Hits 1 - 10 (out of 6606 matching entities) [13026 mentions] (36 ms):
1. chronic myeloid leukemias

10653 articles, score 3878.900

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  • With the global rise in chronic health conditions, health care is transforming, and patient empowerment is being emphasized to improve treatment outcomes and reduce health care costs. Patient-centered innovations are needed. We focused on patients with chronic myeloid leukemia (CML), a chronic disease with a generally good long-term prognosis because of the advent of tyrosine kinase inhibitors. However, both medication adherence by patients and guideline adherence by physicians are suboptimal, unnecessarily jeopardizing treatment outcomes. The aim of this study was to develop a patient-centered innovation for patients with CML using a design thinking methodology. The 5 phases of design thinking (ie, empathize, define, ideate, prototype, and test) were completed, and each phase started with the patient. Stakeholders and end users were identified and interviewed, and observations in the care system were made. Using tools in human-centered design, problems were defined and various prototypes of solutions were generated. These were evaluated by patients and stakeholders and then further refined. The patients desired (1) insights into their own disease; (2) insights into the symptoms experienced, both in terms of knowledge and comprehension; and (3) improvements in the organization of care delivery. A web-based platform, CMyLife, was developed and pilot-tested. It has multiple features, all targeting parts of the bigger solution, including a website with reliable information and a forum, a guideline app, personal medical records with logs of symptoms and laboratory results (including a molecular marker and linked to the guideline app), tailored feedback based on the patients' symptoms and/or results, screen-to-screen consulting, delivery of medication, and the collection of blood samples at home. The multifeatured innovation, CMyLife, was developed in a multidisciplinary way and with active patient participation. The aim of developing CMyLife was to give patients the tools to monitor their results, interpret these results, and act on them. With this tool, they are provided with the know-how to consider their results in relation to their personal care process. Whether CMyLife achieves its goal and the evaluation of the added value will be the focus of future studies. CML could become the first malignancy for which patients are able to monitor and manage their disease by themselves.
    The Development of a Web-Based, Patient-Centered Intervention for Patients With Chronic Myeloid Leukemia (CMyLife): Design Thinking Development Approach.
    Journal of medical Internet research, May 2020 [PubMed 32412424]
  • Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.
    The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia.
    Leukemia, Aug 2020 [PubMed 32601376]
  • Priapism as a sign of a severe hematological disease is a rare event, which has to be considered as both a urological and a hematological emergency that requires immediate treatment. This article describes a clinical case of priapism as the first clinical manifestation of a hitherto undiagnosed chronic myeloid leukemia (CML) and discusses the results of a literature review on this topic.
    [When a urological emergency indicates an internal medical crisis : Priapism as the first clinical manifestation of leukemia].
    Der Urologe. Ausg. A, Sep 2020 [PubMed 32936336]

2. acute myeloid leukemias

3042 articles, score 1011.222

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  • Germ line predisposition to myeloid neoplasms has been incorporated in the WHO 2016 classification of myeloid neoplasms and acute leukemia. The new category of disease is named hereditary myeloid disorder (HMD). Although most myeloid neoplasms are sporadic, germ line mutations and familial predisposition can contribute to development of chronic myeloid diseases and acute myeloid leukemia. This finding and upcoming frequent use of genome wide detection of molecular aberrations will lead to a higher detection rate of a genetic predisposition and influence treatment decisions. Hereditary predisposition is responsible for 5-10% of myeloid malignancies. Management of affected patients begins by the awareness of treating physicians of the problem and a precise work up of the patient and family members. Areas covered: This review focuses on current knowledge about germ line predisposition for myeloid neoplasms including diagnostic, prognostic, and therapeutic aspects in adult patients. Essential information for clinical routine is provided. Expert commentary: Compared to a patient without predisposition, adaptation of treatment strategy for patients with an HMD is often necessary, especially to avoid higher risk of relapse or higher toxicity during chemotherapy or transplantation. Mistakes in choice of a related donor can be omitted. Relatives at risk of developing a HMD need specific surveillance.
    Germ line predisposition to myeloid malignancies appearing in adulthood.
    Expert review of hematology, Aug 2018 [PubMed 29958021]
  • Since the discovery of spliceosome mutations in myeloid malignancies, abnormal pre-mRNA splicing, which has been well studied in various cancers, has attracted novel interest in hematology. However, despite the common occurrence of spliceosome mutations in myelo-proliferative neoplasms (MPN), not much is known regarding the characterization and mechanisms of splicing anomalies in MPN. In this article, we review the current scientific literature regarding "splicing and myeloproliferative neoplasms". We first analyse the clinical series reporting spliceosome mutations in MPN and their clinical correlates. We then present the current knowledge about molecular mechanisms by which these mutations participate in the pathogenesis of MPN or other myeloid malignancies. Beside spliceosome mutations, splicing anomalies have been described in myeloproliferative neoplasms, as well as in acute myeloid leukemias, a dreadful complication of these chronic diseases. Based on splicing anomalies reported in chronic myelogenous leukemia as well as in acute leukemia, and the mechanisms presiding splicing deregulation, we propose that abnormal splicing plays a major role in the evolution of myeloproliferative neoplasms and may be the target of specific therapeutic strategies.
    Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues.
    Cancers, Aug 2020 [PubMed 32784800]
  • We sought to study whether survival after haplo-identical transplantation is comparable to that after matched unrelated donor transplantation for 822 patients aged 50-75 years with acute myeloid leukemia in first or second complete remission. One hundred and ninety-two patients received grafts from haplo-identical donors (sibling 25%; offspring 75%) and 631 patients from matched unrelated donors aged 18-40 years. Patient and disease characteristics of the two groups were similar except recipients of matched unrelated donor transplantation were more likely to have poor risk cytogenetics and more likely to receive myeloablative conditioning regimens. Time from documented remission to transplant did not differ by donor type. Five-year overall survival was 32% and 42% after haplo-identical and matched unrelated donor transplant, respectively (p-value=0.1). Multivariable analysis showed higher mortality (hazard ratio 1.27, p-value=0.04) and relapse (hazard ratio 1.32, p-value=0.04) after haplo-identical transplantation, with similar non-relapse mortality risks. Chronic graft-versus-host disease was higher after matched unrelated donor compared to haplo-identical transplantation when bone marrow was the graft (hazard ratio 3.12, p-value<0.001), but when the graft was peripheral blood the risk of chronic graft-versus-host disease did not differ by donor type. These data support matched unrelated donor transplant with donors younger than 40 years is preferred.
    Alternative donor transplantation for acute myeloid leukemia in patients aged ≥50 years: young HLA-matched unrelated or haploidentical Donor?
    Haematologica, May 2019 [PubMed 31101756]

3. imatinib

3523 articles, score 979.437

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Abstracts

  • Tyrosine kinase inhibitors have revolutionized the world of cancer treatment in recent years, profoundly improving survival of patients with chronic myeloid leukemia (CML) and beyond. However, off-target toxicities of these inhibitors are well-described, and resistance has become a paramount concern. Novel allosteric inhibitors of the Abelson (ABL) family of tyrosine kinases, including GNF-2, GNF-5, and ABL-001, are equipped to overcome these issues. Several contemporary studies have demonstrated their potential efficacy in three key areas: primary hematologic and solid malignancies, metastasis, and combination with other small molecules. Further, ongoing clinical trials are investigating the efficacy of ABL-001 for the treatment of CML and recurrent solid tumors. This work reviews the current literature of the preclinical testing of GNF-2 and GNF-5 and the preclinical and clinical testing of ABL-001. Future research will continue to evaluate these promising inhibitors as both first-line therapy for solid tumors and salvage therapy when more traditional drugs such as imatinib fail.
    Allosteric Inhibition of ABL Kinases: Therapeutic Potential in Cancer.
    Molecular cancer therapeutics, Sep 2020 [PubMed 32606014]
  • Blast crisis is one of the remaining challenges in chronic myeloid leukemia (CML). Whether additional chromosomal abnormalities (ACAs) enable an earlier recognition of imminent blastic proliferation and a timelier change of treatment is unknown. One thousand five hundred and ten imatinib-treated patients with Philadelphia-chromosome-positive (Ph+) CML randomized in CML-study IV were analyzed for ACA/Ph+ and blast increase. By impact on survival, ACAs were grouped into high risk (+8, +Ph, i(17q), +17, +19, +21, 3q26.2, 11q23, -7/7q abnormalities; complex) and low risk (all other). The presence of high- and low-risk ACAs was linked to six cohorts with different blast levels (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox model. One hundred and twenty-three patients displayed ACA/Ph+ (8.1%), 91 were high risk. At low blast levels (1-15%), high-risk ACA showed an increased hazard to die compared to no ACA (ratios: 3.65 in blood; 6.12 in marrow) in contrast to low-risk ACA. No effect was observed at blast levels of 20-30%. Sixty-three patients with high-risk ACA (69%) died (n = 37) or were alive after progression or progression-related transplantation (n = 26). High-risk ACA at low blast counts identify end-phase CML earlier than current diagnostic systems. Mortality was lower with earlier treatment. Cytogenetic monitoring is indicated when signs of progression surface or response to therapy is unsatisfactory.
    High-risk additional chromosomal abnormalities at low blast counts herald death by CML.
    Leukemia, Aug 2020 [PubMed 32382082]
  • One of the key challenges in current cancer research is the development of computational strategies to support clinicians in the identification of successful personalized treatments. Control theory might be an effective approach to this end, as proven by the long-established application to therapy design and testing. In this respect, we here introduce the Control Theory for Therapy Design (CT4TD) framework, which employs optimal control theory on patient-specific pharmacokinetics (PK) and pharmacodynamics (PD) models, to deliver optimized therapeutic strategies. The definition of personalized PK/PD models allows to explicitly consider the physiological heterogeneity of individuals and to adapt the therapy accordingly, as opposed to standard clinical practices. CT4TD can be used in two distinct scenarios. At the time of the diagnosis, CT4TD allows to set optimized personalized administration strategies, aimed at reaching selected target drug concentrations, while minimizing the costs in terms of toxicity and adverse effects. Moreover, if longitudinal data on patients under treatment are available, our approach allows to adjust the ongoing therapy, by relying on simplified models of cancer population dynamics, with the goal of minimizing or controlling the tumor burden. CT4TD is highly scalable, as it employs the efficient dCRAB/RedCRAB optimization algorithm, and the results are robust, as proven by extensive tests on synthetic data. Furthermore, the theoretical framework is general, and it might be applied to any therapy for which a PK/PD model can be estimated, and for any kind of administration and cost. As a proof of principle, we present the application of CT4TD to Imatinib administration in Chronic Myeloid leukemia, in which we adopt a simplified model of cancer population dynamics. In particular, we show that the optimized therapeutic strategies are diversified among patients, and display improvements with respect to the current standard regime.
    An Optimal Control Framework for the Automated Design of Personalized Cancer Treatments.
    Frontiers in bioengineering and biotechnology, 2020 [PubMed 32548108]

4. leukemias

2946 articles, score 881.869

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  • The use of myeloablative conditioning (MAC) in umbilical cord blood transplantation (UCBT) has been associated with high nonrelapse mortality (NRM) in patients aged >40 years, especially those having a high HLA disparity, thus limiting wider applications. We hypothesized that the NRM advantage of reduced-intensity conditioning (RIC) and higher graft-versus-leukemia effect associated with greater HLA disparities would expand its use for patients (aged 40 to 60 years) without compromising efficacy and compared outcomes between RIC and MAC regimens. In total, 288 patients aged 40 to 60 years, with de novo acute myeloid leukemia, receiving UCBT with at least 2 HLA mismatches with RIC (n = 166) or MAC (n = 122) regimens were included. As compared to RIC, the MAC cohort included relatively younger patients, having received more single UCBT, with lower total nucleated cell counts and more in vivo T cell depletion. Median time to neutrophil engraftment, infections (bacterial, viral, and fungal), and grade II to IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (hazard ratio [HR], 0.98; P = .9), NRM (HR, 0.68; P = .2), and relapse (HR, 1.24; P = .5) were not different between RIC and MAC. Refractory disease was associated with worse survival. Outcomes of UBCT for patients aged 40 to 60 years having ≥2 HLA mismatches are comparable after the RIC or MAC regimen.
    Reduced-Intensity versus Myeloablative Conditioning in Cord Blood Transplantation for Acute Myeloid Leukemia (40-60 years) across Highly Mismatched HLA Barriers-On Behalf of Eurocord and the Cellular Therapy & Immunobiology Working Party (CTIWP) of EBMT.
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jul 2020 [PubMed 32726672]
  • The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II-IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P < 0.001) and late (HR = 4.9, P < 0.001) mortality after UCBT. The occurrence of grade II-IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD.
    Occurrence of graft-versus-host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT.
    Journal of internal medicine, Feb 2018 [PubMed 28977716]
  • Priapism is a rare urological emergency. It is rarely a telltale sign of myeloid leukemia. We report two cases of acute myeloid leukemia in a child and chronic myeloid leukemia in a young adult presenting with priapism. Puncture irrigation of the corpora cavernosa followed by systemic treatment to lower the hyperviscosity of the blood due to leukemia provided optimal outcome. Prompt emergency management is required to lower the complication of erectile dysfunction.
    Unusual Presentation of Priapism Associated with Acute and Chronic Myeloid Leukemia in Two Patients: Emergency Management.
    Case reports in urology, 2020 [PubMed 32855834]

5. BCR

2392 articles, score 497.213

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Abstracts

  • The management of chronic myeloid leukemia with BCR-ABL1 tyrosine kinase inhibitors has evolved chronic myeloid leukemia into a chronic, manageable disease. A patient-centered approach is important for the appropriate management of chronic myeloid leukemia and optimization of long-term treatment outcomes. The pharmacist plays a key role in treatment selection, monitoring drug-drug interactions, identification and management of adverse events, and educating patients on adherence. The combination of tyrosine kinase inhibitors with unique safety profiles and individual patients with unique medical histories can make managing treatment difficult. This review will provide up-to-date information regarding tyrosine kinase inhibitor-based treatment of patients with chronic myeloid leukemia. Management strategies for adverse events and considerations for drug-drug interactions will not only vary among patients but also across tyrosine kinase inhibitors. Drug-drug interactions can be mild to severe. In instances where co-administration of concomitant medications cannot be avoided, it is critical to understand how drug levels are impacted and how subsequent dose modifications ensure therapeutic drug levels are maintained. An important component of patient-centered management of chronic myeloid leukemia also includes educating patients on the significance of early and regular monitoring of therapeutic milestones, emphasizing the importance of adhering to treatment in achieving these targets, and appropriately modifying treatment if these clinical goals are not being met. Overall, staying apprised of current research, utilizing the close pharmacist-patient relationship, and having regular interactions with patients, will help achieve successful long-term treatment of chronic myeloid leukemia in the age of BCR-ABL1 tyrosine kinase inhibitors.
    BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia.
    Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, Sep 2018 [PubMed 28580869]
  • Nonadherence is common in patients with chronic myeloid leukemia (CML) and leads to treatment failure and poor outcomes. Side effects due to treatment are also common in patients with CML. However, no study has investigated the link between side effects and medication adherence for patients with CML in Taiwan. Therefore, the aim of our study was to explore the influence of side effects on medication adherence in Taiwanese patients with CML.CML in chronic-phase patients treated with breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 tyrosine kinase inhibitors were recruited. We designed a questionnaire to collect baseline patient information, medication adherence (measured using the 8-item Morisky Medication Adherence Scale), and side effects. Clinical outcomes were assessed by the 3-month early molecular response rate and the 12-month major molecular response rate. Statistical comparisons of different parameters between adherent and nonadherent groups were conducted.Fifty-eight patients were enrolled in this study, and 31% of them had poor adherence. The lack of information about treatment and medication was the major reason for poor medication adherence. Patients who were younger and unmarried were prone to poor adherence. The occurrence of side effects carried no statistically significant influence on adherence. Poor adherence resulted in a poor treatment response (lower 3-month early molecular response rate and lower 12-month major molecular response rate).Poor adherence is common in Taiwanese patients with CML. The main reason for a decrease in the adherence rate is the lack of comprehensive information about treatment and medication, particularly in young and single population. The next urgent step is to educate patients about their treatment and management of side effects to improve adherence and treatment outcome for patients with CML in Taiwan.
    Side effects and medication adherence of tyrosine kinase inhibitors for patients with chronic myeloid leukemia in Taiwan.
    Medicine, Jun 2018 [PubMed 29953021]
  • Russia took part in the multicenter population-based study (Europe) and included 6.8% adult patients with newly diagnosed chronic myeloid leukemia (CML). The objective of this study was to analyze the mortality in the Russian cohort of patients with newly diagnosed CML in the EUTOS PBS observational study. The analyzed cohort consisted of 197 patients (>18 years) with Ph+/BCR-ABL1+ CML diagnosed in the period from October 1, 2009 through December 31, 2012 from 6 regions of Russia. The distribution of the phases of CML were: chronic phase (CP), 93.4% and accelerated phase (AP) + blast crisis (BC), 6% + 0.6%. The median age was 50 years (range, 18-82 years); the male/female ratio was equal. The overall survival (OS) at 5, 6, and 7 years was 80% (95% confidence interval [CI], 72%-86%), 78% (95% CI, 65%-80%), and 73% (95% CI, 65%-80%), respectively (P < .001). The 5-year OS in patients with AP and BC was 39%. In Russia, the study was prolonged, with a median follow-up of 77 months (range, 0.7-108 months): 141 (71.5%) patients were alive, 47 (24%) patients died, and the status of 9 (4.5%) patients is was unknown. Forty-seven (23.8%) patients died during the follow-up period. The largest number of deaths was observed in the first year after the CML diagnosis: 17 (36%) of 47 cases, 3 of 17 died refusing the CML treatment. At the seventh year of CML therapy, 1 patient died after allogenic hematopoietic stem cell transplantation. The causes of death were: (1) progression of CML to AP/BC in 20 (43%) patients; (2) death in remission in 5 (11%) patients with complete cytogenetic response (CCyR) and/or major molecular response; and (3) death without progression to AP/BC but with signs of leukemia in 22 (46%) patients. The 5-year cumulative incidence of death from all reasons was 20%; the cumulative incidence of CML-related and non-CML-related death at the fifth year was 18% and 11%, respectively. In general, the results of treatment in the Russian population sample of non-selected patients with CML were comparable with the data of the total European cohort. The CML-related deaths prevailed in the first year of CML therapy. The appropriate monitoring and therapy interventions during the first year of CML treatment are apparently important for the long-term treatment results.
    Analysis of the Mortality of Russian Patients With Chronic Myeloid Leukemia in the Multicenter EUTOS ELN Population-based Study (EUTOS-PBS).
    Clinical lymphoma, myeloma & leukemia, Jun 2020 [PubMed 32192976]

6. lymphoblastic leukemia

1437 articles, score 371.249

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Abstracts

  • Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
    Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Aug 2020 [PubMed 32434056]
  • Sequential treatment with targeted therapies can result in complex combinations of resistance mutations in drug targets. This mutational complexity has spurred the development of pan-target inhibitors, i.e. therapies for which no single target mutation can cause resistance. Since the propensity for on- versus off-target resistance varies across cancer types, a deeper understanding of the mutational burden in drug targets could rationalize treatment outcomes, and prioritize pan-target inhibitors for indications where on-target mutations are most likely. To measure and model the mutational landscape of a drug target at high resolution, we integrated single-molecule Duplex Sequencing of the ABL1 gene in Philadelphia-positive (Ph+) leukemias with computational simulations. A combination of drug target mutational burden and tumor-initiating cell fraction is sufficient to predict that most patients with chronic myeloid leukemia (CML) are unlikely to harbor ABL1 resistance mutations at the time of diagnosis, rationalizing the exceptional success of targeted therapy in this setting. In contrast, our analysis predicts that many patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL) harbor multiple pre-existing resistant cells with single mutants. The emergence of compound mutations can be traced to initial use of an ABL1 inhibitor that is susceptible to resistance from single point mutations. These results argue that early use of therapies that achieve pan-inhibition of ABL1 resistance mutants might improve outcomes in Ph+ ALL. Our findings show how a deep understanding of the mutational burden in drug targets can be quantitatively coupled to phenotypic heterogeneity to rationalize clinical phenomena.
    Single-molecule sequencing reveals patterns of pre-existing drug resistance that suggest treatment strategies in Philadelphia-positive leukemias.
    Clinical cancer research : an official journal of the American Association for Cancer Research, Jul 2018 [PubMed 30042204]
  • Treatment of relapsed/refractory acute lymphoblastic leukemia (RR-ALL) remains a clinical challenge with generally dismal prognosis. Allogeneic stem-cell transplantation using sequential conditioning ("FLAMSA"-like) has shown promising results in relapsed/refractory acute myeloid leukemia, but little is known about its efficacy in RR-ALL. We identified 115 patients (19-66 years) with relapsed (74%) or primary-refractory (26%) ALL allografted from matched related (31%), matched unrelated (58%), or haploidentical donor (11%). Median follow-up was 37 (13-111) months. At day 100, cumulative incidences of grade II-IV/III-IV acute graft-versus-host-disease (GVHD) were 30% and 17%, respectively. Two-year cumulative incidence of chronic GVHD was 25% with 11% extensive cases. Two-year relapse incidence (RI) was 45%, non-relapse mortality was 41%. Two-year leukemia free survival (LFS) was 14%, overall survival (OS) 17%, and GVHD relapse-free survival (GRFS) was 14%. In multivariable analysis, Karnofsky score <90 negatively affected RI, LFS, OS, and GRFS. Conditioning with chemotherapy alone, compared with total body irradiation (TBI) negatively affected RI (HR = 3.3; p = 0.008), LFS (HR = 1.94; p = 0.03), and OS (HR = 2.0; p = 0.03). These patients still face extremely poor outcomes, highlighting the importance of incorporating novel therapies (e.g., BITE antibodies, inotuzumab, CAR-T cells). Nevertheless, patients with RR-T-cell ALL remain with an unmet treatment need, for which TBI-based sequential conditioning could be one of few available options.
    Allogeneic stem-cell transplantation with sequential conditioning in adult patients with refractory or relapsed acute lymphoblastic leukemia: a report from the EBMT Acute Leukemia Working Party.
    Bone marrow transplantation, Mar 2020 [PubMed 31562398]

7. MTTP

1855 articles, score 333.520

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Enriched GO Terms

Abstracts

  • To analyze the relationship between cytogenetic changes and the progression in the patients with chronic myeloid leukemia (CML) during the treatment with tyrosine kinase inhibitor (TKI). The chromosome G banding of 150 patients with CML treated in our hospital, was carried out to analyze the karyotype by the 24 h short-term culture or direct method of bone marrow cells, and the point mutation of the ABL kinase area was detected, the relationship between cytogenetic changes and the evolution of the disease course was analyzed. The indirect fluorescence in situ hybridization showed that the BCR-ABL fusion gene of 150 patients was positive, out of which 142 cases showed positive Philadelphia (Ph) (94.67%), 8 cases with Ph negative (5.33%). Among 142 cases with Ph positive on the first diagnosis, and 14 cases (9.86%) with additional chromosome abnormality (9.86%), 4 cases (2.82%) with mutation translocation with 124 cases (87.32%), standard translocation t (9; 22) (q34; Q11) were found. Out of the 14 patients with additional chromosomal abnormalities, 8 cases with "main pathmay" abnormalities, 2 case with -Y abnormalities, and 4 cases with "secondary pathway" abnormalities were observed. During TKI treatment, additional chromosomal abnormalities were found in 46 patients with standard translocation and abnormal number of chromosomes, and the incidence of disease progression and point mutation were higher (P<0.05). Compared with patients with the standard translocation, the disease-free survival rate of the patients diagnosed as CML at 1st visit and with additional chromosome abnormality was significantly decreased (P<0.05), but the overall survival rate showed no significantly different (P>0.05). Compared with patients without additional cvtogenetic aberrations, the disease free and overall survival rate of the patients with additional cytogenetic aberrations during the TKI treatment of CML in chronic phase were significantly decreased (P<0.05). Some CML patients may have additional chromosomal abnormalities during the onset and development of the disease, and these patients are at higher risk of disease progression.
    [Analysis of the Relationship between Cytogenetic Changes and Course Evolution of Patients with CML during TKI Treatment].
    Zhongguo shi yan xue ye xue za zhi, Feb 2020 [PubMed 32027266]
  • Imatinib, the breakpoint cluster region protein (BCR)/Abelson murine leukemia viral oncogene homolog (ABL) inhibitor, is widely used to treat chronic myeloid leukemia (CML). However, imatinib resistance develops in many patients. Therefore, new drugs with improved therapeutic effects are urgently needed. Berberine (BBR) is a potent BCR-ABL inhibitor for imatinib-sensitive and -resistant CML. in mice, and in human CML bone marrow cells as a potential strategy to overcome imatinib resistance. We discovered that BBR bound to the protein tyrosine kinase domain of BCR-ABL. BBR inhibited the activity of BCR-ABL and BCR-ABL with the T315I mutation, and it also degraded these proteins via the autophagic lysosome pathway by recruiting E3 ubiquitin-protein ligase LRSAM1. BBR inhibited the cell viability and colony formation of CML cells and prolonged survival in CML mouse models with imatinib sensitivity and resistance. .
    Discovery of Berberine that Targetedly Induces Autophagic Degradation of both BCR-ABL and BCR-ABL T315I through Recruiting LRSAM1 for Overcoming Imatinib Resistance.
    Clinical cancer research : an official journal of the American Association for Cancer Research, Aug 2020 [PubMed 32098768]
  • findings using a functional pre-clinical mouse model of chronic myeloid leukemia (CML), whereby we demonstrated the ability of NOX-A12, combined with the ABL kinase inhibitor, nilotinib, to reduce the leukemia burden in mice to a greater extent than either agent alone. Overall, the data support the idea of using SDF-1 inhibition in combination with targeted kinase inhibition to override drug resistance in oncogene-driven leukemia to significantly diminish or eradicate residual leukemic disease.
    Inhibition of SDF-1-induced migration of oncogene-driven myeloid leukemia by the L-RNA aptamer (Spiegelmer), NOX-A12, and potentiation of tyrosine kinase inhibition.
    Oncotarget, Dec 2017 [PubMed 29299123]

8. myelodysplastic syndromes

1092 articles, score 312.187

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Enriched GO Terms

Abstracts

  • Atypical chronic myeloid leukemia is an esoteric myeloid malignancy with features of both myeloproliferative and myelodysplastic syndromes. This disease is characterized primarily by morphologic-based criteria, and has clinical and molecular features overlapping with other myeloid malignancies. No one molecular abnormality is specific, and multiple mutations are often present in various combinations, due to the malignant multi-step clonal evolution of myeloid malignancies. In this review, we will address what we know about atypical chronic myeloid leukemia; evaluate how the molecular landscape in myeloid malignancies overlaps, and discuss what we can learn by incorporating individualized precision genomic strategies.
    Atypical CML- the role of morphology and precision genomics.
    Best practice & research. Clinical haematology, Jun 2020 [PubMed 32460981]
  • The aim of this study was to evaluate the diagnostic and prognostic role of multiparameter flow cytometry (FC) in patients with idiopathic cytopenia of undetermined significance (ICUS) and clonal cytopenia of undetermined significance (CCUS). We performed FC using a standardized panel and two different diagnostic algorithms (Ogata, Wells) in a well-characterized cohort of 79 patients with ICUS/CCUS and compared it with a retrospective blinded morphological evaluation and data from targeted next-generation DNA sequencing of 20 myelodysplastic syndrome (MDS)-related genes. Our data show that FC has low sensitivity in distinguishing CCUS from ICUS patients (40.5% for Ogata score and 59.5% for Wells score). The Wells score was suggestive of dysplasia in ICUS/CCUS patients with concurrent morphological signs of dysplasia in the bone marrow (following re-evaluation by two hematopathologists) and in CCUS patients with a higher mutational burden. Eight patients with ICUS/CCUS from our cohort progressed to another myeloid malignancy (MDS, acute myeloid leukemia, or chronic myelomonocytic leukemia), all showing flow cytometric signs of dysplasia. FC performs poorly in diagnosing CCUS versus ICUS. However, it can potentially provide prognostic information in cytopenic patients by identifying a subgroup of patients with a higher grade of dysplasia, higher mutational burden, and higher risk of progression and, together with mutational screening, also identify a group of patients who might require morphological reassessment of dysplastic changes in their bone marrow.
    The diagnostic and prognostic role of flow cytometry in idiopathic and clonal cytopenia of undetermined significance (ICUS/CCUS): A single-center analysis of 79 patients.
    Cytometry. Part B, Clinical cytometry, May 2020 [PubMed 31479199]
  • We analyzed clinical cutoffs for defining computed tomography (CT) methods for sarcopenia and examined the prognostic value of CT for allogeneic hematopoietic stem cell transplantation (allo-HCST) outcomes of patients with myeloid malignancy. One hundred twenty-five adult patients with acute myeloid leukemia and myelodysplastic syndrome who underwent first allo-HSCT between 2000 and 2017 were included. Sarcopenia was assessed using CT-based skeletal muscle index (SMI) and mean muscle attenuation at L3. A statistical difference in SMI was confirmed between sarcopenia (n = 52) and nonsarcopenia (n = 73) patients. There were no significant correlations of muscularity with age, performance status, or other characteristics of HSCT. After 2 years, overall survival (OS) was 43.5% and 70.1%, disease-free survival was 52.9% and 68.6%, nonrelapse mortality (NRM) was 20.8% and 8.4%, incidence of acute GVHD (≥ grade 2) was 38.8% and 39.1%, that of chronic GVHD was 53.2% and 37.3%, and median duration of hospitalization was 88 days and 74 days (P = 0.026), respectively, in the sarcopenia and nonsarcopenia groups. Multivariate analysis showed that presence of sarcopenia is a novel adverse factor for high NRM and poor OS. Pretransplant CT-defined sarcopenia is correlated with decreased OS, increased NRM, and prolonged hospitalization.
    Computed tomography-defined sarcopenia: prognostic predictor of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation: a multicenter retrospective study.
    International journal of hematology, Jul 2020 [PubMed 32451786]

9. dasatinib

924 articles, score 288.658

Entity Information

Molecular Interaction Network

Enriched GO Terms

Abstracts

  • The effects of immunotherapy are numerous and are still being discovered. We present a case report of a patient who received dasatinib for chronic myeloid leukemia. A colonoscopy was performed due to a positive fecal occult blood test and colitis was observed. Furthermore, she also had a cytomegalovirus infection. This case highlights the importance to detect cases of immunomodulatory drugs induced colitis by the fecal occult blood test.
    Dasatinib-induced colitis: discovering the side effects of immunotherapy.
    Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva, Aug 2020 [PubMed 32686430]
  • To design, develop, optimize and evaluate sustained-release dasatinib-loaded gold nanoparticles (DSB-GNPs) to treat chronic myeloid leukemia (CML) by using quality by design. In this study, we performed risk assessment, optimization, in vitro characterizations, stability study, drug release studies, cytotoxicity study and in vivo pharmacokinetic evaluation. DSB-GNPs of desired size, entrapment, smooth, spherical, stable and sustained drug release for 48 h were achieved. DSB-GNPs exhibited significantly more percentage growth inhibition and enhanced systemic bioavailability compared with pure DSB. The in vitro and in vivo evaluation exhibited that the DSB-GNPs have a potential cytotoxic effect, systemic bioavailability and sustained release making them a promising system of DSB delivery in the treatment of chronic myeloid leukemia.
    Gold nanoparticles for sustained antileukemia drug release: development, optimization and evaluation by quality-by-design approach.
    Nanomedicine (London, England), Apr 2019 [PubMed 30901283]
  • Dasatinib is currently approved for clinical use as a first-line treatment agent for newly diagnosed chronic myeloid leukemia (CML). However, only a few clinical trials have been performed to evaluate dasatinibinduced PE following first-line therapy. We investigated the incidence and clinical features of dasatinib-induced PE following first-line therapy in Japanese CML patients of real world clinical practice settings. Among 22 patients, the median age of PE-positive patients was higher than that of PE-negative patients. Major molecular response was achieved in 75% of PE-positive patients and 50% of PE-negative patients. Most patients developed PE more than 1 year after treatment. Appearance of PE is associated with better clinical response during dasatinib treatment, however it is developed at any time. Elderly and high-risk patients tend to develop PE. The clinical features of dasatinib-induced PE following first-line therapy might be late onset and might not immediately follow the increasing of large granular lymphocyte.
    chronic myeloid leukemia.
    Hematology reports, Sep 2018 [PubMed 30283618]

10. hematologic malignancies

962 articles, score 284.752

Entity Information

Molecular Interaction Network

Not available

Enriched GO Terms

Not available

Abstracts

  • Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT). We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS). A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434). Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.
    Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Feb 2019 [PubMed 30403573]
  • Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy arising from plasmacytoid dendritic cell precursors. The disease typically manifests in the skin, but it also evolves into a leukemic phase or can be complicated by other myeloid malignancies, especially myelomonocytic tumors. The association between these neoplasms is not fully elucidated. We report a case of BPDCN with a history of cytopenia that was supposed to be chronic myelomonocytic leukemia. The patient received intensive chemotherapy and achieved complete remission, but soon relapsed. The successive occurrence of myelomonocytic neoplasm and BPDCN is in accordance with the fact that they evolve from a common cell origin with a multilineage potential for myelomonocytic and plasmacytoid dendritic cell differentiation. This case may shed further light on the mystery of biology and the histogenesis of BPDCN.
    Blastic plasmacytoid dendritic cell neoplasm with a history of cytopenia: A case report.
    Diagnostic cytopathology, May 2020 [PubMed 32374950]
  • pathways. Several proteins regulate Wnt signaling through a variety of sophisticated mechanisms. Disorders within the pathway can contribute to various human diseases, and the dysregulation of Wnt pathways by different molecular mechanisms is implicated in the pathogenesis of many types of cancer, including the hematological malignancies. The types of leukemia differ considerably and can be subdivided into chronic, myeloid or lymphocytic, and acute, myeloid or lymphocytic, leukemia, according to the differentiation stage of the predominant cells, the progenitor lineage, the diagnostic age strata, and the specific molecular drivers behind their development. Here, we review the role of Wnt signaling in normal hematopoiesis and discuss in detail the multiple ways canonical Wnt signaling can be dysregulated in acute leukemia, including alterations in gene expression and protein levels, epigenetic regulation, and mutations. Furthermore, we highlight the different impacts of these alterations, considering the distinct forms of the disease, and the therapeutic potential of targeting Wnt signaling.
    The multiple ways Wnt signaling contributes to acute leukemia pathogenesis.
    Journal of leukocyte biology, Jun 2020 [PubMed 32573851]


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