scholarly journals Inferring immunological control mechanisms from TKI dose alterations in CML patients

2019 ◽  
Author(s):  
Tom Hähnel ◽  
Christoph Baldow ◽  
Artur C. Fassoni ◽  
Joëlle Guilhot ◽  
François Guilhot ◽  
...  
Keyword(s):  
Immune Response ◽  
Kinase Inhibitors ◽  
Clinical Findings ◽  
Term Treatment ◽  
Control Mechanisms ◽  
Treatment Cessation ◽  
Long Term Treatment ◽  
Time Courses ◽  
The Individual

AbstractRecent clinical findings in chronic myeloid leukemia (CML) patients suggest that the risk of molecular recurrence after stopping tyrosine kinase inhibitors (TKI) treatment substantially depend on an individual, leukemia-specific immune response. However, it is still not possible to prospectively identify patients that will most likely remain in a long-term treatment free remission (TFR). Here, we use a mathematical model for CML, which explicitly includes an anti-leukemic (presumably immunological) effect and apply it to a set of patients (n=60) for whom BCR-ABL/ABL time courses had been quantified before and after TKI stop. We demonstrate that such a feedback control is conceptually necessary to explain long-term remission as observed in about half of the patients. Based on simulation results we classify the patient data sets into three different groups according to their predicted immune system configuration. While one class of patients requires a complete CML eradication to achieve TFR, other patients are able to control the leukemia after treatment cessation. Among them, we identified a third class of patients, which only maintains TFR if an optimal balance between leukemia abundance and immunological activation is achieved before treatment cessation. Further, we demonstrate that the immune response classification of the patients cannot be obtained solely from BCR-ABL measurements before treatment cessation. However, our results strongly suggest that changes in the BCR-ABL dynamics arising after system perturbations, such as TKI dose reduction, holds the information to predict the individual outcome after treatment cessation.

scholarly journals Behaviour of Factors II, VII, IX and X in Bleeding Complications During Long-Term Treatment with Coumarin

1963 ◽  
Vol 10 (02) ◽  
pp. 278-281 ◽  
Author(s):  
E. A Loeliger ◽  
A Hensen ◽  
Mieke J. Mattern ◽  
H. C Hemker
Keyword(s):  
Term Treatment ◽  
Bleeding Complications ◽  
Factor Activity ◽  
Normal Individuals ◽  
Individual Variations ◽  
Long Term Treatment ◽  
Average Factor ◽  
Average Activity ◽  
The Individual

SummaryIn 20 patients suffering from bleeding complications during long-term treatment with phenprocoumon, the depression of the activity of Factors II, VII, IX and X, on the average, was found to be stronger than in so-called adequately treated patients, whereas no statistically significant differences could be demonstrated between the average activity of the 4 factors. The individual variations between the 4 factors were higher than those found in normal individuals and adequately treated patients.Thrombotest activity appeared to be considerably lower than the average factor activity. This discrepancy is mainly caused by the action of the recently discovered circulating anticoagulant occurring in coumarin-treated or vitamin K-deficient patients.

scholarly journals The Role of Rho Kinase in Sex-Dependent Vascular Dysfunction in Type 1 Diabetes

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Daniel W. Nuno ◽  
Kathryn G. Lamping
Keyword(s):  
Kinase Inhibitors ◽  
Vascular Dysfunction ◽  
Rho Kinase ◽  
Term Treatment ◽  
Compensatory Mechanisms ◽  
Rho Kinase Inhibitors ◽  
Long Term Treatment

We hypothesized that rho/rho kinase plays a role in sex differences in vascular dysfunction of diabetics. Contractions to serotonin were greater in isolated aortic rings from nondiabetic males versus females and increased further in streptozotocin-induced diabetic males but not females. The increased contractions to serotonin in males were reduced by inhibitors of rho kinase (fasudil, Y27632 and H1152) despite no change in expression of rhoA or rho kinase. Contractions to U46619 were not altered by fasudil or Y27632 or the presence of diabetes. In contrast to acute effects of fasudil, chronic treatment with fasudil increased contractions to serotonin in aorta from both non-diabetic and diabetic males. In summary, serotonin-induced contractions were increased in aorta from diabetic males but not females. Although administration of rho kinase inhibitors acutely decreased contractions to serotonin, long-term treatment with fasudil increased contractions. Long-term fasudil treatment may increase compensatory mechanisms to enhance vasoconstrictions.

scholarly journals BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia

2017 ◽  
Vol 24 (6) ◽  
pp. 433-452 ◽  
Author(s):  
Sandra Cuellar ◽  
Michael Vozniak ◽  
Jill Rhodes ◽  
Nicholas Forcello ◽  
Daniel Olszta
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Drug Interactions ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Term Treatment ◽  
Patient Centered ◽  
Long Term Treatment

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.

Effect of Long-Term Treatment on Personality Change of High-Risk Alcoholics

1972 ◽  
Vol 31 (3) ◽  
pp. 799-802 ◽  
Author(s):  
Paul C. Nelson ◽  
Helmut Hoffmann
Keyword(s):  
High Risk ◽  
Term Treatment ◽  
Personality Change ◽  
Special Treatment ◽  
Social Stability ◽  
Recidivism Rate ◽  
Clinical Scales ◽  
Long Term Treatment ◽  
The Individual

The Differential Personality Inventory was administered 6 wk. after admission to 40 male high-risk alcoholics. Participants in a long-term special treatment program were characterized by a high recidivism rate. Retests were obtained 16 wk. later and Ss scored significantly lower on 5 of the 27 clinical scales. The reliability coefficient of the individual scales ranged from 0.57 to 0.92. Data show that high-risk alcoholics change relatively little over a 16-wk. period. It was suggested that certain alcoholics needed long-term treatment because they repeatedly failed to respond to treatment and were unable to control their drinking. It was also hypothesized that repeated, uncontrolled drinking might be due to a lack of social stability.

scholarly journals Clinical Findings of Long-Term Treatment with LDL-Apheresis

1989 ◽  
Vol 17 (4) ◽  
pp. 517-522 ◽  
Author(s):  
Masaki SHINOMIYA ◽  
Tetsuto KANZAKI ◽  
Kohji SHIRAI ◽  
Yasushi SAITO ◽  
Sho YOSHIDA ◽  
...  
Keyword(s):  
Clinical Findings ◽  
Term Treatment ◽  
Ldl Apheresis ◽  
Long Term Treatment

scholarly journals Long-Term Patterns of Oral Anticancer Agent Adoption, Duration, and Switching in Patients With CML

2019 ◽  
Vol 17 (10) ◽  
pp. 1166-1172 ◽  
Author(s):  
Matthew P. Banegas ◽  
Donna R. Rivera ◽  
Maureen C. O’Keeffe-Rosetti ◽  
Nikki M. Carroll ◽  
Pamala A. Pawloski ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Standard Of Care ◽  
Term Treatment ◽  
Oral Agent ◽  
Financial Outcomes ◽  
Long Term Treatment ◽  
Comorbidity Burden ◽  
Line Setting

Background: Oral tyrosine kinase inhibitors (TKIs) have been the standard of care for chronic myeloid leukemia (CML) since 2001. However, few studies have evaluated changes in the treatment landscape of CML over time. This study assessed the long-term treatment patterns of oral anticancer therapies among patients with CML. Methods: This retrospective cohort study included patients newly diagnosed with CML between January 1, 2000, and December 31, 2016, from 10 integrated healthcare systems. The proportion of patients treated with 5 FDA-approved oral TKI agents—bosutinib, dasatinib, imatinib, nilotinib, and ponatinib—in the 12 months after diagnosis were measured, overall and by year, between 2000 and 2017. We assessed the use of each oral agent through the fourth-line setting. Multivariable logistic regression estimated the odds of receiving any oral agent, adjusting for sociodemographic and clinical characteristics. Results: Among 853 patients with CML, 81% received an oral agent between 2000 and 2017. Use of non-oral therapies decreased from 100% in 2000 to 5% in 2005, coinciding with imatinib uptake from 65% in 2001 to 98% in 2005. Approximately 28% of patients switched to a second-line agent, 9% switched to a third-line agent, and 2% switched to a fourth-line agent. Adjusted analysis showed that age at diagnosis, year of diagnosis, and comorbidity burden were statistically significantly associated with odds of receiving an oral agent. Conclusions: A dramatic shift was seen in CML treatments away from traditional, nonoral chemotherapy toward use of novel oral TKIs between 2000 and 2017. As the costs of oral anticancer agents reach new highs, studies assessing the long-term health and financial outcomes among patients with CML are warranted.

Long-Term Treatment of Patients with Recurrent Unipolar Major Depression: Evidence to Clinical Practice

CNS Spectrums ◽  
2006 ◽  
Vol 11 (S15) ◽  
pp. 4-5 ◽  
Author(s):  
Martin B. Keller
Keyword(s):  
Treatment Strategies ◽  
Patient Characteristics ◽  
Evidence Base ◽  
Term Treatment ◽  
Recurrent Depression ◽  
Long Term Treatment ◽  
Risk Factors For Recurrence ◽  
The Individual ◽  
Term Management

Major depressive disorder (MDD) is almost exclusively recurrent. The vast majority of patients who experience one episode of MDD will eventually experience at least one more episode during their lifetime. The recurrent nature of MDD increases the burden to both the individual and society. Hence, it is imperative that treatment strategies focus on achieving remission acutely, as well as maintaining of remission and preventing recurrence. The articles in this supplement are based on presentations and a dialogue among a group of experts who convened for a roundtable discussion on improving long-term outcomes with antidepressant therapy.Improving long-term treatment of MDD begins with understanding the clinical course of recurrent depression and the ability to recognize those patients who are at greatest risk for recurrence. James H. Kocsis, MD, reviews the course of recurrent depression, emphasizing the tendency for it to progressively worsen. He also discusses patient characteristics and other risk factors for recurrence as well as current recommendations for long-term management of recurrent depression.Although long-term antidepressant maintenance treatment studies are somewhat limited in number, they provide the evidence base that shapes existing guidelines for long-term management of recurrent depression. Michael E. Thase, MD, examines this evidence for the different classes of antidepressants. In addition, Thase reviews evidence for the efficacy of psychotherapy and discusses its potentially important role in long-term depression management.

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