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1
Rocchi, Miriana. "A case of double leukemia: chronic myeloid leukemia intolerant to imatinib and chronic lymphocytic leukemia." Clinical Management Issues 4, no. 2S (October 13, 2015): 13–16. http://dx.doi.org/10.7175/cmi.v4i2s.1071.
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Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common leukemias of the elderly. However, the sequential occurrence of CML followed by CLL in the same patient is extremely rare. We present a report of a 70-year-old man who developed CLL six years after the diagnosis of CML in molecular, cytogenetic and morphologic remission. The diagnosis of CLL is confirmed by peripheral lymphocytosis. The first line therapy in CML in chronic phase is still imatinib, but in the present case the patient was intolerant to imatinib, therefore he switched to nilotinib after few months.
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Melo, Junia V., Timothy P. Hughes, and Jane F. Apperley. "Chronic Myeloid Leukemia." Hematology 2003, no. 1 (January 1, 2003): 132–52. http://dx.doi.org/10.1182/asheducation-2003.1.132.
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Abstract Chronic myeloid leukemia (CML) was the first human malignancy to be associated with a specific genetic lesion, the Philadelphia chromosome, harboring the BCR-ABL oncogene. Since then, it has become a paradigm for the discovery of molecular mechanisms and targeted therapeutic approaches in the field of hematologic neoplasias. The past 5 years or so have been particularly fruitful in the dissection of the signal transduction pathways abnormally activated in CML and in the translation of this knowledge to clinical practice. In this report, we discuss the biological basis for such translation and highlight the current and potential tools for the effective treatment of CML patients. The first part presents a review of the basic concepts on the biology of CML and their application to the design of targeted therapy. The mechanisms of action of the molecular-specific drugs currently used in clinical trials are discussed, with emphasis on the description of the most promising new compounds that are enhancing the potential for effective alternative or combination chemotherapy in CML. In the following section, we explain how molecular monitoring of response to imatinib mesylate in patients with CML can be used as a guide to clinical management. In particular, we discuss the relative value of regular quantitative RT/PCR and cytogenetic analyses, how responding patients should be monitored and managed, and how to investigate patients who are refractory or become resistant to imatinib treatment. In the last part of this report, a discussion on the possibility of managing CML with patient-specific strategies is presented. We review the current treatment options, highlight the factors impacting on decision making, discuss the range of possibilities for future therapeutic strategies and propose a systematic approach for individualizing treatment for patients in different disease categories.
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Wahyuni, Rosa Dwi, Agus Alim Abdullah, and Mansyur Arif. "CHRONIC MYELOID LEUKEMIA IN PREGNANCY." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 24, no. 3 (July 1, 2018): 286. http://dx.doi.org/10.24293/ijcpml.v24i3.1338.
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Chronic Myeloid Leukemia (CML) is one of leukemias characterized by abnormal growth of myeloid cells in bone marrow. The Philadelphia chromosome is diagnostic parameter for CML. This chromosome is t(9;22) (q32;q21), a translocation chromosome 9 and 22 relocates a portion of proto-oncogene c-ABL from chromosome 9 to BCR on chromosome 22. Chronic myeloid leukemia consisting of three phases; Chronic, Accelerating and the Blast crisis phase. The clinicaling symptoms of CML are hypercatabolism, splenomegaly, anemia, bruising and sign of Gout. Chronic myeloid leukemia in pregnancy shows a better prognosis than acute leukemia in pregnancy. Chronic myeloid leukemia has the risk of leukocytosis which can lead to uteroplacental insufficiency giving rise to various consequences: fetal growth retardation and perinatal mortality. Moreover, the therapy of CML should be carefully administered considering the fetal effects. Both sexes have the same risk, mostly in the range of 40 to 60 years old. In this case report, a 38-year-old pregnant female (G1P0A0) with 37 weeks of gestational age was diagnosed as CML on August 2013 and was treated with 500 mg of Cytodrox/Hydroxyurea twice to three times a day until January 2014. Laboratory evaluation on November 10th, 2014, showed leucocytes 449500/µL, erythrocytes 2.58.106/µL, hemoglobin 8.0 g/dL, thrombocytes 437,000/µL and hematocrit 23%. The peripheral blood smear showed normocytic normochromic erythrocytes, anisocytosis, ovalocytes, significantly increased leucocyte count, predominance polymorphonuclear series, all maturation series of myelocytes, 7% myeloblast, normal thrombocyte count and morphology. Based on these evaluations, the patient was diagnosed as CML. The evaluation of Neutrophil Alkaline Phosphatase (NAP) scored 1.
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Jamieson, Catriona H. "Chronic Myeloid Leukemia Stem Cells." Hematology 2008, no. 1 (January 1, 2008): 436–42. http://dx.doi.org/10.1182/asheducation-2008.1.436.
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Abstract Chronic myeloid leukemia (CML) is typified by robust marrow and extramedullary myeloid cell production. In the absence of therapy or sometimes despite it, CML has a propensity to progress from a relatively well tolerated chronic phase to an almost uniformly fatal blast crisis phase. The discovery of the Philadelphia chromosome followed by identification of its BCR-ABL fusion gene product and the resultant constitutively active P210 BCR-ABL tyrosine kinase, prompted the unraveling of the molecular pathogenesis of CML. Ground-breaking research demonstrating that BCR-ABL was necessary and sufficient to initiate chronic phase CML provided the rationale for targeted therapy. However, regardless of greatly reduced mortality rates with BCR-ABL targeted therapy, most patients harbor quiescent CML stem cells that may be a reservoir for disease progression to blast crisis. While the hematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, only recently have the HSC and progenitor cell–specific effects of the molecular mutations that drive CML been investigated. This has provided the impetus for investigating the genetic and epigenetic events governing HSC and progenitor cell resistance to therapy and their role in disease progression. Accumulating evidence suggests that the acquired BCR-ABL mutation initiates chronic phase CML and results in aberrant stem cell differentiation and survival. This eventually leads to the production of an expanded progenitor population that aberrantly acquires self-renewal capacity resulting in leukemia stem cell (LSC) generation and blast crisis transformation. Therapeutic recalcitrance of blast crisis CML provides the rationale for targeting the molecular pathways that drive aberrant progenitor differentiation, survival and self-renewal earlier in disease before LSC predominate.
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Frolova, Olga, Rui-Yu Wang, Borys Korchin, Julie C. Watt, Jorge Cortes, Arthur E. Frankel, Hagop M. Kantarjian, Michael Andreeff, and Marina Konopleva. "Targeting IL3 Receptor in Chronic Myeloid Leukemia." Blood 114, no. 22 (November 20, 2009): 2172. http://dx.doi.org/10.1182/blood.v114.22.2172.2172.
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Abstract Abstract 2172 Poster Board II-149 Despite the great success of imatinib therapy in chronic myeloid leukemia (CML), the presence of a residual leukemic clone is detectable in a proportion of patients with CML. Further, patients with accelerated and blast phase of the disease respond poorly to imatinib. Imatinib and other potent tyrosine kinase inhibitors (TKIs) have limited activity against CD34+38- leukemic stem cells, necessitating the need for novel agents capable of eradicating highly resistant CML stem cells. Expression of IL3 receptor, CD123, was demonstrated on CD34+CD38- leukemic stem cells in AML (Jordan et al., Leukemia, 14: 1777, 2000) and CML (Neering et al., Blood, 110: 2578, 2007; Florian et al., Leuk Lymphoma, 47: 207, 2006) and has been shown to be an effective therapeutic target in pre-clinical AML models (Jin et al,,Cell Stem Cell, 5:31, 2009; Feuring-Buske et al., Cancer Res, 62: 1730, 2002). However, its role in CML stem cells has not been investigated. In this study, we examined expression of CD123 on CML progenitor cells and the therapeutic potential of the CD123 targeting agents, DT388IL3 and DT388K116W, both recombinant IL3-diphtheria toxin (DT) conjugates in in vitro and in vivo CML models. DT388IL3 has been shown to eradicate NOD/Scid-initiating AML stem cells and is currently undergoing Phase I/II clinical trials in AML and MDS. DT388K116W is a new DT fusion protein with high binding affinity to the IL3 receptor that demonstrated high potency anti-leukemic activity. These novel agents are directed to the leukemia stem cell surface, trigger receptor-mediated endocytosis, inhibit protein synthesis, and cause programmed cell death. In a series of nine primary CML samples (five from patients with chronic phase CML and four from patients in blast crisis), CD123 was expressed in 86%±5.7% of CD34+CD38- progenitor cells as determined by flow cytometry. Notably, 86%±3.4% of FACS-sorted CD34+38-123+ cells from 7 primary CML samples were Bcr-Abl(+) by fluorescent in situ hybridization analysis, confirming the leukemic origin of this cell population. We next examined the cytotoxic activity of DT-IL3 agents in KBM5 cells and in primary leukemic blasts. DT388K116W induced a dose-dependent decrease in viability and induction of apoptosis in KBM5 (44.6±4.3% apoptotic cells at 10μg/mL, p≤0.001) and in primary CML cells (69.5±15 % apoptosis, n=4, p=0.04) as determined by viable cell counts and annexin V flow cytometry at 72 hours. DT388K116W induced a greater degree of cell death compared to DT388IL3 in KBM5 cells (44.6% vs 21.3%, p=0.009). In two primary CML samples DT-IL3 agents reduced the absolute numbers of CD34+CD38-CD123+ cells by induction of apoptosis (DT388IL3, by 69% (sample#1) and 21% (sample#2); DT388K116W, by 71% and 62%, respectively). Importantly, combination of imatinib with DT-IL3 further enhanced the apoptotic rate in KBM5 (p=0.0001) and primary leukemic cells (n=3, p=0.035). To examine anti-leukemic activity of these agents in vivo, NOD/Scid/IL2Rγ-KO mice were transplanted with leukemic cells from primary myeloid blast crisis CML. After engraftment of the leukemic cells documented by CD45 flow cytometry in murine blood 20 days post transplantation, mice were left untreated or received 5-day intraperitoneal administration of DT388IL3 or DT388K116W at 0.2mg/kg. These IL3 receptor-targeted agents significantly prolonged survival of treated mice compared to vehicle control (median survival: vehicle= 37, DT388IL3 = 48, DT388K116W = 57 days; p= 0.0005) and reduced leukemia burden as detected by CD45 flow cytometry. These data indicate that the IL3 receptor is highly expressed on CD34+38- Bcr-Abl(+) CML stem cells and represents an exciting new and feasible target for therapeutic intervention. Moreover, DT-IL3 conjugates represent a novel therapeutic modality for selective targeting of highly resistant CML stem cells. DT-IL3 agents, alone or in combination with TKIs, might benefit CML patients by reducing/eliminating leukemic stem cells, a concept to be tested in the future clinical trials. Disclosures: No relevant conflicts of interest to declare.
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Al-Qudah, Bara M., Mohamed A. Yassin, Mohammad A. J. Abdulla, Mahmood S. Aldapt, and Mohamad M. Abufaied. "Chronic Myeloid Leukemia Preceded by Tuberculosis." Case Reports in Oncology 13, no. 2 (June 24, 2020): 708–11. http://dx.doi.org/10.1159/000507822.
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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, classically described as a triphasic disease. However, little is known about risk factors for developing CML. Currently, ionizing radiation is the only established risk factor. Here, we report on a 37-year-old man treated for tuberculosis; 2 years later, he developed CML in a chronic phase. We would like to shed light on tuberculosis as a possible risk factor for CML.
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Mathews, Sharon T. "Atypical Infections in Chronic Myeloid Leukaemia- Staphylococcus furunculosis and Aspergillosis." Journal of Advanced Research in Medicine 07, no. 01 (August 25, 2020): 17–19. http://dx.doi.org/10.24321/2349.7181.202004.
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Incidence of opportunistic infection in patients of Chronic Myeloid Leukemia (CML) on Imatinib therapy is low. We report a case of a 47 year old lady, a known case of CML for one year on imatinib therapy who presented with CML in blast crisis with Staphylococcus furunculosis. Two weeks later she developed fever, cough and expectoration. She had cavitatory lesion in the right middle zone on chest x-ray. CECT Chest was suggestive of aspergilloma in right middle lobe. Infections in chronic myeloid leukemia are not very common. Also, developing such infections within such a short span of time, within one year of initiation of imatinib therapy is also rare. Hence, this case of CML with Staphylococcal furunculosis and Aspergillosis is being reported.
8
Deininger, Michael W. "Diagnosing and Managing Advanced Chronic Myeloid Leukemia." American Society of Clinical Oncology Educational Book, no. 35 (May 2015): e381-e388. http://dx.doi.org/10.14694/edbook_am.2015.35.e381.
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Clinical staging of chronic myeloid leukemia (CML) distinguishes between chronic phase (CP-CML), accelerated phase (AP-CML), and blastic phase (BP-CML), reflecting its natural history in the absence of effective therapy. Morphologically, transformation from CP-CML to AP/BP-CML is characterized by a progressive or sudden loss of differentiation. Multiple different somatic mutations have been implicated in transformation from CP-CML to AP/BC-CML, but no characteristic mutation or combination of mutations have emerged. Gene expression profiles of AP-CML and BP-CML are similar, consistent with biphasic evolution at the molecular level. Gene expression of tyrosine kinase inhibitor (TKI)–resistant CP-CML and second CP-CML resemble AP/BP-CML, suggesting that morphology alone is a poor predictor of biologic behavior. At the clinical level, progression to AP/BP-CML or resistance to first-line TKI therapy distinguishes a good risk condition with survival close to the general population from a disease likely to reduce survival. Progression while receiving TKI therapy is frequently caused by mutations in the target kinase BCR-ABL1, but progression may occur in the absence of explanatory BCR-ABL1 mutations, suggesting involvement of alternative pathways. Identifying patients in whom milestones of TKI response fail to occur or whose disease progress while receiving therapy requires appropriate molecular monitoring. Selection of salvage TKI depends on prior TKI history, comorbidities, and BCR-ABL1 mutation status. Despite the introduction of novel TKIs, therapy of AP/BP-CML remains challenging and requires accepting modalities with substantial toxicity, such as hematopoietic stem cell transplantation (HSCT).
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Jiang, Xiaoyan, Yun Zhao, Donna Forrest, Clayton Smith, Allen Eaves, and Connie Eaves. "Stem Cell Biomarkers in Chronic Myeloid Leukemia." Disease Markers 24, no. 4-5 (2008): 201–16. http://dx.doi.org/10.1155/2008/146871.
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Chronic myeloid leukemia (CML) is a clonal multi-step myeloproliferative disease that is initially produced and ultimately sustained by a rare subpopulation of BCR-ABL+ cells with multi-lineage stem cell properties. These BCR-ABL+ CML stem cells are phenotypically similar to normal hematopoietic stem cells which are also maintained throughout the course of the disease at varying levels in different patients. Defining the unique properties of the leukemic stem cells that produce the chronic phase of CML has therefore had to rely heavily on access to samples from rare patients in which the stem cell compartment is dominated by leukemic elements. Here we review past and ongoing approaches using such samples to identify biologically and clinically relevant biomarkers of BCR-ABL+ stem cells that explain their unusual biology and that may help to design, or at least predict, improved treatment responses in CML patients. These studies are of particular interest in light of recent evidence that chronic phase CML stem cells are not only innately resistant to imatinib mesylate and other drugs that target the BCR-ABL oncoprotein, but are also genetically unstable.
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Mahon, François-Xavier. "Is going for cure in chronic myeloid leukemia possible and justifiable?" Hematology 2012, no. 1 (December 8, 2012): 122–28. http://dx.doi.org/10.1182/asheducation.v2012.1.122.3798214.
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Abstract After more than a decade of treatment of chronic myeloid leukemia (CML) patients with the BCR-ABL tyrosine kinase inhibitor imatinib, and despite the impressive clinical results of this targeted therapeutic, many questions remain unresolved. One major question is how to cure CML, and the next step for the future will be to address this key issue. CML is a good model of cancer. The fact that the majority of CML patients who respond very well but discontinue tyrosine kinase inhibitors later show evidence of molecular recurrence focuses attention on the need for further research on leukemic stem cells. The challenge now is to understand why, after stopping treatment, the leukemia recurs in some patients but not in others. If we win this battle, this progress will certainly benefit the treatment and management of other leukemias and solid tumors and will validate this new topic.
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Buhring, HJ, I. Sures, B. Jallal, FU Weiss, FW Busch, WD Ludwig, R. Handgretinger, HD Waller, and A. Ullrich. "The receptor tyrosine kinase p185HER2 is expressed on a subset of B- lymphoid blasts from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia." Blood 86, no. 5 (September 1, 1995): 1916–23. http://dx.doi.org/10.1182/blood.v86.5.1916.bloodjournal8651916.
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The class I receptor tyrosine kinase (RTK) HER2 is an oncoprotein that is frequently involved in the pathogenesis of tumors of epithelial origin. Here we report mRNA expression in peripheral blood and bone marrow cells from healthy donors in hematopoietic cell lines and leukemic blasts from patients with acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphoblastic leukemia (CLL), and chronic myeloid leukemia (CML). However, cell surface expression of HER2 protein (p185HER2) was found exclusively on a subset of leukemic cells of the B-lymphoblastic lineage. p185HER2 expression was found on blasts in 2 of 15 samples from infants, 9 of 19 samples from adult patients with C-ALL (CD19+CD10+), and 1 of 2 samples from patients with pro-B ALL (CD19+CD10-), whereas none of the leukemic cells from patients with AML (0/30), T-ALL (0/7), CLL (0/5) (CD19+CD5+), or CML in chronic and accelerated phase (0/5) or in blast crisis with myeloid differentiation (0/14) were positive for p185HER2. However, cells from 3 of 4 patients with CML in B-lymphoid blast crisis (CD19+CD10+) expressed high levels of p185HER2, which was also found on the surface of the CML-derived B-cell lines BV-173 and Nalm-1. Our study shows p185HER2 expression on malignant cells of hematopoietic origin for the first time. Aberrant expression of this oncogenic receptor tyrosine kinase in hematopoietic cell types may be an oncogenic event contributing to the development of a subset of B- lymphoblastic leukemias.
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Kavalerchik, Edward, Daniel Goff, and Catriona H. M. Jamieson. "Chronic Myeloid Leukemia Stem Cells." Journal of Clinical Oncology 26, no. 17 (June 10, 2008): 2911–15. http://dx.doi.org/10.1200/jco.2008.17.5745.
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Although rare, chronic myeloid leukemia (CML) represents an important paradigm for understanding the molecular events leading to malignant transformation of primitive hematopoietic progenitors. CML was the first cancer to be associated with a defined genetic abnormality, BCR-ABL, that is necessary and sufficient for initiating chronic phase disease as well as the first cancer to be treated with molecular targeted therapy. Malignant progenitors or leukemia stem cells (LSCs) evolve as a result of both epigenetic and genetic events that alter hematopoietic progenitor differentiation, proliferation, survival, and self-renewal. LSCs are rare and divide less frequently, and thus, represent a reservoir for relapse and resistance to a molecularly targeted single agent. On subverting developmental processes normally responsible for maintaining robust life-long hematopoiesis, the LSCs are able to evade the majority of current cancer treatments that target rapidly dividing cells. Enthusiasm for the enormous success of tyrosine kinase inhibitors at controlling the chronic phase disease is tempered somewhat by the persistence of the LSC pool in the majority of the patients. Combined therapies targeting aberrant properties of LSC may obviate therapeutic resistance and relapse in advanced phase and therapeutically recalcitrant CML.
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Aguayo, Alvaro, Hagop Kantarjian, Taghi Manshouri, Cristi Gidel, Elihu Estey, Deborah Thomas, Charles Koller, et al. "Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes." Blood 96, no. 6 (September 15, 2000): 2240–45. http://dx.doi.org/10.1182/blood.v96.6.2240.
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Abstract Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-α (TNF-α), tumor growth factor-α (TGF-α), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-α, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-α levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-α in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.
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Aguayo, Alvaro, Hagop Kantarjian, Taghi Manshouri, Cristi Gidel, Elihu Estey, Deborah Thomas, Charles Koller, et al. "Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes." Blood 96, no. 6 (September 15, 2000): 2240–45. http://dx.doi.org/10.1182/blood.v96.6.2240.h8002240_2240_2245.
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Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-α (TNF-α), tumor growth factor-α (TGF-α), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-α, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-α levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-α in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.
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Hochhaus, Andreas. "Prognostic Factors in Chronic Myeloid Leukemia (CML)." Oncology Research and Treatment 31, no. 11 (2008): 576–78. http://dx.doi.org/10.1159/000163070.
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Williams, L. A., P. Ault, C. S. Cleeland, R. J. Reynolds, N. A. Shah, P. K. Shah, and J. E. Cortes. "Symptom burden in chronic myeloid leukemia (CML)." Journal of Clinical Oncology 28, no. 15_suppl (May 20, 2010): 6133. http://dx.doi.org/10.1200/jco.2010.28.15_suppl.6133.
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Kenealy, Laureen K., Courtney B. Christenson, and Casey B. Williams. "Current Therapies for Chronic Myeloid Leukemia." Journal of Pharmacy Practice 21, no. 2 (April 2008): 116–25. http://dx.doi.org/10.1177/0897190008314778.
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Management strategies for patients with chronic-phase chronic myeloid leukemia (CML) have changed dramatically since the introduction of imatinib into clinical trials in 1998. Imatinib is generally accepted, at present, to be the most appropriate initial therapy for newly diagnosed chronic-phase CML; however, a proportion of patients will not respond adequately. Many of these patients may benefit from alternative treatment strategies, including second- and third-generation BCR-ABL kinase inhibitors and allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, with continued improvements in molecular monitoring, it is much more clinically routine to measure ongoing treatment efficacy or characterize pending disease relapse via molecular analysis. The challenge is to now combine molecular monitoring information with timely treatment decisions to achieve the best possible outcomes. Additionally, unanswered questions about HSCT remain, and include (1) What is the role of allogeneic HSCT in CML? (2) What type of transplant, reduced-intensity or myeloablative, should be performed? The goal of this article is to provide an overview of where we stand in the treatment of CML in 2008.
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Vincelli, Iolanda Donatella, Patrizia Cufari, Carmelo Toscano, Al Sayyad Said, Mauro Campello, Giuseppina Caruso, Maria Grazia D'Errigo, et al. "A Patient with Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia and Multiple Myeloma." Blood 136, Supplement 1 (November 5, 2020): 37. http://dx.doi.org/10.1182/blood-2020-141974.
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Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative disorder and is manifested by progressive accumulation of B cells in the blood, bone marrow and lymphatic tissues. Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of all the stages of myeloid development in the peripheral blood, and it is believed to be driven by the aberrant protein tyrosine kinase, a product of the mutant BCR-ABL1 gene.Multiple Myeloma (MM) is characterized by the accumulation of clonal plasmcells in the bone marrow with skeletal lesions, anemia, hypercalcemia and renal failure. Our patient is a 78 year-old man. In 2014 diagnosis of CLL and monoclonal gammopathy of undetermined significance (MGUS).At diagnosis: HB 13.5 g/dl; normal renal function;calcium 8.7 mg/dl;IgG 1678 mg/dl,serum immunoelectrophoresis: IgG kappa, Bence Jones kappa; total protein 7.5 g/dl, beta1 6,5%, beta2 24,1%;peripheral blood immunophenotyping showed CLL, FISH:negative;Cariotype: 46, XY; RX skeleton: positive for osteolytic lesions, total body TC scan: adenopathies of 18 mm and 15 mm at bilateral axillary level, norma spleen, adenopathy of 22 cm in the left obturator iliac region; presence of left hip prosthesis; bone marrow biopsy: localization by low-grade plasmacytoma.No CLL.The patient was only observed until April 2015, when there was a presence of myelocytes and metamyelocytes in peripheral blood and an increased spleen (18 cm). So he performed : bone marrow aspirate: diagnosis of CML (Sokal Score: 1,34 H; Eutos Score: 60 L, Hasford Score 1488,5);bone marrow biopsy: suggestive for a myeloproliferative disease (CML), MGUS with a modest lymphoid B component,BCR-ABL: 60;FISH: pathological presence of double fusion signal of the ABL1 and BCR loci in 209 of 271 interphase nuclei examined (77%).The patient started therapy with Imatinib, 400mg/die until July 2015, on the basis of the good response to treatment and the progressive increase of the M component that confirmed the progression to MM: Hb 9.1 g/dL, creatinine 1,1 mg/dl;calcium 10,5 mg/dl;total protein: 8,6 g/dl, gamma 48.02% (CM 4 gr); IgG 3536 mg/dl, cariotype: male with t (9; 22) and Philadelphia chromosome (25%);BCR-ABL: 14,32; bone marrow aspirate: plasmacells 15%;bone marrow biopsy: intermediate-interstitial plasmacytoma, CLL / lymphoma; RMN whole body: hyperintensity at the level of the seventh right rib; PET: osteolytic lesions of the side arch tenth right rib, right iliac bone, left iliac region, right tibia third diaphyseal.RX right hemithorax: osteolytic area at the level of the seventh right rib. So the patient started treatment with Bortezomib, Desamethasone, Alkeran (total 7 cycles).On March 2016, he performed a radiography that showed many osteolytic areas of 45 mm on third distal femur, third proximal and intermediate tibia, third proximal and third distal of fibula.A second PET documented a further MM progression due to new bone localizations and a left tibia biopsy showed localization disease. Radiotherapy colleagues have ruled out the usefulness of a radiation therapy program in consideration of the cerebral damage risk. On June 2016 the patient started a treatment with Lenalidomide for 15 days, interspersed by Glivec, maintaining the disease stable. In September 2017 he developed diplopia and with a nasal surgery, only inflammatory tissue was exported. A revision of the material confirmed plasmacytoma localization. In the same period appearance of a right gluteus sore treated initially with surgical dressing.As blood tests revealed increase of paraprotein levels, bone marrow biopsy resulted negative to myeloma and lymphoma diseases, instead a gluteal skin biopsy revealed plasmacytoma. It was decided to treat cerebral localization due to diplopia and peripherical paralysis. Radiotherapy was started on April 2018 (18 sessions). Bone marrow aspirate test showed plasmacells 15%, BCR-ABL dosage: 213,87, M component increase(5gr), IgG 4440 mg/dl, creatinine and serum calcium: normal. Due to disease progression, a rescue chemotherapy was started according to PAD protocol. After 4 cycles, a bone marrow aspirate documented the presence of plasmacells equal to 80%.The cytogenetic study confirmed the presence of a complex karyotype. So the patient started therapy with Daratumumab, Lenalidomide and Desamethasone which is currently ongoing with an excellent hematological and clinical response Disclosures Ciolli: Janssen: Honoraria; Abbvie: Research Funding.
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Shah, Binay K., and Krishna B. Ghimire. "Second Primary Malignancies in Chronic Myeloid Leukemia." Blood 120, no. 21 (November 16, 2012): 4247. http://dx.doi.org/10.1182/blood.v120.21.4247.4247.
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Abstract Abstract 4247 Background: Development of second primary cancers among CML patients is not well studied. With improvement in CML survival, long term risks of CML, including second cancers need to be evaluated. This study was conducted to evaluate second primary malignancies in CML patients using data from the US Surveillance, Epidemiology and End Results (SEER) cancer registries. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER*Stat) database: Incidence - SEER 13 Regs Research Data, Nov 2011 Sub, Vintage 2009 Pops (1992–2009) using MP-SIR Session. We compared secondary cancer rate among adult CML patients (older than 20 years of age) during the period 1992 – 2009. We also evaluated the risk of secondary malignancies in pre- (1992–2000) to post- imatinib (2001–2009) eras. We used SEER MP-SIR session and Graph pad scientific software to calculate p value. Results: The total number of CML patients older than 20 years of age, reported during 1992–2009 period was 8,511. There were 4286 and 4225 CML patients in the pre- (1992–2000) and post- (2001–2009) Imatinib era respectively. All site secondary cancer (n=475) incidence was significantly higher among CML patients compared to general population with observed/expected ratio (O/E):1.28, p=< 0.05, an absolute excess risk of 31.39 per 10,000. Similarly, all sites secondary cancer in post-(2001–2009) Imatinib era was significantly higher compared to pre- imatinib era with O/E ratio of 1.50 vs 1.13, p=0.03. Conclusions: This study showed that overall risk of second malignancies among CML patients is higher compared to general population. The risk of second primary malignancies is higher in post- imatinib era. Disclosures: No relevant conflicts of interest to declare.
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Kinstrie, Ross, Dimitris Karamitros, Nicolas Goardon, Heather Morrison, Mike Hamblin, Lisa Robinson, Richard E. Clark, Mhairi Copland, and Paresh Vyas. "Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemia." Blood Advances 1, no. 3 (December 14, 2016): 160–69. http://dx.doi.org/10.1182/bloodadvances.2016000810.
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Key Points In BP-CML multiple, nonhierarchically arranged immunophenotypic stem/progenitor populations have functional LSC activity. BP-associated cytogenetic abnormalities are detected equally in all immunophenotypic stem/progenitor cells.
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Ganesan, Prasanth, and Lalit Kumar. "Chronic Myeloid Leukemia in India." Journal of Global Oncology 3, no. 1 (February 2017): 64–71. http://dx.doi.org/10.1200/jgo.2015.002667.
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Background In the last decade, the use of imatinib has brought a paradigm shift in the management of chronic myeloid leukemia (CML). In India, imatinib has been available for more than a decade and has been made accessible to all segments of the population because of patient assistance programs and cheaper generic versions. Despite improvements in survival, there are unique challenges in the Indian context. Methods We reviewed published data pertaining to CML in India for the period of 1990 to 2016, using PubMed advanced search with the terms chronic myeloid leukemia and India, and included studies that reported on epidemiology, monitoring for therapy, treatment outcomes, and resistance. Additionally, the references in retrieved articles were also reviewed. Results Thirty-seven studies were identified. The incidence of CML may be slightly lower in India than in the West, but there was only a single article reporting population-based data. Indian patients presented with more advanced disease. Most centers have access to imatinib as first-line therapy, but there is limited availability of molecular monitoring and second-line therapy. Most of the outcome data were retrospective but seemed comparable with that reported in Western centers. Drug adherence was impaired in at least one third of patients and contributed to poor survival. Conclusion Focused prospective studies and cooperative studies might improve the quality of data available. Future studies should focus on adherence, its effects on outcomes, and methods to address this problem.
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Viswanathan, Kartik, Gail Roboz, Amy Chadburn, and Susan Mathew. "Chronic Myelogenous Leukemia Diagnosed in the Setting of Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma." International Journal of Surgical Pathology 28, no. 2 (September 22, 2019): 216–24. http://dx.doi.org/10.1177/1066896919876704.
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Chronic myeloid leukemia (CML) is rarely reported to occur in treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In this article, we report a woman in her 70s, diagnosed with CLL/SLL in 2000, untreated, who subsequently presented 12 years later with de novo CML, BCR-ABL1+. Her IGHV mutated CLL/SLL based on the initial sample in our laboratory showed homozygous and heterozygous 13q14.3 deletions, whereas her CML, at presentation, showed a 46,XX,t(9;22)(q34;q11.2)[7]/46,XX[18] karyotype with a p190 BCR-ABL1 transcript. The tumor burden of each clone varied with treatment, including when treated with dasatinib, used to target both clones. In addition, the cytogenetic abnormalities evolved over time and treatments and included acquisition of an extra chromosome 8 in the CML clone and a novel K1992T ATM missense mutation (47% allele frequency) in the CLL/SLL clone. The patient’s last bone marrow biopsy, 5 years after her CML diagnosis and 17 years after the CLL/SLL diagnosis, showed residual CML with extensive involvement by CLL/SLL (80%). Cytogenetic studies showed a 46,XX karyotype, while FISH identified 13q14.3 deletion and the BCR-ABL1 translocation in the CLL/SLL and CML clones, respectively. To date, this is the fourth case of concurrent CML, BCR-ABL1+ arising in untreated CLL/SLL. Here we show dynamic variation in the size of the 2 clonal processes reflecting the variable responsiveness to specific therapies. In addition to the unusual BCR-ABL1+ p190 transcript in the patient’s CML, a novel ATM K1992T mutation was identified in the CLL/SLL population.
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Losson, Hélène, Michael Schnekenburger, Mario Dicato, and Marc Diederich. "HDAC6—An Emerging Target Against Chronic Myeloid Leukemia?" Cancers 12, no. 2 (January 29, 2020): 318. http://dx.doi.org/10.3390/cancers12020318.
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Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.
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Lewandowski, Krzysztof, Michał Gniot, Maria Lewandowska, Anna Wache, Błażej Ratajczak, Anna Czyż, Małgorzata Jarmuż-Szymczak, and Mieczysław Komarnicki. "B-Cell Chronic Lymphocytic Leukemia with 11q22.3 Rearrangement in Patient with Chronic Myeloid Leukemia Treated with Imatinib." Case Reports in Medicine 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/9806515.
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The coexistence of two diseases chronic myeloid leukemia (CML) and B-cell chronic lymphocytic leukemia (B-CLL) is a rare phenomenon. Both neoplastic disorders have several common epidemiological denominators (they occur more often in men over 50 years of age) but different origin and long term prognosis. In this paper we described the clinical and pathological findings in patient with CML in major molecular response who developed B-CLL with 11q22.3 rearrangement and Coombs positive hemolytic anemia during the imatinib treatment. Due to the presence of the symptoms of autoimmune hemolytic anemia and optimal CML response to the imatinib treatment, the decision about combined therapy with prednisone and imatinib was made. During the follow-up, the normalization of complete blood count and resolution of peripheral lymphadenopathy were noted. The hematologic response of B-CLL was diagnosed. The repeated FISH analysis of cultured peripheral blood lymphocytes showed 2% of cells carrying 11q22.3 rearrangement. At the same time, molecular monitoring confirmed the deep molecular response of CML. The effectiveness of such combination in the described case raises the question about the best therapeutic option in such situation, especially in patients with good imatinib tolerance and optimal response.
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Herrmann, Harald, Irina Sadovnik, Sabine Cerny-Reiterer, Thomas Rülicke, Gabriele Stefanzl, Michael Willmann, Gregor Hoermann, et al. "Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia." Blood 123, no. 25 (June 19, 2014): 3951–62. http://dx.doi.org/10.1182/blood-2013-10-536078.
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Key Points DPPIV (CD26) is a new specific marker of CML LSC that aids CML diagnostics and the measurement, characterization, and purification of LSC. DPPIV on CML LSC degrades SDF-1 and thereby promotes the niche-escape of LSC, which may contribute to extramedullary myeloproliferation in CML.
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Shvachko, L. P. "EMT-mechanizm induces the leukemic stemness phenotype in myeloid leukemias." Faktori eksperimental'noi evolucii organizmiv 23 (September 9, 2018): 256–60. http://dx.doi.org/10.7124/feeo.v23.1024.
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Aim. To study the targeted expression EMT-induced markers N-cadherin, Snail and Twist in patients with the chronic and acute myeloid leukemias. Methods. RT-PCR, electroforesic in agarose gel, TotalLab v. 2.01 densitometry. Results. Have been investigated the relative levels of mRNA expression of N-cadherin and transcriptional factors Snail and Twist, associated with epithelial-to-mesenchymal induction (EMT) in patients with the essential polycytemia (EP), the chronic mieloid leukemia CML), the acute myeloid leukemia (AML) and the acute lymphoblastic leukemia (ALL). Conclusions. Have been highlighted the EMT stemness mechanism in Leukemic stem cell progression.
Keywords: the epithelial-to-mesencymal transition (EMT), EMT-inducer marker, N-cadherin, Snail, Twist, myeloid leukemias, leuklemic stem cell progression.
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Pabst, T., J. Schwaller, MJ Bellomo, M. Oestreicher, D. Muhlematter, A. Tichelli, A. Tobler, and MF Fey. "Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias." Blood 88, no. 3 (August 1, 1996): 1026–34. http://dx.doi.org/10.1182/blood.v88.3.1026.1026.
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Abstract Microsatellites are important highly polymorphic genetic markers dispersed in the human genome. Using a panel of 22 (CA)n repeat microsatellite markers mapped to recurrent breakpoint cluster regions specifically involved in leukemia, we investigated 114 adult leukemias (25 acute lymphocytic leukemia [ALL], 32 acute myeloid leukemia [AML], 36 chronic lymphocytic leukemia [CLL], and 21 chronic myeloid leukemia [CML] in chronic phase) for somatic mutations at these loci. In each patient, DNA from fresh leukemia samples was analyzed alongside normal constitutive DNA from buccal epithelium. We detected loss of heterozygosity (LOH) in 81 of 114 patients (ALL 16/25, AML 25/32, CLL 30/36, CML 10/21). Deletions were most often seen in ALL at 11q23 and 19p13; in AML at 8q22 and 11q23; in CLL at 13q14.3, 11q13, and 11q23; and in CML at 3q26. Only six deletions were reported in 74 karyotypes analyzed, whereas in these same cases, 91 LOH events were detected by microsatellites. Of 26 leukemias with a normal karyotype, 16 nevertheless showed at least one LOH by microsatellite analysis. Replication errors were found in 10 of 114 patients (8.8%). Thus, microsatellite instability is rare in leukemia in contrast to many solid tumors. Our findings suggest that in adult leukemia, LOH may be an important genetic event in addition to typical chromosomal translocations. LOH may point to the existence of tumor suppressor genes involved in leukemogenesis to a degree that has hitherto been underestimated.
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Pabst, T., J. Schwaller, MJ Bellomo, M. Oestreicher, D. Muhlematter, A. Tichelli, A. Tobler, and MF Fey. "Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias." Blood 88, no. 3 (August 1, 1996): 1026–34. http://dx.doi.org/10.1182/blood.v88.3.1026.bloodjournal8831026.
Full textAbstract:
Microsatellites are important highly polymorphic genetic markers dispersed in the human genome. Using a panel of 22 (CA)n repeat microsatellite markers mapped to recurrent breakpoint cluster regions specifically involved in leukemia, we investigated 114 adult leukemias (25 acute lymphocytic leukemia [ALL], 32 acute myeloid leukemia [AML], 36 chronic lymphocytic leukemia [CLL], and 21 chronic myeloid leukemia [CML] in chronic phase) for somatic mutations at these loci. In each patient, DNA from fresh leukemia samples was analyzed alongside normal constitutive DNA from buccal epithelium. We detected loss of heterozygosity (LOH) in 81 of 114 patients (ALL 16/25, AML 25/32, CLL 30/36, CML 10/21). Deletions were most often seen in ALL at 11q23 and 19p13; in AML at 8q22 and 11q23; in CLL at 13q14.3, 11q13, and 11q23; and in CML at 3q26. Only six deletions were reported in 74 karyotypes analyzed, whereas in these same cases, 91 LOH events were detected by microsatellites. Of 26 leukemias with a normal karyotype, 16 nevertheless showed at least one LOH by microsatellite analysis. Replication errors were found in 10 of 114 patients (8.8%). Thus, microsatellite instability is rare in leukemia in contrast to many solid tumors. Our findings suggest that in adult leukemia, LOH may be an important genetic event in addition to typical chromosomal translocations. LOH may point to the existence of tumor suppressor genes involved in leukemogenesis to a degree that has hitherto been underestimated.
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Naka, Kazuhito, Takayuki Hoshii, Yuko Tadokoro, Takako Ooshio, Yukio Kondo, Shinji Nakao, Noboru Motoyama, and Atsushi Hirao. "Molecular Mechanism Regulating Foxo In Leukemia Initiating Cells of Chronic Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 3391. http://dx.doi.org/10.1182/blood.v116.21.3391.3391.
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Abstract Abstract 3391 Chronic myeloid leukemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. Although the development of imatinib, a small molecule inhibitor of ABL, represents a breakthrough in the treatment of CML, major part of patients treated in chronic phase CML are not off therapy due to resistance or intolerance. Recent studies have suggested that imatinib is a potent inhibitor against differentiated leukemia cells, but does not deplete leukemia-initiating cells (LICs) responsible for recurrence of CML. To date, therapeutics that can eradicate CML LICs, however, have remained under investigation. To overcome these clinical problems, here we studied the molecular mechanisms regulating maintenance of imatinib-resistant CML LICs by forkhead transcription factor Foxo3a. We first generated a mouse CML model by using retroviral induction of BCR-ABL-ires-GFP gene into mouse immature hematopoietic cells, and the cells were subsequently transplanted into irradiated recipient mice. These experiments showed that CML LICs were highly enriched in c-Kit+Lin−Sca-1+ (KLS+) population in BCR-ABL+ CML cells. Serial transplantation experiments for CML LICs originated from Foxo3a-deficient mice and littermate wild-type mice indicated that Foxo3a-deficiency reduced lethality of recipient mice at third transplantation. Although recipients that transplanted with wild-type LICs developed CML and acute lymphocytic leukemia (ALL) at third transplantation, we did not observe development of ALL or CML in recipients of Foxo3a deficient LICs after 45 days post-third transplantation, suggesting that the Foxo3a deficient LICs lose their potential to generate malignancies. In addition, a combination of Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo, indicating that Foxo3a plays an essential role for the maintenance of imatinib-resistant CML LICs (Naka et al., Nature 463, 676–680, 2010). Interestingly, when we examined sub-cellular localization of Foxo3a transcription factor in the CML LICs, we found two CML LIC populations; one population was the cells with nuclear localization of Foxo3a (Foxo3a transcription factor is active) and the other population was the cells with cytoplasmic localization of Foxo3a (Foxo3a is inactive). To understand the molecular mechanisms regulating Foxo3a in CML LICs, we next evaluated the activity of upstream BCR-ABL, PI3K, PDK1, and Akt signaling pathway by fluorescence immunohistochemistry. BCR-ABL activity that was determined by phosphorylation levels of CrkL, a down-stream target of BCR-ABL, was detected in almost all of the CML LICs. However, unexpectedly, phosphorylation levels of Akt in the CML LICs with nuclear localization of Foxo3a appeared to be lower than that in the CML LICs with cytoplasmic localization of Foxo3a, despite it is widely believed that BCR-ABL induces activation of Akt signal. Consistent with Akt phosphorylation status, we detected low levels phosphorylation of PDK1 and PI3K p85, upstream regulators for Akt, in the CML LICs with nuclear localization of Foxo3a. Interestingly, expression levels of the cell proliferation antigen Ki67 were lower in the CML LICs with nuclear Foxo3a than that in the CML LICs with cytoplasmic Foxo3a. These results suggest that Foxo3a responsible for maintenance of imatinib-resistant CML LICs may be regulated by molecular mechanisms that are involved in dormancy in CML LICs. Disclosures: No relevant conflicts of interest to declare.
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Gani, Azhari, and Muhammad Jailani. "Priapism in Patients Chronic Myeloid Leukemia." Budapest International Research in Exact Sciences (BirEx) Journal 2, no. 4 (October 9, 2020): 443–51. http://dx.doi.org/10.33258/birex.v2i4.1258.
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The aims of this study are to find out the healing process of Priapism in Patients Chronic Myeloid Leukemia. This study used one case of patient which has some complaint, The patients is man with age 29 years old, The patient complained of an enlarged left stomach since 4 months and became heavy in the last 2 weeks, On vital sign examination, compos mentis awareness was found with blood pressure 110/70 mmHg, pulse 80 times per minute, respiratory rate 20 times per minute and temperature 37oC. On the visual analogue scale (VAS) examination showed a value of 4-6 (moderate pain). The result shows that CML is a hematological malignancy characterized by the Philadelphia chromosome and detected clonal expansion of hematopoietic stem cells from ABL BCR examination on chromosomes 9 and 22 which is characterized by an increase in the number of leukocytes with or without enlargement of the spleen. One of the complications of CML is priapism which occurs due to hyperleukocytosis which causes an increase in the viscosity of the blood and this is a major cause of complications of vascular obstruction. Priapism in CML is classified as low-flow (static / ischemic) caused by venocclusiveness which must be treated immediately to restore blood flow to the cavernous corpora by means of needle aspiration.
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Erika Held, Stefanie, Annkristin Heine, Karin Mayer, Mario Kapelle, Dominik Friedrich Wolf, and Peter Brossart. "Advances in Immunotherapy of Chronic Myeloid Leukemia CML." Current Cancer Drug Targets 13, no. 7 (August 31, 2013): 768–74. http://dx.doi.org/10.2174/15680096113139990086.
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Meena, Anil, Mustafa Ali, Sudha Iyengar, and Jyoti P. Shrivastava. "Clinico Pathological Profile of Chronic Myeloid Leukemia (CML)." International Journal of Clinical and Diagnostic Pathology 3, no. 1 (January 1, 2020): 328–30. http://dx.doi.org/10.33545/pathol.2020.v3.i1e.231.
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Sawyers, CL, ML Gishizky, S. Quan, DW Golde, and ON Witte. "Propagation of human blastic myeloid leukemias in the SCID mouse." Blood 79, no. 8 (April 15, 1992): 2089–98. http://dx.doi.org/10.1182/blood.v79.8.2089.2089.
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Abstract Existing in vitro culture technology does not permit the routine propagation of most human myeloid leukemias. Previous work has shown the usefulness of mice with severe combined immunodeficiency (SCID) for the growth of human lymphoblastic leukemia. We show here that human myeloid cell lines and bone marrow samples from patients with acute myeloid leukemia (AML) and blast crisis of chronic myeloid leukemia (CML) also grow in SCID mice. Human AML or CML cell lines (three of three lines tested) grew in the bone marrow and peripheral blood of the mice after intravenous (IV) inoculation in a pattern closely resembling human AML. To define the best conditions for the growth of primary human myeloid leukemia cells, samples were transplanted into mice at several alternative sites. Using flow cytometry and Southern analysis, mice were analyzed at defined intervals up to 36 weeks after transplantation for the presence of human cells in various tissues. For four of four patients with AML and two of two patients with blast crisis of CML, myeloblasts grew locally at the site of implantation and were detected in the murine hematopoietic tissues. In contrast, marrow implants from patients in the chronic phase of CML (six patients) showed infrequent and limited myeloid growth in the mice. These findings demonstrate that the SCID mouse is a reproducible system for the propagation of blastic human myeloid leukemias. The differential growth of early- versus late-phase CML suggests that the SCID mouse may be a useful assay for identifying biologically aggressive leukemias early in their clinical presentation.
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Sawyers, CL, ML Gishizky, S. Quan, DW Golde, and ON Witte. "Propagation of human blastic myeloid leukemias in the SCID mouse." Blood 79, no. 8 (April 15, 1992): 2089–98. http://dx.doi.org/10.1182/blood.v79.8.2089.bloodjournal7982089.
Full textAbstract:
Existing in vitro culture technology does not permit the routine propagation of most human myeloid leukemias. Previous work has shown the usefulness of mice with severe combined immunodeficiency (SCID) for the growth of human lymphoblastic leukemia. We show here that human myeloid cell lines and bone marrow samples from patients with acute myeloid leukemia (AML) and blast crisis of chronic myeloid leukemia (CML) also grow in SCID mice. Human AML or CML cell lines (three of three lines tested) grew in the bone marrow and peripheral blood of the mice after intravenous (IV) inoculation in a pattern closely resembling human AML. To define the best conditions for the growth of primary human myeloid leukemia cells, samples were transplanted into mice at several alternative sites. Using flow cytometry and Southern analysis, mice were analyzed at defined intervals up to 36 weeks after transplantation for the presence of human cells in various tissues. For four of four patients with AML and two of two patients with blast crisis of CML, myeloblasts grew locally at the site of implantation and were detected in the murine hematopoietic tissues. In contrast, marrow implants from patients in the chronic phase of CML (six patients) showed infrequent and limited myeloid growth in the mice. These findings demonstrate that the SCID mouse is a reproducible system for the propagation of blastic human myeloid leukemias. The differential growth of early- versus late-phase CML suggests that the SCID mouse may be a useful assay for identifying biologically aggressive leukemias early in their clinical presentation.
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Eiring, Anna M., Jamshid S. Khorashad, Anupriya Agarwal, Clinton C. Mason, Russell Bell, Anna Senina, Anthony D. Pomicter, et al. "MS4A3: A New Player in Leukemic Stem Cell Survival in Chronic Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 934. http://dx.doi.org/10.1182/blood.v128.22.934.934.
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Abstract Background: We have previously demonstrated that the transcriptional profile of diagnostic CD34+ cells from chronic phase chronic myeloid leukemia (CP-CML) patients exhibiting primary cytogenetic resistance to imatinib overlaps with that of patients with myeloid blast phase CML (BP-CML) (McWeeney et al. Blood 2010). These data suggest that primary resistance to tyrosine kinase inhibitors (TKIs) and advanced disease are biologically related. The hematopoietic cell cycle regulator, MS4A3, was identified as a principal component of the gene expression classifier predicting response to imatinib. Low MS4A3 correlated not only with primary TKI resistance, but also with shorter overall survival in CP-CML (n=35). Consistently, microarray (n=19 CP-CML; n=16 BP-CML), qRT-PCR (n=22 CP-CML; n=17 BP-CML), and immunoblot (n=3 CP-CML; n=3 BP-CML) analyses demonstrated that MS4A3 mRNA and protein levels are reduced in CD34+ progenitor cells from BP-CML versus CP-CML patients, with no difference between CP-CML and normal CD34+progenitors (n=3) (Eiring et al. ASH 2015 #14). These data suggest that MS4A3 may play a role in both primary TKI resistance and blastic transformation of CML. Results: To assess the functional role of MS4A3 in CML and TKI response, we used ectopic MS4A3 expression and shRNA-mediated MS4A3 knockdown in CD34+ cells from BP-CML and CP-CML patients, respectively. Ectopic expression of MS4A3 in BP-CML CD34+ progenitors (n=5) markedly reduced colony formation in the presence and absence of imatinib, consistent with a tumor suppressor role for MS4A3 in CML. While re-expression of MS4A3 alone did not increase apoptosis compared to empty vector-expressing controls, imatinib-induced apoptosis in BP-CML CD34+ cells was increased by 62%, with no effect on normal CD34+ cord blood cells (n=2). Conversely, shRNA-mediated MS4A3 knockdown (shMS4A3) in CP-CML CD34+ cells (n=7) reduced the effects of imatinib in colony formation and apoptosis assays, with no effect on normal CD34+ progenitors (n=4). In contrast to a previous report (Donato JL, et al. J Clin Invest 2002), we detected no change in cell cycle status of CML or normal CD34+ cells upon MS4A3 ectopic expression or knockdown (n=3). Altogether, these data suggest that MS4A3 positively regulates patient survival and imatinib response in CML progenitor cells. To evaluate MS4A3 in the leukemic stem cell compartment, we performed qRT-PCR on primary CP-CML cells (n=5) and observed that MS4A3 mRNA levels are 22-fold higher in committed CD34+38+ progenitors compared to more primitive CD34+38- stem cells, suggesting a role for MS4A3 in differentiation. Consistently, qRT-PCR, immunoblot, and flow cytometry demonstrated that MS4A3 mRNA and protein were upregulated in CP-CML CD34+ cells upon G-CSF treatment (n=3). Flow cytometry also revealed that shMS4A3 in CP-CML CD34+ cells resulted in a reduction of CD11b+ cells by ~45% in the presence of G-CSF (n=3). To assess the function of MS4A3 in CML stem cells, we performed long-term culture-initiating cell (LTC-IC) assays and xenografts into NSG mice upon MS4A3 knockdown in CP-CML (n=3). shMS4A3 increased Ph+ LTC-IC colony formation in the absence, and even more so in the presence, of imatinib, with no effects on Ph- LTC-ICs. Consistent with these data, shMS4A3 enhanced engraftment of CD34+CD45+GFP+ cells into the bone marrow of NSG recipient mice. Preliminary data in primary TKI-resistant and BP-CML CD34+ cells suggests regulation of this gene by promoter hypermethylation. Conclusions: Altogether, these data suggest that MS4A3 plays a key role in imatinib response of 1) patients with primary TKI resistance, 2) patients with BP-CML, and 3) the CML stem cell compartment. Since the effects of MS4A3 in CML do not involve changes to the cell cycle, experiments are underway to identify the mechanism by which MS4A3 improves imatinib response and survival in CML. Disclosures Druker: Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy. Deininger:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Delord, Marc. "100 Years of Chronic Myeloid Leukemia Prevalence in France." Blood 128, no. 22 (December 2, 2016): 2380. http://dx.doi.org/10.1182/blood.v128.22.2380.2380.
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Abstract Purpose: Imatinib and other rationally designed tyrosine kinase inhibitors (TKI) has dramatically changes the fate of chronic myeloid leukemia (CML) patients. Almost always fatal a few years ago, CML is now associated to a near-normal life expectancy for a majority of patients, provided a lifelong adherence to TKI-based treatment. This situation where CML can be regarded as a chronic disease have had mechanical consequences on the disease prevalence and overall costs supported by health care systems. We present here a fully detailed and comprehensive analysis of the French CML prevalence from 1960 to 2060. Methods: We use the cohort component methodology to evaluate the CML prevalence from French population projection and different hypothesis on age- and sex-specific incidence rate, and relative survival of CML patients. Figure 1 gives an illustration of intermediate results at different time points. Results: The CML prevalence in France, expressed in cases per 100,000 inhabitants, was estimated to be around 3 from 1960 to the 80's, 6 before the 2002, 17 in 2016, 25 in 2030 where the tendency inflects, and 30 after 2040. Considering the 100% relative survival hypothesis, a target CML prevalence were defined, the level of which will be nearly reached by 2060. Based on an annual cost of 40000 euros per patient, the cost per 100,000 inhabitants-year is then estimated to be around 700,000 euros. Figure 2 summarize results: the blue line represents the estimated CML prevalence for France. It corresponds to 10 years relative survival hypothesis as reported in the literature for the different periods and our hypothesis for the future: 5% before the 70's, 10% by the late 80's, 35% before imatinib introduction, 47% in 2002 , 80% in 2006, 84% in 2016 and 90% in 2060. The black line corresponds to the 100% relative survival hypothesis. It is the target CML prevalence, that is, the prevalence of CML if the disease have had no impact on the relative survival of affected people. Green line corresponds in relative survival observed before imatinib use and the gray line corresponds to levels of relative survival observed in the 70's. These different estimates clearly show that not only the increase in CML prevalence is attributable to the use of TKI soon after 2002 but also to populations aging as illustrated by the target CML prevalence line. Conclusion: Due to high rates in relative survival observed in CML patients after introduction of imatinib, the trajectory of the CML prevalence in France, as in other western countries, has changed. Given particular hypothesis on CML incidence rates, this trajectory will bring the CML prevalence to levels fully determined by population aging by the mid century, that is, when the proportion of the population aged 60 or more will stabilized in western countries. For France, we have estimated this level above 30 cases per 100,000 inhabitant. Figure 1 Estimated number of CML patients by single age and sex, corresponding legal or projected population (and period specific relative survival hypothesis) in france in 1970 (A), 1980 (B), 2000 (C), 2010 (D), 2020 (E) and 2040 (F). Figure 1. Estimated number of CML patients by single age and sex, corresponding legal or projected population (and period specific relative survival hypothesis) in france in 1970 (A), 1980 (B), 2000 (C), 2010 (D), 2020 (E) and 2040 (F). Figure 2 CML prevalence estimate in France from 1970 to 2060 (see text). Figure 2. CML prevalence estimate in France from 1970 to 2060 (see text). Disclosures No relevant conflicts of interest to declare.
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Saglio, Giuseppe, Anna Serra, Anna Novarino, Michele Falda, and Felice Gavosto. "N-Ras Mutations in Myeloid Leukemias." Tumori Journal 75, no. 4 (August 1989): 337–40. http://dx.doi.org/10.1177/030089168907500407.
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The presence of mutations activating the N-ras gene was investigated by the polymerase chain reaction technique in twenty patients with acute myeloblastic leukemia (AML) at onset and in four patients with Ph' positive chronic myelogeneous leukemia (CML) either in chronic phase or in blast crisis. Four remission samples and four relapses from the AML cases were also studied. Mutations were found in five out of twenty (25%) untreated AML cases at onset. No mutations were detected in the complete remission samples, two of them with N-ras mutations during the leukemic phase. Two out of the four leukemia relapses were positive for the same N-ras mutation shown at presentation, whereas no new mutations were found in the other two initially negative cases. An N-ras mutation appeared during the blast crisis of one of the four CML, which were all negative during the chronic phase. In conclusion, whereas some data appear to be consistent with a role of the N-ras mutations as initiating events in myeloid leukemias, in other cases N-ras activation seems to represent a factor involved in progression. These data suggest that a partial overlapping between initiation and progression factors could exist in naturally occurring tumors.
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Warfvinge, Rebecca, Mikael Sommarin, Parashar Dhapola, Ulrich Pfisterer, Linda Geironson Ulfsson, Fatemeh Safi, Ram Krishna Thakur, Johan Richter, and Göran Karlsson. "Characterization of Leukemic Stem Cells Heterogeneity in Chronic Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 4140. http://dx.doi.org/10.1182/blood-2019-130956.
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In chronic myeloid leukemia (CML), a rare subset of leukemic stem cells (LSC) persists in patients responding to conventional tyrosine kinase inhibitor (TKI) therapy. The failure to eradicate these LSCs results in indefinite therapy dependence and a risk of leukemic relapse. However, the conventional LSC compartment (Lin-CD34+CD38-) is highly heterogeneous where only a subpopulation is believed to be functional, TKI-insensitive LSCs. Previously, using single-cell gene expression analysis we characterized the heterogeneity within the LSC population (Lin-CD34+CD38-) in CML patients using a selected panel of 96 primers. Interestingly, by comparing LSC heterogeneity at diagnosis with the heterogeneity following 3 months of TKI therapy we uncovered a therapy-insensitive, quiescent subpopulation, which could be isolated at high-purity using a combination of the surface markers: Lin-CD34+CD38-CD45RA-cKIT-CD26+ (Warfvinge, Geironson, Sommarin et al., 2017). Here, we expand the single-cell analysis of CML LSC populations to include combined immunophenotype-/RNA sequencing analysis (CITE-seq). CITE-seq allows for unbiased, further in-depth transcriptome analysis as wells as immunophenotypic characterization by pre-staining cells with a panel of DNA-barcoded antibodies prior to sequencing. DNA-barcoded antibodies convert the protein expression into readable sequences through unique oligo-conjugates as identifiers. Using CITE-seq with a panel of 44 distinct surface markers designed to immunophenotypically differentiate between stem/progenitors cells and leukemic clones we simultaneously characterize the molecular and immunophenotypic heterogeneity within Lin-CD34+/Lin-CD34+CD38- CML stem/progenitor compartment at diagnosis. Additionally by comparing the LSCs transcriptome from patients with different therapeutic outcome after 12 months of therapy we describe how differences in heterogeneity and the presence of immunophenotypic therapy-insensitive LSCs at diagnosis (Lin-CD34+CD38-CD45RA-cKIT-CD26+) contribute to therapy response. Disclosures Richter: Novartis: Consultancy; Pfizer: Consultancy, Research Funding.
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Zawilska, Krystyna M., and Lucyna Malendowicz-Portala. "Chronic Myeloid Leukemia Developing in a Patient with B-Cell Chronic Lymphocytic Leukemia – a Case Report." Blood 118, no. 21 (November 18, 2011): 4421. http://dx.doi.org/10.1182/blood.v118.21.4421.4421.
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Abstract Abstract 4421 The coexistence of B-cell chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) in the same patient is rare. A 61-year-old man developed a lymphocytosis with morphologic and immunophenotypic feature of B-CLL (stage I according to the modified Rai classification), without indications for treatment. Ten months later he presented with a markedly elevated leukocytes count and splenomegaly. Myeloblasts, promyelocytes, myelocytes and metamyelocytes appeared in his peripheral blood. A bone marrow aspirate was hypercellular with an increased proportion of the myeloid series in all maturative stages; the percentage of lymphocytes was 3%. The immunophenotypic study demonstrated the typical feature of chronic phase of CML, simultaneously 2% of CD5+ CD19+ cells have been found. Unstimulated bone marrow culture shoved a 46,XY,t(9;22)(q34;q11.2) karyotype, and interphase FISH detected the presence of BCR/ABL fusion with 4,55×106 of p 210 and 1,55×103of p 190 copies/ml. Previously it has been shown that these two different hematological malignancies derive from distinct progenitors. Disclosures: No relevant conflicts of interest to declare.
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Dao, Kim-Hien T., and Jeffrey W. Tyner. "What's different about atypical CML and chronic neutrophilic leukemia?" Hematology 2015, no. 1 (December 5, 2015): 264–71. http://dx.doi.org/10.1182/asheducation-2015.1.264.
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Abstract Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare myeloid neoplasms defined largely by morphologic criteria. The discovery of CSF3R mutations in aCML and CNL have prompted a more comprehensive genetic profiling of these disorders. These studies have revealed aCML to be a genetically more heterogeneous disease than CNL, however, several groups have reported that SETBP1 and ASXL1 mutations occur at a high frequency and carry prognostic value in both diseases. We also report a novel finding—our study reveals a high frequency of U2AF1 mutations at codon Q157 associated with CSF3R mutant myeloid neoplasms. Collectively, these findings will refine the WHO diagnostic criteria of aCML and CNL and help us understand the genetic lesions and dysregulated signaling pathways contributing to disease development. Novel therapies that emerge from these genetic findings will need to be investigated in the setting of a clinical trial to determine the safety and efficacy of targeting various oncogenic drivers, such as JAK1/2 inhibition in CSF3R-T618I–positive aCML and CNL. In summary, recent advances in the genetic characterization of CNL and aCML are instrumental toward the development of new lines of therapy for these rare leukemias that lack an established standard of care and are historically associated with a poor prognosis.
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Byun, Hyang-Min, Shahrooz Eshaghian, Jia Yi Jiang, Si Ho Choi, John Soussa, Laleh Ramezani, Dan Douer, and Allen S. Yang. "DNA Methylation Analysis of 807 Genes in Chronic Myeloid Leukemia and Acute Promyelocytic Leukemia." Blood 110, no. 11 (November 16, 2007): 2122. http://dx.doi.org/10.1182/blood.v110.11.2122.2122.
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Abstract DNA methylation changes are a common finding in leukemia, and hypermethylation of CpG island promoters is associated with aberrant gene silencing. Some abnormal cancer related methylation changes have been associated with clinical phenotype including pathologic features, prognosis, and treatment response. However, other DNA methylation changes do not appear to have phenotypic consequences and may reflect a stochastic event or a downstream event of tumorogenesis, such as the CpG island methylator phenotype (CIMP). In order to obtain a better understanding of the DNA methylation changes found in leukemia we analyzed 18 acute promyelocytic leukemia (APL) and 36 chronic myeloid leukemia (CML) patients. We specifically chose to study APL and CML as these leukemia are initiated by specific genetic translocation events, t(15:17) and t(9:22) respectively. To measure the DNA methylation status, we used the GoldenGate Assay for Methylation and BeadArray technology from Illumina, Inc. The Standard Methylation Cancer Panel I from Illumina interrogates 1505 CpG sites, selected from 807 genes (231 genes contain one CpG site per gene, 463 genes contain two CpG sites and 114 genes have three or more CpG sites). In our study we found 142 and 269 genes that were hypermethylated in CML and APL. 31 genes were uniquely hypermethylated in CML, 158 genes were hypermethylated only in APL, and 111 genes were hypermethylated in both leukemias. There was a unique pattern of hypermethylated genes in each cancer; such there was a high concordance of hypermethylated genes within each leukemia type. These data suggest that the epigenetic events were a result of the genetic translocation BCR/ABL or PML/RARα (associated with chromosomal aberrations t(9:22) or t(15:17)) that initiates these leukemias. Analysis of the number of hypermethylated genes in these two leukemias showed a bimodal distribution suggestive of CIMP, however, closer examination showed that this bimodal distribution could be attributed to the two different types of leukemia. APL patients had mean of 280 genes hypermethylated while CML patients only had a mean of 193 genes hypermethylated. APL had a stronger methylator phenotype than CML for the loci studied, which underscores the possible relationship of CIMP to a genetic phenotype. Subset analysis of our CML samples by chronic phase (23 patients), accelerated phase (5 patients), and blast crisis (8 patients) revealed 42 genes that became hypermethylated with progression of CML. It is possible that hypermethylation of these genes are clinically important in the leukemia phenotype, and maybe targets for epigenetic therapy. We examined the DNA methylation changes induced by the DNA methylation inhibitor, azacitidine, in a patient with blast crisis CML and refractory to imatinib mesylate therapy. Azacitidine could reverse the aberrant hypermethylation associated with progression of CML to blast crisis and supports the use of this drug as an epigenetic therapy. Our data show that the majority of DNA hypermethylation events in leukemia are dependent on genetic events, but there is a subset of DNA hypermethylation events that are involved in the progression of leukemia and may be therapeutically reversed by DNA methylation inhibitors.
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Hochhaus, Andreas. "Educational Session: Managing Chronic Myeloid Leukemia as a Chronic Disease." Hematology 2011, no. 1 (December 10, 2011): 128–35. http://dx.doi.org/10.1182/asheducation-2011.1.128.
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Abstract Elucidation of the pathogenesis of chronic myeloid leukemia (CML) and the introduction of tyrosine kinase inhibitors (TKIs) has transformed this disease from being invariably fatal to being the type of leukemia with the best prognosis. Median survival associated with CML is estimated at > 20 years. Nevertheless, blast crisis occurs at an incidence of 1%-2% per year, and once this has occurred, treatment options are limited and survival is short. Due to the overall therapeutic success, the prevalence of CML is gradually increasing. The optimal management of this disease includes access to modern therapies and standardized surveillance methods for all patients, which will certainly create challenges. Furthermore, all available TKIs show mild but frequent side effects that may require symptomatic therapy. Adherence to therapy is the key prerequisite for efficacy of the drugs and for long-term success. Comprehensive information on the nature of the disease and the need for the continuous treatment using the appropriate dosages and timely information on efficacy data are key factors for optimal compliance. Standardized laboratory methods are required to provide optimal surveillance according to current recommendations. CML occurs in all age groups. Despite a median age of 55-60 years, particular challenges are the management of the disease in children, young women with the wish to get pregnant, and older patients. The main challenges in the long-term management of CML patients are discussed in this review.
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Kinstrie, Ross, Gillian A. Horne, Heather Morrison, Hothri A. Moka, Jennifer Cassels, Karen Dunn, Pawel Herzyk, David A. Irvine, and Mhairi Copland. "CD93 Is a Novel Biomarker of Leukemia Stem Cells in Chronic Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 49. http://dx.doi.org/10.1182/blood.v126.23.49.49.
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Abstract The introduction of BCR-ABL tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML). However, although the majority of patients with chronic phase (CP)-CML obtain durable complete cytogenetic and major molecular responses, there is low level disease persistence postulated to be due to a population of TKI-insensitive leukemia stem cells (LSC). The aims of this study were (1) to fully characterize differences in gene expression between normal hematopoietic stem cells (HSC) and CP-CML LSC and (2) identify potential novel therapeutic targets specific to CML LSC. Lin-CD34+CD38- CD45RA-CD90+ normal HSC (n=3) and CP-CML LSC (n=6 patients at diagnosis), populations were isolated using a FACSAria and applied to Affymetrix HuGene 1.0ST arrays. The raw data (.CEL files) was imported into Partek Genomics Suite and Ingenuity Pathway Analysis software and principal component analysis and gene ontology ANOVA performed. A total of 1217 genes were significantly deregulated between normal HSC and CP-CML LSC. The most significantly deregulated genes and pathways were involved with the molecular and cellular functions of cell cycle, cell assembly and organisation, cellular movement, cell death and DNA replication, recombination and repair. These results suggested that CML LSC were less quiescent than normal HSC. Importantly, complimentary functional studies indicated that CML LSC have significantly increased proliferation (14 fold expansion; P<0.001) compared to normal HSC (no expansion) after 5 days in vitro culture. In addition, equivalent numbers of CML LSC produce ~4-fold more colonies in colony forming cell (CFC) assays than normal HSC (329±56 versus 86±17 per 2,000 cells, respectively; P<0.05). Fluorescence in situ hybridisation (FISH) demonstrated that >90% of lin- CD34+ CD38- CD45RA- CD90+ CML LSC from all patient samples were BCR-ABL positive (+). In addition to these deregulated intracellular pathways, we sought to assess if there were differences in expression of cell surface molecules that may be amenable to therapeutic manipulation. Of particular interest, our microarray studies demonstrated that CD93 was highly upregulated in CP-CML LSC (6 fold, p = 2.5x10-6). Increased CD93 expression was validated by Fluidigm digital PCR (6 fold increase, p = 0.02; n=6). Furthermore, using flow cytometry, we demonstrated significant upregulation of CD93 protein expression on lin-CD34+ CD38- CD45RA- CD90+ CML LSC from peripheral blood and bone marrow of CP-CML patients (n= 17; mean = 63.8% CD93+) compared to normal HSC from healthy peripheral blood stem cell donors (n=7; mean = 0.8% CD93+) and bone marrow donors (n=4; mean = 0.2% CD93+; p < 0.0001). FISH confirmed that 100% of lin-CD34+ CD38- CD90+ CD93+ CML cells were BCR-ABL+ in all samples assessed. CD93 (also known as C1qRp) is a C-type lectin-like domain (CTLD)-containing glycoprotein which regulates phagocytosis, with roles in cell adhesion and leukocyte migration. It is normally expressed on endothelial cells, hematopoietic precursors and mature cells including neutrophils, monocytes and platelets. Previous studies have shown CD93 to be upregulated in a proportion of AML patients (Saito et al, Sci Transl Med, 2010. 2(17): p. 17ra9). Short term (24h) in vitro exposure of lin-CD34+CD38- CD45RA- CD90+ CML LSC to TKIs (Imatinib or Dasatinib; n=3) reduced, but did not fully eliminate CD93 expression (Imatinib, 48.5% to 22.9%; Dasatinib, 47.7% to 9.2%). Importantly, following long-term TKI treatment of patients, lin-CD34+CD38-CD45RA-CD90+ cells from CP-CML patient bone marrow samples (n=2) taken in major molecular response demonstrated a small, but persistent population of CD93+ LSC which were BCR-ABL+ by FISH. Furthermore, in xenograft transplantation experiments (n = 5), after 16 weeks, CD34+CD93+ CML LSC engrafted lethally irradiated NOD/SCID/IL-2Rg-/- (NSG) mice with BCR-ABL+ cells, whereas CD34+CD93- cells from the same patient samples failed to engraft to significant levels (3.5-30 fold increase in engraftment with CD34+CD93- cells; p < 0.03). FISH confirmed that engrafted human cells were BCR-ABL+. Taken together, our results identify CD93 as a potential novel biomarker of CML LSC, which may also be helpful in assessing minimal residual disease at the LSC level. Further studies are ongoing to assess the therapeutic potential of inhibiting CD93 in CML LSC. Disclosures Copland: Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Falkenburg, J. H. Frederik, Amon R. Wafelman, Peter Joosten, Willem M. Smit, Cornelis A. M. van Bergen, Rian Bongaerts, Ellie Lurvink, et al. "Complete Remission of Accelerated Phase Chronic Myeloid Leukemia by Treatment With Leukemia-Reactive Cytotoxic T Lymphocytes." Blood 94, no. 4 (August 15, 1999): 1201–8. http://dx.doi.org/10.1182/blood.v94.4.1201.
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Abstract Relapse of chronic myeloid leukemia (CML) in chronic phase after allogeneic stem cell transplantation (SCT) can be successfully treated by donor lymphocyte infusion (DLI). However, relapse of accelerated phase CML, blast crisis, or acute leukemia after allogeneic SCT are resistant to DLI in the majority of cases. In vitro-selected and expanded leukemia-reactive T-cell lines may be more effective in inducing an antileukemic response in vivo. To treat a patient with accelerated phase CML after allogeneic SCT, leukemia-reactive cytotoxic T-lymphocyte (CTL) lines were generated from her HLA-identical donor. Using a modification of a limiting dilution assay, T cells were isolated from the donor, selected based on their ability to inhibit the in vitro growth of CML progenitor cells, and subsequently expanded in vitro to generate CTL lines. Three CTL lines were generated that lysed the leukemic cells from the patient and inhibited the growth of leukemic progenitor cells. The CTL did not react with lymphocytes from donor or recipient and did not affect donor hematopoietic progenitor cells. The 3 leukemia-reactive CTL lines were infused at 5-week intervals at a cumulative dose of 3.2 × 109 CTL. Shortly after the third infusion, complete eradication of the leukemic cells was observed, as shown by cytogenetic analysis, fluorescence in situ hybridization, molecular analysis of BCR/ABL-mRNA, and chimerism studies. These results show that in vitro cultured leukemia-reactive CTL lines selected on their ability to inhibit the proliferation of leukemic progenitor cells in vitro can be successfully applied to treat accelerated phase CML after allogeneic SCT.
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Falkenburg, J. H. Frederik, Amon R. Wafelman, Peter Joosten, Willem M. Smit, Cornelis A. M. van Bergen, Rian Bongaerts, Ellie Lurvink, et al. "Complete Remission of Accelerated Phase Chronic Myeloid Leukemia by Treatment With Leukemia-Reactive Cytotoxic T Lymphocytes." Blood 94, no. 4 (August 15, 1999): 1201–8. http://dx.doi.org/10.1182/blood.v94.4.1201.416k08_1201_1208.
Full textAbstract:
Relapse of chronic myeloid leukemia (CML) in chronic phase after allogeneic stem cell transplantation (SCT) can be successfully treated by donor lymphocyte infusion (DLI). However, relapse of accelerated phase CML, blast crisis, or acute leukemia after allogeneic SCT are resistant to DLI in the majority of cases. In vitro-selected and expanded leukemia-reactive T-cell lines may be more effective in inducing an antileukemic response in vivo. To treat a patient with accelerated phase CML after allogeneic SCT, leukemia-reactive cytotoxic T-lymphocyte (CTL) lines were generated from her HLA-identical donor. Using a modification of a limiting dilution assay, T cells were isolated from the donor, selected based on their ability to inhibit the in vitro growth of CML progenitor cells, and subsequently expanded in vitro to generate CTL lines. Three CTL lines were generated that lysed the leukemic cells from the patient and inhibited the growth of leukemic progenitor cells. The CTL did not react with lymphocytes from donor or recipient and did not affect donor hematopoietic progenitor cells. The 3 leukemia-reactive CTL lines were infused at 5-week intervals at a cumulative dose of 3.2 × 109 CTL. Shortly after the third infusion, complete eradication of the leukemic cells was observed, as shown by cytogenetic analysis, fluorescence in situ hybridization, molecular analysis of BCR/ABL-mRNA, and chimerism studies. These results show that in vitro cultured leukemia-reactive CTL lines selected on their ability to inhibit the proliferation of leukemic progenitor cells in vitro can be successfully applied to treat accelerated phase CML after allogeneic SCT.
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Bedi, A., BA Zehnbauer, JP Barber, SJ Sharkis, and RJ Jones. "Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia." Blood 83, no. 8 (April 15, 1994): 2038–44. http://dx.doi.org/10.1182/blood.v83.8.2038.2038.
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Abstract BCR-ABL expression is presumed to effect clonal expansion in chronic myeloid leukemia (CML) by deregulation of cell proliferation. However, most studies have found that relative rates of cell proliferation are not increased in CML. Moreover, we found that CML progenitors display a normal proliferative response to growth factors and do not manifest greater proliferative potential than normal progenitors. Growth of malignancies depends on an imbalance between the rate of cell production and the rate of cell death. We found that BCR-ABL expression inappropriately prolongs the growth factor-independent survival of CML myeloid progenitors and granulocytes by inhibiting apoptosis, a genetically programmed process of active cell death; inhibition of BCR- ABL expression by antisense oligonucleotides reversed the suppression of apoptosis as well as the enhancement of survival. The decreased rate of programmed cell death appears to be the primary mechanism by which BCR-ABL effects expansion of the leukemic clone in CML.
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Bedi, A., BA Zehnbauer, JP Barber, SJ Sharkis, and RJ Jones. "Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia." Blood 83, no. 8 (April 15, 1994): 2038–44. http://dx.doi.org/10.1182/blood.v83.8.2038.bloodjournal8382038.
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BCR-ABL expression is presumed to effect clonal expansion in chronic myeloid leukemia (CML) by deregulation of cell proliferation. However, most studies have found that relative rates of cell proliferation are not increased in CML. Moreover, we found that CML progenitors display a normal proliferative response to growth factors and do not manifest greater proliferative potential than normal progenitors. Growth of malignancies depends on an imbalance between the rate of cell production and the rate of cell death. We found that BCR-ABL expression inappropriately prolongs the growth factor-independent survival of CML myeloid progenitors and granulocytes by inhibiting apoptosis, a genetically programmed process of active cell death; inhibition of BCR- ABL expression by antisense oligonucleotides reversed the suppression of apoptosis as well as the enhancement of survival. The decreased rate of programmed cell death appears to be the primary mechanism by which BCR-ABL effects expansion of the leukemic clone in CML.
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Cotoraci, Coralia, Alina Ciceu, Alciona Sasu, Eftimie Miutescu, and Anca Hermenean. "The Anti-Leukemic Activity of Natural Compounds." Molecules 26, no. 9 (May 5, 2021): 2709. http://dx.doi.org/10.3390/molecules26092709.
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The use of biologically active compounds has become a realistic option for the treatment of malignant tumors due to their cost-effectiveness and safety. In this review, we aimed to highlight the main natural biocompounds that target leukemic cells, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their therapeutic potential in the treatment of leukemia: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL). It provides a basis for researchers and hematologists in improving basic and clinical research on the development of new alternative therapies in the fight against leukemia, a harmful hematological cancer and the leading cause of death among patients.
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Hutchinson, Catherine, David P. Sheridan, John F. DeCoteau, and Ron Geyer. "Chaetocin Exhibits Anti-Leukemia Activity Against Chronic Myeloid Leukemia Stem Cells." Blood 120, no. 21 (November 16, 2012): 1667. http://dx.doi.org/10.1182/blood.v120.21.1667.1667.
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Abstract Abstract 1667 Treatment of chronic myeloid leukemia (CML) patients with tyrosine kinase inhibitors (TKIs) targeting BCR-ABL kinase results in a dramatic reduction in proliferating BCR-ABL expressing leukemia cells. However, these agents do not eliminate the CML stem cell population, indicating that inhibiting BCR-ABL kinase activity alone is not sufficient to eradicate the disease, and implicating TKI-insensitive CML stem cells in relapse. Thus, there is great interest in identifying new therapeutic agents that can be combined with TKIs to eliminate TKI-insensitive CML stem cells that are not fully addicted to BCR-ABL. Chaetocin, a mycotoxin that inhibits histone methyltransferase SUV39H1, exhibits anticancer properties against myeloma and AML cells. To investigate a potential role for chaetocin in CML treatment, we first compared its cytotoxic effects with those of imatinib on TonB210, a murine hematopoietic cell line with doxycycline-inducible BCR-ABL expression that is dependent on BCR-ABL for survival and proliferation in the absence of exogenous IL-3. As expected, imatinib treatment produced cytotoxic effects in TonB210 cells induced to express BCR-ABL, but not in uninduced TonB210 cells, as assessed by trypan blue viability assays and Annexin V expression by flow cytometry. In contrast, chaetocin, displayed significant cytotoxicity against both TonB210 cells induced to express BCR-ABL and uninduced TonB210 cells. We then used a standard murine retroviral transduction system that models CML blast crisis (BC-CML) to study chaetocin effects on BCR-ABL expressing cells highly enriched for leukemia initiating potential. Purified LIN-, Sca-1+, CD117+ cells (LSKs) were isolated from the bone marrow of C57BL6/J mice and retrovirally-transduced with BCR-ABL-GFP and Nup98/HoxA9-YFP then injected intravenously into recipient C57BL6/J mice. All animals developed leukemia within 21 days characterized by leukocytosis and extensive infiltration of bone marrow and spleen with leukemic blasts. LSKs expressing both BCR-ABL-GFP and Nup98/HoxA9-YFP (GFP+/YFP+ LSKs) were purified from the spleens or bone marrows of leukemic mice and cultured for 48 hrs in chaetocin across a range of concentrations (0 – 400 nM). Chaetocin exhibited cytotoxic effects against GFP+/YFP+ LSKs as assessed by trypan blue, Annexin V, and colony forming assays. Chaetocin effects on CML stem cell self-renewal in vivo were assessed by performing secondary transplantation assays and limiting dilution analysis (LDA). GFP+/YFP+ LSKs were purified from primary CML mice and transplanted into secondary recipients following in vitro exposure to IC50 concentrations of chaetocin and/or imatinib. Survival after transplantation and LSC frequency were compared in four treatment cohorts: Group 1 (untreated control), Group 2 (chaetocin), Group 3 (imatinib) and Group 4 (chaetocin + imatinib). Compared to untreated mice, survival was significantly prolonged in mice treated with imatinib alone and the survival benefit of imatinib was enhanced by co-treatment with chaetocin. LDA showed both chaetocin and imatinib treatment alone decreased LSC frequency (1 in 10,143 in chaetocin treated, and 1 in 95,782 in imatinib treated vs. 1 in 4,036 in untreated control) but that the combination of chaetocin and imatinib treatment resulted in a dramatic decrease in LSC frequency (1 in 293,628 in chaetocin + imatinib treatment vs. 1 in 4036 in untreated control). Chaetocin, imatinib, and chaetocin + imatinib treatment of normal murine hematopoietic stem cells resulted in only minimal cytotoxicity as assessed by trypan blue, Annexin V, and colony forming assays. Our findings suggest that chaetocin, or chaetocin-related compounds, might serve to complement TKI therapy in the treatment of CML. Disclosures: No relevant conflicts of interest to declare.
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Baccarani, Michele, Fausto Castagnetti, Gabriele Gugliotta, Francesca Palandri, and Gianantonio Rosti. "TREATMENT RECOMMENDATIONS FOR CHRONIC MYELOID LEUKEMIA." Mediterranean Journal of Hematology and Infectious Diseases 6, no. 1 (January 2, 2014): e2014005. http://dx.doi.org/10.4084/mjhid.2014.005.
Full textAbstract:
The first treatment of chronic myeloid leukemia (CML) included spleen x-radiation and conventional drugs, mainly Busulfan and Hydroxyurea. This therapy improved the quality of life during the chronic phase of the disease, without preventing nor significantly delaying the progression towards advanced phases. The introduction of allogeneic stem cell transplantation (alloSCT) marked the first important breakthrough in the evolution of CML treatment, because about 50% of the eligible patients were cured. The second breakthrough was the introduction of human recombinant interferon-alfa, able to achieve a complete cytogenetic remission in 15% to 30% of patients, with a significant survival advantage over conventional chemotherapy. At the end of the last century, about 15 years ago, all these treatments were quickly replaced by a class of small molecules targeting the tyrosine kinases (TK), which were able to induce a major molecular remission in most of the patients, without remarkable side effects, and a very prolonged life-span. The first approved TK inhibitor (TKI) was Imatinib Mesylate (Glivec or Gleevec, Novartis). Rapidly, other TKIs were developed tested and commercialized, namely Dasatinib (Sprycel, Bristol-Myers Squibb), Nilotinib (Tasigna, Novartis), Bosutinib (Busulif, Pfizer) and Ponatinib (Iclusig, Ariad). Not all these compounds are available worldwide; some of them are approved only for second line treatment, and the high prices are a problem that can limit their use. A frequent update of treatment recommendations is necessary. The current treatment goals include not only the prevention of the transformation to the advanced phases and the prolongation of survival, but also a length of survival and of a quality of life comparable to that of non-leukemic individuals. In some patient the next ambitious step is to move towards a treatment-free remission. The CML therapy, the role of alloSCT and the promising experimental strategies are reviewed in the context of the new therapeutic goals.