Correlation Between Imatinib Trough Concentration and Long-Term Tolerability in CML Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3751-3751
Author(s):  
Masayoshi Masuko ◽  
Tatsuo Furukawa ◽  
Toyoyuki Tanaka ◽  
Syukuko Miyakoshi ◽  
Takashi Kozakai ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
High Plasma ◽  
Rank Test ◽  
Molecular Response ◽  
Log Rank Test ◽  
High Plasma Concentration ◽  
Term Tolerability ◽  
Plasma Assay ◽  
Observation Period

Abstract Abstract 3751 Background and Purpose: The introduction of imatinib to the treatment regimen of chronic myeloid leukemia (CML) has markedly changed its outcome. Several reports have shown that the efficacy of imatinib correlates with the trough plasma concentration in CML patients. However, little is known about the correlation between plasma concentration and long-term outcomes, including adverse effects. We analyzed the correlation between long term tolerability and plasma concentration in Japanese patients. Patients: Forty-three patients with chronic phase CML who had good adherence with daily 300mg (n=8) or 400mg (n=35) imatinib administration at hospitals in our study group were enrolled in this study. The median age of patients starting imatinib was 57 years (range 15–82). Imatinib was started between Dec. 2001 and May 2007. Plasma trough concentration was examined on a day between Nov. 2007 and Aug. 2008. Median time from the start of imatinib until the plasma assay was 1548 days (range 91–2390). Results: Clinical data were reviewed in Sep 2011. We excluded patients who had been switched from imatinib to a second tyrosine kinase inhibitor (TKI) despite major molecular response (MMR). Median plasma concentration was 925 ng/ml (range 200–3280). Median follow-up was 2632 days (range 884–3496) and median follow-up after the plasma assay was 1216 days (range 361–1323). We divided the patients into two groups: the low plasma concentration group (<925ng/ml n=22) and high plasma concentration group (>925ng/ml n=21). Overall survival and achievement of complete molecular response (negative by RT-PCR) did not differ between the two groups. We defined all death, progression, switch to a second TKI and imatinib dose reduction as events. Also we defined death by adverse effect, imatinib dose reduction or switch to a second TKI due to adverse effects as intolerance-related events and progression, switch to a second TKI due to failure of achieve MMR or loss of MMR as efficacy-related events. Event-free survival (EFS) showed no difference between the two groups. However cumulative incidence of intolerance-related event was significantly higher in the high plasma concentration group than in the low plasma concentration group (whole observation period, p=0.02 by log-rank test; observation period after the plasma assay, p=0.01 by log-rank test). Grade 3 or 4 anemia occurred in 4 patients only in the high plasma concentration group. Cumulative incidence of efficacy-related event was slightly higher in the low plasma concentration group than the high plasma concentration group (whole observation period, p=0.06 by log-rank test; observation period after the plasma assay p=0.05 by log-rank test). Conclusion: Trough imatinib plasma concentration at steady-state after initiation of therapy has been demonstrated to have correlation with the early efficacy of imatinib. Our findings suggest that imatinib plasma concentration also correlates with intolerance or adverse effect in long-term clinical observation. Although further studies are required to confirm the current data prospectively, imatinib plasma level testing seems to be helpful to optimize clinical outcomes for patients with CML. Disclosures: No relevant conflicts of interest to declare.

Intoxication with Phenprocoumon (Marcoumar) Pharmacokinetics and Side Effects

1969 ◽  
Vol 21 (02) ◽  
pp. 320-324 ◽  
Author(s):  
K Seiler ◽  
F Duckert
Keyword(s):  
Plasma Concentration ◽  
Side Effects ◽  
Half Life ◽  
Plasma Proteins ◽  
Repeated Administration ◽  
High Plasma ◽  
Vitamin K1 ◽  
Clotting Factors ◽  
Therapeutic Concentration ◽  
High Plasma Concentration

SummaryA case of severe Marcoumar intoxication is described. Eleven hours after the intake a plasma concentration of 15.75 µg/ml was found which corresponds approximately to the 5-fold therapeutic concentration. Repeated administration of vitamin K1 made it possible to avoid extreme lowering of the activity of the clotting factors II, VII and X and to prevent bleeding. Side effects were not observed. The biologic half-life of Phenprocoumon has been found to be shortened at high plasma concentration (3.7 instead of 5.9 days). It is probable that in extreme concentration the drug is less strongly bound to the plasma proteins.

scholarly journals AB0621 TOLERABILITY AND SAFETY OF ACETYLSALICYLIC ACID IN PATIENTS WITH SYSTEMIC SCLEROSIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1606.2-1606
Author(s):  
L. Verardi ◽  
E. De Lorenzis ◽  
G. Natalello ◽  
L. Gigante ◽  
U. La Porta ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Adverse Events ◽  
Low Dose ◽  
Disease Duration ◽  
Rank Test ◽  
Digital Ulcers ◽  
Log Rank Test ◽  
Gastrointestinal Intolerance ◽  
Male Sex ◽  
Observation Period

Background:Systemic Sclerosis (SSc) is characterized by an increased incidence of macro- and microvascular complications. Current evidences on efficacy, safety and tolerability of acetylsalicylic acid (ASA) in SSc patients are limited, and the indication to this treatment is based on the experience of each single centre or physician. Esophagus and stomach are the portions of the digestive tract that are more frequently affected by adverse events due to ASA exposure.Objectives:We evaluated the incidence of adverse events associated with low-dose ASA treatment in a cohort of patients affected by SSc.Methods:Demographic data and disease features of 302 patients affected by SSc treated with low-dose ASA were collected and patients were followed-up for a median period of 6.9 years (range: 0-20 years). The proportion of patients taking ASA for secondary prevention for cardiovascular disease was also noted. The incidence of discontinuation of the drug, gastrointestinal intolerance, bleeding and death in the observation period was recorded.Results:Patients had a median age of 54.0 years (19.6-89.4); 91.9% were female, 13.2% were smokers and 44.0% had a BMI≥30Kg/m2. The prevalence of ischemic heart disease, peripheral vascular disease and stroke was of 8.6%, 5.3% and 3.3%, respectively; 48.7% of the patient took ASA in primary cardiovascular prevention. Therapy started after a median disease duration of 4.8 years (range: 0.0- 30.1 years) since the first non-Raynaud symptom and 56.6% of patients had an early disease (less than three years of disease duration). During the observation period, 30 patients (14.3 per 1000 person-years) discontinued ASA after an average period of assumption of 4.6 years (range: 0.3-18.0 years). The main adverse events were heartburn, dyspepsia and hematochezia, recorded in 18 patients (8.6 per 1000 person-years). Eight of them (3.8 per 1000 person-years) had evidence of digestive tract bleeding. Five patients (2.4 per 1000 person-years) discontinued ASA due to recurrent epistaxis. Twenty-eight patients (13.4 per 1000 person-years) died in the follow-up period, 16 of these (7.6 per 1000 person-years) because of SSc-related causes. None of them had evidence of major bleeding. We used Kaplan-Meier analysis to evaluate the incidence of ASA discontinuation. The history of digital ulcers (Log rank test X24.7, p=0.037) and male sex (Log rank test X24.3, p=0.03) were associated with a higher cumulative ASA discontinuation rate due to gastrointestinal intolerance.Conclusion:In our cohort of SSc patients, ASA resulted safe and well tolerated in most cases, despite the risk of gastroesophageal abnormalities due to disease. Although this comforting results, taking in account the lack of controlled-randomized trials about efficacy and safety, the choice to start antiplatelet therapy with ASA should be mandatorily preceded by a careful evaluation of risks and benefits. Furthermore, an attentive monitoring for possible adverse effects is needed during ASA treatment. Patients with digital ulcers and male sex could present less drug tolerability.References:[1]Valentini G et al. Ann Rheum Dis 2019. Beckett VL et al. Arthritis Rheum 1984. Kavian N et al. Vascul Pharmacol 2015. Lavie CJ et al. Curr Probl Cardiol 2017.Disclosure of Interests:Lucrezia Verardi: None declared, Enrico De Lorenzis: None declared, Gerlando Natalello: None declared, Laura Gigante: None declared, Umberto La Porta: None declared, Elisa Gremese Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Silvia Laura Bosello Speakers bureau: Abbvie, Pfizer, Boehringer

scholarly journals The relationship of the prolonged PR interval with the long-term survival in patients with heart failure undergoing cardiac resynchronization therapy

2020 ◽  
Vol 25 (1) ◽  
pp. 33-38
Author(s):  
A. M. Soldatova ◽  
V. A. Kuznetsov ◽  
T. P. Gizatulina ◽  
L. M. Malishevsky ◽  
S. M. Dyachkov
Keyword(s):  
Cardiac Resynchronization ◽  
Rank Test ◽  
Term Survival ◽  
Log Rank Test ◽  
Group I ◽  
Pr Interval ◽  
Qrs Duration ◽  
Group Ii ◽  
The Relationship

Aim. To assess the relationship between the prolonged PR interval (≥200 ms) and the long-term survival of patients undergoing cardiac resynchronization therapy (CRT).Material and methods. A total of 85 patients (mean age — 55,1Ѓ}9,9 years; men — 81,2%) with NYHA class II-IV heart failure (HF) were examined. The mean follow-up was 34,0Ѓ}21,2 months. Patients with PR<200 ms (n=52) made up group I, with PR≥200 ms (n=33) — group II. Then the patients were divided into subgroups depending on the QRS duration: ≥150 ms (n=33 in group I and n=14 in group II, respectively) <150 ms (n=19 in group I and n=19 in group II, respectively).Results. In patients of group II, a history of myocardial infarction (MI) was more often registered (p=0,005), left ventricular ejection fraction (LVEF) was lower (p=0,032). In a multivariate analysis, MI (OR 3,217; CI 95% 1,188-8,712; p=0,022) and LVEF value (OR 0,869; CI 95% 0,780-0,968; p=0,011) had a significant relationship with the PR interval prolongation (≥200 ms). The survival of patients of group I was 59,6%, group II — 18,2% (Log-rank test p<0,001). According to Cox regression model, the initial left ventricle end-systolic volume (OR 1,012; 95% CI 1,006-1,017; p<0,001), inferior wall MI (OR 1,690; 95% CI 1,131-2,527; p=0,011) and PR interval ≥200 ms (OR 2,179; 95% CI 1,213–3,915; p=0,009) were associated with long-term mortality. In patients with PR≥200 ms, survival rate was low, regardless of the QRS duration (21,4% in patients with QRS≥150 ms, 15,8% in patients with QRS<150 ms; Log-rank test p=0,698) In patients with PR<200 ms, the survival rate of patients with QRS≥150 ms was 72,7%, and for patients with QRS<150 ms — 36,8% (Log-rank test p=0,031).Conclusion. In HF patients, PR interval prolongation (≥200 ms) is associated with long-term mortality increase. The highest survival rates were observed in patients with PR<200 ms and QRS≥150 ms. In patients with QRS≥150 ms, the presence of PR≥200 ms should be considered as an additional criterion for CRT.

Long-Term Reduction in Sperm Count After Chemotherapy With and Without Radiation Therapy for Non-Hodgkin's Lymphomas

1993 ◽  
Vol 11 (5) ◽  
pp. 1007-1007 ◽  
Author(s):  
Rodger M. Pryzant ◽  
Marvin L. Meistrich ◽  
Gene Wilson ◽  
Barry Brown ◽  
Peter McLaughlin
Keyword(s):  
Radiation Therapy ◽  
Clin Oncol ◽  
Sperm Count ◽  
Rank Test ◽  
Log Rank Test ◽  
Hodgkin's Lymphomas

The last sentence of the Results section of the February 1993 report "Long-Term Reduction in Sperm Count After Chemotherapy With and Without Radiation Therapy for Non-Hodgkin's Lymphomas" by Pryzant et al (J Clin Oncol 11:239–247, 1993) should have read: "The recovery of those patients who received less than 9.5 g/m2 of cyclophosphamide was significantly greater than those who received more than 9.5 g/m2 of cyclophosphamide (P = .00092, log-rank test)." The unit of measure for cyclophosphamide in the legend for Fig 4 and in the next to last paragraph of the Discussion should have been g/m2.

scholarly journals Comparison of Long-Term Results After Nephron-Sparing Surgery and Radical Nephrectomy in Treating 4- to 7-cm Renal Cell Carcinoma

Medicina ◽  
2013 ◽  
Vol 49 (5) ◽  
pp. 36 ◽  
Author(s):  
Daimantas Milonas ◽  
Giedrius Skulčius ◽  
Ruslanas Baltrimavičius ◽  
Stasys Auškalnis ◽  
Marius Kinčius ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Radical Nephrectomy ◽  
Nephron Sparing Surgery ◽  
Rank Test ◽  
Cancer Specific Survival ◽  
Log Rank Test ◽  
Nephron Sparing

Objective. The aim of our study was to compare long-term oncological outcomes following nephron-sparing surgery (NSS) and radical nephrectomy (RN) for renal cell carcinoma (RCC) 4 to 7 cm in diameter. Material and Methods. The study included patients who underwent RN or NSS for RCC 4 to 7 cm in diameter between 1998 and 2009. The studied groups were compared with respect to the patients’ age, sex, physical status according to the American Society of Anesthesiologists Physical classification, histological type, stage, tumor size, grade, duration of the operation, and complications. Survival was established using the Kaplan-Meier method. The risk factors for survival were analyzed using a multivariate Cox regression model. Results. During the study, 351 patients underwent surgery: 317 patients (90.3%) underwent RN, and 34 (9.7%), NSS. The compared groups differed with respect to tumor size (P=0.001) and stage (P=0.006). The overall estimated 12-year survival was 53.7% after RN and 55.2% after NSS (log-rank test P=0.437). The 12-year cancer-specific survival in the RN and NSS groups was 69.6% and 80.6%, respectively (log-rank test P=0.198). Pathological stage and patients’ age were the major factors affecting both overall and cancer-specific survival. The type of surgery (NSS or RN) had no effect on survival. Conclusions. Our study showed that nephron-sparing surgery is a safe technique compared with radical nephrectomy that ensures good oncological control in the treatment of renal cell carcinoma measuring 4 to 7 cm and may be proposed as the treatment of choice for renal tumors not only up to 4 cm, but also 4 to 7 cm in size.

scholarly journals Assessing Long-Term Survival Benefits of Immune Checkpoint Inhibitors Using the Net Survival Benefit

2019 ◽  
Vol 111 (11) ◽  
pp. 1186-1191 ◽  
Author(s):  
Julien Péron ◽  
Alexandre Lambert ◽  
Stephane Munier ◽  
Brice Ozenne ◽  
Joris Giai ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Survival Benefit ◽  
Rank Test ◽  
Cure Rate ◽  
Term Survival ◽  
Long Term Survival ◽  
Delayed Treatment ◽  
Net Survival ◽  
Log Rank Test

Abstract Background The treatment effect in survival analysis is commonly quantified as the hazard ratio, and tested statistically using the standard log-rank test. Modern anticancer immunotherapies are successful in a proportion of patients who remain alive even after a long-term follow-up. This new phenomenon induces a nonproportionality of the underlying hazards of death. Methods The properties of the net survival benefit were illustrated using the dataset from a trial evaluating ipilimumab in metastatic melanoma. The net survival benefit was then investigated through simulated datasets under typical scenarios of proportional hazards, delayed treatment effect, and cure rate. The net survival benefit test was computed according to the value of the minimal survival difference considered clinically relevant. As comparators, the standard and the weighted log-rank tests were also performed. Results In the illustrative dataset, the net survival benefit favored ipilimumab [Δ(0) = 15.8%, 95% confidence interval = 4.6% to 27.3%, P = .006]. This favorable effect was maintained when the analysis was focused on long-term survival differences (eg, >12 months, Δ(12) = 12.5% (95% confidence interval = 4.4% to 20.6%, P = .002). Under the scenarios of a delayed treatment effect and cure rate, the power of the net survival benefit test compared favorably to the standard log-rank test power and was comparable to the power of the weighted log-rank test for large values of the threshold of clinical relevance. Conclusion The net long-term survival benefit is a measure of treatment effect that is meaningful whether or not hazards are proportional. The associated statistical test is more powerful than the standard log-rank test when a delayed treatment effect is anticipated.

scholarly journals Long-term effect of azithromycin in bronchiolitis obliterans syndrome

2019 ◽  
Vol 6 (1) ◽  
pp. e000465
Author(s):  
C.Tji-Joong Gan ◽  
Chris Ward ◽  
Gerard Meachery ◽  
James Laurence Lordan ◽  
Andrew J Fisher ◽  
...  
Keyword(s):  
Overall Survival ◽  
Placebo Group ◽  
Bronchiolitis Obliterans ◽  
Bronchiolitis Obliterans Syndrome ◽  
Term Effect ◽  
Rank Test ◽  
Open Label ◽  
Log Rank Test ◽  
Long Term Effect

IntroductionAzithromycin stabilises and improves lung function forced expiratory volume in one second (FEV1) in lung transplantation patients with bronchiolitis obliterans syndrome (BOS). A post hoc analysis was performed to assess the long-term effect of azithromycin on FEV1, BOS progression and survival .MethodsEligible patients recruited for the initial randomised placebo-controlled trial received open-label azithromycin after 3 months and were followed up until 6 years after inclusion (n=45) to assess FEV1, BOS free progression and overall survival.ResultsFEV1 in the placebo group improved after open-label azithromycin and was comparable with the treatment group by 6 months. FEV1 decreased after 1 and 5 years and was not different between groups. Patients (n=18) with rapid progression of BOS underwent total lymphoid irradiation (TLI). Progression-free survival (log-rank test p=0.40) and overall survival (log-rank test p=0.28) were comparable. Survival of patients with early BOS was similar to late-onset BOS (log-rank test p=0.74).DiscussionLong-term treatment with azithromycin slows down the progression of BOS, although the effect of TLI may affect the observed attenuation of FEV1 decline. BOS progression and long-term survival were not affected by randomisation to the placebo group, given the early cross-over to azithromycin and possibly due to TLI in case of further progression. Performing randomised placebo-controlled trials in lung transplantation patients with BOS with a blinded trial duration is feasible, effective and safe.

scholarly journals Reopening of an obstructed third ventriculostomy: long-term success and factors affecting outcome in 215 infants

2015 ◽  
Vol 15 (4) ◽  
pp. 399-405 ◽  
Author(s):  
Paul J. Marano ◽  
Scellig S. D. Stone ◽  
John Mugamba ◽  
Peter Ssenyonga ◽  
Ezra B. Warf ◽  
...  
Keyword(s):  
Cox Regression ◽  
Operation Time ◽  
Cox Proportional Hazards Model ◽  
Wilcoxon Test ◽  
Rank Test ◽  
Third Ventriculostomy ◽  
Time To Failure ◽  
Factors Affecting ◽  
Log Rank Test

OBJECT The role of reopening an obstructed endoscopic third ventriculostomy (ETV) as treatment for ETV failure is not well defined. The authors studied 215 children with ETV closure who underwent successful repeat ETV to determine the indications, long-term success, and factors affecting outcome. METHODS The authors retrospectively reviewed the CURE Children's Hospital of Uganda database from August 2001 through December 2012, identifying 215 children with failed ETV (with or without prior choroid plexus cauterization [CPC]) who underwent reopening of an obstructed ETV stoma. Treatment survival according to sex, age at first and second operation, time to failure of first operation, etiology of hydrocephalus, prior CPC, and mode of ETV obstruction (simple stoma closure, second membrane, or cisternal obstruction from arachnoid scarring) were assessed using the Kaplan-Meier survival method. Survival differences among groups were assessed using log-rank and Wilcoxon methods and a Cox proportional hazards model. RESULTS There were 125 boys and 90 girls with mean and median ages of 229 and 92 days, respectively, at the initial ETV. Mean and median ages at repeat ETV were 347 and 180 days, respectively. Postinfectious hydrocephalus (PIH) was the etiology in 126 patients, and nonpostinfectious hydrocephalus (NPIH) in 89. Overall estimated 7-year success for repeat ETV was 51%. Sex (p = 0.46, log-rank test; p = 0.54, Wilcoxon test), age (< vs > 6 months) at initial or repeat ETV (p = 0.08 initial, p = 0.13 repeat; log-rank test), and type of ETV obstruction (p = 0.61, log-rank test) did not affect outcome for repeat ETV (p values ≥ 0.05, Cox regression). Those with a longer time to failure of initial ETV (> 6 months 91%, 3–6 months 60%, < 3 months 42%, p < 0.01; log-rank test), postinfectious etiology (PIH 58% vs NPIH 42%, p = 0.02; log-rank and Wilcoxon tests) and prior CPC (p = 0.03, log-rank and Wilcoxon tests) had significantly better outcome. CONCLUSIONS Repeat ETV was successful in half of the patients overall, and was more successful in association with later failures, prior CPC, and PIH. Obstruction of the original ETV by secondary arachnoid scarring was not a negative prognostic factor, and should not discourage the surgeon from proceeding. Repeat ETV may be a more durable solution to failed ETV/CPC than shunt placement in this context, especially for failures at more than 3 months after the initial ETV. Some ETV closures may result from an inflammatory response that is less robust at the second operation.

A single-center retrospective study of patients treated with trabectedin (TRB) with long-term follow up.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11061-11061
Author(s):  
Brett A. Schroeder ◽  
Chad He ◽  
Yuzheng Zhang ◽  
Michael Wagner ◽  
Robin Lewis Jones ◽  
...  
Keyword(s):  
Demographic Variables ◽  
Rank Test ◽  
Prior Chemotherapy ◽  
Pairwise Correlation ◽  
Log Rank Test ◽  
Long Term Follow Up ◽  
Line Of Therapy ◽  
Clinical Trial Information

11061 Background: TRB is FDA approved drug for the treatment of liposarcoma (Lipo) and leiomyosarcoma (LMS). The aim of this study was to evaluate potential biomarkers associated with prolonged benefit in patients treated with TRB at our center prior to 2016. Methods: We performed a retrospective search of UW/FHCRC CASIS database to identify patients treated with TRB prior to 2016. Demographic variables and clinical variables (such as histology and treatment) were retrieved. Statistics were performed with R 3.4.1 software. Pairwise Pearson’s correlation was calculated for the # of prior chemotherapy regimens with # of TRB cycles. The Kaplan-Meir method was used to evaluate overall survival (OS). Log-rank test was conducted to compare groups in terms of OS. Results: 145 sarcoma patients treated with TRB were identified with a mean follow up of 5 years (generally on NCT01427582 or NCT01343277). Patients averaged 1.9 prior chemotherapy regimens prior to TRB (range 0-7 regimens) and received an average of 5.6 TRB doses (range 1-25 doses). Subtypes are listed on table. The # of prior regimens was negatively correlated with the # of TRB cycles that patients received (pairwise correlation coefficient = -1.77; p=0.034), suggesting that multiple prior treatment lines either made TRB less tolerable or made sarcoma less sensitive to TRB. The median OS for this heavily treated metastatic population was 0.5 years. However, patients who were able to stay on TRB for more than 5 cycles had a significantly higher OS (p=0.001). While only 23% of patients who received less than 5 cycles of TRB were alive at 5 years (95% CI: 0.15, 0.32), 53% of those who received 5 or more cycles of (95% CI: 0.39, 0.65) were alive at 5 years. Conclusions: TRB may be more effective when administered as an earlier line of therapy. Patients who are able to stay on TRB for a longer duration had a significant improvement in OS. Detailed subset analysis will be presented as will initial findings of our biomarker work. These retrospective data warrant further evaluation. Clinical trial information: NCT01427582 or NCT01343277. [Table: see text]

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