%), at home (47%), or in an indoor swimming pool (31%). Regarding the training frequency, sports-inactive patients preferred a frequency of 1-2 training sessions per week, whereas sports-active patients preferred 3-4 sessions per week (p <0.001). Sports-inactive patients preferred a training time of 15-45 minutes, while sports-active patients preferred 30-60 minutes (p = 0.002). Subsequently, PE recommendations were developed for patients with CML. Combined resistance and endurance training (moderate intensity twice per week for 30 minutes) was recommended for beginners. Obese patients should prioritize joint-relieving sports. To reduce the risk of skin reactions, direct sunlight and possibly water sports should be avoided, and UV protection should be used. Conclusion Counseling and motivation of CML patients to be physically active should be part of the standard of care as well as support for implementation.
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Affiliation(s)
- Lina Hollenbach
- Department of Internal Medicine, Clinic III – Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Julia Rogahn
- Department of Internal Medicine, Clinic III – Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Philipp le Coutre
- Department of Hematology, Oncology, and Cancer Immunology, Campus Virchow‐Klinikum, Charité ‐ Universitätsmedizin Berlin, Berlin, Germany
| | - Susann Schulze
- Krukenberg Cancer Center Halle, University Hospital Halle, Halle (Saale), Germany
- Department of Medicine, Medical Clinic II, Carl-von-Basedow-Klinikum, Merseburg, Germany
| | - Lars-Olof Muegge
- Department of Internal Medicine III, Heinrich Braun Klinikum Zwickau, Zwickau, Germany
| | - Jan Geissler
- LeukaNET/Leukemia-Online e. V., Riemering, Germany
| | - Julia Gruen
- Department of Internal Medicine, Clinic III – Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Christian Junghanss
- Department of Internal Medicine, Clinic III – Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Sabine Felser
- Department of Internal Medicine, Clinic III – Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany
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Yakobson A, Neime AE, Abu Saleh O, Al Athamen K, Shalata W. Bullous Pemphigoid Occurring after Stopping Imatinib Therapy of CML: Is a Continuation of Post-Treatment Follow-Up Needed? Clin Pract 2023; 13:1082-1089. [PMID: 37736932 PMCID: PMC10514788 DOI: 10.3390/clinpract13050096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/24/2023] [Accepted: 09/04/2023] [Indexed: 09/23/2023] Open
Abstract
Advancements and the use of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of Chronic Myeloid Leukemia (CML), achieving unprecedented success rates and expanding their applications to various neoplasms. However, the use of TKIs is not without its drawbacks. Skin, gastrointestinal, and central nervous systems are particularly susceptible to adverse effects, including a higher incidence of autoimmune responses in treated individuals. In this report, we present a unique case of bullous pemphigoid, a rare autoimmune disease, which has not been previously associated with TKI therapy as an adverse effect, particularly appearing after discontinuing Imatinib® treatment.
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Affiliation(s)
- Alexander Yakobson
- The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Ben Gurion University, Beer Sheva 84105, Israel
| | - Ala Eddin Neime
- Department of Internal Medicine, Soroka Medical Center & Ben-Gurion University, Beer Sheva 84105, Israel
| | - Omar Abu Saleh
- Dermatology and Venereology, The Emek Medical Centre, Afula 18341, Israel
| | - Kayed Al Athamen
- The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Ben Gurion University, Beer Sheva 84105, Israel
| | - Walid Shalata
- The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Ben Gurion University, Beer Sheva 84105, Israel
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Jiang Y, Yao J, Yao Z, Huang Y, Li Z, Fan Z, Zhou Y, Li G, Li Z, Xu B. CD4 T cells in chronic myeloid leukemia present MHC class II-dependent and IFN-γ-dependent cytotoxic capacity. Med Oncol 2023; 40:253. [PMID: 37498412 DOI: 10.1007/s12032-023-02123-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/05/2023] [Indexed: 07/28/2023]
Abstract
At present, many therapeutic schemes have been used to improve the prognosis of patients with chronic myeloid leukemia (CML), but response remains poor in a small group of patients. CD4 T cell-mediated cytotoxicity has been found in various autoimmune diseases. This study analyzed the characteristics of CD4 T cell mediated cytotoxicity in CML patients and healthy people. The cytotoxicity of CD4 T cells was tested in using two CML cell lines, including the MHC class II-deficient K562 cells and the MHC class II-expressing KU812 cells. CD4 T cell-mediated lysis was minimal in K562 cells but was much higher in KU812 cells. In CML patients, the level of CD4 T cell-mediated lysis was limited to a certain level. Interestingly, pre-treating KU812 cells with IFN-γ could significantly elevate the expression of MHC class II and elevate the level of CD4 T cell-mediated lysis. Overall, these data indicated CD4 T cells could become a potential candidate for cytotoxic elimination of CML cells.
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Affiliation(s)
- Yirong Jiang
- Department of Hematology, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, P.R. China
| | - Jingwei Yao
- Department of Hematology, Institute of Hematology, School of Medicine, The First Affiliated Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, Fujian, 361003, P.R. China
| | - Zhuoxin Yao
- Department of Hematology, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, P.R. China
| | - Yueting Huang
- Department of Hematology, Institute of Hematology, School of Medicine, The First Affiliated Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, Fujian, 361003, P.R. China
| | - Zhangkun Li
- Department of Hematology, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, P.R. China
| | - Ziying Fan
- Department of Hematology, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, P.R. China
| | - Yong Zhou
- Department of Hematology, Institute of Hematology, School of Medicine, The First Affiliated Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, Fujian, 361003, P.R. China
| | - Guowei Li
- Department of Hematology, Huizhou Municipal Central Hospital, Huizhou, 516001, P.R. China
| | - Zhifeng Li
- Department of Hematology, Institute of Hematology, School of Medicine, The First Affiliated Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, Fujian, 361003, P.R. China.
| | - Bing Xu
- Department of Hematology, Institute of Hematology, School of Medicine, The First Affiliated Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, Fujian, 361003, P.R. China.
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Li Y, Deng K, Kaner J, Geyer JT, Ouseph M, Fang F, Xu K, Roboz G, Kluk MJ. Detection of Hybrid Fusion Transcripts, Aberrant Transcript Expression, and Specific Single Nucleotide Variants in Acute Leukemia and Myeloid Disorders with Recurrent Gene Rearrangements. Pathobiology 2023; 91:76-88. [PMID: 37490880 PMCID: PMC11524540 DOI: 10.1159/000532085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 06/19/2023] [Indexed: 07/27/2023] Open
Abstract
INTRODUCTION A variety of gene rearrangements and molecular alterations are key drivers in the pathobiology of acute leukemia and myeloid disorders; current classification systems increasingly incorporate these findings in diagnostic algorithms. Therefore, clinical laboratories require versatile tools, which can detect an increasing number and variety of molecular and cytogenetic alterations of clinical significance. METHODS We validated an RNA-based next-generation sequencing (NGS) assay that enables the detection of: (i) numerous hybrid fusion transcripts (including rare/novel gene partners), (ii) aberrantly expressed EVI1 (MECOM) and IKZF1 (Del exons 4-7) transcripts, and (iii) hotspot variants in KIT, ABL1, NPM1 (relevant in the context of gene rearrangement status). RESULTS For hybrid fusion transcripts, the assay showed 98-100% concordance for known positive and negative samples, with an analytical sensitivity (i.e., limit of detection) of approximately 0.8% cells. Samples with underlying EVI1 (MECOM) translocations demonstrated increased EVI1 (MECOM) expression. Aberrant IKZF1 (Del exons 4-7) transcripts detectable with the assay were also present on orthogonal reverse transcription PCR. Specific hotspot mutations in KIT, ABL1, and NPM1 detected with the assay showed 100% concordance with orthogonal testing. Lastly, several illustrative samples are included to highlight the assay's clinically relevant contributions to patient workup. CONCLUSION Through its ability to simultaneously detect various gene rearrangements, aberrantly expressed transcripts, and hotspot mutations, this RNA-based NGS assay is a valuable tool for clinical laboratories to supplement other molecular and cytogenetic methods used in the diagnostic workup and in clinical research for patients with acute leukemia and myeloid disorders.
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Affiliation(s)
- Yuewei Li
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Kaifang Deng
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Justin Kaner
- Department of Medicine, Hematology and Medical Oncology, Clinical and Translational Leukemia Program, Weill Cornell Medicine, New York, NY, USA
| | - Julia T. Geyer
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Madhu Ouseph
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Frank Fang
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Kemin Xu
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Gail Roboz
- Department of Medicine, Hematology and Medical Oncology, Clinical and Translational Leukemia Program, Weill Cornell Medicine, New York, NY, USA
| | - Michael J. Kluk
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
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Loh KP, McLaughlin EM, Krok-Schoen JL, Odejide OO, El-Jawahri A, Qi L, Shadyab AH, Johnson LG, Paskett ED. Correlates of common concerns in older cancer survivors of leukemia and lymphoma: results from the WHI LILAC study. J Cancer Surviv 2023; 17:769-780. [PMID: 35982359 PMCID: PMC9938088 DOI: 10.1007/s11764-022-01249-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 08/12/2022] [Indexed: 11/24/2022]
Abstract
PURPOSE Older survivors of leukemia and lymphoma often experience long-term effects of chemotherapy. We described common concerns related to their cancer and treatment in older survivors of leukemia and non-Hodgkin lymphoma (NHL) and assessed correlates of these concerns. METHODS We utilized data from the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study that recruited post-menopausal women aged 50-79. Participants diagnosed with leukemia and NHL were included (n = 420). They were asked about 14 areas of current concerns related to their cancer and treatment and to rate each from 0 (no concern) to 2 (major concern), with total scores ranging from 0 to 28. Linear regression was used to assess factors correlated with the concern score, and logistic regression for factors correlated with the three most common concerns. RESULTS Mean age at assessment was 81 years (range 69-99); 72% reported at least one concern, and median concern score among these survivors was 3.5 (Q1-Q3 2-5). Factors significantly correlated with concern scores were sadness, pain, distress, higher prior symptom count, and loneliness (all p < 0.05). Significant factors correlated with common concerns were (1) fatigue/sleep: sadness/depression, distress, higher prior symptom count, greater loneliness, and worse physical functioning; (2) physical functioning/activity: older age, public insurance, higher body mass index, pain, worse QoL, and higher treatment-related comorbidities; (3) memory/concentration: prior chemotherapy or radiation, worse QoL, higher prior symptom count, and greater loneliness (all p < 0.05). CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS Almost three-quarters of older survivors of leukemia and lymphoma reported at least one concern; a multifaceted intervention may be needed to address these concerns.
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Affiliation(s)
- Kah Poh Loh
- Division of Hematology/Oncology, Department of Medicine, James P. Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY, 14642, USA.
| | - Eric M McLaughlin
- Center for Biostatistics, The Ohio State University, Columbus, OH, USA
| | - Jessica L Krok-Schoen
- Division of Health Sciences, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Oreofe O Odejide
- Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Center for Lymphoma, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Areej El-Jawahri
- Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Lihong Qi
- Department of Public Health Sciences, University of California Davis, Davis, CA, USA
| | - Aladdin H Shadyab
- Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA
| | - Lisa G Johnson
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Electra D Paskett
- Division of Epidemiology, College of Public Health, The Ohio State University, Columbus, OH, USA
- Division of Cancer Prevention and Control, College of Medicine, The Ohio State University, Columbus, OH, USA
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10
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Elhadary M, Elsabagh AA, Ferih K, Elsayed B, Elshoeibi AM, Kaddoura R, Akiki S, Ahmed K, Yassin M. Applications of Machine Learning in Chronic Myeloid Leukemia. Diagnostics (Basel) 2023; 13:diagnostics13071330. [PMID: 37046547 PMCID: PMC10093579 DOI: 10.3390/diagnostics13071330] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/11/2023] [Accepted: 03/15/2023] [Indexed: 04/14/2023] Open
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by dysregulated growth and the proliferation of myeloid cells in the bone marrow caused by the BCR-ABL1 fusion gene. Clinically, CML demonstrates an increased production of mature and maturing granulocytes, mainly neutrophils. When a patient is suspected to have CML, peripheral blood smears and bone marrow biopsies may be manually examined by a hematologist. However, confirmatory testing for the BCR-ABL1 gene is still needed to confirm the diagnosis. Despite tyrosine kinase inhibitors (TKIs) being the mainstay of treatment for patients with CML, different agents should be used in different patients given their stage of disease and comorbidities. Moreover, some patients do not respond well to certain agents and some need more aggressive courses of therapy. Given the innovations and development that machine learning (ML) and artificial intelligence (AI) have undergone over the years, multiple models and algorithms have been put forward to help in the assessment and treatment of CML. In this review, we summarize the recent studies utilizing ML algorithms in patients with CML. The search was conducted on the PubMed/Medline and Embase databases and yielded 66 full-text articles and abstracts, out of which 11 studies were included after screening against the inclusion criteria. The studies included show potential for the clinical implementation of ML models in the diagnosis, risk assessment, and treatment processes of patients with CML.
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Affiliation(s)
- Mohamed Elhadary
- College of Medicine, QU Health, Qatar University, Doha 2713, Qatar
| | | | - Khaled Ferih
- College of Medicine, QU Health, Qatar University, Doha 2713, Qatar
| | - Basel Elsayed
- College of Medicine, QU Health, Qatar University, Doha 2713, Qatar
| | | | - Rasha Kaddoura
- Pharmacy Department, Heart Hospital, Hamad Medical Corporation (HMC), Doha 3050, Qatar
| | - Susanna Akiki
- Diagnostic Genomic Division, Hamad Medical Corporation (HMC), Doha 3050, Qatar
| | - Khalid Ahmed
- Department of Hematology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation (HMC), Doha 3050, Qatar
| | - Mohamed Yassin
- Hematology Section, Medical Oncology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation (HMC), Doha 3050, Qatar
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11
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Asif M, Hussain A, Ali I, Baloch Z, Rasool M, Achakzai NM. Cytogenetical and hematological analysis of chronic myelogenous leukemia patients with a novel case 52XX, t (1;9;22) (q23.3; q34; q11.2), +6, +8, i(9) (q10;q10), +18,+19,+21+der22 t(9;22)(q34;q11). Medicine (Baltimore) 2022; 101:e31670. [PMID: 36397339 PMCID: PMC9666132 DOI: 10.1097/md.0000000000031670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
(9;22) (q34; q11) translocation is appear in above ninety percent of chronic myelogenous leukemia patients while variant/complex translocations were observed in almost 5% to 8% chronic myelogenous leukemia (CML) positive cases. Gleevec (Imatinib Mesylate) is the first choice breakpoint cluster region (BCR)/ABL targeted oral therapy that produced a complete response almost in 71% to 80% of patients affected with CML. A complete blood count (CBC) of 37 patients was done during diagnosis, however only 21 showed abnormal CBC values which were selected for the study. Karyotyping study using bone marrow samples was performed on 21 CML patients for the conformation of 9;22, however, fluorescence in situ hybridisation was performed for the detection of the BCR-ABL fusion gene of 15 patients. Out of 21, 17 patients showed Ph-positive (9;22) (q34; q11) translocation. Sixteen CML patients showed standard translocation however only CML patients showed a three-way variant/complex translocation with six additional chromosomes, 52XX, t(1;9;22) (q23.3;q34;q11),+6,+8, i(9)(q10;q10), +18,+19,+21 + der22 t(9;22)(q34;q11)). Here we report we report a novel case of six additional chromosomes with the three-way translocation of 52XX, t(1;9;22) (q23.3;q34;q11),+6,+8, i(9)(q10;q10), +18,+19,+21 + der22 t(9;22)(q34;q11) in blast phase.
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Affiliation(s)
- Muhammad Asif
- Department of Biotechnology, BUITEMS, Quetta, Pakistan
- Office of Research Innovation and Commercialization, BUITEMS, Quetta, Pakistan
| | - Abrar Hussain
- Department of Biotechnology, BUITEMS, Quetta, Pakistan
- * Correspondence: Niaz M. Achakzai, Department of Molecular Biology, DNA Section, Legal Medicine Directorate, Ministry of Public Health, Kabul, Afghanistan (e-mail: )
| | - Irfan Ali
- Centre of Agricultural Biochemistry and Biotechnology, University of Agriculture Faisalabad, Faisalabad, Pakistan
| | - Zarak Baloch
- Faisalabad Medical University, Faisalabad, Pakistan
| | - Mahmood Rasool
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Niaz M. Achakzai
- Department of Molecular Biology, DNA Section, Legal Medicine Directorate, Ministry of Public Health, Kabul, Afghanistan
- * Correspondence: Niaz M. Achakzai, Department of Molecular Biology, DNA Section, Legal Medicine Directorate, Ministry of Public Health, Kabul, Afghanistan (e-mail: )
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12
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Hnatiuk AP, Bruyneel AA, Tailor D, Pandrala M, Dheeraj A, Li W, Serrano R, Feyen DA, Vu MM, Amatya P, Gupta S, Nakauchi Y, Morgado I, Wiebking V, Liao R, Porteus MH, Majeti R, Malhotra SV, Mercola M. Reengineering Ponatinib to Minimize Cardiovascular Toxicity. Cancer Res 2022; 82:2777-2791. [PMID: 35763671 PMCID: PMC9620869 DOI: 10.1158/0008-5472.can-21-3652] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 03/29/2022] [Accepted: 05/24/2022] [Indexed: 01/07/2023]
Abstract
Small molecule tyrosine kinase inhibitors (TKI) have revolutionized cancer treatment and greatly improved patient survival. However, life-threatening cardiotoxicity of many TKIs has become a major concern. Ponatinib (ICLUSIG) was developed as an inhibitor of the BCR-ABL oncogene and is among the most cardiotoxic of TKIs. Consequently, use of ponatinib is restricted to the treatment of tumors carrying T315I-mutated BCR-ABL, which occurs in chronic myeloid leukemia (CML) and confers resistance to first- and second-generation inhibitors such as imatinib and nilotinib. Through parallel screening of cardiovascular toxicity and antitumor efficacy assays, we engineered safer analogs of ponatinib that retained potency against T315I BCR-ABL kinase activity and suppressed T315I mutant CML tumor growth. The new compounds were substantially less toxic in human cardiac vasculogenesis and cardiomyocyte contractility assays in vitro. The compounds showed a larger therapeutic window in vivo, leading to regression of human T315I mutant CML xenografts without cardiotoxicity. Comparison of the kinase inhibition profiles of ponatinib and the new compounds suggested that ponatinib cardiotoxicity is mediated by a few kinases, some of which were previously unassociated with cardiovascular disease. Overall, the study develops an approach using complex phenotypic assays to reduce the high risk of cardiovascular toxicity that is prevalent among small molecule oncology therapeutics. SIGNIFICANCE Newly developed ponatinib analogs retain antitumor efficacy but elicit significantly decreased cardiotoxicity, representing a therapeutic opportunity for safer CML treatment.
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MESH Headings
- Antineoplastic Agents/adverse effects
- Cardiotoxicity/drug therapy
- Cardiotoxicity/etiology
- Cardiotoxicity/prevention & control
- Drug Resistance, Neoplasm
- Fusion Proteins, bcr-abl/genetics
- Humans
- Imidazoles
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Protein Kinase Inhibitors/adverse effects
- Pyridazines/pharmacology
- Pyridazines/therapeutic use
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Affiliation(s)
- Anna P. Hnatiuk
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California
| | - Arne A.N. Bruyneel
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California
| | - Dhanir Tailor
- Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health Sciences University School of Medicine, Portland, Oregon
| | - Mallesh Pandrala
- Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health Sciences University School of Medicine, Portland, Oregon
| | - Arpit Dheeraj
- Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health Sciences University School of Medicine, Portland, Oregon
| | - Wenqi Li
- Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health Sciences University School of Medicine, Portland, Oregon
| | - Ricardo Serrano
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California
| | - Dries A.M. Feyen
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California
| | - Michelle M. Vu
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California
| | - Prashila Amatya
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California
| | - Saloni Gupta
- Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health Sciences University School of Medicine, Portland, Oregon
| | - Yusuke Nakauchi
- Division of Hematology Institute for Stem cell Biology and Regenerative Medicine, Stanford School of Medicine, California
| | - Isabel Morgado
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California
| | - Volker Wiebking
- Department of Pediatrics, Stanford School of Medicine, Stanford, California
| | - Ronglih Liao
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California
| | - Matthew H. Porteus
- Department of Pediatrics, Stanford School of Medicine, Stanford, California
| | - Ravindra Majeti
- Division of Hematology Institute for Stem cell Biology and Regenerative Medicine, Stanford School of Medicine, California
| | - Sanjay V. Malhotra
- Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health Sciences University School of Medicine, Portland, Oregon
| | - Mark Mercola
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California
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13
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Hu T, Zhou G, Li W. Association Between the Individual and Combined Effects of the GSTM1 and GSTT1 Polymorphisms and Risk of Leukemia: A Meta-Analysis. Front Genet 2022; 13:898937. [PMID: 35938012 PMCID: PMC9355274 DOI: 10.3389/fgene.2022.898937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 06/06/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Fourteen meta-analyses reported the individual effects of the GSTM1 and GSTT1 polymorphisms on leukemia risk. However, over 40 studies were not included in previously published meta-analyses. Moreover, one key aspect was that previous meta-analyses did not conduct the false-positive test on the aforementioned issues. Furthermore, previous meta-analyses did not observe the combined effects of GSTM1 present/null and GSTT1 present/null polymorphism with leukemia risk. Therefore, we conducted the current study to further analyze these associations. Objectives: This study aimed to investigate the association between the individual and combined effects of the GSTM1 present/null and GSTT1 present/null polymorphisms and the risk of leukemia. Methods: A meta-analysis was performed applying Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Moreover, false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP) were applied to investigate the false-positive results. Results: The individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes were associated with a significantly increased leukemia risk in overall and several subgroup analyses, such as Asians, Caucasians, and so on. Then, further analysis was conducted using FPRP and BFDP. Significant associations were considered as "positive" results on the GSTM1 null genotype with leukemia risk in overall populations (FPRP < 0.001 and BFDP = 0.006), Asians (FPRP < 0.001 and BFDP < 0.001), and East Asian population (FPRP < 0.001 and BFDP = 0.002). For the GSTT1 null genotype, significant associations were regarded "positive" results in overall populations, acute myeloid leukemia (AML), Asians, and East Asian population. For the combined effects of the GSTM1 and GSTT1 polymorphisms, significant associations were also considered "positive" results in the overall analysis of Asians, Indians, and East Asian population. Conclusion: This study strongly indicates that the individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes are associated with increased leukemia risk in Asians, especially in the East Asian population; the GSTT1 null genotype is associated with increased AML risk; the combined effects of the two genes are associated with increased leukemia risk in Indians.
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Affiliation(s)
- Ting Hu
- Department of Hematology, Pingxiang People’s Hospital, Pingxiang, China
| | - Guozhong Zhou
- Department of Cardiology, Pingxiang People’s Hospital, Pingxiang, China
| | - Wenjin Li
- Department of Hematology, Pingxiang People’s Hospital, Pingxiang, China
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14
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Pettit K, Rezazadeh A, Atallah EL, Radich J. Management of Myeloproliferative Neoplasms in the Molecular Era: From Research to Practice. Am Soc Clin Oncol Educ Book 2022; 42:1-19. [PMID: 35658498 DOI: 10.1200/edbk_349615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The 1960 discovery of the Philadelphia chromosome in chronic myeloid leukemia (CML) marked the beginning of the modern genomic era of oncology. In the following years, the molecular underpinnings of CML were unraveled, culminating in the development of the first molecularly targeted therapy: imatinib. Imatinib revolutionized CML management, inducing deep molecular responses for most patients and aligning survival curves with those of age-matched control participants. Five additional tyrosine kinase inhibitors are now approved for CML: dasatinib, nilotinib, bosutinib, ponatinib, and asciminib (approved October 2021). The 2005 discovery of JAK2 mutations in myelofibrosis (MF) sparked enthusiasm that molecularly targeted therapies could have a similar impact in that disease. Three JAK inhibitors are now available for MF: ruxolitinib, fedratinib, and pacritinib (approved February 2022). JAK inhibitors are helpful for improving symptoms and splenomegaly but still only scratch the surface of MF pathophysiology. Clinical research testing novel agents, next-generation JAK inhibitors, and combinations of JAK inhibitors plus novel agents is moving at a tremendous pace in the hope that outcomes for patients with MF may mirror those with CML one day. This review provides an update on the status of clinical care and research for MF and addresses ongoing issues related to CML management.
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Affiliation(s)
| | | | | | - Jerald Radich
- Global Oncology Program and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
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15
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Brown NJ, Kaya EA, Haymore JG, Gioia LV. Bilateral vision loss as initial presentation of chronic myeloid leukemia in a young adult: A case report and review of the literature. Am J Ophthalmol Case Rep 2022; 26:101579. [PMID: 35602313 PMCID: PMC9114453 DOI: 10.1016/j.ajoc.2022.101579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 04/06/2022] [Accepted: 05/05/2022] [Indexed: 11/15/2022] Open
Abstract
Purpose To report a case of bilateral vision loss as the primary presenting symptom of chronic myeloid leukemia in a young adult. Observations The 28-year-old male patient presented to clinic with visual acuity of 20/200 in both eyes after several months of episodic bilateral vision loss. Intraretinal and pre-retinal hemorrhages were appreciated, as well as Roth spots and peripheral neovascularization. Initial lab findings were consistent with a diagnosis of acute myeloid leukemia, later, upon bone marrow examination, the diagnosis was edited to chronic myeloid leukemia. Dasatinib therapy resulted in a complete hematologic resolution after six weeks. After intravitreal injections of bevacizumab in both eyes, visual acuity improved to 20/25 in the right eye and 20/20 in the left eye. Conclusion and importance After review, this is one of only a few reported cases of bilateral blurry vision as the primary presenting symptom of chronic myeloid leukemia in a young adult. Because visual disturbances occur more frequently in acute myeloid leukemia, and lab results may be inconclusive, careful consideration should be given to differentiate myelogenous leukemias, as the acute and chronic subtypes may present similarly.
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16
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Barbosa ADP, Rodrigues Martins M, Dewulf NDLS, Carneiro WJ, Oliveira FNMD, Lemes GA, Cunha MMBD, Cruz ADC, Cunha LCD. Pro-adherence complementary audiovisual educational intervention model for chronic myeloid leukemia patients treated with imatinib mesylate. J Oncol Pharm Pract 2022; 29:521-528. [PMID: 35044256 DOI: 10.1177/10781552211073894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Imatinib mesylate (IM) treatment adherence is a challenge, especially in an economic-social population neglected from developing countries. OBJECTIVE To create a new complementary audiovisual educational intervention model to improve IM treatment adherence of CML patients. METHODS Two adherence verification methods were applied before and after intervention: modified Morisky-Green test and molecular responses (BCR-ABL transcripts quantification). Adherence estimates were calculated using univariate and multivariate component analysis (MCA) for the socio-demographic and clinical characteristics of patients. RESULTS Modified Morisky-Green test results demonstrated a substantial increase of CML patient adherence from 23% (pre-film) to 65% (post-film). Greater improvement was obtained for patients presenting major molecular response (MMR) from 38% (pre-film) to 60% (post-film). Although slight gain for complete molecular response (CMR) from 23% (pre-film) to 26% (post-film) was achieved, it represents a total tumour regression. MCA identified that females <50 years-old, using less than two medications (no disease associated) and CMR condition were the most benefited with intervention. CONCLUSION Audiovisual educational intervention was an effective complementary pro-adherence model, activating patient memory and improving IM treatment adherence. Although this intervention shows effective, not all patients responded as expected, being necessary a combination of educational and clinical interventions to improve IM adherence.
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Affiliation(s)
- Adriana do Prado Barbosa
- Toxic-Pharmacological Studies and Research Center (NEPET), School of Pharmacy, 67824Federal University of Goiás, Goiânia, Brazil
| | - Marcelo Rodrigues Martins
- Toxic-Pharmacological Studies and Research Center (NEPET), School of Pharmacy, 67824Federal University of Goiás, Goiânia, Brazil
| | - Nathalie de Lourdes Souza Dewulf
- Toxic-Pharmacological Studies and Research Center (NEPET), School of Pharmacy, 67824Federal University of Goiás, Goiânia, Brazil
| | - Wilsione José Carneiro
- Toxic-Pharmacological Studies and Research Center (NEPET), School of Pharmacy, 67824Federal University of Goiás, Goiânia, Brazil
| | - Flávia Neri Meira de Oliveira
- Toxic-Pharmacological Studies and Research Center (NEPET), School of Pharmacy, 67824Federal University of Goiás, Goiânia, Brazil
| | - Guilherme Andrade Lemes
- Toxic-Pharmacological Studies and Research Center (NEPET), School of Pharmacy, 67824Federal University of Goiás, Goiânia, Brazil
| | | | - Alessandro de Carvalho Cruz
- Toxic-Pharmacological Studies and Research Center (NEPET), School of Pharmacy, 67824Federal University of Goiás, Goiânia, Brazil
| | - Luiz Carlos da Cunha
- Toxic-Pharmacological Studies and Research Center (NEPET), School of Pharmacy, 67824Federal University of Goiás, Goiânia, Brazil
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17
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Abdulmawjood B, Costa B, Roma-Rodrigues C, Baptista PV, Fernandes AR. Genetic Biomarkers in Chronic Myeloid Leukemia: What Have We Learned So Far? Int J Mol Sci 2021; 22:12516. [PMID: 34830398 PMCID: PMC8626020 DOI: 10.3390/ijms222212516] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/11/2021] [Accepted: 11/18/2021] [Indexed: 12/20/2022] Open
Abstract
Chronic Myeloid Leukemia (CML) is a rare malignant proliferative disease of the hematopoietic system, whose molecular hallmark is the Philadelphia chromosome (Ph). The Ph chromosome originates an aberrant fusion gene with abnormal kinase activity, leading to the buildup of reactive oxygen species and genetic instability of relevance in disease progression. Several genetic abnormalities have been correlated with CML in the blast phase, including chromosomal aberrations and common altered genes. Some of these genes are involved in the regulation of cell apoptosis and proliferation, such as the epidermal growth factor receptor (EGFR), tumor protein p53 (TP53), or Schmidt-Ruppin A-2 proto-oncogene (SRC); cell adhesion, e.g., catenin beta 1 (CTNNB1); or genes associated to TGF-β, such as SKI like proto-oncogene (SKIL), transforming growth factor beta 1 (TGFB1) or transforming growth factor beta 2 (TGFB2); and TNF-α pathways, such as Tumor necrosis factor (TNFA) or Nuclear factor kappa B subunit 1 (NFKB1). The involvement of miRNAs in CML is also gaining momentum, where dysregulation of some critical miRNAs, such as miRNA-451 and miRNA-21, which have been associated to the molecular modulation of pathogenesis, progression of disease states, and response to therapeutics. In this review, the most relevant genomic alterations found in CML will be addressed.
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Affiliation(s)
- Bilal Abdulmawjood
- i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; (B.A.); (B.C.); (C.R.-R.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
| | - Beatriz Costa
- i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; (B.A.); (B.C.); (C.R.-R.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
| | - Catarina Roma-Rodrigues
- i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; (B.A.); (B.C.); (C.R.-R.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
| | - Pedro V. Baptista
- i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; (B.A.); (B.C.); (C.R.-R.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
| | - Alexandra R. Fernandes
- i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; (B.A.); (B.C.); (C.R.-R.)
- UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
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Hu Y, Li Q, Hou M, Peng J, Yang X, Xu S. Magnitude and Temporal Trend of the Chronic Myeloid Leukemia: On the Basis of the Global Burden of Disease Study 2019. JCO Glob Oncol 2021; 7:1429-1441. [PMID: 34591599 PMCID: PMC8492379 DOI: 10.1200/go.21.00194] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/11/2021] [Accepted: 08/06/2021] [Indexed: 01/13/2023] Open
Abstract
PURPOSE To map the magnitudes and temporal trends of chronic myeloid leukemia (CML) along with its attributable risk factors, providing the essential foundation for targeted public policies at the national, regional, and global levels. MATERIALS AND METHODS We retrieved annual data on CML burden in 204 countries and regions from the Global Burden of Disease Study 2019 in 1990-2019. The estimated annual percentage change (EAPC) was calculated to quantify the temporal trends of CML burden by region, sex, and age group. RESULTS Globally, the age-standardized incidence rate of CML declined weakly over the past few years (EAPC: -1.04), but the number of incident cases increased by 54.1% to 65.8 × 103 in 2019. By contrast, a dramatic drop in death and disability-adjusted life years (DALYs) rate (EAPCs: -2.55; -2.69) led to a reduction in deaths and DALYs, especially in high-income regions. In 2019, the highest age-standardized death rate was observed in Ethiopia (1.89 per 100,000). The death rate of CML was pronounced among the population age above 70 years. DALYs of CML worldwide were primarily attributable to smoking (12.2%), high body mass index (5.0%), occupational exposure to benzene (0.9%), and occupational exposure to formaldehyde (0.3%) in 2019. CONCLUSION Although the mortality rate of CML has decreased significantly, the management of patients with CML cannot be neglected, especially in elders and developing regions.
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Affiliation(s)
- Yuefen Hu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Qizhao Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ming Hou
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jun Peng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaorong Yang
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Shuqian Xu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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19
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Asif M, Hussain A, Wali A, Ahmed N, Ali I, Iqbal Z, Amir M, Shafiq M, Rasool M. Molecular, Cytogenetic, and Hematological Analysis of Chronic Myeloid Leukemia Patients and Discovery of Two Novel Translocations. Anal Cell Pathol (Amst) 2021; 2021:4909012. [PMID: 34422550 PMCID: PMC8378985 DOI: 10.1155/2021/4909012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/12/2021] [Accepted: 07/26/2021] [Indexed: 11/18/2022] Open
Abstract
Chronic myeloid leukemia (CML) is a disease of hematopoietic stem cells and is caused by the balanced translocations among the long arms of chromosomes 9 and 22, which are called the Philadelphia (Ph) chromosome. In this study, 131 CML patients were enrolled. Complete blood cell count was performed at the time of diagnosis for all the patients. Cytogenetic (karyotyping) examination using bone marrow samples was conducted on 76 CML patients for the confirmation of Ph-positive (9;22)(q34;q11) standard translocation, complex variant translocation, and additional chromosome abnormalities. FISH was performed on 38 patients for diagnostic purposes and on 39 patients for monitoring purposes. Twenty-two samples of CML patients were evaluated by reverse transcriptase PCR and real-time PCR for the patients who failed to respond against imatinib mesylate. In this study, 72 (54.96%) were males and 59 (45.03%) were females with a median age of 38.5 years. CBC values in the diagnosis process showed that 75 patients had high values of WBC being >100 × 103/μl, while 71 (58.01) patients exhibited reduced values of hemoglobin, i.e., <10.00 mg/dl, and high values of PLTs > 100 were observed in 40 (30.53%) patients. Cytogenetic results show that standard translocation was developed in 63 (82.89%), development of complex variant translocations in 4 (5.32%), additional chromosomal abnormalities (ACAs) in 3 (3.94%), and ACAs together with complex variant translocations in 1 (1.31%) patient. At the time of diagnosis, 61 (92.95%) patients were in the chronic phase, 4 (5.63%) were in the accelerated phase, and only 1 (1.40%) was in the blast crisis. Out of twenty-two patients, only 6 CML patients who were shifted from imatinib mesylate to nilotinib showed BCR-ABL-positive amplification. However, only 7 out of twenty-one patients exhibit BCR-ABL gene values ≥ 1 after three months of follow-up when analyzed by the quantitative real-time PCR. In conclusion, we found a novel five-way translocation 46XX,t(1;2;2;17;9;22)(p36.3,q21;q11.2,q21,q34,q11.2) and a novel four-way complex variant translocation 48XY,+8(8;17)(9;22),+der(22)(q11.2;q23)(q34;q11.2) in the accelerated phase.
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MESH Headings
- Adolescent
- Adult
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/genetics
- Drug Substitution
- Female
- Humans
- Imatinib Mesylate/therapeutic use
- In Situ Hybridization, Fluorescence
- Karyotyping
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Male
- Middle Aged
- Philadelphia Chromosome
- Protein Kinase Inhibitors/therapeutic use
- Pyrimidines/therapeutic use
- Translocation, Genetic
- Treatment Outcome
- Young Adult
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Affiliation(s)
- Muhammad Asif
- Department of Biotechnology, BUITEMS, Quetta, Pakistan
- Office of Research Innovation and Commercialization, BUITEMS, Quetta, Pakistan
| | - Abrar Hussain
- Department of Biotechnology, BUITEMS, Quetta, Pakistan
| | - Abdul Wali
- Department of Biotechnology, BUITEMS, Quetta, Pakistan
| | - Nazeer Ahmed
- Department of Biotechnology, BUITEMS, Quetta, Pakistan
| | - Irfan Ali
- Centre of Agricultural Biochemistry and Biotechnology, Agriculture University of Faisalabad, Pakistan
| | - Zafar Iqbal
- Clinical Laboratory Sciences Program, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences/KAIMRC/SSBMT, National Guard Health Affairs, King Abdulaziz Medical City, Al-Ahsa, Saudi Arabia
| | - Muhammad Amir
- Department of Biotechnology, BUITEMS, Quetta, Pakistan
| | - Muhammad Shafiq
- Department of Biotechnology, University of Sialkot, Pakistan
| | - Mahmood Rasool
- Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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20
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Lakkireddy S, Aula S, Kapley A, Gundeti S, Kutala VK, Jamil K. Association of DNA repair gene XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) polymorphisms with the risk of chronic myeloid leukemia: A case-control study in a South Indian population. J Gene Med 2021; 23:e3339. [PMID: 33829606 DOI: 10.1002/jgm.3339] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 02/27/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Xeroderma pigmentosum complementation group C (XPC), a DNA repair protein, plays an important role in the maintenance of genomic integrity and is essential for the nucleotide excision repair pathway. Polymorphisms in the XPC gene may alter DNA repair leading to genetic instability and oncogenesis. The present study aimed to assess the relationship between the XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) non-synonymous polymorphisms and susceptibility to chronic myeloid leukemia (CML) pathogenesis, disease progression and the response to targeted therapeutic regimen, imatinib mesylate. METHODS This case-control study included 212 cases and 212 controls, and the genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism assays. RESULTS Our results showed significant association of variant CT (odds ratio = 1.92, 95% confidence interval = 1.21-3.06, p = 0.003) and TT (odds ratio = 2.84, 95% confidence interval = 1.22-6.71, p = 0.007) genotypes in patients with the XPC Ala499Val polymorphism and CML risk. In addition, these genotypes were associated with CML progression to advanced phases (p = 0.006), splenomegaly (p = 0.017) and abnormal lactate dehydrogenase levels (p = 0.03). XPC Lys939Gln was found to correlate with a poor response to therapy, showing borderline significant association with minor cytogenetic response (p = 0.08) and a poor molecular response (p = 0.06). Significant association of the Ala499Val and Lys939Gln polymorphisms with prognosis was observed (Hasford high risk, p = 0.031 and p = 0.019, respectively). Haplotype analysis showed a strong correlation of variant TC haplotype with poor therapy responses (minor cytogenetic response, p = 0.019; poor molecular response, p < 0.0001). CONCLUSIONS In conclusion, our results suggest that XPC Ala499Val is a high-penetrance CML susceptibility polymorphism. Both polymorphisms studied are considered as genetic markers with respect to assessing disease progression, therapy response and prognosis in CML patients.
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Affiliation(s)
- Samyuktha Lakkireddy
- Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), Hyderabad, Telangana, India.,Department of Biotechnology, Jawaharlal Nehru Technological University Anantapur (JNTUA), Ananthapuramu, Andhra Pradesh, India
| | - Sangeetha Aula
- Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), Hyderabad, Telangana, India.,Department of Biotechnology, Jawaharlal Nehru Technological University Anantapur (JNTUA), Ananthapuramu, Andhra Pradesh, India
| | - Atya Kapley
- Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), Hyderabad, Telangana, India.,Environmental Genomics Division, Council of Scientific and Industrial Research-National Environmental Engineering Research Institute (CSIR-NEERI), Nagpur, Maharashtra, India
| | - Sadashivudu Gundeti
- Department of Medical Oncology, Nizam's Institute of Medical Sciences (NIMS), Hyderabad, Telangana, India
| | - Vijay Kumar Kutala
- Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences (NIMS), Hyderabad, Telangana, India
| | - Kaiser Jamil
- Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), Hyderabad, Telangana, India.,Department of Biotechnology, Jawaharlal Nehru Technological University Hyderabad (JNTUH), Hyderabad, Telangana, India
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21
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Goel S, Saroya A, Agrawal BK, Gogia K. Leukaemic retinopathy in a patient with chronic myeloid leukaemia. Clin Exp Optom 2021; 104:809-810. [PMID: 33689573 DOI: 10.1080/08164622.2021.1878858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Affiliation(s)
- Sugandha Goel
- Department of Ophthalmology, Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, India
| | - Arnav Saroya
- Department of Ophthalmology, Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, India
| | - Bimal K Agrawal
- Department of Medicine, Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, India
| | - Kritika Gogia
- Department of Ophthalmology, Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, India
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22
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Sampaio MM, Santos MLC, Marques HS, Gonçalves VLDS, Araújo GRL, Lopes LW, Apolonio JS, Silva CS, Santos LKDS, Cuzzuol BR, Guimarães QES, Santos MN, de Brito BB, da Silva FAF, Oliveira MV, Souza CL, de Melo FF. Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review. World J Clin Oncol 2021; 12:69-94. [PMID: 33680875 PMCID: PMC7918527 DOI: 10.5306/wjco.v12.i2.69] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 12/22/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly - the presence of the Philadelphia chromosome. The advances in cytogenetic and molecular assays are of great importance to the diagnosis, prognosis, treatment, and monitoring of CML. The discovery of the breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) 1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (known as TKIs) are the standard therapy for CML and greatly increase the survival rates, despite adverse effects and the odds of residual disease after discontinuation of treatment. As therapeutic alternatives, the subsequent TKIs lead to faster and deeper molecular remissions; however, with the emergence of resistance to these drugs, immunotherapy appears as an alternative, which may have a cure potential in these patients. Against this background, this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.
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Affiliation(s)
- Mariana Miranda Sampaio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil
| | | | - Glauber Rocha Lima Araújo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Weber Lopes
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Jonathan Santos Apolonio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Camilo Santana Silva
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Kauany de Sá Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Beatriz Rocha Cuzzuol
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Mariana Novaes Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Márcio Vasconcelos Oliveira
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Cláudio Lima Souza
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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23
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Inhibition of cystathionine β-synthase promotes apoptosis and reduces cell proliferation in chronic myeloid leukemia. Signal Transduct Target Ther 2021; 6:52. [PMID: 33558454 PMCID: PMC7870845 DOI: 10.1038/s41392-020-00410-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 10/23/2020] [Accepted: 11/01/2020] [Indexed: 01/30/2023] Open
Abstract
Increased endogenous hydrogen sulfide (H2S) level by cystathionine β-synthase (CBS) has been shown to closely relate tumorigenesis. H2S promotes angiogenesis, stimulates bioenergy metabolism and inhibits selective phosphatases. However, the role of CBS and H2S in chronic myeloid leukemia (CML) remains elusive. In this study, we found that CBS and H2S levels were increased in the bone marrow mononuclear cells of pediatric CML patients, as well as in the CML-derived K562 cells and CBS expression levels were correlated with different disease phases. Inhibition of CBS reduced the proliferation of the CML primary bone marrow mononuclear cells and induced growth inhibition, apoptosis, cell cycle arrest, and migration suppression in K562 cells and tumor xenografts. The knockdown of CBS expression by shRNA and inhibiting CBS activity by AOAA decreased the endogenous H2S levels, promoted mitochondrial-related apoptosis and inhibited the NF-κB-mediated gene expression. Our study suggests that inhibition of CBS induces cell apoptosis, as well as limits cell proliferation and migration, a potential target for the treatment of chronic myeloid leukemia.
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24
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Future Approaches for Treating Chronic Myeloid Leukemia: CRISPR Therapy. BIOLOGY 2021; 10:biology10020118. [PMID: 33557401 PMCID: PMC7915349 DOI: 10.3390/biology10020118] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/27/2021] [Accepted: 02/02/2021] [Indexed: 12/11/2022]
Abstract
Simple Summary In the last two decades, the therapeutic landscape of several tumors have changed profoundly with the introduction of drugs against proteins encoded by oncogenes. Oncogenes play an essential role in human cancer and when their encoded proteins are inhibited by specific drugs, the tumoral process can be reverted or stopped. An example of this is the case of the chronic myeloid leukemia, in which all the pathological features can be attributed by a single oncogene. Most patients with this disease now have a normal life expectancy thanks to a rationality designed inhibitor. However, the drug only blocks the protein, the oncogene continues unaffected and treatment discontinuation is only an option for a small subset of patients. With the advent of genome-editing nucleases and, especially, the CRISPR/Cas9 system, the possibilities to destroy oncogenes now is feasible. A novel therapeutic tool has been developed with unimaginable limits in cancer treatment. Recent studies support that CRISPR/Cas9 system could be a definitive therapeutic option in chronic myeloid leukemia. This work reviews the biology of chronic myeloid leukemia, the emergence of the CRISPR system, and its ability as a specific tool for this disease. Abstract The constitutively active tyrosine-kinase BCR/ABL1 oncogene plays a key role in human chronic myeloid leukemia development and disease maintenance, and determines most of the features of this leukemia. For this reason, tyrosine-kinase inhibitors are the first-line treatment, offering most patients a life expectancy like that of an equivalent healthy person. However, since the oncogene stays intact, lifelong oral medication is essential, even though this triggers adverse effects in many patients. Furthermore, leukemic stem cells remain quiescent and resistance is observed in approximately 25% of patients. Thus, new therapeutic alternatives are still needed. In this scenario, the interruption/deletion of the oncogenic sequence might be an effective therapeutic option. The emergence of CRISPR (clustered regularly interspaced short palindromic repeats) technology can offer a definitive treatment based on its capacity to induce a specific DNA double strand break. Besides, it has the advantage of providing complete and permanent oncogene knockout, while tyrosine kinase inhibitors (TKIs) only ensure that BCR-ABL1 oncoprotein is inactivated during treatment. CRISPR/Cas9 cuts DNA in a sequence-specific manner making it possible to turn oncogenes off in a way that was not previously feasible in humans. This review describes chronic myeloid leukemia (CML) disease and the main advances in the genome-editing field by which it may be treated in the future.
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25
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Omran MM, Abdelfattah R, Moussa HS, Alieldin N, Shouman SA. Association of the Trough, Peak/Trough Ratio of Imatinib, Pyridine-N-Oxide Imatinib and ABCG2 SNPs 34 G>A and SLCO1B3 334 T>G With Imatinib Response in Egyptian Chronic Myeloid Leukemia Patients. Front Oncol 2020; 10:1348. [PMID: 32974132 PMCID: PMC7466443 DOI: 10.3389/fonc.2020.01348] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022] Open
Abstract
Imatinib mesylate (IM) is highly efficacious in the treatment of chronic myeloid leukemia (CML). Therapeutic drug monitoring and pharmacogenetic screening are affirmed for better management of IM therapy. The goal of this study was to gain a greater mechanistic understanding of the factors controlling variability in IM level and its relation to the response. One hundred and two patients with CML at chronic phase were recruited in this study. Blood samples were withdrawn at least 30 days after drug administration, and trough and peak concentrations of imatinib, N-des-methyl imatinib, and pyridine-N-oxide imatinib were determined by HPLC/MS/MS. Genetic polymorphism of the genes ABCG2 SNPs 34 G>A and 421C >A; ABCB1 SNPs 2677 G>A/T, 1236 C>T, 3435 C>T; SLCO1B3 SNPs 334 T>G and CYP3A5 were studied using PCR-RFLP technique. Our study presented significant higher trough IM (1,281 ± 578 ng/ml), lower Peak/Trough ratio, clearance (Cl), and elimination rate constant, ke, among patients who achieved favorable responses (N = 64) than those for patients who suffered unfavorable response (N = 37). The P/T ratio was the only significant independent factor affecting response, as the P/T ratio increased by one, the risk of unfavorable response increased by more than double as compared to favorable response with 95% CI (1.28-3.92, P = 00.005). Moreover, like the results of IM, the trough concentration of Pyridine-N-oxide imatinib was significantly higher (P = 0.01) and its P/T ratio was significantly lower (P = 0.008) in patients achieved favorable response than those without. The wild GG genotype of the ABCG2.34 G>A gene was associated with favorable response (P = 0.01), lower Cl, Ke and high plasma IM trough level than both (AA+GA) genotypes. ABCG2.421C >A (CC) genotype had a significantly higher plasma peak of IM, N-des-methyl imatinib and higher Css. The GG and TG alleles of the SLCO1B3.334 T>G gene were significantly correlated to favorable response, while the wild allele TT was linked to unfavorable response (P = 0.03). In conclusion, the trough and P/ T ratio for both IM and Pyridine-N-oxide imatinib, in addition to Polymorphism of ABCG2 SNPs 34 G>A and SLCO1B3.334 T>G gene, is a good predictor for response of IM in CML Egyptian patients.
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Affiliation(s)
- Mervat M Omran
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Raafat Abdelfattah
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Heba S Moussa
- Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Nelly Alieldin
- Medical Statistics Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Samia A Shouman
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
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Abstract
Most cancer cases occur in areas of low resources. The diagnosis, treatment and monitoring of cancers is especially challenging in these locations. Unique partnerships exist between non-profit organisations and pharmaceutical companies to provide free drugs to CML patients throughout the world if the diagnosis can be rigorously and unambiguously established. But there lies the rub: How do you perform molecular diagnostics in areas where even electricity is unreliable? Here we describe the evolution of testing patients from low resource areas, which, when merged with a remarkable effort to bring tyrosine kinase inhibitors to patients across the globe, have led to survival outcomes similar to cases in industrialised countries.
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Affiliation(s)
- Jerald Radich
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,the University of Washington, Seattle, WA, USA
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27
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New approaches to molecular monitoring in CML (and other diseases). Blood 2020; 134:1578-1584. [PMID: 31533919 DOI: 10.1182/blood.2019000838] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 08/29/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic myeloid leukemia (CML) is the model cancer, demonstrating the clinical benefits of targeted therapy and the power of molecular diagnostics and monitoring. In CML, the BCR-ABL1 fusion gene and its companion messenger RNA offers a unique target differentiating cancer from the normal cell, affording the potential for very sensitive and specific assays. Because CML is such an ideal model, new methods are arising that should make testing in CML faster, more reliable, and reach a greater sensitivity. New ultrasensitive sequencing approaches, coupled with single-cell genomic approaches, further the study of measurable residual disease, clonal heterogeneity, and promise to make clinical trials more innovative and informative. These methods should be able to be transferred to other hematological and solid malignancies.
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Algahtani FH, Alqahtany FS. Evaluation and characterisation of Chronic myeloid leukemia and various treatments in Saudi Arabia: A retrospective study. J Infect Public Health 2020; 13:295-298. [PMID: 31953021 DOI: 10.1016/j.jiph.2019.12.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 11/26/2019] [Accepted: 12/16/2019] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Chronic myeloid leukemia (CML) is a clonal BCR-ABL1-positive myelo-proliferative disorder resulting from an acquired genetic mutation, characterized by the presence of the Philadelphia (Ph) chromosome. CML is associated with significantly high granulocyte numbers in the bone marrow and peripheral blood. MATERIALS AND METHODS This retrospective study conducted at the Hematology Unit of King Saud University Medical City aimed to evaluate the incidence and characteristics of CML and the various treatments in Saudi Arabia. We have evaluated the demographic, clinical, and hematological data of 56 consecutive patients who visited the hospital from Jan 2012 to Jan 2018. RESULTS The diagnosis and stage of CML were determined based on the World Health Organization criteria, following polymerase chain reaction analysis of bone marrow aspirates. Our study group had equal numbers of genders with a age mean of 43.3+18.1 years. The predominance of younger patients and equal incidence in males and females could be due to the racial and socioeconomic disparities among our patients compared to those in previous studies. While the most predominant symptom was fatigue and bone pain, the most common clinical sign was hepato-splenomegaly, followed by remarkable weight loss, and epistaxis. CONCLUSION A patient with an increased WBC count, abdominal pain, left side distension, and hepato-splenomegaly should clearly be evaluated for CML.
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Affiliation(s)
- Farjah H Algahtani
- Department of Medicine, Division of Oncology/Hematology, College of Medicine, King Saud University, Kind Saud University Medical City, Riyadh, Saudi Arabia.
| | - Fatmah S Alqahtany
- Department of Pathology, Hematopathology Unit, College of Medicine, King Saud University, Kind Saud University Medical City, Riyadh, Saudi Arabia
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El Fakih R, Chaudhri N, Alfraih F, Rausch CR, Naqvi K, Jabbour E. Complexity of chronic-phase CML management after failing a second-generation TKI. Leuk Lymphoma 2019; 61:776-787. [PMID: 31739705 DOI: 10.1080/10428194.2019.1691196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The treatment landscape of chronic myeloid leukemia (CML) was radically changed with the introduction of imatinib in 2001. With the emergence of treatment failure with imatinib, more specific and potent second- and third-generation tyrosine kinase inhibitors (TKIs) were developed. Currently, 6 TKIs and one protein synthesis inhibitor are available on the market for CML treatment. Despite the availability of these agents, it is not uncommon for some patients to experience treatment failure across several lines of therapy. Sequencing the available treatment options is a challenging task that becomes more complex after patients fail the more potent second- and third-generation TKIs. The ability to successfully salvage such patients is limited. In this paper, we will briefly review the mechanisms of treatment failure in chronic-phase CML (CP-CML) and focus on the complexity of managing patients who fail a second-generation TKI.
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Affiliation(s)
- Riad El Fakih
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Naeem Chaudhri
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Feras Alfraih
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Caitlin R Rausch
- The University of Texas MD Anderson Cancer Center, LEUKEMIA, Houston, TX, USA
| | - Kiran Naqvi
- The University of Texas MD Anderson Cancer Center, LEUKEMIA, Houston, TX, USA
| | - Elias Jabbour
- The University of Texas MD Anderson Cancer Center, LEUKEMIA, Houston, TX, USA
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Cortes J, Huynh L, Mendelson E, Brandt P, Dalal D, DerSarkissian M, Cortina D, Narkhede S, Sheng Duh M. Treatment patterns and deep molecular response in chronic phase - chronic myeloid leukemia patients treated with second-line nilotinib or dasatinib: a multi-country retrospective chart review study. Leuk Lymphoma 2019; 61:98-107. [PMID: 31409168 DOI: 10.1080/10428194.2019.1644332] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Achievement of MR4.5 (BCR-ABL1 ≤ 0.0032% on international scale) is an important goal of tyrosine kinase inhibitor (TKI) treatment for patients with chronic myeloid leukemia (CML). This study describes treatment patterns by region and assesses time to achieve MR4.5 in patients with CML - chronic phase (CP) treated with second-line nilotinib or dasatinib in 10 countries. A multivariate Cox proportional hazards model was used to assess time to MR4.5 for nilotinib versus dasatinib. The model accounted for the competing-risk event of TKI resistance, included random effects for country clustering, and was adjusted for baseline covariates. The study included 280 patients treated with either nilotinib (N = 135 [48%]) or dasatinib (N = 145 [52%]) as second-line TKI with median treatment durations of 19.1 and 18.7 months, respectively. Nilotinib was observed to be better in achieving MR4.5 than dasatinib (adjusted hazard ratio = 1.37, 95% CI [1.11, 1.69]) suggesting second-line nilotinib may perform better in achieving MR4.5 than dasatinib.
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Affiliation(s)
- Jorge Cortes
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | | | - Darshan Dalal
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | | | - Diego Cortina
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - Sahil Narkhede
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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31
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Ozkan T, Hekmatshoar Y, Ertan-Bolelli T, Hidayat AN, Beksac M, Aki-Yalcin E, Yalcin I, Sunguroglu A. Determination of the Apoptotic Effect and Molecular Docking of Benzamide Derivative XT5 in K562 Cells. Anticancer Agents Med Chem 2019; 18:1521-1530. [DOI: 10.2174/1871520618666171229222534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 07/12/2017] [Accepted: 12/06/2017] [Indexed: 11/22/2022]
Abstract
Background:
The tyrosine kinase inhibitor, imatinib, used as a first line treatment in Chronic Myeloid
Leukemia (CML) patients, may lead to resistance and failure to therapy. Novel combinations of imatinib
with other drugs is a strategy to improve treatment efficiency.
Objective:
In this study, the antileukemic and apoptotic effects of a benzamide derivative XT5 and benzoxazole
derivative XT2B and their combination with imatinib were investigated in imatinib-sensitive (K562S) and
imatinib-resistant (K562R) CML cells.
Methods:
In vitro cytotoxicity was determined by MTT assay. Then, apoptotic effect of XT5 on CML cell lines
was tested by Annexin V flow cytometry, caspase activation and RT-PCR. Docking calculation was performed
using AutoDock Vina in PyMOL environment using AutoDock/Vina plugin for PyMOL.
Results:
According to our MTT assay data, XT5 indicated significant antiproliferative effect on cell lines, therefore
we investigated apoptotic effects of XT5. Treatment of K562 cell lines with a combination of XT5 and
imatinib-XT5 increased cytotoxicity, the Annexin V binding and caspase 3/7 activation. In addition to apoptosis
assays, we observed an increase in the expression levels of the pro-apoptotic (BAX, BAD and BIM) genes in
XT5 treated K562R and K562S cells. Molecular modelling experiments showed that XT5 showed hydrogenbonding
interactions with important amino acids of BCR-ABL kinase receptor; however XT2B did not show
any hydrogen bond interaction.
Conclusion:
Our results indicate that XT5 could be a potential candidate to be used as a new anticancer drug
and XT5 combination with imatinib as an alternate treatment strategy for overcoming imatinib resistance.
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Affiliation(s)
- Tulin Ozkan
- Department of Medical Biology, School of Medicine, Ankara University, Ankara, Turkey
| | - Yalda Hekmatshoar
- Department of Medical Biology, School of Medicine, Ankara University, Ankara, Turkey
| | - Tugba Ertan-Bolelli
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | | | - Meral Beksac
- Department of Hematology and Cord Blood Bank, Ankara University, Ankara, Turkey
| | - Esin Aki-Yalcin
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | - Ismail Yalcin
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | - Asuman Sunguroglu
- Department of Medical Biology, School of Medicine, Ankara University, Ankara, Turkey
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Umsumarng S, Mapoung S, Yodkeeree S, Pyne SG, Limtrakul Dejkriengkraikul P. A Pharmacological Strategy Using Stemofoline for more Efficacious Chemotherapeutic Treatments Against Human Multidrug Resistant Leukemic Cells. Asian Pac J Cancer Prev 2018; 19:3533-3543. [PMID: 30583680 PMCID: PMC6428543 DOI: 10.31557/apjcp.2018.19.12.3533] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 11/12/2018] [Indexed: 01/12/2023] Open
Abstract
Our previous study reported that stemofoline (STF) exhibited a synergistic effect with chemotherapeutic drugs in human multidrug-resistant (MDR) leukemic cells (K526/Adr) by inhibiting the function of P-glycoprotein, which is a membrane transporter that is overexpressed in several types of MDR cancers. This study further investigated the effects of a combination treatment of STF and doxorubicin (DOX) in vitro and in vivo. The combination treatment of 50 mg/kg of STF strongly enhanced the anti-tumor activity of DOX in SCID-beige mice bearing K562/Adr xenografts without additional toxicity when compared to the single treatment groups. Additionally, an examination of the proliferation markers (Ki67) and the apoptotic marker (TUNEL) in tumor tissues in each group revealed that the combination therapy significantly reduced Ki67 positive cells and increased apoptotic cells. From the in vitro experiments we also found that this combination treatment dramatically induced G1 and G2M arrest in K562/Adr when compared to a single treatment of DOX. STF treatment alone did not show any cytotoxic effect to the cells. These results suggest that the accumulation of DOX enhanced by STF was sufficient to induce cell cycle arrest in K562/Adr. These findings support our previous in vitro data and indicate the possibility of developing STF as an adjuvant therapy in cancer treatments.
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Affiliation(s)
- Sonthaya Umsumarng
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Excellent Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand.
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Bettiol A, Marconi E, Lombardi N, Crescioli G, Gherlinzoni F, Walley T, Vannacci A, Chinellato A, Giusti P. Pattern of Use and Long-Term Safety of Tyrosine Kinase Inhibitors: A Decade of Real-World Management of Chronic Myeloid Leukemia. Clin Drug Investig 2018; 38:837-844. [PMID: 30043130 DOI: 10.1007/s40261-018-0676-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND OBJECTIVES First-line treatment of chronic phase (CP) chronic myeloid leukemia (CML) is based on the first-generation tyrosine kinase inhibitor (TKI) imatinib or the second-generation TKIs dasatinib or nilotinib. Thanks to the efficacy of TKIs, CML has switched from a fatal to a 'chronic' pathology, and data from clinical trials have become insufficient to drive physicians' prescription choices and address long-term treatment outcomes. On the brink of commercialization of generic imatinib, this study aims to evaluate the therapeutic pattern of CP-CML and the occurrence of adverse events (AEs) over a decade of local real clinical practice. METHODS A retrospective cohort study was performed on CP-CML patients followed up in the Local Health Unit of Treviso (Veneto Region, Italy) during the period 2005-2015. Data were captured from both administrative databases and physicians' patient diaries. RESULTS Of 81 CP-CML patients, 73 were treated with first-line imatinib; among the second-generation TKIs, only nilotinib was used (n = 8). Overall, 38% of imatinib-treated subjects needed to switch, mainly due to intolerance, whereas no switches occurred in the nilotinib cohort. Osteoarticular pain was the most common AE and was significantly more frequent in the imatinib cohort (68.49 vs. 25.00%, p = 0.022). Other common AEs were dermatologic manifestations, asthenia, and diarrhea. CONCLUSION Although based on a small population, this study represents an unbiased reference on the long-term management of CML in an Italian clinical setting. Our results indicate a better profile of first-line nilotinib, both in terms of persistency and tolerability. AEs remain a major concern, highlighting the importance of close monitoring.
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Affiliation(s)
- Alessandra Bettiol
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy. .,Department of Neurosciences, Psychology, Drug Research and Children's Health, University of Florence, Florence, Italy.
| | - Ettore Marconi
- Department of Neurosciences, Psychology, Drug Research and Children's Health, University of Florence, Florence, Italy
| | - Niccolò Lombardi
- Department of Neurosciences, Psychology, Drug Research and Children's Health, University of Florence, Florence, Italy
| | - Giada Crescioli
- Department of Neurosciences, Psychology, Drug Research and Children's Health, University of Florence, Florence, Italy
| | - Filippo Gherlinzoni
- Department of Hematology, Local Health Unit n.2 Marca Trevigiana, Treviso, Italy
| | - Thomas Walley
- Institute of Psychology Health and Society, University of Liverpool, Liverpool, UK
| | - Alfredo Vannacci
- Department of Neurosciences, Psychology, Drug Research and Children's Health, University of Florence, Florence, Italy
| | | | - Pietro Giusti
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
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Behzad MM, Shahrabi S, Jaseb K, Bertacchini J, Ketabchi N, Saki N. Aberrant DNA Methylation in Chronic Myeloid Leukemia: Cell Fate Control, Prognosis, and Therapeutic Response. Biochem Genet 2018; 56:149-175. [DOI: 10.1007/s10528-018-9841-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 01/18/2018] [Indexed: 01/24/2023]
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Asif M, Hussain A, Wali A, Ahmad N, Sajjad N, Amir M, Ali I, Pushparaj PN, Rasool M. A rare case of three-way complex variant translocation in chronic myeloid leukemia t(6;9;22)(p21;q34;q11): A case report. Biomed Rep 2017; 7:377-379. [PMID: 29085635 DOI: 10.3892/br.2017.967] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 07/20/2017] [Indexed: 11/05/2022] Open
Abstract
Philadelphia (Ph)-positive chromosome or Ph translocation has been recognized in 90-95 chronic myeloid leukemia (CML) cases worldwide. However, only 5-8% CML patients show complex variant translocations. In the present study, hematological tests for a 47-year-old female CML patient were performed to determine the hemoglobin, platelets and total leukocyte values. A FISH test was carried out to recognize the BCR/ABL gene fusion, and a cytogenetic analysis was performed. The hematological results showed an increase in WBC (414000/mm3) and a decrease in hemoglobin (8.9 mg/dl), indicating the anemic condition in the CML patient. Furthermore, cytogenetic karyotyping results showed 46,XX,t(6;9;22)(p21;q34;q11) and positive for Ph chromosome. In conclusion, in the present study, we report a rare three-way complex variant translocation in a CML patient.
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Affiliation(s)
- Muhammad Asif
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta 87300, Pakistan
| | - Abrar Hussain
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta 87300, Pakistan
| | - Abdul Wali
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta 87300, Pakistan
| | - Nazeer Ahmad
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta 87300, Pakistan
| | - Naheed Sajjad
- Department of Biotechnology, Sardar Bahadur Khan Women's University, Quetta 87500, Pakistan
| | - Muhammad Amir
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta 87300, Pakistan
| | - Irfan Ali
- Akhuwat Faisalabad Institute of Research Science and Technology, Faisalabad 38000, Pakistan
| | - Peter Natesan Pushparaj
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia
| | - Mahmood Rasool
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia
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Abstract
In chronic myeloid leukemia (CML), the BCR-ABL fusion gene is both the therapeutic target of tyrosine kinase inhibitors and the indisputable direct marker of disease burden. Thus, sensitive assays for BCR-ABL now drive therapeutic options and are good surrogates for short- and long-term outcomes. Because CML is such an ideal model, new methods are arising that should make testing in CML faster, more reliable, and reach a greater sensitivity. These methods should be able to be transferred to other hematological malignancies that have mutation markers.
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Affiliation(s)
- Cecilia C S Yeung
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave North, G7-910, Seattle, WA, 98109, USA.
| | - Daniel Egan
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave North, G7-910, Seattle, WA, 98109, USA
| | - Jerald Radich
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave North, G7-910, Seattle, WA, 98109, USA
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37
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Molecular study of ABCB1 gene and its correlation with imatinib response in chronic myeloid leukemia. Cancer Chemother Pharmacol 2017; 80:829-839. [PMID: 28836054 DOI: 10.1007/s00280-017-3424-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 08/14/2017] [Indexed: 01/11/2023]
Abstract
PURPOSE The introduction and success of imatinib mesylate have become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, despite its high efficiency, resistance to imatinib has emerged as a significant problem, which may in part be caused by pharmacogenetic variability. Three single-nucleotide polymorphisms (C1236T, G2677T/A, C3435T) and/or mRNA expression changes of ABCB1 gene were demonstrated to be associated with inter-individual variability of imatinib response in CML patients. In this study, we aimed to examine whether genetic variations and/or altered expression of ABCB1 gene may influence response to imatinib. METHODS Sixty nine CML Tunisian patients, undergoing imatinib therapy, were enrolled in this study. These were divided into two groups: responders and non-responders to imatinib. The relative transcript expression levels of ABCB1 gene and the distribution of allele and genotype frequency of ABCB1 SNPs were compared between these two categories of patients. Linkage disequilibrium tests and haplotypes analysis were also studied. RESULTS Our results showed that the mRNA expression level of ABCB1 gene did not differ significantly between the two categories of patients. In addition, results obtained from ABCB1 polymorphisms study and their correlation with imatinib response showed that the optimal response rate to imatinib did not differ significantly between C1236T, G2677T/A or C3435T genotypes. However, haplotype analysis showed that the 1236C-2677A-3435C haplotype was observed only in imatinib non-responders' patients suggesting that CAC haplotype was linked to higher risk of imatinib resistance. CONCLUSION Furthermore, analyses of ABCB1 haplotypes should be taken into account to study the relationship between ABCB1 genotypes and imatinib efficacy.
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Ali MAM. Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: An Evolving Paradigm of Molecularly Targeted Therapy. Mol Diagn Ther 2017; 20:315-33. [PMID: 27220498 DOI: 10.1007/s40291-016-0208-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent hematopoietic stem cells. CML was the first malignancy in which a unique chromosomal abnormality was identified and a pathophysiologic association was suggested. The hallmark of CML is a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22, t(9; 22)(q34; q11), creating a derivative 9q+ and a shortened 22q-. The latter, known as the Philadelphia (Ph) chromosome, harbors the breakpoint cluster region-abelson (BCR-ABL) fusion gene, encoding the constitutively active BCR-ABL tyrosine kinase that is necessary and sufficient for initiating CML. The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of CML remains a flagship for molecularly targeted therapy in cancer. TKIs have changed the clinical course of CML; however, some patients nonetheless demonstrate primary or secondary resistance to such therapy and require an alternative therapeutic strategy. Therefore, the assessment of early response to treatment with TKIs has become an important tool in the clinical monitoring of CML patients. Although mutations in the BCR-ABL have proven to be the most prominent mechanism of resistance to TKIs, other mechanisms-either rendering the leukemic cells still dependent on BCR-ABL activity or supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling-have been identified. This article provides an overview of the current understanding of CML pathogenesis; recommendations for diagnostic tools, treatment strategies, and management guidelines; and highlights the BCR-ABL-dependent and -independent mechanisms that contribute to the development of resistance to TKIs.
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Affiliation(s)
- Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Abbassia, 11566, Cairo, Egypt.
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Shen N, Yan F, Pang J, Zhao N, Gangat N, Wu L, Bode AM, Al-Kali A, Litzow MR, Liu S. Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia. Clin Cancer Res 2017; 23:6254-6266. [PMID: 28720666 DOI: 10.1158/1078-0432.ccr-17-0235] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 06/18/2017] [Accepted: 07/12/2017] [Indexed: 01/05/2023]
Abstract
Purpose: Receptor tyrosine kinases (RTKs) are frequently deregulated in leukemia, yet the biological consequences of this deregulation remain elusive. The mechanisms underlying aberrant methylation, a hallmark of leukemia, are not fully understood. Here we investigated the role of RTKs in methylation abnormalities and characterized the hypomethylating activities of RTK inhibitors.Experimental Design: Whether and how RTKs regulate expression of DNA methyltransferases (DNMTs), tumor suppressor genes (TSGs) as well as global and gene-specific DNA methylation were examined. The pharmacologic activities and mechanisms of actions of RTK inhibitors in vitro, ex vivo, in mice, and in nilotinib-treated leukemia patients were determined.Results: Upregulation of RTKs paralleled DNMT overexpression in leukemia cell lines and patient blasts. Knockdown of RTKs disrupted, whereas enforced expression increased DNMT expression and DNA methylation. Treatment with the RTK inhibitor, nilotinib, resulted in a reduction of Sp1-dependent DNMT1 expression, the diminution of global DNA methylation, and the upregulation of the p15INK4B gene through promoter hypomethylation in AML cell lines and patient blasts. This led to disruption of AML cell clonogenicity and promotion of cellular apoptosis without obvious changes in cell cycle. Importantly, nilotinib administration in mice and human patients with AML impaired expression of DNMTs followed by DNA hypomethylation, TSG re-expression, and leukemia regression.Conclusions: Our findings demonstrate RTKs as novel regulators of DNMT-dependent DNA methylation and define DNA methylation status in AML cells as a pharmacodynamic marker for their response to RTK-based therapy, providing new therapeutic avenues for RTK inhibitors in overcoming epigenetic abnormalities in leukemia. Clin Cancer Res; 23(20); 6254-66. ©2017 AACR.
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Affiliation(s)
- Na Shen
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Fei Yan
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Jiuxia Pang
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Na Zhao
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Naseema Gangat
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Laichu Wu
- Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, Ohio
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Aref Al-Kali
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Mark R Litzow
- Division of Hematology, Mayo Clinic, Rochester, Minnesota.
| | - Shujun Liu
- The Hormel Institute, University of Minnesota, Austin, Minnesota.
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40
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He X, Deng Y, Yue W. Investigating critical genes and gene interaction networks that mediate cyclophosphamide sensitivity in chronic myelogenous leukemia. Mol Med Rep 2017; 16:523-532. [PMID: 28560425 PMCID: PMC5482156 DOI: 10.3892/mmr.2017.6636] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 02/15/2017] [Indexed: 01/06/2023] Open
Abstract
Drug resistance is an obstacle in the treatment of chronic myelogenous leukemia (CML), and is a common reason for treatment failure or disease progression. However, the underlying mechanisms of cyclophosphamide resistance remain poorly defined. In the present study, microarray data concerning cyclophosphamide‑sensitive and ‑resistant chronic myelogenous leukemia cell lines were analyzed. A total of 258 differentially‑expressed genes (DEGs) were identified between these two groups, from which 139 DEGs were upregulated and 119 were downregulated. Several candidate genes that were associated with cyclophosphamide resistance were also identified. These DEGs were subsequently classified using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis. A total of 487 biological processes and 17 KEGG pathways were revealed to be enriched. Furthermore, an interaction network was established to identify the core genes that regulated cyclophosphamide resistance. Signal transducer and activator of transcription 5A (STAT5A), FYN proto‑oncogene, Src family tyrosine kinase and spleen associated tyrosine kinase were revealed to be the hub genes in multiple enriched biological processes and signaling pathways, indicating that these were involved in mediating cyclophosphamide sensitivity in CML cells. The expression levels of 5 DEGs were also confirmed in two human CML cell lines (K‑562 and KU812) by reverse transcription‑quantitative polymerase chain reaction. Furthermore, selective knockdown of STAT5A and S100 calcium binding protein A4 (S100A4) recovered cyclophosphamide sensitivity in K‑562 cells, suggesting their involvement in drug resistance. The present study identified several potential genes and pathways contributing to cyclophosphamide resistance, and confirmed the involvement of STAT5A and S100A4 in drug resistance. These results enable improved understanding of the mechanisms underlying drug resistance in CML cells.
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MESH Headings
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Cell Line, Tumor
- Computational Biology/methods
- Cyclophosphamide/pharmacology
- Cyclophosphamide/therapeutic use
- Databases, Nucleic Acid
- Drug Resistance, Neoplasm/genetics
- Epistasis, Genetic
- Gene Expression Profiling
- Gene Expression Regulation, Leukemic/drug effects
- Gene Ontology
- Gene Regulatory Networks
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Reproducibility of Results
- S100 Calcium-Binding Protein A4/genetics
- S100 Calcium-Binding Protein A4/metabolism
- STAT5 Transcription Factor/genetics
- STAT5 Transcription Factor/metabolism
- Transcriptome
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Affiliation(s)
- Xiao He
- Blood Transfusion Department, The First People's Hospital of Yancheng City, Yancheng, Jiangsu 224006, P.R. China
| | - Yuying Deng
- Blood Transfusion Department, The First People's Hospital of Yancheng City, Yancheng, Jiangsu 224006, P.R. China
| | - Wei Yue
- Blood Transfusion Department, The First People's Hospital of Yancheng City, Yancheng, Jiangsu 224006, P.R. China
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Eskandari S, Yazdanparast R. Bcl6 gene-silencing facilitates PMA-induced megakaryocyte differentiation in K562 cells. J Cell Commun Signal 2017; 11:357-367. [PMID: 28589317 DOI: 10.1007/s12079-017-0395-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 05/17/2017] [Indexed: 12/23/2022] Open
Abstract
Targeted therapy via imatinib appears to be a promising approach for chronic myeloid leukemia (CML) therapy. However, refractory and resistance to imatinib therapy has encouraged many investigators to get involved in development of new therapeutic agents such as Phorbol 12-myrestrat 13-acetate (PMA) for patients with CML. In that line, we attempted to investigate the chemosensitizing effect of PMA on the imatinib-resistant cells. Based on our western blot analyses, resistant K562 cells (K562R) showed high levels of FoxO3a and Bcl6 expressions which were not modulated by imatinib treatment. However, upon PMA treatment, the levels of both FoxO3a and Bcl6 were up-regulated among both the sensitive and the resistant cells and this treatment was associated with initiation of megakaryocytic differentiation of the cells. SiRNA-silencing of FoxO3a led to augmentation of megakaryocytic differentiation of the cells. Similarly, siRNA gene silencing of Bcl6 enhanced the differentiation and induced cell apoptosis among both types of cells. Regarding these results, it might be concluded that Bcl6 knockdown combined with PMA therapy could present a new therapeutical strategy for refractory CML patients to imatinib.
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Affiliation(s)
- Sedigheh Eskandari
- Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box, Tehran, 13145-1384, Iran
| | - Razieh Yazdanparast
- Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box, Tehran, 13145-1384, Iran.
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Kayastha GK, Ranjitkar N, Gurung R, KC RK, Karki S, Shrestha R, Rajbhandari P, Thapa RK, Poudyal B, Acharya P, Roberts DJ, Hayes B, Zimmerman M, Basnyat B. The use of Imatinib resistance mutation analysis to direct therapy in Philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukaemia patients failing Imatinib treatment, in Patan Hospital, Nepal. Br J Haematol 2017; 177:1000-1007. [DOI: 10.1111/bjh.14683] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Gyan K. Kayastha
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | - Nora Ranjitkar
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | - Radha Gurung
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | - Raj Kumar KC
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | - Sanjit Karki
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | - Roshan Shrestha
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | | | - Raj K. Thapa
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | - Buddhi Poudyal
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | - Paras Acharya
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | - David J. Roberts
- National Health Service Blood and Transplant; John Radcliffe Hospital; Oxford UK
- Radcliffe Department of Medicine; John Radcliffe Hospital; Oxford UK
| | - Bruce Hayes
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | - Mark Zimmerman
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
| | - Buddha Basnyat
- Patan Academy of Health Science; Patan Hospital; Kathmandu Nepal
- Oxford University Clinical Research Unit-Nepal; Centre for Tropical Medicine and Global Health; University of Oxford; Oxford UK
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Winn AN, Keating NL, Dusetzina SB. Factors Associated With Tyrosine Kinase Inhibitor Initiation and Adherence Among Medicare Beneficiaries With Chronic Myeloid Leukemia. J Clin Oncol 2016; 34:4323-4328. [PMID: 27998234 DOI: 10.1200/jco.2016.67.4184] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Purpose There is substantial concern surrounding affordability of orally administered anticancer therapies, particularly for Medicare beneficiaries. We examined rates of initiation and adherence to tyrosine kinase inhibitors (TKIs) among Medicare beneficiaries with chronic myeloid leukemia (CML) with and without cost-sharing subsidies. We selected TKIs given their effectiveness and strong indication for use among patients diagnosed with CML. Patients and Methods Using SEER-Medicare data, we identified individuals diagnosed with CML from 2007 to 2011. We used Cox proportional hazards regression to assess time from diagnosis to TKI initiation. We used generalized estimating equations to examine treatment initiation within 180 days and TKI adherence among initiators. We defined adherence as at least 80% of days covered during the 6 months after TKI initiation. Results Among 393 individuals diagnosed with CML from 2007 to 2011, 68% initiated TKI treatment within 180 days after diagnosis. In multivariate analysis, individuals with cost-sharing subsidies, younger age, lower comorbidity, and later year of diagnosis were significantly more likely to initiate TKIs. Among TKI initiators, 61% were adherent; adherence was lower for individuals age 80 years or older versus 66 to 69 years. Conclusion Only 68% of Medicare beneficiaries with CML initiated TKI therapy within 6 months of diagnosis. Delayed initiation among individuals without cost-sharing subsidies suggests that out-of-pocket costs may be a barrier to timely initiation of therapy among individuals diagnosed with CML.
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Affiliation(s)
- Aaron N Winn
- Aaron N. Winn and Stacie B. Dusetzina, University of North Carolina at Chapel Hill, Chapel Hill, NC; and Nancy L. Keating, Harvard Medical School and Brigham and Women's Hospital, Boston, MA
| | - Nancy L Keating
- Aaron N. Winn and Stacie B. Dusetzina, University of North Carolina at Chapel Hill, Chapel Hill, NC; and Nancy L. Keating, Harvard Medical School and Brigham and Women's Hospital, Boston, MA
| | - Stacie B Dusetzina
- Aaron N. Winn and Stacie B. Dusetzina, University of North Carolina at Chapel Hill, Chapel Hill, NC; and Nancy L. Keating, Harvard Medical School and Brigham and Women's Hospital, Boston, MA
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Lakkireddy S, Aula S, Kapley A, Swamy AVN, Digumarti RR, Kutala VK, Jamil K. Association of Vascular Endothelial Growth Factor A (VEGFA) and its Receptor (VEGFR2) Gene Polymorphisms with Risk of Chronic Myeloid Leukemia and Influence on Clinical Outcome. Mol Diagn Ther 2016; 20:33-44. [PMID: 26476544 DOI: 10.1007/s40291-015-0173-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Vascular endothelial growth factor A (VEGFA) and its kinase insert domain receptor (VEGFR2/KDR) were reported to be upregulated in chronic myeloid leukemia (CML); however, the influence of polymorphisms in VEGFA and VEGFR2 in CML pathogenesis and therapeutic response, have not yet been elucidated. METHODS We aimed to analyze these polymorphisms in 212 CML patients and 212 healthy controls by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. RESULTS The VEGFA+936C>T polymorphism did not differ significantly between the CML patients and controls. The frequency of CT genotype was higher in CML patients than in controls (25 vs. 18%), higher in males than in females (29 vs. 18%), was more prevalent in the patients with splenomegaly (p = 0.03), and was negatively associated with lactate dehydrogenase (LDH) levels (p = 0.01). The frequency of VEGFR2 mutant T-allele was higher in CML patients than controls (p < 0.0001). In the dominant model, patients having the combined AT and TT genotypes were associated with 2.6-fold higher risk of CML [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.71–3.97, p < 0.0001]. VEGFR2 AT genotype was significantly associated with high blast count (p = 0.006), minor hematological response (p = 0.03) and poor cytogenetic response (p = 0.003), indicating its role in therapeutic resistance. In contrast, poor molecular response was observed in patients with TT genotype (p = 0.02). VEGFA+936C>T polymorphism was found to have synergistic interaction with VEGFR2+1416A>T in inflating the risk for CML further (P(interaction) = 0.0002). CONCLUSION Our results indicate that VEGFR2+1416A>T polymorphism may be a useful marker in assessing the disease progression in CML patients. In addition, VEGFA+936C>T was observed to have additive effect in inflating the risk further.
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Jamison C, Nelson D, Eren M, Gauchan D, Ramaekers R, Norvell M, Copur MS. What Is the Optimal Dose and Schedule for Dasatinib in Chronic Myeloid Leukemia: Two Case Reports and Review of the Literature. Oncol Res 2016; 23:1-5. [PMID: 26802644 PMCID: PMC7842568 DOI: 10.3727/096504015x14452563485986] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Efficacy and safety of dasatinib in chronic phase (CP) chronic myelogenous leukemia (CML) patients has been well established. Initially approved dose and schedule of 70 mg twice daily has been changed to 100 mg once daily after demonstration of the same efficacy with less toxicity. Some patients require significant dose reductions to enable continued treatment with dasatinib. Even at a dose of 80 mg once daily, several patients may require further dose reductions due to substantial toxicity while maintaining good control of their disease. We report two CP-CML patients achieving and maintaining major molecular responses while on very low doses of dasatinib, ultimately achieving undetectable levels of BCR-ABL fusion transcript in their peripheral blood. Observations of several CP-CML cases responding remarkably well to dasatinib despite very low dose and frequent dose interruptions challenge our current understanding and the accuracy of the data regarding the optimum dose and schedule of this drug. In selected intolerant patients, low-dose dasatinib therapy may be a safe and effective alternative treatment option before a treatment discontinuation or change considered.
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Affiliation(s)
- Caroline Jamison
- University of Nebraska Medical Center College of Pharmacy, Omaha, NE, USA
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Zhang X, Liu R, Huang B, Zhang X, Yu W, Bao C, Li J, Sun C. Programmed cell death 4 and BCR-ABL fusion gene expression are negatively correlated in chronic myeloid leukemia. Oncol Lett 2016; 12:2976-2981. [PMID: 27698886 DOI: 10.3892/ol.2016.4942] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 07/20/2016] [Indexed: 02/07/2023] Open
Abstract
Programmed cell death 4 (PDCD4) is a tumor suppressor that inhibits carcinogenesis, tumor progression and invasion by preventing gene transcription and translation. Downregulation of PDCD4 expression has been identified in multiple types of human cancer, however, to date, the function of PDCD4 in leukemia has not been investigated. In the present study, PDCD4 mRNA and protein expression was investigated in 50 patients exhibiting various phases of chronic myeloid leukemia (CML) and 20 healthy individuals by reverse transcription-quantitative polymerase chain reaction and western blot analysis. PDCD4 expression and cell proliferation was also investigated following treatment with the tyrosine kinase inhibitor, imatinib, in K562 cells. The results demonstrated that PDCD4 mRNA and protein expression was decreased in all CML samples when compared with healthy controls, who expressed high levels of PDCD4 mRNA and protein. No significant differences in PDCD4 expression were identified between chronic phase, accelerated phase and blast phase CML patients. In addition, PDCD4 expression was negatively correlated with BCR-ABL gene expression (r=-0.6716; P<0.001). Furthermore, K562 cells treated with imatinib exhibited significantly enhanced PDCD4 expression. These results indicate that downregulation of PDCD4 expression may exhibit a critical function in the progression and malignant proliferation of human CML.
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Affiliation(s)
- Xia Zhang
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Riming Liu
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Baohua Huang
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Xiaolu Zhang
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Weijuan Yu
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Cuixia Bao
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Jie Li
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Chengming Sun
- Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
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Asif M, Hussain A, Rasool M. A rare case of a three way complex variant positive Philadelphia translocation involving chromosome (9;11;22)(q34;p15;q11) in chronic myeloid leukemia: A case report. Oncol Lett 2016; 12:1986-1988. [PMID: 27602125 DOI: 10.3892/ol.2016.4821] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Accepted: 12/02/2015] [Indexed: 11/05/2022] Open
Abstract
The t(9;22)(q34;q11) translocation is present in 90-95% of patients with chronic myeloid leukemia (CML). Variant complex translocations have been observed in 5-8% of CML patients, in which a third chromosome other than (9;22) is involved. Imatinib mesylate is the first line breakpoint cluster region-Abelson gene (BCR/ABL)-targeted oral therapy for CML, and may produce a complete response in 70-80% of CML patients in the chronic phase. In the present study, a bone marrow sample was used for conventional cytogenetic analysis, and the fluorescence in situ hybridization (FISH) test was used for BCR/ABL gene detection. A hematological analysis was also performed to determine the white blood cell (WBC) count, red blood cell count, hemoglobin levels, packed and mean cell volumes, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and platelet values of the patient. The hematological analysis of the patient indicated the increased WBC of 186.5×103 cells/µl, and decreased hemoglobin levels of 11.1 g/dl. The FISH test revealed that 67% cells demonstrated BCR/ABL gene translocation. The patient was treated with 400 mg imatinib mesylate daily, and was monitored at various intervals over a 6-month period. The present study reports the rare case of a patient that demonstrates a three-way Philadelphia chromosome-positive translocation involving 46XY,t(9;11;22)(q34;p15;q11)[10], alongside CML in the chronic phase. The translocation was analyzed using cytogenetic and FISH tests.
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Affiliation(s)
- Muhammad Asif
- Department of Biotechnology and Informatics, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Balochistan 87300, Pakistan; Office of Research Innovation and Commercialization, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Balochistan 87300, Pakistan
| | - Abrar Hussain
- Department of Biotechnology and Informatics, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Balochistan 87300, Pakistan
| | - Mahmood Rasool
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Makkah 21589, Saudi Arabia
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Yeung CCS, Egan D, Radich JP. Molecular monitoring of chronic myeloid leukemia: present and future. Expert Rev Mol Diagn 2016; 16:1083-1091. [PMID: 27552202 DOI: 10.1080/14737159.2016.1227243] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Fusion of BCR-ABL1 genes causes chronic myeloid leukemia (CML). As a reliable marker of disease burden, it also serves as the target of tyrosine kinase inhibitors (TKIs). New more sensitive molecular diagnostic tools for BCR-ABL1 can contribute to therapeutic decision-making, especially in considering drug discontinuation for patients enjoying prolonged deep molecular response. Areas covered: Several novel platforms are transforming CML molecular diagnostics to enable faster point-of-care devices, better understanding of clonal diversity and resistance mutations. Here, we review these molecular platforms, knowing implementation in other hematological malignancies will ensue. Expert commentary: Treatment with TKI in CML is the first example of a highly effective targeted therapy. Monitoring of BCR-ABL1 mRNA is standard in assessing disease burden being highly predictive of outcomes recommended by both European LeukemiaNet (ELN) and National Comprehensive Cancer Network (NCCN); however, studies has demonstrated poor adherence to these recommendations. In both clinical practice and assay performance, further optimizing of BCR-ABL1 monitoring can be envisioned including point-of-care methods for increased availability of rapid, standardized testing and increasingly sensitive molecular assays that allow for quantification of MRD and detecting resistance mutations.
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Affiliation(s)
- Cecilia Ching Sze Yeung
- a Clinical Research Division , Fred Hutchinson Cancer Research Center Ringgold standard institution , Seattle , WA , USA.,b Pathology , University of Washington School of Medicine Ringgold standard institution , Seattle , WA , USA
| | - Daniel Egan
- a Clinical Research Division , Fred Hutchinson Cancer Research Center Ringgold standard institution , Seattle , WA , USA
| | - Jerald P Radich
- c Fred Hutchinson Cancer Research Center , Seattle , WA , USA
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Egan D, Radich J. Monitoring disease burden in chronic myeloid leukemia: Past, present, and future. Am J Hematol 2016; 91:742-6. [PMID: 27059166 DOI: 10.1002/ajh.24381] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 03/29/2016] [Accepted: 04/04/2016] [Indexed: 01/01/2023]
Abstract
Tyrosine kinase inhibitor (TKI) therapy yields sustained cytogenetic remissions in most patients with chronic-phase chronic myeloid leukemia (CML). Peripheral blood quantitative reverse transcription polymerase chain reaction (qRT-PCR) monitoring of the chimeric BCR-ABL1 mRNA transcript levels is a very sensitive method to measure disease burden in patients with cytogenetic remission. qRT-PCR allows identification of patients (1) at high risk of progression early (3-6 months) after treatment initiation, (2) with no response to TKI therapy, (3) with undetectable disease who could be eligible for TKI discontinuation trials. Molecular monitoring is a minimally invasive method to optimize treatment and outcomes in CML. Am. J. Hematol. 91:742-746, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Daniel Egan
- Clinical Research Division; Fred Hutchinson Cancer Research Center; Seattle Washington
| | - Jerald Radich
- Clinical Research Division; Fred Hutchinson Cancer Research Center; Seattle Washington
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50
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Asif M, Jamal MS, Khan AR, Naseer MI, Hussain A, Choudhry H, Malik A, Khan SA, Mahmoud MM, Ali A, Iram S, Kamran K, Iqbal A, Abduljaleel Z, Pushparaj PN, Rasool M. A Novel Four-Way Complex Variant Translocation Involving Chromosome 46,XY,t(4;9;19;22)(q25:q34;p13.3;q11.2) in a Chronic Myeloid Leukemia Patient. Front Oncol 2016; 6:124. [PMID: 27303656 PMCID: PMC4885335 DOI: 10.3389/fonc.2016.00124] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 05/02/2016] [Indexed: 11/13/2022] Open
Abstract
Philadelphia (Ph) chromosome (9;22)(q34;q11) is well established in more than 90% of chronic myeloid leukemia (CML) patients, and the remaining 5-8% of CML patients show variant and complex translocations, with the involvement of third, fourth, or fifth chromosome other than 9;22. However, in very rare cases, the fourth chromosome is involved. Here, we found a novel case of four-way Ph+ chromosome translocation involving 46,XY,t(4;9;19;22)(q25:q34;p13.3;q11.2) with CML in the chronic phase. Complete blood cell count of the CML patient was carried out to obtain total leukocytes count, hemoglobin, and platelets. Fluorescence in situ hybridization technique was used for the identification of BCR-ABL fusion gene, and cytogenetic test for the confirmation of Ph (9;22)(q34;q11) and the mechanism of variant translocation in the bone marrow. The patient is successfully treated with a dose of 400 mg/day imatinib mesylate (Gleevec). We observed a significant decrease in white blood cell count of 11.7 × 10(9)/L after 48-month follow-up. Patient started feeling better generally. There was a reduction in the swelling of the body, fatigue, and anxiety.
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Affiliation(s)
- Muhammad Asif
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences (BUITEMS), Quetta, Pakistan
- Office of Research Innovation and Commercialization, Balochistan University of Information Technology, Engineering and Management Sciences (BUITEMS), Quetta, Pakistan
| | - Mohammad Sarwar Jamal
- King Fahd Medical Research Center (KFMRC), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdul Rehman Khan
- Obesity and Diabetes Research Laboratory, Department of Chemistry, University of Azad Jammu and Kashmir, Muzaffarabad, Pakistan
| | - Muhammad Imran Naseer
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abrar Hussain
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences (BUITEMS), Quetta, Pakistan
| | - Hani Choudhry
- Department of Biochemistry, Faculty of Science, Center of Innovation in Personalized Medicine, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Arif Malik
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan
| | - Shahida Aziz Khan
- King Fahd Medical Research Center (KFMRC), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Maged Mostafa Mahmoud
- King Fahd Medical Research Center (KFMRC), King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Molecular Genetics and Enzymology, Division of Human Genetics and Genome Research, National Research Centre, Giza, Egypt (Affiliation ID 60014618)
| | - Ashraf Ali
- King Fahd Medical Research Center (KFMRC), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saima Iram
- Bolan Medical Hospital, Quetta, Balochistan, Pakistan
| | - Kashif Kamran
- Faculty of Life Sciences, University of Balochistan, Quetta, Pakistan
| | - Asim Iqbal
- Faculty of Life Sciences, University of Balochistan, Quetta, Pakistan
| | | | - Peter Natesan Pushparaj
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmood Rasool
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
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