Treatment Of Chronic Myeloid Leukemia Patients Research Articles

Target Inhibition of CBP Induced Cell Senescence in BCR-ABL- T315I Mutant Chronic Myeloid Leukemia.

The treatment of chronic myeloid leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, has yielded clinical success. However, the direct targeting of BCR-ABL does not eradicate CML cells expressing mutant BCR-ABL, especially the T315I mutation in BCR-ABL. Moreover, increasing mutations were identified in BCR-ABL domain, resulting in TKIs resistance recently. It is necessary to find BCR-ABL-independent target for treating CML patients with various mutations, including T315I mutation in BCR-ABL. The dichotomous behavior of CREB binding protein (CBP) and E1A protein (p300), recruited by β-catenin associated with self-renewal and differentiation, have been identified in hematopoietic stem cells, respectively. In this study, CBP was aberrantly expressed in CML cells on the basis of Oncomine dataset. The β-catenin bound with much more CBP than p300 in CML cells. Down-regulation of CBP inhibited cell proliferation capacity and increased the binding of β-catenin to p300, thus promoting cell differentiation and p53-dependent cell senescence in CML cells with either wild type or T315I mutant BCR-ABL in vitro and in vivo models. These demonstrate CBP blockage can be developed for the treatment of CML independent of BCR-ABL mutation status including T315I.

Chronic myeloid leukemia: aiming for treatment free remission

BCR-ABL tyrosine kinase inhibitors (TKIs) dramatically improve the chronic myeloid leukemia (CML) prognosis, and most CML patients in the chronic phase are now able to lead lives that are comparable to those of healthy individuals. However, the high cost and adverse effects associated with long-term treatment remain issues in the treatment of CML patients. At the setout, a clinical study involving the discontinuation of imatinib was conducted in France. Thereafter, several TKI stop studies of first-generation (imatinib) and second-generation TKIs (dasatinib, nilotinib) have shown an earlier response than that with imatinib. These studies revealed that almost 50% of CML patients who were treated with TKIs and achieved a certain period of sustained deep molecular response can stop TKIs safely and obtain sustained treatment-free remission (TFR). Adverse effects of TKI withdrawal and predicting factors for successful discontinuation including immunity are gradually becoming clear via these studies. For superior CML treatment, several promising agents, including ABL001, are being developed. I trust that these efforts will enable CML patients to maintain TFR in the near future.

Anti-proliferative effects of a small molecule inhibitor of CDK AT7519 on chronic myeloid leukemia (CML) cells through halting the transition of cells from G2/M phase of the cell cycle

Pathogenesis of chronic myeloid leukemia (CML) has mostly been studied with regard to the oncogenic role of BCR/ABL fusion; however, recent disclosures have declared that the challenges with the treatment of CML patients would not be resolved until the role of other aberrancies is ignored. Given the involvement of cyclin-dependent kinases (CDKs) in the pathogenesis of CML, the present study aimed to investigate the effects of a multi-CDK inhibitor AT7519 on BCR/ABL-harboring CML-derived K562 cells. Our results showed that AT7519 effectively reduced the survival of K562 and induced its anti-proliferative effect through the induction of G2/M arrest due to elevated p21 and p27. The resulting data also revealed that either direct or indirect suppression of c-Myc using specific c-Myc inhibitor 10058-F4 and selective PI3K inhibitor CAL-101 resulted in a superior cytotoxicity, suggesting that the activation of PI3K pathway could attenuate antileukemic effects of the inhibitor, at least partly, through a c-Mycdependent mechanism. To the best of our knowledge, to date, no study has addressed the effect of autophagy on CML cell response to AT7519, and, herein, we proposed for the first time that the suppression of autophagy boosted AT7519 cytotoxicity against K562. Overall, we suggested that selective CDK inhibitor AT7519 exerted antileukemic effect against CML cells and propose a novel therapeutic application for the inhibitor either as a single agent or in combination with c-Myc and/or PI3K inhibitors.

Human telomerase reverse transcriptase depletion potentiates the growth-inhibitory activity of imatinib in chronic myeloid leukemia stem cells.

Although tyrosine kinase inhibitors (TKIs) revolutionized the management of chronic myeloid leukemia (CML), resistance against TKIs and leukemia stem cell (LSC) persistence remain a clinical concern. Therefore, new therapeutic strategies combining conventional and novel therapies are urgently needed. Since telomerase is involved in oncogenesis and tumor progression but is silent in most human normal somatic cells, it may be an interesting target for CML therapy by selectively targeting cancer cells while minimizing effects on normal cells. Here, we report that hTERT expression is associated with CML disease progression. We also provide evidence that hTERT-deficient K-562cells do not display telomere shortening and that telomere length is maintained through the ALT pathway. Furthermore, we show that hTERT depletion exerts a growth-inhibitory effect in K-562cells and potentiates imatinib through alteration of cell cycle progression leading to a senescence-like phenotype. Finally, we demonstrate that hTERT depletion potentiates the imatinib-induced reduction of the ALDH+-LSC population. Altogether, our results suggest that the combination of telomerase and TKI should be considered as an attractive strategy to treat CML patients to eradicate cancer cells and prevent relapse by targeting LSCs.

Enestpath Leukemic Stem Cell (LSC) Sub-Study: Analyzing Characteristics of LSC-Positive Patients and Impact of Switch from Imatinib to Nilotinib Therapy on LSCs in Patients with Chronic Myeloid Leukemia

Enestpath Leukemic Stem Cell (LSC) Sub-Study: Analyzing Characteristics of LSC-Positive Patients and Impact of Switch from Imatinib to Nilotinib Therapy on LSCs in Patients with Chronic Myeloid Leukemia

Dasatinib Inhibits Procoagulant and Clot Retracting Activities of Human Platelets.

Tyrosine kinase inhibitors (TKI) such as the BCR-ABL inhibitor dasatinib and nilotinib are highly effective therapies for chronic myeloid leukemia (CML). However, several lines of evidence suggest that dasatinib can induce bleeding which may be due to impaired collagen-induced platelet adhesion, aggregation, and secretion. Sarcoma family kinases (SFK) play central role in the GPVI-induced signaling pathway. We aimed to investigate whether and how dasatinib can modulate SFK-mediated platelet procoagulant activity in a purified system and in dasatinib/nilotinib treated CML patients. In platelet rich plasmas of healthy volunteers, dasatinib dose-dependently reduced convulxin-induced phosphatidylserine exposure and attenuated thrombin formation. Similarly to these changes, integrin activation and clot retraction were also significantly inhibited by 100 nM dasatinib. Platelets isolated from dasatinib treated patients showed a significantly lower phosphatidylserine expression upon convulxin activation compared to premedication levels. In these samples, thrombin generation was significantly slower, and the quantity of formed thrombin was less compared to the trough sample. Western blot analyses showed decreased phosphorylation levels of the C-terminal tail and the activation loop of SFKs upon dasatinib administration. Taken together, these results suggest that dasatinib inhibits the formation of procoagulant platelets via the GPVI receptor by inhibiting phosphorylation of SFKs.

Haematological and cytogenetic changes in CML patients treated with imatinib mesylate in Western Libya

Background: Chronic myeloid leukemia (CML) is a clonal myeloid proliferative disorder of primitive haemopoietic progenitor cells. The incidence of CML ranges between 10 and 15 cases/106 /year without any major geographic or ethnic differences. Imatinib mesylate provides good results in the treatment of CML. Early studies demonstrated that Imatinib mesylate can produce clear hematologic and cytogenetic response when used as a treatment of CML patients with positive BCR-ABL gene. Nevertheless, some patient with different stages of CML (chronic, accelerated, or acute phases) either relapse or stay unchanged for a long time after initial doses of treatment. This phenomenon led to the fact that we must explore the possible changes expected to appear if we make some changes in the treatment strategy. Objectives: The present study aimed to evaluate hematologic and molecular responses of CML patients to Imatinib mesylate treatment. Methods: Eighteen CML patients in chronic phase aged (24–65 years) males and females were treated with Imatinib mesylate (400, 500 or 600 mg/day) for sixteen months. Hematologic and cytogenetic changes were analyzed periodically. Results: Overall 18 cases, hematologic response of 14 cases was complete white blood cells (WBCs) decrease to normal range within 4 months) with P value of less than 0.0001 whereas in 4 cases WBCs were decreased slowly (after 8 months). A major cytogenetic response was noticed in 4 cases while in others the response was partially or in minor range. The major hematologic and cytogenetic response was noticed when using 600mg/day of Imatinib mesylate. The correlation appeared as a significant positive correlation between the treatment doses and Hb, hematocrit, MCV, MCH, esinophils%, and monocytes %. And a significant negative correlation between the treatment doses and RDW %, platelets count, WBCs count, and basophils %. On the other hand, no correlation between the treatment doses and RBCs Count, MCHC, Neutrophil % and BCR/APL ratio % Conclusion: It can be concluded that treatment of CML patients with Imatinib mesylate caused complete WBCs decrease to normal range. The major hematologic and cytogenetic response was noticed when using a higher dose of Imatinib mesylate.

Haematological and cytogenetic changes in CML patients treated with imatinib mesylate in Western Libya

Background: Chronic myeloid leukemia (CML) is a clonal myeloid proliferative disorder of primitive haemopoietic progenitor cells. The incidence of CML ranges between 10 and 15 cases/106 /year without any major geographic or ethnic differences. Imatinib mesylate provides good results in the treatment of CML. Early studies demonstrated that Imatinib mesylate can produce clear hematologic and cytogenetic response when used as a treatment of CML patients with positive BCR-ABL gene. Nevertheless, some patient with different stages of CML (chronic, accelerated, or acute phases) either relapse or stay unchanged for a long time after initial doses of treatment. This phenomenon led to the fact that we must explore the possible changes expected to appear if we make some changes in the treatment strategy. Objectives: The present study aimed to evaluate hematologic and molecular responses of CML patients to Imatinib mesylate treatment. Methods: Eighteen CML patients in chronic phase aged (24–65 years) males and females were treated with Imatinib mesylate (400, 500 or 600 mg/day) for sixteen months. Hematologic and cytogenetic changes were analyzed periodically. Results: Overall 18 cases, hematologic response of 14 cases was complete white blood cells (WBCs) decrease to normal range within 4 months) with P value of less than 0.0001 whereas in 4 cases WBCs were decreased slowly (after 8 months). A major cytogenetic response was noticed in 4 cases while in others the response was partially or in minor range. The major hematologic and cytogenetic response was noticed when using 600mg/day of Imatinib mesylate. The correlation appeared as a significant positive correlation between the treatment doses and Hb, hematocrit, MCV, MCH, esinophils%, and monocytes %. And a significant negative correlation between the treatment doses and RDW %, platelets count, WBCs count, and basophils %. On the other hand, no correlation between the treatment doses and RBCs Count, MCHC, Neutrophil % and BCR/APL ratio % Conclusion: It can be concluded that treatment of CML patients with Imatinib mesylate caused complete WBCs decrease to normal range. The major hematologic and cytogenetic response was noticed when using a higher dose of Imatinib mesylate.

Immunomodulatory Activity of Tyrosine Kinase Inhibitors to Elicit Cytotoxicity Against Cancer and Viral Infection.

Tyrosine kinase inhibitors (TKIs) of aberrant tyrosine kinase (TK) activity have been widely used to treat chronic myeloid leukemia (CML) for decades in clinic. An area of growing interest is the reported ability of TKIs to induce immunomodulatory effects with anti-tumor and anti-viral activity, which appears to be mediated by directly or indirectly acting on immune cells. In selected cases of patients with CML, TKI treatment may be interrupted and a non-drug remission may be observed. In these patients, an immune mechanism of increased anti-tumor cytotoxic activity induced by chronic administration of TKIs has been suggested. TKIs increase some populations of natural killer (NK), NK-LGL, and T-LGLs cells especially in dasatinib treated CML patients infected with cytomegalovirus (CMV). In addition, dasatinib increases responses against CMV and is able to inhibit HIV replication in vitro. Recent studies suggest that subclinical reactivation of CMV could drive expansion of specific subsets of NK- and T-cells with both anti-tumoral and anti-viral function. Therefore, the underlying mechanisms implicated in the expansion of this increased anti-tumor and anti-viral cytotoxic activity induced by TKIs could be a new therapeutic approach to take into account against cancer and viral infections such as HIV-1 infection. The present review will briefly summarize the immunomodulatory effects of TKIs on T cells, NKs, and B cells. Therapeutic implications for modulating immunity against cancer and viral infections and critical open questions are also discussed.

Clinical characteristics and prognostic significance of chronic myeloid leukemia with rare BCR-ABL1 transcripts

The prognostic significance of rare BCR-ABL1 transcripts is uncertain in the tyrosine kinase inhibitor (TKI) era. In this retrospective study, 40 (1.7%) patients with rare BCR-ABL1 transcripts were identified from a cohort of 2331 chronic myeloid leukemia (CML) patients; 4 types of rare transcripts were identified, including e1a2 (0.9%), e19a2 (0.4%), e13a3 (0.1%), and e14a3 (0.3%). Compared to patients with the typical transcript, those with the e1a2 transcript had an inferior response to TKIs and a worse outcome. Patients with the e19a2 transcript had a high rate of early optimal response to TKIs, but most of them later lost the complete cytogenetic response (CCyR) due to BCR-ABL1 mutations, resulting in a poor prognosis. Patients with the e13a3/e14a3 transcript responded well to TKIs and had a good outcome. These findings indicate that the type of BCR-ABL1 transcript should be considered when determining the treatment for CML patients in the TKI era.

SIRT1 regulates metabolism and leukemogenic potential in CML stem cells.

Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the BCR-ABL kinase. Despite the success of BCR-ABL tyrosine kinase inhibitors (TKIs) in treating CML patients, leukemia stem cells (LSCs) resist elimination and persist as a major barrier to cure. Previous studies suggest that overexpression of the sirtuin 1 (SIRT1) deacetylase may contribute to LSC maintenance in CML. Here, by genetically deleting SIRT1 in transgenic CML mice, we definitively demonstrated an important role for SIRT1 in leukemia development. We identified a previously unrecognized role for SIRT1 in mediating increased mitochondrial oxidative phosphorylation in CML LSCs. We showed that mitochondrial alterations were kinase independent and that TKI treatment enhanced inhibition of CML hematopoiesis in SIRT1-deleted mice. We further showed that the SIRT1 substrate PGC-1α contributed to increased oxidative phosphorylation and TKI resistance in CML LSCs. These results reveal an important role for SIRT1 and downstream signaling mechanisms in altered mitochondrial respiration in CML LSCs.

PS1187 ASSOCIATION OF CELLULAR IMMUNITY WITH MOLECULAR RESPONSE IN CHRONIC MYELOID LEUKEMIA PATIENTS ON TYROSINE KINASE INHIBITORS THERAPY

Background:Chronic myeloid leukemia (CML) is considered to be one of the cancers most sensitive to immunological manipulation. The most recent goal in CML treatment tyrosine kinase inhibitors (TKIs) is to induce a durable deep molecular response (DMR; BCR‐ABL1 ≤ 0.01%) as a prelude to successful treatment‐free remission. The lack of overt relapse in such pts has been attributed to immunological control of CML, although its precise mechanisms are as yet unclear.Aims:The aim of the study was to assess the relative (%) and absolute counts (AC) of major lymphocytic populations in correlation with the molecular response in a large series of patients with CML on TKI therapy.Methods:A total of 171 consecutive patients with CML treated with TKIs were enrolled in the study ‐ 91 men and 80 women. Immunophenotypic analysis of major T/B/NK cell populations was performed by flow cytometry at diagnosis and in the course of the disease in parallel with the monitoring of the molecular response (MR) by quantitative PCR analysis using GeneXpert fully automated platform (n = 523 tests).Results:At diagnosis, significant lymphocytosis was detected in all CML pts (mean 8.7 ± 4.4 x109/l), due to higher % and AC of T‐cells (mean 79.4% ± 11.6%; 7.1 ± 4.2 x109/l) with normal CD4:CD8 ratio (Th:Tc). The AC of NK and CD19+ B‐cells were within or close to the reference ranges. After therapy was given, all lymphocytic populations demonstrated a decrease of AC. However, significant differences in major lymphocytic populations were observed between pts with hematological response to TKIs who had never achieved MR compared to those with DMR in terms of higher mean values of WBC counts (p = 0.009); % and AC of CD3+ T‐cells (mean 68.4% ± 11.9% vs 67.3% ± 11.7%; mean 1.6 ± 8.3x109/l vs 1.4 ± 5.5 x109/l, p = 0.000); % and AC of CD8+ T‐cells (mean 24.8% ± 8.0% vs 22.1% ± 7.3%; mean 0.6 ± 0.4x109/l vs 0.4 ± 0.2x109/l, p = 0.000) resulting in lower Th:Tc. Further, within the group of MR4.5log/MR5log, pts with undetectable BCR‐ABL1 transcripts demonstrated lower % of CD8+ T‐cells compared to BCR‐ABL1 positive cases (mean 20.9% ± 6.7% vs 23.2 ± 7.4%, p = 0.011). Pts with optimal MR according to ELN criteria were characterized with lower % of CD8+ (mean 22.4% ± 7.2% vs 26.1 ± 9.2%, p = 0.000) and CD3+ (mean 72.1% ± 12.6% vs 76.4% ± 11.5%, p = 0.001) T‐cells; higher % of CD19+ B‐cells (mean 11.8 ± 6.1% vs 8.8 ± 4.8%, p = 0.000) and Th:Tc ratio (p = 0.006).Summary/Conclusion:Our data demonstrated dynamics in lymphocyte counts with treatment of CML patients as well as the differences in the lymphocytic populations, and clearly in the cytotoxic cells, depending on the depth of the therapeutic response achieved, thus supporting the idea that, in addition to the specific inhibition of the hybrid BCR‐ABL oncoprotein by TKIs in CML pts, the cellular immunity may further play role in disease control.

Detecting the stable point of therapeutic effect of chronic myeloid leukemia based on dynamic network biomarkers

BackgroundMost researches of chronic myeloid leukemia (CML) are currently focused on the treatment methods, while there are relatively few researches on the progress of patients’ condition after drug treatment. Traditional biomarkers of disease can only distinguish normal state from disease state, and cannot recognize the pre-stable state after drug treatment.ResultsA therapeutic effect recognition strategy based on dynamic network biomarkers (DNB) is provided for CML patients’ gene expression data. With the DNB criteria, the DNB with 250 genes is selected and the therapeutic effect index (TEI) is constructed for the detection of individual disease. The pre-stable state before the disease condition becomes stable is 1 month. Through functional analysis for the DNB, some genes are confirmed as key genes to affect the progress of CML patients’ condition.ConclusionsThe results provide a certain theoretical direction and theoretical basis for medical personnel in the treatment of CML patients, and find new therapeutic targets in the future. The biomarkers of CML can help patients to be treated promptly and minimize drug resistance, treatment failure and relapse, which reduce the mortality of CML significantly.

Use of a Popular‐press Non‐fiction Book to Improve Student Learning and Vocational Outcomes in a Biochemical Techniques Course

Students in our Biochemistry program are required to take a Biochemical Techniques course, which utilizes a semester‐long project focused on the molecular basis of Chronic Myeloid Leukemia (CML). Students learn about and perform a range of techniques in order to over‐express and purify the Abl kinase, a key player in the development of CML. They subsequently use their Abl protein to assay the effectiveness of a variety of kinase inhibitors used clinically for treating CML patients. Students enjoy the real‐world connections of the course but struggle to connect the details of the work they complete in class with both the scientific discoveries that led to the development of these drugs, as well as how this story is relevant to their own development as scientists. For the past two years, the course has incorporated the book, “The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment”. The book, written by science journalist J. Wapner, blends patient stories, interviews with scientists, and summaries of major scientific discoveries to tell the story of the first highly effective treatment for CML patients. Students find the story compelling, and specific assignments help them connect the scientists and experiments described in the book to their own laboratory work. Substantial improvements in the quality of the introductions written for the final research paper (in the style of a primary literature journal article) have also been scaffolded off the readings from the book. Ethics discussions have been richer, as students have real‐world situations to analyze; discussions of major scientific discoveries of the past 60 years have been easily embedded into various assignments in ways that allowed students to connect them to their current studies. The course also includes a core curriculum iteration focused on Vocation, intended to help students “identify their calling(s) and to connect to needs in the world for the purpose of being fully engaged with life”. Embedding this reading into the curriculum has provided new opportunities for student to connect more deeply with science as a vocational path. Overall, utilizing “The Philadelphia Chromosome” as part of a Biochemical Techniques course has led to improved student outcomes in content acquisition, vocational discernment, and student understanding of both scientific ethics and science history.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

BCR-ABL Kinase Domain Mutations Exist in Few Imatinib Treated Chronic Myeloid Leukemia (CML) Patients Exhibiting Stable Cytogenetic and Hematologic Responses

Introduction: Complete hematologic response (CHR) and complete cytogenetic response (CCyR) is observed in almost 80-90% freshly diagnosed chronic phase chronic myeloid leukemia patients treated with Imatinib, a tyrosine kinase inhibitor (TKI). The responses are usually persistent; however the residual disease may be detected molecularly by amplifying BCR-ABL transcript. Furthermore, the leukemogenic potential of the residual BCR-ABL positive cells is reflected when disease reoccurs after discontinuation of therapy. There are evidences of occurrence of mutations in patients who have achieved CCyR, which indicates their role in disease persistence and drug resistance.Patients and Methods: We performed BCR-ABL kinase domain (KD) mutation screening in 150 Imatinib treated CML patients (either resistant or sensitive to therapy) including 84 (56%) individuals manifesting CHR and and 67 (44.7%) with CCyR. For this purpose, nested reverse transcription PCR followed by direct sequence analysis was implemented as previously described. Statistical analysis was performed using SPSS version 19 (IBM, Chicago, IL, USA).Results and Conclusion: Thirty five of 150 patients exhibited mutations in BCR-ABL KD, out of which 11 (31.4%) had achieved CHR and 08 (22.9%) attained CCyR. Single rather than multiple mutated sites in ABL-KD was observed in most of mutant patients achieving CHR (27.3%) or CCyR (27.3%) (Figure 1). Eleven nucleotide substitutions were observed in more than one patient, including Imatinib sensitive individuals with CHR and CCyR (Table 1). Those include C-Helix, SH2 contact, Imatinib binding site (IBS), and A-loop mutations within ABL kinase domain. Overall survival among chronic myeloid leukemia patients achieving different levels of hematologic and cytogenetic response irrespective of mutation status show a favorable survival outcome in those attaining CHR and CCyR (Figure 2). Presence of mutations in cytogenetically stable patients of CML with good hematologic outcomes indicates a likely suboptimal response or TKI resistance during the course of treatment. It is believed by some researchers that mutations do not exist previously, but emerge after Imatinib exposure. Whereas, some believe that TKI's do not induce mutations, rather they select them. Many studies reported a rise in BCR-ABL transcript levels during follow up studies in patients who co-exhibited mutated ABL-KD and CCyR. This suggests that emergence of mutations is a disease evolution process independent of TKI therapy. Studies report that monitoring of nucleotide substitutions in optimally responding patients plays an important role in well managed therapeutic approach. Our studies reveal occurrence of ABL-KD mutations in patints with stable hematologic and cytogenetic response, therefore we suggest for regular mutation screening in CML paients irrespective of their response towards TKIs. DisclosuresNo relevant conflicts of interest to declare.

Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence.

Bosutinib in chronic myeloid leukemia: patient selection and perspectives

During recent years, the therapeutic landscape in chronic myeloid leukemia (CML) has changed significantly. Since the clinical introduction of tyrosine kinase inhibitors (TKIs) approximately 15 years ago, patients’ concerns have shifted from reduced life expectancy toward long-term toxicities of TKI, depth of remission, and the probability of successful treatment discontinuation. Patients with newly diagnosed CML in chronic phase (at least with a Sokal score not exceeding intermediate) may now expect an almost normal life expectancy. However, even if almost 30% of all newly diagnosed chronic-phase patients might eventually be facing the prospect of a life without CML-specific treatment, based on current knowledge, most, if not all, patients would have to undergo an expected minimum of 5–8 years of TKI treatment and the majority would face a life-long exposure to the side-effects of TKIs. At present, 5 different TKIs are licensed for the treatment of CML, that is, imatinib, which is a first-generation TKI (including its generic derivatives); nilotinib, dasatinib, and bosutinib, which are second-generation TKIs; as well as ponatinib, which is a so-called third-generation TKI and is supposed to be used for patients harboring the T315I-mutation. One of the important, yet unanswered questions is the choice of the best possible TKI upfront for each individual patient. Bosutinib is currently licensed for patients with CML after failure or intolerance of at least 2 other TKIs. It can also be prescribed according to label if after failure of the first TKI therapy, another option does not seem feasible. This review focuses on the existing data on clinical efficacy, tolerability, and side effects of bosutinib treatment in CML patients with the aim to identify patient characteristics and treatment scenarios most suitable for treatment with bosutinib.

Simultaneously occurred pleural and pericardial effusion related to dasatinib treatment: A case report

Dasatinib is a proven potent tyrosine kinase inhibitor which is used in the newly diagnosed Philadelphia Chromosome (Ph1) positive chronic myeloid leukemia (CML) treatment when there is no hematological and/or cytogenetic response to imatinib treatment. Pleural and pericardial effusions due to dasatinib therapy may be seen 5 to 30 weeks after the onset of the treatment, but may also develop at any time interval. Pleural effusions are frequently bilateral and exudative, and lymphocyte cell dominance is often observed . It has been observed that when dasatinib treatment is stopped, the side effects which occurred with the treatment are greatly regressed. In this article, we present a case with New York Heart Association (NYHA) functional class III dyspnea under the treatment of dasatinib and developed simultaneous pleural and pericardial effusion, which is rare in the literature. Our aim of presenting this case is to emphasize once again the rarity of simultaneous pleural and pericardial effusion development in dasatinib therapy, and the importance of intermittent cardiopulmonary evaluation before and during the treatment of CML patients.

Patients' and hematologists' concerns regarding tyrosine kinase-inhibitor therapy in chronic myeloid leukemia.

To explore patients' and hematologists' concerns regarding tyrosine kinaseinhibitor (TKI)-therapy and identify variables associated these concerns. Methods A cross-sectional questionnaire including 16 common issues related to TKI-therapy was distributed to adults with chronic myeloid leukemia (CML) receiving TKIs and hematologists treating CML patients and answered anonymously. Data from 1518 patient respondents receiving TKI-therapy ≥ 3months were analyzed. 939 (62%) were male. Median age was 42years. 72% were receiving imatinib. Median TKI-therapy duration was 27months. Data from 259 hematologist respondents were analyzable. 154 (59%) treated > 5 persons with CML per month. Median number of concerns was 5 (range 0-16) for both patients and hematologists. The top five issues for both cohorts were new drug development, stopping TKI-therapy, TKI-reimbursement policies, TKI-related adverse effects and long-term efficacy of TKIs. 12 issues attracted proportionally discordant attention between patients and hematologists. Patients were more concerned with TKI-reimbursement policies, price reduction of TKIs, TKI-related adverse effects, restrictions to daily life, CML knowledge and interpretation of laboratory data, whereas hematologists were more concerned with stopping TKI-therapy, TKI choice, monitoring, TKI dose-adjustment, quality of generics and switching between branded and generic TKIs. In multivariate analyses female sex [OR = 1.4 (1.1-1.7); p = 0.008], education level ≥ bachelor e[OR = 1.8 (1.4-2.2); p < 0.001], TKI-therapy duration 36-<60months [OR = 1.4 (1.0-1.9); p = 0.049] and having adverse impact on daily life and work [OR = 1.5 (1.2-1.8]; p = 0.001] were associated with greater numbers of patients' concerns. Our data suggested hematologists need to be aware of CML patients' concerns to improve their quality-of-life and patient-hematologist communication.

Anthelmintic niclosamide suppresses transcription of BCR-ABL fusion oncogene via disabling Sp1 and induces apoptosis in imatinib-resistant CML cells harboring T315I mutant

Tyrosine kinase BCR-ABL fusion protein is the driver in patients with chronic myeloid leukemia (CML). The gate-keeper mutation T315I is the most challenging mutant due to its resistance to most tyrosine kinase inhibitors (TKIs). The third generation TKI ponatinib is the only effective TKI to treat CML patients harboring T315I-BCR-ABL mutation, but with high rate of major arterial thrombotic events. Alternative strategies to specifically target T315I-BCR-ABL are needed for the treatment of CML patients harboring such a mutation. Given that Sp1 is a fundamental transcriptional factor to positively regulate WT-BCR-ABL fusion oncogene, the purpose of this investigation was aimed at evaluating the anti-tumor activity and the underlying mechanism in terms of Sp1 regulational effect on the transcription of T315I-BCR-ABL fusion oncogene. Like in WT-BCR-ABL, we identified enrichment of Sp1 on the promoter of T315I-BCR-ABL fusion gene. Treatment of WT- and T315I-BCR-ABL-expressing CML cells by niclosamide diminished such an enrichment of Sp1, and decreased WT- and T315I-BCR-ABL transcription and its downstream signaling molecules such as STAT5 and Akt. Further, niclosamide significantly inhibited the proliferation and induced apoptosis through intrinsic pathway. The in vivo efficacy validation of p-niclosamide, a water soluble derivative of niclosamide, showed that p-niclosamide significantly inhibited the tumor burden of nude mice subcutaneously bearing T315I-BCR-ABL-expressing CML cells, and prolonged the survival of allografted leukemic mice harboring BaF3-T315I-BCR-ABL. We conclude that niclosamide is active against T315I-BCR-ABL-expressing cells, and may be a promising agent for CML patients regardless of T315I mutation status.