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Journal articles on the topic 'Leukemia Chemotherapy'
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1
Narayanan, Geetha, M. T. Sugeeth, and Lali V. Soman. "Mixed Phenotype Acute Leukemia Presenting as Leukemia Cutis." Case Reports in Medicine 2016 (2016): 1–3. http://dx.doi.org/10.1155/2016/1298375.
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Leukemia cutis (LC) is defined as infiltration of the skin by leukemic cells resulting in clinically recognizable cutaneous lesions. It is common in congenital leukemia and acute myeloid leukemia. However, LC has rarely been reported with mixed phenotypic acute leukemia (MPAL). We report the case of a lady who presented with erythematous papular and nodular lesions all over the body. Skin biopsy showed leukemic infiltration and bone marrow aspiration showed MPAL of the T/myeloid with monocytic differentiation lineage. This is the first report of an adult patient with MPAL of the T/myeloid with monocytic differentiation type presenting with leukemia cutis. She was started on chemotherapy with Hyper-CVAD. There is complete resolution of the skin lesions and she has achieved bone marrow remission after the first cycle of chemotherapy.
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Dias, Sergio, Margaret Choy, Kari Alitalo, and Shahin Rafii. "Vascular endothelial growth factor (VEGF)–C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy." Blood 99, no. 6 (March 15, 2002): 2179–84. http://dx.doi.org/10.1182/blood.v99.6.2179.
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Abstract Similar to solid tumors, growth of leukemias may also be angiogenesis dependent. Furthermore, tyrosine kinase receptors specific to endothelial cells are expressed on certain subsets of leukemias. We have previously demonstrated the existence of a VEGF/VEGFR-2 autocrine loop on leukemic cells that supports their growth and migration. Here, we demonstrate that in response to leukemia-derived proangiogenic and proinflammatory cytokines such as basic fibroblast growth factor and IL-1, endothelial cells release increasing amounts of another vascular endothelial growth factor (VEGF) family member, VEGF-C. In turn, interaction of VEGF-C with its receptor VEGFR-3 (FLT-4) promotes leukemia survival and proliferation. We demonstrate in 2 cell lines and 5 FLT-4+ leukemias that VEGF-C and a mutant form of the molecule that lacks the KDR-binding motif induce receptor phosphorylation, leukemia proliferation, and increased survival, as determined by increased Bcl-2/Bax ratios. Moreover, VEGF-C protected leukemic cells from the apoptotic effects of 3 chemotherapeutic agents. Because most leukemic cells release proangiogenic as well as proinflammatory cytokines, our data suggest that the generation of a novel paracrine angiogenic loop involving VEGF-C and FLT-4 may promote the survival of a subset of leukemias and protect them from chemotherapy-induced apoptosis. These results identify the VEGF-C/FLT-4 pathway as a novel therapeutic target for the treatment of subsets of acute leukemia.
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Wu, K. H., H. P. Wu, H. J. Lin, C. H. Wang, H. Y. Chen, T. Weng, C. T. Peng, and Y. H. Chao. "Concurrent hypopituitarism and leukemic retinopathy in a child with B-precursor acute lymphoblastic leukemia and isolated central nervous system relapse." Current Oncology 23, no. 4 (August 8, 2016): 431. http://dx.doi.org/10.3747/co.23.3006.
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Hypopituitarism in leukemia is very rare. In addition, central nervous system (cns) relapse and leukemic retinopathy in childhood acute lymphoblastic leukemia (all) have declined with the use of modern systemic chemotherapy that includes cns prophylaxis. Here, we report the case of a 4-year-old girl who received chemotherapy and intrathecal therapy without cns radiation after a diagnosis of B-precursor all without cns involvement. Three months after chemotherapy completion, she presented with lower-extremity weakness and was diagnosed with an isolated cns relapse. Concurrent hypopituitarism and leukemic retinopathy were also found. After receiving craniospinal radiotherapy and systemic chemotherapy, her retinopathy and vision improved. She is now in complete remission, and she is still on chemotherapy according to the guideline from the Pediatric Oncology Group. Although rare, hypopituitarism and leukemic retinopathy should be taken into consideration in patients with cns involvement by leukemia.
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Falqués, Ton, Mattias Pilheden, Qirui Zhang, Louise Ahlgren, Helena Sturesson, Lars Ronnstrand, Axel Hyrenius Wittsten, Julhash U. Kazi, and Anna Hagstroem-Andersson. "Treatment Shapes Clonal Evolution and Resistance Patterns in Murine KMT2A-Rearranged Leukemia with Subclonal FLT3 N676K." Blood 138, Supplement 1 (November 5, 2021): 3354. http://dx.doi.org/10.1182/blood-2021-144760.
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Abstract Our understanding of how individual mutations, whether present in all or just a fraction of the leukemia cells, affect cellular responses to therapy is limited. Leukemia mouse models provide a unique possibility to explore how therapy affects the evolution of genetically distinct clones and identify mechanisms of resistance allowing transfer to human disease. Herein, we studied how different therapies influenced survival, clonal evolution, and resistance patterns in mouse KMT2A-MLLT3 leukemia with subclonal FLT3 N676K. Bone marrow (BM) from a leukemia expressing KMT2A-MLLT3-mCherry in all cells and a FLT3 N676K-GFP in 40% of cells, were re-transplanted to sublethally irradiated recipients (Hyrenius-Wittsten el al, Nat Commun, 2018). Upon engraftment, treatment was started with either chemotherapy (cytarabine for 5 days + doxorubicin for 3 days), the FLT3 inhibitor AC220, chemotherapy followed by AC220, or AC220+Trametinib, a MEK inhibitor. Targeted treatment was given for 28 days; controls received vehicle (Fig. 1a). Survival was estimated by Kaplan-Meier and the developing leukemias were analyzed by flow-cytometry, RNA-sequencing and targeted gene re-sequencing. Each treatment prolonged survival with a median latency of 30 days for chemotherapy , 37.5 days for AC220, 42 days for chemotheraphy+AC220, and 45 days for AC220+Trametenib, versus 25.5 days for the control (Fig. 1b). Most leukemia cells expressed GFP/mCherry and mice displayed splenomegaly and leukocytosis. Next, we investigate how treatment impacted evolution of the KMT2A-MLLT3+FLT3 N676K cells and while they constituted all cells in control and chemotherapy-treated mice, the other treatments impacted their evolution. Three distinct patterns were discerned with either >80% of KMT2A-MLLT3+FLT3 N676K cells, >80% of cells expressing KMT2A-MLLT3 alone, or dual similar sized clones of cells expressing KMT2A-MLLT3 alone or KMT2A-MLLT3+FLT3 N676K(Fig. 1c). Eradication of the FLT3-leukemia cells was rare, but most common in mice receiving AC220+Trametinib and the frequency of dual clones increased when mice received chemotherapy followed by AC220, in line with treatment selectively affecting evolution of genetically distinct cells (Fig. 1d). To find clues to treatment resistance, RNA-sequencing (N=44) revealed segregation into three major clusters: 1) leukemias expressing KMT2A-MLLT3 alone, 2) control and chemotherapy-treated leukemias and 3) AC220 treated leukemias. Notably, a set of AC220-treated mice clustered close to the control and chemotherapy-treated mice (Fig. 1e). Flow-cytometry data showed that similar to the control and chemotherapy-treated leukemias, the myeloid BM cells of those AC220 samples, aberrantly expressed B220 (Fig. 1f). Gene set enrichment analysis revealed enrichment of gene sets correlating with stem cells and oxidative phosphorylation in those AC220-treated leukemias, suggesting a switch in cellular phenotype and metabolic state upon treatment. By contrast, the other AC220 leukemias (cluster 3), instead showed enrichment of gene sets correlating with granulocyte/macrophage progenitors and immune regulatory pathways, indicating selective dependence of distinct cellular pathways upon resistance (Fig. 1g). Finally, acquisition of AC220 resistance mutations was rare with a FLT3 D835Y and a Ptpn11 G503V detected in two leukemias only. Taken together, these results show that the specific treatment given not only affected survival of the FLT3 N676K mutated KMT2A-MLLT3 leukemia, but also impacted how the genetically distinct cells evolved. The general lack of acquired mutations upon targeted treatment suggests that target-independent mechanisms that result in alternate activation of survival/proliferation explains acquired resistance in a majority of mice and provides novel insights into treatment resistance. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
5
Moha, Rico. "Chemotherapy medication of Vincristine and Vinblastine." Cancer Research and Cellular Therapeutics 1, no. 1 (December 8, 2017): 01–02. http://dx.doi.org/10.31579/2640-1053/007.
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Cancers treated with Vincristine and vinblastine include: acute leukemia, Hodgkin's and non- Hodgkin's lymphoma, neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, Wilms' tumor, multiple myeloma, chronic leukemias, thyroid cancer, brain tumors, non-small cell lung cancer, bladder cancer, melanoma, and testicular cancer andIt is also used to treat some blood disorders. It is given by injection into a vein. Vincristine and vinblastine exhibit differential activity against tumors and normal tissues. In this work, a number of cultured cell lines were assayed for their sensitivity to the antiproliferative and cytotoxic effects of the two drugs following short-term (4 hr) or during continuous exposures. Differential activity was not seen when cells were subjected to continuous exposures. The concentrations of Vincristine and vinblastine, respectively, that inhibited growth rates by 50% were: mouse leukemia L1210 cells, 4.4 and 4.0 nw; mouse lymphoma S49 cells, 5 and 3.5 nM; mouse neuroblastoma cells, 33 and 15 nw; HeLa cells, 1.4 and 2.6 nw; and human leukemia HL-60 cells, 4.1 and 5.3 nM. In contrast, differential toxicity was seen when cells were subjected to 4-hr exposures and transferred to drug-free medium: the 50% growth-inhibitory concentrations for Vincristine and vinblastine, respectively, for inhibition (a) of proliferation of L1210 cells were 100 and 380 nM and of HL-60 cells were 23 and 900 nM and (b) of colony formation of L1210 cells were 6 and >600 nM and of HeLa cells were 33 and 62 nM. Uptake and release of [3H]- vincristine and [3H]vinblastine were examined in L1210 cells under the conditions of growth experiments. Uptake of both drugs was dependent on the pH of culture media, and signifi cantly greater amounts of [3H]vinblastine than of [3H]vincristine were associated with cells after 4-hr exposures to equal concen trations of either drug. When cells were transferred to drug-free medium after 4-hr exposures, vinblastine was released much more rapidly from cells than was Vincristine, and by 0.5 hr after resuspension of cells, the amount of Vincristine associated with the cells was greater than the amount of vinblastine and remained so for up to at least 6 hr.
6
Becker, Pamela S. "Dependence of Acute Myeloid Leukemia on Adhesion within the Bone Marrow Microenvironment." Scientific World Journal 2012 (2012): 1–4. http://dx.doi.org/10.1100/2012/856467.
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Acute myeloid leukemia (AML) cells home to the endosteal region of the bone marrow. They interact with bone marrow stromal components including extracellular matrix proteins, glycosaminoglycans, and stromal cells, by which they derive proliferative and growth inhibitory signals. Furthermore, adhesion to marrow stroma confers chemotherapy drug resistance and thereby promotes leukemia survival. A subpopulation of the leukemic blasts, known as leukemia stem cells, that are capable of propagating the leukemia, remain sheltered in the bone marrow microenvironment, exhibit resistance to chemotherapy, and serve as the origin of relapse after a variable period of remission. Detachment of these cells from the bone marrow in combination with chemotherapy may improve the outcome of therapy for AML.
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Frankfurt, Olga, and Martin S. Tallman. "Growth Factors in Leukemia." Journal of the National Comprehensive Cancer Network 5, no. 2 (February 2007): 203–15. http://dx.doi.org/10.6004/jnccn.2007.0020.
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The role of myeloid growth factors, such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, in the management of acute myeloid and acute lymphoblastic leukemias has been evaluated extensively in multiple clinical trials. Growth factors have been given before, concurrently, or sequentially with chemotherapy with the goal of reducing the duration of neutropenia and consequently the incidence and severity of infections, and improving the rate of remissions and overall survival. They also have been studied as chemotherapy-sensitizing agents in an effort to recruit dormant myeloid stem cells into the sensitive phase of the cycle. Additionally, growth factors, shown to stimulate proliferation and differentiation of leukemia cells in vitro, were evaluated as monotherapy in patients with acute leukemia. Most studies show modest improvement in the duration of the neutropenia, which does not consistently correlate with the severity of infection, rate or duration of remissions, or disease-free and overall survival. Attempts to enhance the chemosensitivity of the leukemic cells and decrease drug resistance failed to improve the rate of remission and survival in several large series. However, more recent reports suggested an improved outcome in younger patients with acute myeloid leukemia with normal karyotype. Several anecdotal case reports have shown that growth factor monotherapy can induce a complete remission in patients with acute leukemia. Data from the published clinical trials do not seem to support emergence of drug-resistant leukemia, worsening toxicity, and bone marrow failure with growth factor administration.
8
DeAngelo, Daniel J., Eytan M. Stein, and Farhad Ravandi. "Evolving Therapies in Acute Myeloid Leukemia: Progress at Last?" American Society of Clinical Oncology Educational Book, no. 36 (May 2016): e302-e312. http://dx.doi.org/10.1200/edbk_161258.
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Acute myeloid leukemia (AML) is an acquired disease characterized by chromosomal translocations and somatic mutations that lead to leukemogenesis. Systemic combination chemotherapy with an anthracycline and cytarabine remains the standard induction regimen for “fit” adults. Patients who achieve complete remission generally receive postinduction therapy with cytarabine-based chemotherapy or an allogeneic bone marrow transplant. Those unfit for induction chemotherapy are treated with hypomethylating agents (HMAs), low-dose cytarabine, or they are offered supportive care alone with transfusions and prophylactic antimicrobials. The revolution in understanding the genetics of AML, facilitated by next-generation sequencing, has led to many new drugs against driver mutations. Better methods of identification of leukemic blasts have provided us with better means to detect the disease left behind after cytotoxic chemotherapy regimens. This measurable residual disease has been correlated with poorer relapse-free survival, demonstrating the need for novel strategies to eradicate it to improve the outcome of patients with acute leukemias. In this article, we discuss adapting and improving AML therapy by age and comorbidities, emerging targeted therapies in AML, and minimal residual disease (MRD) assessment in AML.
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Kumar, Bijender, Marvin Orellana, Jamison Brooks, Srideshikan Sargur Madabushi, Liliana E Parra, Darren Zuro, Qiong Wang, Ching-Cheng Chen, and Susanta Hui. "Leukemia Cells Remodel Adipocyte Niches and Their Progenitor Functions to Generate Leukemia Favoring Niche." Blood 132, Supplement 1 (November 29, 2018): 1294. http://dx.doi.org/10.1182/blood-2018-99-115689.
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Abstract Increasing evidence suggests that the cancer cells take shelter in different osteoblastic and adipocytic niches, where they hide from chemotherapy and continue to survive. As yet, how leukemia cells alter the bone marrow (BM) adipocytic niches to facilitate their expansion and assist them in evading chemotherapy is unclear. We have previously shown that the acute myeloid leukemia (AML) cells directly or through their exosomes, reprogram BM osteoblastic niche which facilitates their expansion and suppress normal hematopoiesis(Kumar B et al, Leukemia 2018,32(3):575-587). In this study , we provide further evidences that AML and Acute lymphoid leukemia (ALL) transformed the BM adipocytic niche to facilitate their expansion and suppress normal hematopoiesis. Using MLL-AF9 (AML) knock-in mouse, MLL-AF9 or BCR-ABL(p190, ALL) HSC transduction transplantation leukemia mice models, we performed flow cytometry analysis to show that the leukemia cells stimulate expansion of BM derived CD45-Ter119-CD31-CD166-Sca1+CD140a+(PaS)MSCs population compared to normal mice (p=0.04, p=0.001 and p=0.002 respectively).Further, the BM osteoblasts specific Osteocalcin mRNA expression in sorted stroma cells and flow cytometry based osteoblasts population (CD45-Ter119-CD31- CD166+Sca1-) numbers were also significantly reduced in AML (p=0.04) and ALL (p=0.02) mice models suggesting bone loss with the leukemia development. Similar to osteoblasts loss, mature adipocytes (Perilipin, PPARg mRNA) were also significantly reduced in the ALL/AML mice compared to control. The triglyceride content and white adipose tissue(WAT) mass was diminished in leukemic mice , suggesting leukemia may have utilized adipocyte for survival. Adipocyte loss in the leukemia mice was accompanied by long term hematopoietic stem cells(LT-HSC ) and erythroid megakaryocyte progenitor (MEP) populations reduction in the leukemic mice (p=0.01 and p=0.02 respectively). To dissect the mechanism of adipocytes reduction is either due to adipocyte loss or adipocytes maturation defect in leukemic mice, we analyzed different stromal progenitors in normal and leukemic mice and identified that the leukemia cells stimulate the growth of BM derived adipocytic committed progenitors (CD45-Ter119-CD31-CD166-Sca1+CD140a+CD29+CD24-) and blocked the chondrocyte/osteoblastic/adipocytic multipotent progenitors (CD45-Ter119-CD31- CD166-Sca1+CD140a+CD29+CD24+) population (p=0.02,p=0.01 respectively).Despite the increase in number of MSCs and adipocytic progenitors, the in-vitro adipocytic differentiation potential of sorted adipocyte committed progenitors was severely compromised in ALL and AML compared to control. The WAT western blot analysis showed significantly increased expression of ATGL and pHSL(Ser-563) expression involved in triglyceride lipolysis in the leukemic mice .The ALL leukemic adipocytic stroma had increased expression of IL-1β and IL-6 cytokine levels compared to normal stroma and provided more survival advantage to leukemia cells in in-vitro co-culture experiments in nutrient deprived conditions and during chemo-radiotherapy treatment. Further, the ATGL and HSL pharmacological inhibitors rescued leukemia induced lipolysis, reduced leukemia proliferation and increased chemotherapy induced apoptosis in leukemia cells. Overall, this data strongly suggests the notion of progressive decline in functional LT-HSCs & normal hematopoiesis, adipocytes and osteoblasts numbers with leukemia progression due to activation of lipolytic enzymes resulting in increased availability of fatty acids for leukemia expansion and is a common feature in both lymphoid and myeloid leukemias. Disclosures No relevant conflicts of interest to declare.
10
Hapsari, Happy Indri. "INCREASING KNOWLEDGE OF PARENTS IN CARE OF THE SIDE EFFECTS OF CHEMOTHERAPY IN LEUKEMIA CHILDREN THROUGH BOOKLET IN DR. MOEWARDI GENERAL HOSPITAL SURAKARTA." Jurnal Ilmiah Kesehatan Media Husada 8, no. 2 (October 24, 2019): 39–47. http://dx.doi.org/10.33475/jikmh.v8i2.196.
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Leukemia is the number one cancer that attacks children aged 0 to 18 years. Parents who have children with leukemia will experience a heavy burden in caring for children. Health education is one way for nurses to ease the burden of parents in finding information about leukemia. The use of booklets has long been known as a medium in health education, where effectiveness is very significant in increasing parental knowledge. The purpose of the study: to determine the effect of health education with booklets on the level of knowledge of parents in caring for leukemic children who are on chemotherapy. Method: quasi experiment and using Wilcoxon data analysis. Results: p-value 0.00, where the p - value <0.005 so that there is an effect of booklets in increasing parental knowledge about the treatment of side effects of chemotherapy in children with leukemia. Conclusion: booklet administration increases parental knowledge about the treatment of chemotherapy side effects in leukemic children.
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Kampa-Schittenhelm, Kerstin M., Charles D. Lopez, and Marcus Schittenhelm. "ASPP2 Expression In Acute Leukemia Modulates Response to Therapy." Blood 116, no. 21 (November 19, 2010): 3143. http://dx.doi.org/10.1182/blood.v116.21.3143.3143.
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Abstract Abstract 3143 Acute myeloid leukemias (AML) remain difficult to treat and therapy outcome is far from satisfactory for most disease subgroups. Inactivation of the p53 tumor suppressor pathway by mutation is a frequent event in many cancers that promotes tumorigenesis and resistance to chemotherapy. Although p53 mutations are rare in AML it is not well studied whether the p53 pathway is influenced by other mechanisms instead. ASPP2 (Apoptosis Stimulating Protein of p53 2) is a highly regulated member of a family of p53-binding proteins that enhance apoptosis at least in part through stimulation of p53-transactivation of selected pro-apoptotic target genes. We previously demonstrated in a mouse model that ASPP2 is a haploinsufficient tumor suppressor (Kampa et al., PNAS 2009), and low ASPP2 expression levels have been associated with aggressive courses of different tumors such as breast cancer and lymphoma. We have now studied how ASPP2 expression correlates with response to therapy using in vitro models as well as patient-derived acute leukemia cells collected pre- and post- chemotherapy. We first analyzed changes in ASPP2 protein expression after treatment with chemotherapy or small molecule tyrosine-kinase inhbitors. We found that ASPP2-induction was cell-type specific in various established leukemia lines including Jurkat and HL60 (ASPP2 levels induced) and MOLM14 cells (ASPP2 levels unchanged). To test if ASPP2 levels modulated growth or response to therapy of leukemia cells, we generated three different ASPP2-siRNA constructs and transiently introduced them by lipofection into various lymphoid and myelogenous leukemia cell lines, including K562, Kasumi1, HL60, MOLM14 and Jurkat. After ASPP2 silencing, we observed, with the exception of MOLM14 cells, an up to 3-fold increase in cell proliferation measured by an XTT-assay compared to an empty vector control. We also treated siRNA-silenced K562, Kasumi1, HL60 and Jurkat cell lines with daunorubicin or small molecules targeting cell line-specific mutations in FLT3, KIT or ABL. Cell lines with attenuated ASPP2 expression displayed a significantly (∼50%) lower rate of apoptosis-induction in AnnexinV-assays after chemotherapy as well as small molecule inhibitor treatment as compared to a negative control. Interestingly, treated and siRNA-silenced leukemic cells frequently demonstrated enlarged morphology consistent with mitotic catastrophe. To study ASPP2 expression in humans, we quantified ASPP2 levels by qRT-PCR and intracellular immunophenotyping in circulating leukemic cells derived from patients at several timepoints before and during induction-chemotherapy (n=63). We found that pre-treatment ASPP2 basal levels were variable in acute leukemias. Additionally, we found that induction-chemotherapy increased ASPP2 expression in leukemic cells in a subgroup of patients. Univariate and multivariate analysis of the correlation of available clinical data and patient outcomes with ASPP2 expression in these patient datasets is ongoing. Taken together, our results demonstrate that dysfunctional regulation of ASPP2 expression may contribute to the biology of leukemogenesis and to primary therapy resistance in a subgroup of patients with acute leukemia. This data provides important and clinically relevant insight into how the p53 pathway can be inactivated in acute leukemia and opens new avenues for investigation. Prospective clinical studies are warranted in order to further define the role of the ASPP2 pathway as a therapeutic target and as biomarker for response to therapy. Disclosures: No relevant conflicts of interest to declare.
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Ptasiewicz, Maja, Paweł Maksymiuk, and Renata Chałas. "Changes of Dentition State in Leukemic Patients during Chemotherapy." International Journal of Environmental Research and Public Health 18, no. 15 (August 2, 2021): 8193. http://dx.doi.org/10.3390/ijerph18158193.
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A number of systemic diseases including hematological disorders have manifestations in the oral cavity region. These manifestations may often represent early signs of the underlying hematopoietic disease and occur frequently in leukemia. Despite the fact that leukemia has long been known to be associated with oral health deterioration, the available literature on this topic consists mostly of case reports, without data to conclude these. The aim of the study was to assess dentition state in leukemic patients during one cycle of chemotherapy and its correlation with blood parameters. The study included 102 adults treated because of leukemia at the Clinic of Haemato-Oncology and Bone Marrow Transplantation at the university hospital in Lublin, Poland. The sample group consisted of 51 women and 51 men aged 22 to 72 (54.07 ± 10.33) with following diagnoses: Acute myelogenous leukemia (AML)—55 patients (53.92%), Chronic lymphocytic leukemia (CLL)—17 patients (16.67%), Acute lymphoblastic leukemia (ALL)—16 patients (15.69%), Chronic myelogenous leukemia (CML)—10 patients (9.80%), Acute promyelocytic leukemia (APL) —3 patients (2.94%), Chronic hairy cell leukemia (HCL)—1 patient (0.98%). DMFT index was used to assess dentition state. After the cycle of chemotherapy, their dentition state changed in terms of decayed, missing and filled teeth and correlated with hematological parameters. Adult patients with leukemia have high dental treatment needs, and high number of missing teeth; thus, a comprehensive and fast dental treatment is necessary to avoid systemic complications and ensure better quality of life.
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Swatler, Julian, Laura Turos-Korgul, Ewa Kozlowska, and Katarzyna Piwocka. "Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias." Cancers 13, no. 6 (March 10, 2021): 1203. http://dx.doi.org/10.3390/cancers13061203.
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Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously promoting development of immunosuppressive regulatory T cells and suppressive myeloid cells. This facilitates disease progression, spreading of leukemic blasts outside the bone marrow niche and therapy resistance. The following review focuses on main immunosuppressive features of myeloid leukemias. Firstly, factors derived directly from leukemic cells – inhibitory receptors, soluble factors and extracellular vesicles, are described. Further, we outline function, properties and origin of main immunosuppressive cells - regulatory T cells, myeloid derived suppressor cells and macrophages. Finally, we analyze interplay between recovery of effector immunity and therapeutic modalities, such as tyrosine kinase inhibitors and chemotherapy.
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Swatler, Julian, Laura Turos-Korgul, Marta Brewinska-Olchowik, Sara De Biasi, Wioleta Dudka, Bac Viet Le, Agata Kominek, et al. "4-1BBL–containing leukemic extracellular vesicles promote immunosuppressive effector regulatory T cells." Blood Advances 6, no. 6 (March 17, 2022): 1879–94. http://dx.doi.org/10.1182/bloodadvances.2021006195.
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Abstract Chronic and acute myeloid leukemia evade immune system surveillance and induce immunosuppression by expanding proleukemic Foxp3+ regulatory T cells (Tregs). High levels of immunosuppressive Tregs predict inferior response to chemotherapy, leukemia relapse, and shorter survival. However, mechanisms that promote Tregs in myeloid leukemias remain largely unexplored. Here, we identify leukemic extracellular vesicles (EVs) as drivers of effector proleukemic Tregs. Using mouse model of leukemia-like disease, we found that Rab27a-dependent secretion of leukemic EVs promoted leukemia engraftment, which was associated with higher abundance of activated, immunosuppressive Tregs. Leukemic EVs attenuated mTOR-S6 and activated STAT5 signaling, as well as evoked significant transcriptomic changes in Tregs. We further identified specific effector signature of Tregs promoted by leukemic EVs. Leukemic EVs-driven Tregs were characterized by elevated expression of effector/tumor Treg markers CD39, CCR8, CD30, TNFR2, CCR4, TIGIT, and IL21R and included 2 distinct effector Treg (eTreg) subsets: CD30+CCR8hiTNFR2hi eTreg1 and CD39+TIGIThi eTreg2. Finally, we showed that costimulatory ligand 4-1BBL/CD137L, shuttled by leukemic EVs, promoted suppressive activity and effector phenotype of Tregs by regulating expression of receptors such as CD30 and TNFR2. Collectively, our work highlights the role of leukemic extracellular vesicles in stimulation of immunosuppressive Tregs and leukemia growth. We postulate that targeting of Rab27a-dependent secretion of leukemic EVs may be a viable therapeutic approach in myeloid neoplasms.
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Buss, Eike C., Alexander Kalinkovich, Amir Schajnovitz, Orit Kollet, Ayelet Dar, Melania Tesio, Stefan Fruehauf, et al. "In Vivo Mobilization of Leukemic Human Precursor-B-ALL Cells by the CXCR4-Antagonist AMD3100 Is Via Secretion of SDF-1 and Synergistically by Catecholamine Action." Blood 112, no. 11 (November 16, 2008): 1920. http://dx.doi.org/10.1182/blood.v112.11.1920.1920.
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Abstract Introduction Mobilization of leukemic cells from the bone marrow (BM) to the circulation in order to better kill them with DNA damaging chemotherapy agents is emerging as a new experimental therapeutic intervention, however the mechanism is not entirely clear. Currently CXCR4-antagonists such as the mobilizing agent AMD3100 (AMD) are becoming available for clinical usage. The aim of this study is to explore mechanisms of human precursor-B-ALL cell mobilization from the BM in a functional, pre-clinical immune deficient mouse model. Methodology Immunodeficient mice were stably engrafted with the childhood pre-B-ALL leukemic cell line G2 (4 weeks after transplantation in NOD/SCID mice) and with primary childhood precursor-B-ALL cells from 4 patients (4-8 weeks after transplantation in NOD/SCID IL2R {gamma} null and NOD/SCID/B2m(null) mice). Two of the patients had a translocation (t4;11) (pro-B-ALL). All human leukemias were engrafted without prior irradiation of the mice. This approach prevents possible irradiation damage to the host microenvironment and thereby leads to a model which better mimics growth of human leukemias. To accommodate for differences in the level of leukemic BM engraftment (FACS analysis for huCD45+ cells), we assessed the leukemia mobilization level by calculating a leukemia mobilization index: WBC x % leukemic cells in the PB / % leukemic cells in the BM. Results and Discussion Treatment with AMD leads to a significant mobilization of all transplanted leukemias with a mobilization level of between 3 – 8 times above baseline. As we recently showed for mobilization of normal murine progenitors, AMD induces a strong release of SDF-1 from the BM (Dar et al. ASH 2006). To examine if this is also instrumental for the leukemia mobilization process, we inhibited SDF-1 action by injection of neutralizing CXCR4 antibodies (clone 12G5) in leukemic chimeras. This led to an abrogation of AMD-induced leukemia mobilization. Pointing towards the same mechanism, 3 daily injections of fucoidan, a known SDF-1 releasing agent, also led to significant leukemia mobilization in G2 and precursor-B-ALL chimeras. Recently we demonstrated that human hematopoietic stem and progenitor cells express receptors for catecholamines, such as dopamine and epinephrine (Epi) and that treatment with catecholamines leads to mobilization of murine progenitor cells (Spiegel et al. Nat. Immunol. 2007). Accordingly, we examined the effect of neurotransmitters. First, we found that the G2 cell line and all 4 examined precursor-BALL samples express the catecholamine receptors D3, D5 and beta-2. The expression is dynamic, as it was, in part, increased after engraftment of immunodeficient mice. Treatment of chimeras with high doses of Epi alone led to leukemia mobilization in vivo similar to AMD-induced mobilization. In combination with AMD, lower doses of norepinephrine increased leukemia obilization synergistically and significantly, resulting in dramatic leukemia mobilization up to 20 times above baseline. Unexpectedly and in contrast to normal cells, treatment of chimeras with the beta-2 agonist clenbuterol was accompanied by inhibition of AMD-induced mobilization of leukemic cells. These observations suggest similarities and differences in the activation of catecholamine receptors in the mobilization process of normal and leukemic cells. Conclusions Our results show that SDF-1 has a crucial role in AMD-induced leukemic cell mobilization. Human leukemias can be mobilized by catecholamine action synergistically with AMD in immunodeficient mice. This approach could be potentially used for future mobilization protocols of leukemia in combination with established chemotherapy to improve eradication of minimal residual disease of leukemia.
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Lam, Wilbur A., Michael J. Rosenbluth, and Daniel A. Fletcher. "Chemotherapy Exposure Decreases Leukemia Cell Deformability as Determined by Atomic Force Microscopy: Implications for Leukostasis in Acute Leukemia." Blood 108, no. 11 (November 1, 2006): 2359. http://dx.doi.org/10.1182/blood.v108.11.2359.2359.
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Abstract Leukostasis, a life-threatening complication of acute leukemia, occurs when leukemia cells obstruct the circulation of vital organs like the brain and lungs leading to intracranial hemorrhage or respiratory failure. Although the pathophysiology of leukostasis is poorly understood, an elevated concentration of circulating leukemia cells, pathologic adhesion, and decreased cell deformability are thought to play significant roles. Clinical deterioration can occur soon after chemotherapy is initiated, suggesting that chemotherapy itself may be a risk factor for leukostasis. To investigate the effects of chemotherapy on cell stiffness, we performed serial single cell deformability measurements with an atomic force microscope (AFM), a commonly used tool in nanoscience for imaging and characterizing mechanical properties of materials on a submicron level, and modified the AFM to operate in cell culture conditions at 37°C. Leukemia cells from patients with acute lymphoblastic leukemia and acute myeloid leukemia as well as leukemia cell lines were incubated with chemotherapeutic agents, and changes in cell stiffness were tracked over time with AFM as the cells underwent chemotherapy-induced cell death. In the presence of dexamethasone or daunorubicin, leukemia cells exhibited increases in stiffness by as much as two orders of magnitude. Cell stiffness appeared to increase before caspase activation and peaked after completion of cell death, and the rate at which cell stiffness increased was dependent on chemotherapy type. Stiffening with cell death was found to occur for all cell types and chemotherapies investigated and is due, at least in part, to dynamic changes in the actin cytoskeleton. This observed correlation between cell death and cell stiffening may partially explain why some leukemia patients develop leukostasis shortly after starting chemotherapy, and it suggests that leukocytoreduction should remain an important treatment for hyperleukocytosis in acute leukemia. Figure 1. Average apparent stiffness of dead (dark gray) leukemic cells exposed to chemotherapy is significantly higher compared to untreated (light gray) cells (n > 15, p < 0.05 for all comparisons of dead/untreated populations). (A) Primary ALL cells and lymphoid leukemic cell lines exposed to 1 μM dexamethasone (B) Primary AML and myeloid leukemic cell lines exposed to 1μM daunorubicin. Error bars are standard error. Figure 1. Average apparent stiffness of dead (dark gray) leukemic cells exposed to chemotherapy is significantly higher compared to untreated (light gray) cells (n > 15, p < 0.05 for all comparisons of dead/untreated populations). (A) Primary ALL cells and lymphoid leukemic cell lines exposed to 1 μM dexamethasone (B) Primary AML and myeloid leukemic cell lines exposed to 1μM daunorubicin. Error bars are standard error. Figure 2. Apparent stiffness of leukemic cells increases with progression of cell death. (A) A typical stiffness trace of a single M5 AML cell exposed to 1μM daunorubicin (circles). The apparent stiffness of a typical control cell remains relatively constant (triangles) and does not undergo apoptosis or cell death during the course of the experiment. Transition from open to filled shapres represents onset of cell death. Early apoptosis is defined as caspase 3 or 7 postivie staining and late apoptosis/dead is defined as Sytox Green (marker for cell membrane integrity loss) positive staining. (B) From the same patient sample, the average apparent stiffness of a population of late apoptotic/dead AML cells was significantly stiffer than early apoptopic cells and controls (n = 15, p< 0.05). Error bars are standard error. Figure 2. Apparent stiffness of leukemic cells increases with progression of cell death. (A) A typical stiffness trace of a single M5 AML cell exposed to 1μM daunorubicin (circles). The apparent stiffness of a typical control cell remains relatively constant (triangles) and does not undergo apoptosis or cell death during the course of the experiment. Transition from open to filled shapres represents onset of cell death. Early apoptosis is defined as caspase 3 or 7 postivie staining and late apoptosis/dead is defined as Sytox Green (marker for cell membrane integrity loss) positive staining. (B) From the same patient sample, the average apparent stiffness of a population of late apoptotic/dead AML cells was significantly stiffer than early apoptopic cells and controls (n = 15, p< 0.05). Error bars are standard error.
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Subramaniam, Priya, K. Girish Babu, and J. Nagarathna. "Oral Manifestations In Acute Lymphoblastic Leukemic Children Under Chemotherapy." Journal of Clinical Pediatric Dentistry 32, no. 4 (July 1, 2008): 319–24. http://dx.doi.org/10.17796/jcpd.32.4.0p1462t621w20477.
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Leukemia is a common malignancy seen in young children and acute lymphoblastic leukemia (ALL) accounts for 75% of all leukemias. Advances in the treatment regimen include multi-agent chemotherapy and central nervous system directed radiotherapy. Immune suppression caused due to disease and therapy makes these children more prone to bacterial, fungal infections and at times reactivation of viral diseases. Hence, the present study was taken to assess, the oral conditions among ALL children during chemotherapy.
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Dunussi-Joannopoulos, Kyriaki, Werner Krenger, Howard J. Weinstein, James L. M. Ferrara, and James M. Croop. "CD8+ T Cells Activated During the Course of Murine Acute Myelogenous Leukemia Elicit Therapeutic Responses to Late B7 Vaccines After Cytoreductive Treatment." Blood 89, no. 8 (April 15, 1997): 2915–24. http://dx.doi.org/10.1182/blood.v89.8.2915.
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Abstract We have previously shown in a murine acute myelogenous leukemia (AML) model that leukemic mice can be cured with a B7 vaccine if immunized early in the disease and that CD8+ T cells are necessary for tumor rejection. However, when B7 vaccine is administered 2 weeks after leukemia inoculation, the effect is only prolonged survival, ending in death virtually of all the mice. To distinguish between tumor kinetics and tumor-induced immunosuppression as potential mechanisms eliminating the therapeutic potential of late B7 vaccines, we performed in vitro T-cell studies during leukemia progression and in vivo studies on the clinical outcome of late B7 vaccines in combination with prior cytoreductive chemotherapy. Our results show that CD8+ T cells from leukemic mice 1 and 2 weeks after leukemia inoculation proliferate more vigorously in response to in vitro activation than cells from normal mice and produce Th1-type cytokines interleukin-2 and interferon-γ. Cytotoxic T lymphocyte (CTL) assays demonstrate that cells from week-2 vaccinated mice (which succumb to their leukemia), surprisingly develop a stronger CTL activity than cells from week-1 vaccinated mice (which reject their leukemia). Finally, the combination of late chemotherapy and late B7 vaccine administration can cure only 20% of leukemic mice, whereas early chemotherapy and the same late B7 vaccine administration cure 100% of leukemic mice. These results demonstrate that in murine AML tumor growth does not induce T-cell anergy or a Th2 cytokine profile and suggest that tumor growth is most likely to be the limiting factor in the curative potential of late B7 vaccines.
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Diamandidou, E., A. U. Buzdar, T. L. Smith, D. Frye, M. Witjaksono, and G. N. Hortobagyi. "Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: the University of Texas M.D. Anderson Cancer Center experience." Journal of Clinical Oncology 14, no. 10 (October 1996): 2722–30. http://dx.doi.org/10.1200/jco.1996.14.10.2722.
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PURPOSE Adjuvant chemotherapy for breast cancer has been the routine practice in the past decade. A number of studies have observed an increased incidence of treatment-related leukemias following chemotherapy with alkylating agents and/or topoisomerase II inhibitors. We evaluated the incidence of treatment-related leukemias in breast cancer patients treated in four adjuvant and two neoadjuvant chemotherapy trials at The University of Texas M.D. Anderson Cancer Center. PATIENTS AND METHODS Between 1974 and 1989, 1,474 patients with stage II or III breast cancer were treated in six prospective trials of adjuvant (n = 4) or neoadjuvant (n = 2) chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (CTX) (FAC) with or without other drugs. The median observation time was 97 months. In 1,107 patients, FAC chemotherapy was given postoperatively; 367 patients received induction chemotherapy, as well as postoperative chemotherapy. Eight hundred ten patients had surgery followed by radiotherapy and chemotherapy; 664 patients had surgery and chemotherapy only. Patients in two adjuvant and one neoadjuvant study received higher cumulative doses of CTX compared with those in the other studies. RESULTS Fourteen cases of leukemia were observed. Twelve of these patients had received radiotherapy and chemotherapy, and two had received chemotherapy only. Six of the reported patients with leukemia were treated with a cumulative CTX dose of greater than 6 g/ m2. Five of these patients had received both radiotherapy and chemotherapy. The median latency period in the 14 patients was 66 months (range, 22 to 113). Six of 10 patients with adequate cytogenetic analyses had abnormalities that involved chromosomes 5 and/or 7. The rest of the patients had nonspecific cytogenetic abnormalities or lacked cytogenetic information. The 10-year estimated leukemia rate was 1.5% (95% confidence interval [CI], 0.7% to 2.9%) for all patients treated, 2.5% (95% CI, 1.0% to 5.1%) for the radiotherapy-plus-chemotherapy group, and 0.5% (95% CI, 0.1% to 2.4%) for the chemotherapy-only group; this difference was statistically significant (P = .01). The 10-year estimated leukemia risk for the higher-dose (> 6 g/m2) CTX group was 2% (95% CI, 0.5% to 5.0%) compared with 1.3% (95% CI, 0.4% to 3.0%) for the lower-dose group, a difference that was not statistically significant (P = .53). CONCLUSION These data illustrate that patients treated with adjuvant FAC chemotherapy plus radiotherapy have a slightly increased risk of leukemia. This information needs to be considered in the treatment plans for patients with breast cancer. However, for most patients, the benefits of adjuvant therapy exceed the risk of treatment-related leukemia.
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Sohn, CC, DW Blayney, JL Misset, G. Mathe, G. Flandrin, EM Moran, FC Jensen, CD Winberg, and H. Rappaport. "Leukopenic chronic T cell leukemia mimicking hairy cell leukemia: association with human retroviruses." Blood 67, no. 4 (April 1, 1986): 949–56. http://dx.doi.org/10.1182/blood.v67.4.949.949.
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Abstract We report two cases of a T cell lymphoproliferative disease not previously described, with cytologic and clinical features similar to those associated with Galton's “prolymphocytic” leukemia (PL). Our patients, like those with Galton's PL, had massive splenomegaly and minimal or absent hepatomegaly and lymphadenopathy. In contrast, however, our patients had leukopenia, as well as low percentages of leukemic cells in the peripheral blood and in the bone marrow. In splenic imprints, the nuclear chromatin pattern of most of the leukemic cells was intermediate between those of mature lymphocytes and those of lymphoblasts, and the nuclei contained single, centrally located, conspicuous nucleoli. In sections of the spleen, the leukemic cells diffusely infiltrated the red pulp in a pattern strikingly similar to that of hairy cell leukemia; however, when the leukemic cells were studied cytochemically, the cytoplasmic acid phosphatase positivity was punctate and tartrate-sensitive. The leukemic cells were sheep erythrocyte rosette-positive and expressed T cell-associated antigens. Initially, both patients responded well to therapeutic splenectomy. One patient received combination chemotherapy after splenectomy and is alive and well 24 months after diagnosis. The other patient was in complete clinical remission for one year after splenectomy and received chemotherapy at relapse. He died, however, 23 months after splenectomy, with disseminated disease. IgG antibody titers against human T lymphotropic virus type I (HTLV-I) were detected in one patient and against HTLV-II in the other. The leukemia in these patients represents a distinct clinicopathologic entity within the spectrum of peripheral T cell lymphoproliferative diseases that includes Galton's PL of T cell derivation, T cell chronic lymphocytic leukemia, T cell hairy cell leukemia, and adult T cell leukemia/lymphoma.
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Sohn, CC, DW Blayney, JL Misset, G. Mathe, G. Flandrin, EM Moran, FC Jensen, CD Winberg, and H. Rappaport. "Leukopenic chronic T cell leukemia mimicking hairy cell leukemia: association with human retroviruses." Blood 67, no. 4 (April 1, 1986): 949–56. http://dx.doi.org/10.1182/blood.v67.4.949.bloodjournal674949.
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We report two cases of a T cell lymphoproliferative disease not previously described, with cytologic and clinical features similar to those associated with Galton's “prolymphocytic” leukemia (PL). Our patients, like those with Galton's PL, had massive splenomegaly and minimal or absent hepatomegaly and lymphadenopathy. In contrast, however, our patients had leukopenia, as well as low percentages of leukemic cells in the peripheral blood and in the bone marrow. In splenic imprints, the nuclear chromatin pattern of most of the leukemic cells was intermediate between those of mature lymphocytes and those of lymphoblasts, and the nuclei contained single, centrally located, conspicuous nucleoli. In sections of the spleen, the leukemic cells diffusely infiltrated the red pulp in a pattern strikingly similar to that of hairy cell leukemia; however, when the leukemic cells were studied cytochemically, the cytoplasmic acid phosphatase positivity was punctate and tartrate-sensitive. The leukemic cells were sheep erythrocyte rosette-positive and expressed T cell-associated antigens. Initially, both patients responded well to therapeutic splenectomy. One patient received combination chemotherapy after splenectomy and is alive and well 24 months after diagnosis. The other patient was in complete clinical remission for one year after splenectomy and received chemotherapy at relapse. He died, however, 23 months after splenectomy, with disseminated disease. IgG antibody titers against human T lymphotropic virus type I (HTLV-I) were detected in one patient and against HTLV-II in the other. The leukemia in these patients represents a distinct clinicopathologic entity within the spectrum of peripheral T cell lymphoproliferative diseases that includes Galton's PL of T cell derivation, T cell chronic lymphocytic leukemia, T cell hairy cell leukemia, and adult T cell leukemia/lymphoma.
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Zeng, Zhihong, Yue Xi Shi, Ismael J. Samudio, Rui-Yu Wang, Xiaoyang Ling, Olga Frolova, Mark Levis, et al. "Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML." Blood 113, no. 24 (June 11, 2009): 6215–24. http://dx.doi.org/10.1182/blood-2008-05-158311.
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Abstract SDF-1α/CXCR4 signaling plays a key role in leukemia/bone marrow microenvironment interactions. We previously reported that bone marrow–derived stromal cells inhibit chemotherapy-induced apoptosis in acute myeloid leukemia (AML). Here we demonstrate that the CXCR4 inhibitor AMD3465 antagonized stromal-derived factor 1α (SDF-1α)–induced and stroma-induced chemotaxis and inhibited SDF-1α–induced activation of prosurvival signaling pathways in leukemic cells. Further, CXCR4 inhibition partially abrogated the protective effects of stromal cells on chemotherapy-induced apoptosis in AML cells. Fetal liver tyrosine kinase-3 (FLT3) gene mutations activate CXCR4 signaling, and coculture with stromal cells significantly diminished antileukemia effects of FLT3 inhibitors in cells with mutated FLT3. Notably, CXCR4 inhibition increased the sensitivity of FLT3-mutated leukemic cells to the apoptogenic effects of the FLT3 inhibitor sorafenib. In vivo studies demonstrated that AMD3465, alone or in combination with granulocyte colony-stimulating factor, induced mobilization of AML cells and progenitor cells into circulation and enhanced antileukemic effects of chemotherapy and sorafenib, resulting in markedly reduced leukemia burden and prolonged survival of the animals. These findings indicate that SDF-1α/CXCR4 interactions contribute to the resistance of leukemic cells to signal transduction inhibitor– and chemotherapy-induced apoptosis in systems mimicking the physiologic microenvironment. Disruption of these interactions with CXCR4 inhibitors represents a novel strategy of sensitizing leukemic cells by targeting their protective bone marrow microenvironment.
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YORIMITSU, Seiichi. "Induction Chemotherapy for Acute Leukemia." Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 97, no. 3-4 (1985): 277–87. http://dx.doi.org/10.4044/joma1947.97.3-4_277.
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YORIMITSU, Seiichi. "Induction Chemotherapy for Acute Leukemia." Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 97, no. 3-4 (1985): 289–99. http://dx.doi.org/10.4044/joma1947.97.3-4_289.
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HARA, Masamichi. "Induction chemotherapy for acute leukemia." Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 98, no. 3-4 (1986): 243–54. http://dx.doi.org/10.4044/joma1947.98.3-4_243.
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HARA, Masamichi. "Induction chemotherapy for acute leukemia." Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 98, no. 3-4 (1986): 255–64. http://dx.doi.org/10.4044/joma1947.98.3-4_255.
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ONO, RYUZO. "Blood. Chemotherapy of the leukemia." Nihon Naika Gakkai Zasshi 86, no. 3 (1997): 477–80. http://dx.doi.org/10.2169/naika.86.477.
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Pieters, Rob, Annemiek M. Schans-Dop, A. Ine Brenk, Annette HM Taets Amerongen, and Anjo JP Veerman. "OSTEONECROSIS FOLLOWING CHEMOTHERAPY FOR LEUKEMIA." European Journal of Haematology 43, no. 3 (April 24, 2009): 262–64. http://dx.doi.org/10.1111/j.1600-0609.1989.tb00295.x.
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Chasen, Martin R., and Geoffrey Falkson. "Leukemia after Chemotherapy for Cancer." Cancer Biotherapy 8, no. 2 (January 1993): 115–22. http://dx.doi.org/10.1089/cbr.1993.8.115.
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Adra, Nabil, Hamid Sayar, and Lawrence H. Einhorn. "Chemotherapy-Related Chronic Myelogenous Leukemia." JAMA Oncology 2, no. 3 (March 1, 2016): 391. http://dx.doi.org/10.1001/jamaoncol.2015.4837.
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Lu, Hongbo, Zhihong Zeng, Yuexi Shi, Sergej Konoplev, Donald Wong, Marina Konopleva, and Michael Andreeff. "Disruption of Leukemia/Stroma Cell Interactions by CXCR4 Antagonist CTCE-9908 Enhances Chemotherapy-Induced Apoptosis in AML." Blood 112, no. 11 (November 16, 2008): 2415. http://dx.doi.org/10.1182/blood.v112.11.2415.2415.
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Abstract The chemokine receptor CXCR4 is critically involved in the migration of hematopoietic cells towards the stromal derived factor (SDF-1α)-producing bone marrow microenvironment. We and others have previously demonstrated that stroma/leukemia interactions mediate protection of leukemic cells from chemotherapy-induced apoptosis (Konopleva, Leukemia 2002). Using a peptide analog of SDF-1α designated CTCE-9908, we tested the hypothesis that CXCR4 inhibition interferes with stromal/leukemia cell interactions resulting in increased sensitivity to chemotherapy. Our results showed that CTCE-9908 significantly inhibits SDF-1α-induced migration of U937 (43% inhibition) and OCI-AML3 cells (40% inhibition) in a dose-dependent manner. In three of the four primary AML samples which expressed CXCR4 on cell surface and migrated in response to SDF-1α, 50 μg/ml CTCE-9908 reduced SDF-1α-induced migration of leukemic blasts (60%, 19% and 50% inhibition respectively). In in vitro co-culture systems, stromal cells significantly protected OCI-AML3 cells from chemotherapy induced apoptosis [no MS-5, 75.2±5.2% annexinV(+); with MS-5, 59±1.1% annexinV(+)]. Western blot analysis revealed that CTCE-9908 inhibits Akt and Erk phosphorylation in a dose-dependent manner in the OCI-AML3 cell line stimulated by SDF-1α. Blockade of CXCR4 expression with CTCE-9908 markedly abrogated the protective effects of stromal cells on OCI-AML3 [Ara-C, 59±1.1% annexinV(+); Ara-C + CTCE-9908, 76.9±1.35 annexinV(+)]. Most importantly, it decreased stroma-mediated protection from AraC-induced apoptosis in four out of five primary AML samples with surface expression of functional CXCR4 (mean increase, 25.1±9.3% compared to chemotherapy alone). In vivo, subcutaneous administration of 1.25mg CTCE-9908 induced mobilization of leukemic cells from primary AML patient transplanted into NOD/Scid-IL2Rγ-KO mice (from 15% to 27% circulating leukemic cells 1 hour post CTCE-9908 injection). Taken together, our data suggest that SDF-1α/CXCR4 interactions contribute to the resistance of leukemic cells to chemotherapy-induced apoptosis via retention of leukemic cells in the bone marrow microenvironment niches. Disruption of these interactions by the potent CXCR4 inhibitor CTCE-9908 represents a novel strategy for targeting leukemia cell/bone marrow microenvironment interaction. Based on these observations, in vivo experiments are ongoing to characterize the efficacy of chemotherapy combined with CTCE-9908.
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Barve, Vega, Shah, Ghare, Casson, Wunderlich, Siskind, and Beverly. "Perturbation of Methionine/S-adenosylmethionine Metabolism as a Novel Vulnerability in MLL Rearranged Leukemia." Cells 8, no. 11 (October 25, 2019): 1322. http://dx.doi.org/10.3390/cells8111322.
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Leukemias bearing mixed lineage leukemia (MLL) rearrangement (MLL-R) resulting in expression of oncogenic MLL fusion proteins (MLL-FPs) represent an especially aggressive disease subtype with the worst overall prognoses and chemotherapeutic response. MLL-R leukemias are uniquely dependent on the epigenetic function of the H3K79 methyltransferase DOT1L, which is misdirected by MLL-FPs activating gene expression, driving transformation and leukemogenesis. Given the functional necessity of these leukemias to maintain adequate methylation potential allowing aberrant activating histone methylation to proceed, driving leukemic gene expression, we investigated perturbation of methionine (Met)/S-adenosylmethionine (SAM) metabolism as a novel therapeutic paradigm for MLL-R leukemia. Disruption of Met/SAM metabolism, by either methionine deprivation or pharmacologic inhibition of downstream metabolism, reduced overall cellular methylation potential, reduced relative cell numbers, and induced apoptosis selectively in established MLL-AF4 cell lines or MLL-AF6-expressing patient blasts but not in BCR-ABL-driven K562 cells. Global histone methylation dynamics were altered, with a profound loss of requisite H3K79 methylation, indicating inhibition of DOT1L function. Relative occupancy of the repressive H3K27me3 modification was increased at the DOT1L promoter in MLL-R cells, and DOT1L mRNA and protein expression was reduced. Finally, pharmacologic inhibition of Met/SAM metabolism significantly prolonged survival in an advanced, clinically relevant patient–derived MLL-R leukemia xenograft model, in combination with cytotoxic induction chemotherapy. Our findings provide support for further investigation into the development of highly specific allosteric inhibitors of enzymatic mediators of Met/SAM metabolism or dietary manipulation of methionine levels. Such inhibitors may lead to enhanced treatment outcomes for MLL-R leukemia, along with cytotoxic chemotherapy or DOT1L inhibitors.
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Ratain, MJ, LS Kaminer, JD Bitran, RA Larson, MM Le Beau, C. Skosey, S. Purl, PC Hoffman, J. Wade, and JW Vardiman. "Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung." Blood 70, no. 5 (November 1, 1987): 1412–17. http://dx.doi.org/10.1182/blood.v70.5.1412.1412.
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Abstract Combination chemotherapy is frequently used in the therapy of advanced non-small-cell lung cancer (NSCLC), but late complications are rarely recognized because of the short survival of most patients. Of 119 patients with advanced NSCLC treated with cisplatin and other drugs, four patients developed acute nonlymphocytic leukemia (ANLL). All four patients received etoposide and cisplatin with or without vindesine. Leukemia was diagnosed at 13, 19, 28, and 35 months after start of treatment. Three patients had morphologic and/or cytogenetic features of acute leukemia with significant monoblastic involvement; the fourth patient had trilineage dysplasia and cytogenetic abnormalities more commonly associated with therapy-related leukemia. Detailed analysis of the subgroup who survived longer than 1 year (24 patients) suggests that high cumulative doses of etoposide are leukemogenic; the median etoposide dose was 6,795 mg/m2 (first year only) in the four leukemic patients compared with 3,025 mg/m2 in the 20 nonleukemic patients (P less than .01). The rate of ANLL was 0.30 per person-year after the first year (95% confidence limits 0.11 to 0.90), with a cumulative risk of 15% +/- 11% at 2 years, and 44% +/- 24% at 2.5 years. We conclude that high doses of etoposide are potentially leukemogenic, and can induce a syndrome with features of acute monoblastic leukemia de novo that is distinct from other secondary leukemias.
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Ratain, MJ, LS Kaminer, JD Bitran, RA Larson, MM Le Beau, C. Skosey, S. Purl, PC Hoffman, J. Wade, and JW Vardiman. "Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung." Blood 70, no. 5 (November 1, 1987): 1412–17. http://dx.doi.org/10.1182/blood.v70.5.1412.bloodjournal7051412.
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Combination chemotherapy is frequently used in the therapy of advanced non-small-cell lung cancer (NSCLC), but late complications are rarely recognized because of the short survival of most patients. Of 119 patients with advanced NSCLC treated with cisplatin and other drugs, four patients developed acute nonlymphocytic leukemia (ANLL). All four patients received etoposide and cisplatin with or without vindesine. Leukemia was diagnosed at 13, 19, 28, and 35 months after start of treatment. Three patients had morphologic and/or cytogenetic features of acute leukemia with significant monoblastic involvement; the fourth patient had trilineage dysplasia and cytogenetic abnormalities more commonly associated with therapy-related leukemia. Detailed analysis of the subgroup who survived longer than 1 year (24 patients) suggests that high cumulative doses of etoposide are leukemogenic; the median etoposide dose was 6,795 mg/m2 (first year only) in the four leukemic patients compared with 3,025 mg/m2 in the 20 nonleukemic patients (P less than .01). The rate of ANLL was 0.30 per person-year after the first year (95% confidence limits 0.11 to 0.90), with a cumulative risk of 15% +/- 11% at 2 years, and 44% +/- 24% at 2.5 years. We conclude that high doses of etoposide are potentially leukemogenic, and can induce a syndrome with features of acute monoblastic leukemia de novo that is distinct from other secondary leukemias.
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Ueda, Yutaka. "Problems in anti-leukemic drugs chemotherapy of childhood acute leukemia." Journal of Nippon Medical School 54, no. 6 (1987): 573–80. http://dx.doi.org/10.1272/jnms1923.54.573.
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Cavanna, Luigi, Daniele Vallisa, Michele Di Stasi, Fabio Fornari, Elisabetta Buscarini, Claudio Schena, Giuseppe Civardi, Giorgio Sbolli, Raffaella Berte, and Luigi Buscarini. "Acute Myelocytic Leukemia and Chronic Myelomonocytic Leukemia Simultaneously with Resectable Breast Cancer: A Report of two Cases." Tumori Journal 78, no. 5 (October 1992): 356–58. http://dx.doi.org/10.1177/030089169207800516.
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This report describes 2 patients who developed acute myelocytic leukemie (AML) type M2 and chronic myelomonocytic leukemia (CMML) of the FAB classification, respectively 2 months and 2 weeks after diagnosis of operable breast cancer. The patient with AML showed pancytopenia 2 months before the diagnosis of AML, had a normal karyotype, and showed a good response to chemotherapy. The patient with CMML had a normal karyotype, and she was treated with hydroxyurea and supportive therapy. The 2 patients had no previous exposure to irradiation or cytotoxic therapy. These cases show that breast cancer and either leukemia or myelodysplastic syndrome may be associated even without previous irradiation or combination chemotherapy.
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Milojkovic, Dragana, and Jane F. Apperley. "How I treat leukemia during pregnancy." Blood 123, no. 7 (February 13, 2014): 974–84. http://dx.doi.org/10.1182/blood-2013-08-283580.
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Leukemia in pregnancy remains a challenging therapeutic prospect. The prevalence is low at ∼1 in 10 000 pregnancies, and as a result data are limited to small retrospective series and case reports, rendering evidence-based recommendations for management strategies difficult. The management of the leukemias in pregnancy requires close collaboration with obstetric and neonatology colleagues as both the maternal and fetal outcomes must be taken into consideration. The decision to introduce or delay chemotherapy must be balanced against the impact on maternal and fetal survival and morbidity. Invariably, acute leukemia diagnosed in the first trimester necessitates intensive chemotherapy that is likely to induce fetal malformations. As delaying treatment in this situation is usually inappropriate, counseling with regard to termination of pregnancy is often essential. For chronic disease and acute leukemia diagnosed after the second trimester, therapeutic termination of the pregnancy is not inevitable and often, standard management approaches similar to those in nongravid patients can be used. Here, the management of the acute and chronic leukemias will be addressed.
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Shi, Yang, and Endi Wang. "Blastic Plasmacytoid Dendritic Cell Neoplasm: A Clinicopathologic Review." Archives of Pathology & Laboratory Medicine 138, no. 4 (April 1, 2014): 564–69. http://dx.doi.org/10.5858/arpa.2013-0101-rs.
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Blastic plasmacytoid dendritic cell neoplasm is a rare entity grouped with the acute myeloid leukemia–related precursor neoplasms in the 2008 World Health Organization classification. It was previously postulated to originate from natural killer cells, T cells, or monocytes but is now believed to arise from the plasmacytoid dendritic cell. The pathogenesis of blastic plasmacytoid dendritic cell neoplasm is not well understood, although the neoplasm demonstrates frequent deletion of tumor suppressor genes, including RB1, CDKN1B, CDKN2A, and TP53. Blastic plasmacytoid dendritic cell neoplasm is a clinically aggressive tumor that often initially presents as cutaneous lesions and subsequently progresses to bone marrow involvement and leukemic dissemination. It is characterized by enhanced expression of CD56, CD4, and CD123, which can be detected by flow cytometry/immunohistochemistry. The differential diagnoses include myeloid sarcoma/acute myeloid leukemia, T-cell lymphoblastic leukemia/lymphoma, NK-cell lymphoma/leukemia, and some mature T-cell lymphomas/leukemias. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplant may improve survival.
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Yeasmin, S., K. Nakayama, M. Ishibashi, A. Oride, A. Katagiri, I. N. Purwana, K. Iida, N. Nakayama, H. Ishikura, and K. Miyazaki. "Therapy-related myelodysplasia and acute myeloid leukemia following paclitaxel- and carboplatin-based chemotherapy in an ovarian cancer patient: a case report and literature review." International Journal of Gynecologic Cancer 18, no. 6 (2008): 1371–76. http://dx.doi.org/10.1111/j.1525-1438.2007.01185.x.
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Alkylating agents have strong leukemogenic potential. There are a number of recent acute myeloid leukemia (t-AML) cases related to previous paclitaxel exposure. These leukemias tend to be of aggressive subtypes with long-latency periods. Unlike previously reported cases, the present case was of the secondary acute megakaryoblastic myeloid leukemia (AML M7) subtype. Additionally, it did not harbor a translocation in chromosome 19. A 73-year-old woman was diagnosed with t-AML M7 with antecedent myelodysplasia. Leukemia followed a second induction of paclitaxel- and carboplatin-based chemotherapy for recurrent ovarian cancer. Her second induction began 25 months after completion of her first course of chemotherapy. The increased incidence of postpaclitaxel leukemia suggests a probable role for paclitaxel as a leukemogenic agent. It highlights the importance of assessing for leukemia risk factors prior to beginning paclitaxel therapy.
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Freireich, Emil J. "Prevention of chemotherapy-induced leukemia and of leukemia relapses." Medical Oncology and Tumor Pharmacotherapy 8, no. 3 (September 1991): 155–58. http://dx.doi.org/10.1007/bf02987173.
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Eshghabadi, M., A. M. Shojania, and I. Carr. "Isolated granulocytic sarcoma: report of a case and review of the literature." Journal of Clinical Oncology 4, no. 6 (June 1986): 912–17. http://dx.doi.org/10.1200/jco.1986.4.6.912.
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Granulocytic sarcoma (GS) is an extramedullary tumor composed of granulocytic precursor cells. The tumor usually develops during the course of myelogenous leukemia or myeloproliferative disorders and may represent the initial manifestation of leukemia. Rarely, GS is recognized as an isolated tumor without any evidence of leukemia. However, in such cases, leukemia generally develops within 1 to 2 years of the diagnosis of GS. We are reporting a case of a 45-year-old woman who was diagnosed as having an isolated GS of the right breast in August 1980. She was treated with a partial mastectomy followed by 1 year of combination chemotherapy as used in the cases of acute myeloblastic leukemia and has remained free of disease to the present time. That is, she has not developed leukemia or recurrence of GS for 64 months. Based on this experience and on the review of the literature, we recommend that all cases of GS be treated with combination chemotherapy as in cases of acute myeloblastic leukemias.
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Zhang, Ziting, Kun Yang, and Han Zhang. "Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?" Cancers 14, no. 22 (November 17, 2022): 5655. http://dx.doi.org/10.3390/cancers14225655.
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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of hematological malignancy characterized by its high heterogeneity and potentially life-threatening clinical features. Despite the advances in risk stratification and therapeutic management of T-ALL, patients often suffer from treatment failure and chemotherapy-induced toxicity, calling for greater efforts to improve therapeutic efficacy and safety in the treatment of T-ALL. During the past decades, increasing evidence has shown the indispensable effects of leukemia-initiating cells (LICs) and leukemic niches on T-ALL initiation and progression. These milestones greatly facilitate precision medicine by interfering with the pathways that are associated with LICs and leukemic niches or by targeting themselves directly. Most of these novel agents, either alone or in combination with conventional chemotherapy, have shown promising preclinical results, facilitating them to be further evaluated under clinical trials. In this review, we summarize the latest discoveries in LICs and leukemic niches in terms of T-ALL, with a particular highlight on the current precision medicine. The challenges and future prospects are also discussed.
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Chistyakova, Natalia V. "Ophthalmic manifestation of leukemia." Ophthalmology journal 9, no. 2 (June 15, 2016): 81–99. http://dx.doi.org/10.17816/ov9281-99.
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This paper includes a literature review on the ophthalmic manifestations of leukemia. Various eye disorder types in leukemia with concurrent anemia, hypoxia, increased blood viscosity, as well as the compression of tissues by tumor cells conglomerates and/or presence of direct leukemic infiltration were considered. Ophthalmic diseases in patients with hematological malignancies may occur due to opportunistic infections and the impact of such treatments as chemotherapy, radiotherapy and bone marrow transplantation. Reliable estimation of eye involvement rates in leukemic process is difficult, as many patients are asymptomatic at early stages of the disease. However, the predictive value of visual impairment assessment in leukemia is high, which requires close cooperation between ophthalmologists and hematologists, and appropriate adjustment of both local and systemic therapies.
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Jabbour, Elias, Susan O’Brien, Farhad Ravandi, and Hagop Kantarjian. "Monoclonal antibodies in acute lymphoblastic leukemia." Blood 125, no. 26 (June 25, 2015): 4010–16. http://dx.doi.org/10.1182/blood-2014-08-596403.
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Abstract With modern intensive combination polychemotherapy, the complete response (CR) rate in adults with acute lymphoblastic leukemia (ALL) is 80% to 90%, and the cure rate is 40% to 50%. Hence, there is a need to develop effective salvage therapies and combine novel agents with standard effective chemotherapy. ALL leukemic cells express several surface antigens amenable to target therapies, including CD20, CD22, and CD19. Monoclonal antibodies target these leukemic surface antigens selectively and minimize off-target toxicity. When added to frontline chemotherapy, rituximab, an antibody directed against CD20, increases cure rates of adults with Burkitt leukemia from 40% to 80% and those with pre-B ALL from 35% to 50%. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has resulted in marrow CR rates of 55% and a median survival of 6 to 7 months when given to patients with refractory-relapsed ALL. Blinatumomab, a biallelic T cell engaging the CD3-CD19 monoclonal antibody, also resulted in overall response rates of 40% to 50% and a median survival of 6.5 months in a similar refractory-relapsed population. Other promising monoclonal antibodies targeting CD20 (ofatumumab and obinutuzumab) or CD19 or CD20 and bound to different cytotoxins or immunotoxins are under development. Combined modalities of chemotherapy and the novel monoclonal antibodies are under investigation.
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V.E., Mayorova,, Mollaev, M.D., Vikhreva, P.N., Kulakovskaya, E.A., Pershin, D.E., Kibardin, A.V., Maschan, M.A., and Larin, S.S. "ANTIBODY-FREE CHIMERIC FLT3-CAR RECEPTOR FOR TARGETING THE FLT3 RECEPTOR, A MARKER OF POOR PROGNOSIS IN ACUTE MYELOID LEUKEMIA." CARDIOMETRY, no. 24 (November 30, 2022): 63–65. http://dx.doi.org/10.18137/cardiometry.2022.24.conf.35.
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Therapy in acute myeloid leukemia (AML) usually begins with a course of induction chemotherapy using anthracyclines and cytarabine to eliminate blast cells. Chemotherapy is a necessary step in preparing a patient for transplantation of donor hematopoietic stem cells (HSCs). However, leukemia stem cells often show their chemoresistance and initiate the AML recurrence. Specific elimination of the leukemic stem cells during the preparation of a patient for HSC transplantation may reduce the probability of recurrence. For this purpose, an active development of chimeric antigen receptors (CAR) to address various markers of AML is being in progress.
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Journal, Baghdad Science. "Evaluation of ELectrolytes in Adult Patients with Acute Leukemia before and after Chemotherapy." Baghdad Science Journal 10, no. 2 (June 2, 2013): 362–67. http://dx.doi.org/10.21123/bsj.10.2.362-367.
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Abstract:Leukemia is a cancer of early blood forming cells. Most of them are cancers of white blood cells , however some leukemias start in other blood cell types.Electrolytes have modulatory effects on several biological mechanisms in the body namely as stabilizers,element of structures, essential element for hormonal function and also co-factors for a number of enzymes.In this study serum electrolytes levels were measured in patients with acute leukemia (AL) disorders before and after chemotherapy(anthracycline, doxorubicin, cytarabine ,prednisone, vincristine and doxorubicin) during one month and compared with that of control group. Blood samples were obtained from (43) patients (28 males and 15 females) aged (15-55)years;juset before and after chemotherapy. The control group contained samples from (40) healthy volunteers (26 males and 14 females) aged (15-55) years.Serum electrolytes levels(sodium Na+1,potassium K+1,calcium Ca+1,chloride Cl-1,magnesium Mg+2and phosphate PO4-3) were estimated using flame atomic absorbtion photometry. Serum levels of Na, K,Ca and Cl were significantly decreased in patients before chemotherapy in comparasion with that of control group. The mean concentration of serum phosphoruse and magnesium in acute leukemia patients was non significant compared with that of control group. In this study, determination of serum electrolytes in leukemic patients indicates an abnormal metabolic process in these patients
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Shahjahani, Mohammad, Amirreza Abroun, Najmaldin Saki, Seyed Mohammad Bagher Mohammadi, and Hadi Rezaeeyan. "STAT5: From Pathogenesis Mechanism to Therapeutic Approach in Acute Leukemia." Laboratory Medicine 51, no. 4 (December 20, 2019): 345–51. http://dx.doi.org/10.1093/labmed/lmz074.
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Abstract Background Based on the results of multiple studies, multiple signaling pathways is a major cause of resistence to chemotherapy in leukemia cells. Signal transducer and activator of transcription 5 (STAT5) is among these factors; it plays an essential role in proliferation of leukemic cells. Methods We obtained the materials used in our study via PubMed search from 1996 through 2019. The key search terms included “STAT5,” “acute leukemia,” “leukemogenesis,” and “mutation.” Results On activation, STAT5 not only inhibits apoptosis of leukemic cells via activating the B-cell lymphoma 2 (BCL-2) gene but also inhibits resistance to chemotherapy by enhancing human telomerase reverse transcriptase (hTERT) expression and maintaining telomere length in cells. It has also been shown that a number of mutations in the STAT5 gene and in related genes alter the expression of STAT5. Conclusion The identification of STAT5 and the factors activated in its up- or downstream expression, affecting its function, contribute to better treatments such as targeted therapy rather than chemotherapy, improving the quality of life patients.
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Lotem, J., and L. Sachs. "Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells." Blood 80, no. 7 (October 1, 1992): 1750–57. http://dx.doi.org/10.1182/blood.v80.7.1750.1750.
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Abstract Transforming growth factor-beta 1 (TGF-beta 1) induces cell death in myeloid leukemia by apoptosis. In the M1 myeloid leukemia, this induction of apoptosis was inhibited by granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6) and to a lesser extent by IL-1 alpha. IL-3 and stem cell factor/mast cell growth factor (SCF) showed only a marginal effect, and granulocyte-macrophage and macrophage CSFs (GM-CSF and M-CSF, respectively) were inactive. The induction of apoptosis by TGF-beta 1 in a different myeloid leukemia (7-M12) was inhibited by GM-CSF and IL-3 but not by the other cytokines. In the absence of TGF-beta 1, both M1 and 7-M12 leukemic cells were independent of hematopoietic cytokines for cell viability and growth. The cytotoxic compounds vincristine, vinblastine, adriamycin, cytosine arabinoside, cycloheximide, and sodium azide, some of which are used in cancer chemotherapy, induced cell death by apoptosis in both leukemias. As with TGF-beta 1, apoptosis induced by these cytotoxic compounds was inhibited by GM-CSF (7-M12 leukemia) and by G-CSF or IL-6 (M1 leukemia). Cyclosporine A decreased cell multiplication in M1 cells without inducing apoptosis, and G-CSF and IL-6 inhibited the cytostatic effect of cyclosporine A. It is suggested that the clinical use of cytokines to correct therapy-associated myelosuppression should be carefully timed to avoid protection of malignant cells from the cytotoxic action of the therapeutic compounds.
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Lotem, J., and L. Sachs. "Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells." Blood 80, no. 7 (October 1, 1992): 1750–57. http://dx.doi.org/10.1182/blood.v80.7.1750.bloodjournal8071750.
Full textAbstract:
Transforming growth factor-beta 1 (TGF-beta 1) induces cell death in myeloid leukemia by apoptosis. In the M1 myeloid leukemia, this induction of apoptosis was inhibited by granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6) and to a lesser extent by IL-1 alpha. IL-3 and stem cell factor/mast cell growth factor (SCF) showed only a marginal effect, and granulocyte-macrophage and macrophage CSFs (GM-CSF and M-CSF, respectively) were inactive. The induction of apoptosis by TGF-beta 1 in a different myeloid leukemia (7-M12) was inhibited by GM-CSF and IL-3 but not by the other cytokines. In the absence of TGF-beta 1, both M1 and 7-M12 leukemic cells were independent of hematopoietic cytokines for cell viability and growth. The cytotoxic compounds vincristine, vinblastine, adriamycin, cytosine arabinoside, cycloheximide, and sodium azide, some of which are used in cancer chemotherapy, induced cell death by apoptosis in both leukemias. As with TGF-beta 1, apoptosis induced by these cytotoxic compounds was inhibited by GM-CSF (7-M12 leukemia) and by G-CSF or IL-6 (M1 leukemia). Cyclosporine A decreased cell multiplication in M1 cells without inducing apoptosis, and G-CSF and IL-6 inhibited the cytostatic effect of cyclosporine A. It is suggested that the clinical use of cytokines to correct therapy-associated myelosuppression should be carefully timed to avoid protection of malignant cells from the cytotoxic action of the therapeutic compounds.
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Coustan-Smith, Elaine, Jose Sancho, Frederick G. Behm, Michael L. Hancock, Bassem I. Razzouk, Raul C. Ribeiro, Gaston K. Rivera, et al. "Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia." Blood 100, no. 1 (July 1, 2002): 52–58. http://dx.doi.org/10.1182/blood-2002-01-0006.
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Abstract Early clearance of leukemic cells is a favorable prognostic indicator in childhood acute lymphoblastic leukemia (ALL). However, identification of residual leukemic cells by their morphologic features is subjective and lacks sensitivity. To improve estimates of leukemia clearance, we applied flow cytometric techniques capable of detecting 1 leukemic cell in 10 000 or more normal cells and prospectively measured residual leukemia in bone marrow samples collected on day 19 of remission-induction chemotherapy from 248 children with newly diagnosed ALL. In 134 samples (54.0%), we identified at least 0.01% leukemic cells (0.01%-< 0.1% in 51 samples [20.6%], 0.1%-< 1% in 36 [14.5%], and ≥ 1% in 47 [19.0%]). Among 110 children treated within a single chemotherapy program, the 5-year mean ± SE cumulative incidence of relapse or failure to achieve remission was 32.2% ± 6.5% for the 59 patients with 0.01% residual leukemic cells or greater on day 19 and 6.0% ± 3.4% for the 51 patients with less than 0.01% leukemic cells (P < .001). The prognostic value of day-19 bone marrow status defined by flow cytometry was superior to that defined by morphologic studies and remained significant after adjustment for other clinical and biologic variables. Lack of detectable leukemic cells on day 19 was more closely associated with relapse-free survival than was lack of detectable residual disease at the end of remission induction (day 46). Thus, approximately half of the children with ALL achieve profound clearance of leukemic cells after 2 to 3 weeks of remission-induction chemotherapy, and these patients have an excellent treatment outcome.