2231HsCRP predicts mortality beyond troponin in 102,337 patients with suspected acute coronary syndrome (CRP-RISK study)

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Kaura ◽  
A Hartley ◽  
V Panoulas ◽  
B Glampson ◽  
J Davies ◽  
...  
Keyword(s):  
Real World ◽  
Health Informatics ◽  
Cox Regression ◽  
White Cell ◽  
Research Centre ◽  
Troponin Level ◽  
Cox Regression Analysis ◽  
Cumulative Mortality ◽  
Coronary Syndrome ◽  
Cell Counts

Abstract Background The incremental long-term prognostic value of high-sensitivity C-reactive protein (hsCRP) above troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndromes (ACS) is unknown. Purpose We hypothesised that a mildly elevated hsCRP is associated with mortality risk in patients with suspected ACS, independent of troponin level. Methods We used the National Institute for Health Research Health Informatics Collaborative data of 257,948 patients who had a troponin measured at 5 cardiac centres. We excluded patients with clinically abnormal white cell counts and hsCRP >15 mg/L to try limiting the population to those without overt infections, malignancies or systemic inflammatory conditions that may confound our analyses. Patients were divided into four hsCRP groups (<2, 2–4.9, 5–9.9 and 10–15 mg/L) and the association between hsCRP levels and all-cause mortality assessed. Results There were 102,337 patients included in the analysis (hsCRP <2 mg/L (n=38,390), 2–4.9 mg/L (n=27,397), 5–9.9 mg/L (n=26,957) and 10–15 mg/L (n=9,593)). Figure 1A displays cumulative mortality per hsCRP group, revealing increasing mortality with each consecutive group. Figure 1B further stratifies the groups according to dichotomised peak troponin level as positive or negative. This shows the greatest mortality for patients in the highest hsCRP group who also had a positive troponin assay (36.0% at 3 years). In Cox regression analysis with time-dependent covariates, even mildly raised hsCRP was an independent predictor of mortality over time, after adjusting for age, gender, haemoglobin, white cell count, platelet count, creatinine and troponin positivity. There was a positive and graded relationship between hsCRP level and mortality at baseline, which remained at 3-years (hazard ratio (95% CI) of 1.32 (1.18–1.48) for those with hsCRP 2.0–4.9mg/L, and 1.40 (1.26–1.57), and 2.00 (1.75–2.28) for those with hsCRP 5–9.9 mg/L and 10–15 mg/L, respectively. We explored whether inclusion of hsCRP could better reclassify the population into at-risk mortality groups. The association with 30-day, 1-year and 3-year mortality was assessed using three different risk models (model 1: age, gender, haemoglobin, creatinine; model 2: model 1 plus troponin (positivity versus negativity); model 3: model 2 plus hsCRP groups. For cumulative mortality at each time point, each successive model was better able to discriminate risk than its precursor (p<0.0001); such that inclusion of troponin and hsCRP gave the most robust risk discrimination. Model 3 achieved an AUROC >0.8 at 30 days, 1-year and 3-year mortality, surpassing the use of troponin on its own. Figure 1. Kaplan-Meier mortality curves Conclusions These multi-centre, real-world data from a large cohort of patients with suspected ACS identify hsCRP as a clinically meaningful prognostic marker in addition to troponin levels and point to its potential utility in selecting patients for novel treatments targeting inflammation. Acknowledgement/Funding Funded by NIHR Imperial Biomedical Research Centre (BRC) using NIHR Health Informatics Collaborative data service, supported by OUH, GSTT & UCLH BRCs

P3592Troponin level and mortality risk in an unselected population of over 250,000 patients (TROP-RISK study)

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Kaura ◽  
V Panoulas ◽  
B Glampson ◽  
J Davies ◽  
A Mulla ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Health Informatics ◽  
Cox Regression ◽  
Cubic Spline ◽  
Research Centre ◽  
Current Evidence ◽  
Diagnostic Code ◽  
Troponin Level ◽  
Elevated Troponin ◽  
Cox Regression Analysis

Abstract Background Current evidence suggests a direct relationship between the magnitude of troponin elevation and mortality, albeit over a limited range of troponin levels, and clinicians generally work under the impression that higher troponins signify higher mortality in all age groups. Purpose The objective was to use big data to determine the relationship between the full spectrum of troponin level and mortality in patients in whom troponin testing has been performed for clinical purposes. Methods As part of the National Institute for Health Research Health Informatics Collaborative project, all troponin values measured during the study period (2010 to 2017) were assembled from five cardiovascular centres. Troponin concentrations were standardised as a multiple of each laboratory's 99th-percentile of the upper limit of normal (ULN). All patients were followed up until death or censoring on 1st April 2017. To model the relation between peak troponin level and all-cause mortality we used restricted cubic spline Cox regression analysis. Splines were adjusted for patient age, gender, haemoglobin, creatinine, white cell count and C-reactive protein. Results 257,948 patients underwent troponin assessment. During a median follow-up of 1,198 (IQR, 514–1,866) days, there were 55,850 (21.7%) deaths. Using multivariable-adjusted restricted cubic spline Cox regression analysis, an inverted-U shaped relationship was observed between peak troponin level and mortality in all patients (Figure 1A). Among patients who were admitted to hospital, the recorded diagnostic code was acute coronary syndrome (ACS) in 14,468 patients and non-ACS in 120,049 patients. The revascularisation rate within 3 months was 61.0% (n=8,820) in ACS versus 4.0% (n=4,793) in non-ACS patients. There was a very different rate of revascularisation across the spectrum of troponin. The rate was only 1.4% for troponins below 1 xULN, and 6.1% between 1 and 10 xULN. Beyond 10 xULN, rate of revascularisation rose rapidly to over 85% for greater than 10,000 xULN (Figure 1B). Stratifying patients by revascularisation, the restricted cubic spline Cox regression curve showed a progressive increase in mortality within both the revascularised and non-revascularised strata, even to very high peak troponin levels (Figure 1C). Overall, revascularisation was associated with lower hazard ratios across all troponin levels. A similar pattern was seen when patients were stratified by the presence or absence of ACS diagnosis. Figure 1. Troponin level and mortality Conclusions An elevated troponin, even slightly above the ULN should be taken seriously. The inverted-U shaped mortality relationship with troponin occurred because patients with the highest troponin formed a different clinical subgroup who underwent different clinical management with a high revascularisation rate. These data on troponin level and mortality may help to inform clinical practice decisions and guide future risk stratification algorithms for patients with elevated troponin. Acknowledgement/Funding Funded by NIHR Imperial Biomedical Research Centre (BRC) using NIHR Health Informatics Collaborative data service, supported by OUH, GSTT & UCLH BRCs

scholarly journals Association of troponin level and age with mortality in 250 000 patients: cohort study across five UK acute care centres

BMJ ◽  
2019 ◽  
pp. l6055 ◽  
Author(s):  
Amit Kaura ◽  
Vasileios Panoulas ◽  
Benjamin Glampson ◽  
Jim Davies ◽  
Abdulrahim Mulla ◽  
...  
Keyword(s):  
Cohort Study ◽  
Health Informatics ◽  
Excess Mortality ◽  
Cox Regression ◽  
Age Groups ◽  
Troponin Level ◽  
Coronary Syndrome ◽  
Upper Limit ◽  
The Uk

Abstract Objective To determine the relation between age and troponin level and its prognostic implication. Design Retrospective cohort study. Setting Five cardiovascular centres in the UK National Institute for Health Research Health Informatics Collaborative (UK-NIHR HIC). Participants 257 948 consecutive patients undergoing troponin testing for any clinical reason between 2010 and 2017. Main outcome measure All cause mortality. Results 257 948 patients had troponin measured during the study period. Analyses on troponin were performed using the peak troponin level, which was the highest troponin level measured during the patient’s hospital stay. Troponin levels were standardised as a multiple of each laboratory’s 99th centile of the upper limit of normal (ULN). During a median follow-up of 1198 days (interquartile range 514-1866 days), 55 850 (21.7%) deaths occurred. A positive troponin result (that is, higher than the upper limit of normal) signified a 3.2 higher mortality hazard (95% confidence interval 3.1 to 3.2) over three years. Mortality varied noticeably with age, with a hazard ratio of 10.6 (8.5 to 13.3) in 18-29 year olds and 1.5 (1.4 to 1.6) in those older than 90. A positive troponin result was associated with an approximately 15 percentage points higher absolute three year mortality across all age groups. The excess mortality with a positive troponin result was heavily concentrated in the first few weeks. Results were analysed using multivariable adjusted restricted cubic spline Cox regression. A direct relation was seen between troponin level and mortality in patients without acute coronary syndrome (ACS, n=120 049), whereas an inverted U shaped relation was found in patients with ACS (n=14 468), with a paradoxical decline in mortality at peak troponin levels >70×ULN. In the group with ACS, the inverted U shaped relation persisted after multivariable adjustment in those who were managed invasively; however, a direct positive relation was found between troponin level and mortality in patients managed non-invasively. Conclusions A positive troponin result was associated with a clinically important increased mortality, regardless of age, even if the level was only slightly above normal. The excess mortality with a raised troponin was heavily concentrated in the first few weeks. Study registration ClinicalTrials.gov NCT03507309 .

scholarly journals One-year outcomes of drug-coated balloon treatment for long femoropopliteal lesions: a multicentre cohort and real-world study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaoxi Yu ◽  
Xin Zhang ◽  
Zhichao Lai ◽  
Jiang Shao ◽  
Rong Zeng ◽  
...  
Keyword(s):  
Real World ◽  
Cox Regression ◽  
Ankle Brachial Index ◽  
Primary Patency ◽  
Critical Limb Ischaemia ◽  
Limb Ischaemia ◽  
Cox Regression Analysis ◽  
Femoropopliteal Artery ◽  
Kaplan Meier ◽  
Multicentre Cohort

Abstract Background Drug-coated balloons (DCBs) have shown superiority in the endovascular treatment of short femoropopliteal artery disease. Few studies have focused on outcomes in long lesions. This study aimed to evaluate the safety and effectiveness of Orchid® DCBs in long lesions over 1 year of follow-up. Methods This study is a multicentre cohort and real-world study. The patients had lesions longer than or equal to 150 mm of the femoropopliteal artery and were revascularized with DCBs. The primary endpoints were primary patency, freedom from clinically driven target lesion revascularization (TLR) at 12 months and major adverse events (all-cause death and major target limb amputation). The secondary endpoints were the changes in Rutherford classification and the ankle brachial index (ABI). Results One hundred fifteen lesions in 109 patients (mean age 67 ± 11 years, male proportion 71.6%) were included in this study. The mean lesion length was 252.3 ± 55.4 mm, and 78.3% of the lesions were chronic total occlusion (CTO). Primary patency by Kaplan–Meier estimation was 98.1% at 6 months and 82.1% at 12 months. The rate of freedom from TLR by Kaplan–Meier estimation was 88.4% through 12 months. There were no procedure- or device-related deaths through 12 months. The rate of all-cause death was 2.8%. Cox regression analysis suggested that renal failure and critical limb ischaemia (CLI) were statistically significant predictors of the primary patency endpoint. Conclusion In our real-world study, DCBs were safe and effective when used in long femoropopliteal lesions, and the primary patency rate at 12 months by Kaplan–Meier estimation was 82.1%.

scholarly journals Real-world evidence and optimization of vocal dysfunction in end-stage renal disease patients with secondary hyperparathyroidism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Geng-He Chang ◽  
Fong-Fu Chou ◽  
Ming-Shao Tsai ◽  
Yao-Te Tsai ◽  
Ming-Yu Yang ◽  
...  
Keyword(s):  
Renal Disease ◽  
Secondary Hyperparathyroidism ◽  
Real World ◽  
End Stage Renal Disease ◽  
Cox Regression ◽  
Electrolyte Imbalance ◽  
Research Database ◽  
Cox Regression Analysis ◽  
Stage Renal Disease ◽  
End Stage

AbstractPatients with end-stage renal disease (ESRD) may demonstrate secondary hyperparathyroidism (SHPT), characterized by parathyroid hormone oversecretion in response to electrolyte imbalance (e.g., hypocalcemia and hyperphosphatemia). Moreover, this electrolyte imbalance may affect vocal cord muscle contraction and lead to voice change. Here, we explored the effects of SHPT on the voices of patients with ESRD. We used data of 147,026 patients with ESRD from the registry for catastrophic illness patients, a sub-database of Taiwan National Health Insurance Research Database. We divided these patients into 2 groups based on whether they had hyperparathyroidism (HPT) and compared vocal dysfunction (VD) incidence among them. We also prospectively included 60 ESRD patients with SHPT; 45 of them underwent parathyroidectomy. Preoperatively and postoperatively, voice analysis was used to investigate changes in vocal parameters. In the real-world database analysis, the presence of HPT significantly increased VD incidence in patients with ESRD (p = 0.003): Cox regression analysis results indicated that patients with ESRD had an approximately 1.6-fold increased VD risk (p = 0.003). In the clinical analysis, the “jitter” and “shimmer” factors improved significantly after operation, whereas the aerodynamic factors remained unchanged. In conclusion, SHPT was an independent risk factor for VD in patients with ESRD, mainly affecting their acoustic factors.

684 Cardiac troponins and adverse outcomes in European patients with atrial fibrillation: a report from the ESC-EHRA EORP atrial fibrillation general long-term registry

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Marrco Vitolo ◽  
Vincenzo Livio Malavasi ◽  
Marco Proietti ◽  
Igor Diemberger ◽  
Laurent Fauchier ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Regression Analysis ◽  
Cox Regression ◽  
Adverse Outcomes ◽  
Cox Regression Analysis ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
History Of ◽  
Cardiac Troponins

Abstract Aims Cardiac troponins (cTn) have been reported to be predictors for adverse outcomes in atrial fibrillation (AF), patients, but their actual use is still unclear. To assess the factors associated with cTn testing in routine clinical practice and to evaluate the association of elevated levels of cTn with adverse outcomes in a large contemporary cohort of European AF patients. Methods and results Patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry were stratified into three groups according to cTn levels as (i) cTn not tested, (ii) cTn in range (≤99th percentile), and (iii) cTn elevated (&gt;99th percentile). The composite outcome of any thromboembolism/any acute coronary syndrome (ACS)/cardiovascular (CV) death, defined as major adverse cardiovascular events (MACE) and all-cause death were the main endpoints. 10 445 (94.1%) AF patients were included in this analysis [median age 71 years, interquartile range (IQR): 63–77; males 59.7%]. cTn were tested in 2834 (27.1%). Overall, cTn was elevated in 904 (8.7%) and in-range in 1930 (18.5%) patients. Patients in whom cTn was tested tended to be younger (P &lt; 0.001) and more frequently presenting with first detected AF and atypical AF-related symptoms (i.e. chest pain, dyspnoea, or syncope) (P &lt; 0.001). On multivariable logistic regression analysis, female sex, in-hospital enrollment, first-detected AF, CV risk factors, history of coronary artery disease (CAD), and atypical AF symptoms were independently associated with cTn testing. After a median follow-up of 730 days (IQR: 692–749), 957 (9.7%) composite endpoints occurred while all-cause death was 9.5%. Kaplan–Meier analysis showed a higher cumulative risk for both outcomes in patients with elevated cTn levels (Figure) (Log Rank tests, P &lt; 0.001). On adjusted Cox regression analysis, elevated levels of cTn were independently associated with a higher risk for MACE [hazard ratio (HR): 1.74, 95% confidence interval (CI): 1.40–2.16] and all-cause death (HR 1.45, 95% CI: 1.21–1.74). Elevated levels of cTn were independently associated with a higher occurrence of MACE, all-cause death, any ACS, CV death and hospital readmission even after the exclusion of patients with history of CAD, diagnosis of ACS at discharge, those who underwent coronary revascularization during the admission and/or who were treated with oral anticoagulants plus antiplatelet therapy. Conclusions Elevated cTn levels were independently associated with an increased risk of all-cause mortality and adverse CV events, even after exclusion of CAD patients. Clinical factors that might enhance the need to rule out CAD were associated with cTn testing.

scholarly journals Does Baseline On-treatment Platelet Reactivity Impact Long-term Prognosis in Patients with Acute Coronary Syndrome and Thrombocytopenia Who Underwent Percutaneous Coronary Intervention?

2021 ◽  
Author(s):  
Ru Liu ◽  
Tianyu Li ◽  
Deshan Yuan ◽  
Yan Chen ◽  
Xiaofang Tang ◽  
...  
Keyword(s):  
Percutaneous Coronary Intervention ◽  
Acute Coronary Syndrome ◽  
Real World ◽  
Cox Regression ◽  
Platelet Reactivity ◽  
Coronary Intervention ◽  
The Real ◽  
Coronary Syndrome ◽  
Percutaneous Coronary

Abstract Objectives: This study analyzed the association between on-treatment platelet reactivity and long-term outcomes of patients with acute coronary syndrome (ACS) and thrombocytopenia (TP) in the real world. Methods: A total of 10724 consecutive cases with coronary artery disease who underwent percutaneous coronary intervention (PCI) were collected from January to December 2013. Cases with ACS and TP under dual anti-platelet therapy were enrolled from the total cohort. 5-year clinical outcomes were evaluated among cases with high on-treatment platelet reactivity (HTPR), low on-treatment platelet reactivity (LTPR) and normal on-treatment platelet reactivity (NTPR), tested by thromboelastogram (TEG) at baseline. Results: Cases with HTPR, LTPR and NTPR accounted for 26.2%, 34.4% and 39.5%, respectively. Cases with HTPR were presented with the most male sex, lowest hemoglobin level, highest erythrocyte sedimentation rate and most LM or three-vessel disease, compared with the other two groups. The rates of 5-year all-cause death, major adverse cardiovascular and cerebrovascular events (MACCE), cardiac death, myocardial infarction (MI), revascularization, stroke and bleeding were all not significantly different among three groups. Multivariable Cox regression indicated that, compared with cases with NTPR, cases with HTPR were not independently associated with all endpoints, as well as cases with LTPR (all P>0.05). Conclusions: In patients with ACS and TP undergoing PCI, 5-year all-cause death, MACCE, MI, revascularization, stroke and bleeding risk were all similar between cases with HTPR and cases with NTPR, tested by TEG at baseline, in the real world. The comparison result was the same between cases with LTPR and NTPR.

Homologous recombination deficiency associated with response to poly (ADP-ribose) polymerase inhibitors in ovarian cancer patients: The first real-word data from China.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17543-e17543
Author(s):  
Xiaoxiang Chen ◽  
Jing Ni ◽  
Xia Xu ◽  
Wenwen Guo ◽  
Xianzhong Cheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Regression Analysis ◽  
Homologous Recombination ◽  
Cancer Patients ◽  
Real World ◽  
Cox Regression ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Homologous Recombination Deficiency ◽  
Polymerase Inhibitors

e17543 Background: Homologous recombination deficiency (HRD) is the first phenotypically defined predictive biomarker for Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. However, the proportion of HRD positive in real world and the relationship of HRD status with PARPi in Chinese ovarian cancer patients remains unknown. Methods: A total of sixty-four ovarian cancer patients underwent PARPi, both Olaparib and Niraparib, were enrolled from August 2018 to January 2021 in Jiangsu Institute of Cancer Hospital. HRD score which was the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) events were calculated using tumor DNA-based next generation sequencing (NGS) assays. HRD-positive was defined by either BRCA1/2 pathogenic or likely pathogenic mutation or HRD score ≥42. Progression-free survival (PFS) was analyzed with a log-rank test using HRD status and summarized using Kaplan-Meier methodology. Univariate and multiple cox-regression analysis were conducted to investigate all possible clinical factors. Results: 71.9% (46/64) patients were HRD positive and the rest 28.1% (18/64) were HRD negative, which was higher than the HRD positive proportion reported in Western countries. The PFS among HRD positive patients was significantly longer than those HRD negative patients (medium PFS 8.9 m vs 3.6 m, hazard ratio [HR]: 0.22, p < 0.001). Among them, 23 patients who were BRCA wild type but HRD positive had longer PFS than those with BRCA wild type and HRD negative (medium PFS 9.2 m vs 3.6 m, HR: 0.20, p < 0.001). Univariate cox-regression analysis found that HRD status, previous treatment lines, secondary cytoreductive surgery (SCS) were significantly associated with PFS after PARPi treatment. After multiple regression correction, HRD status (HR: 0.39, 95% CI: [0.20-0.76], p = 0.006), ECOG score (HR: 2.53, 95% CI: [1.24-5.17], p = 0.011) and SCS (HR: 2.21, 95% CI: [1.09-4.48], p = 0.028) were the independent factors. Subgroup analysis in ECOG = 0 subgroup (N = 36), HRD positive patients had significant longer PFS than HRD negative patients (medium PFS 10.3 m vs 5.8 m, HR: 0.14, p < 0.001). Also in the subgroup of patients without SCS, PFS in patients with HRD was longer than patients without HRD (medium PFS 10.2 m vs 5.7 m, HR: 0.29, p = 0.003). Conclusions: This is the first real-world data of HRD status in ovarian cancer patients from China and demonstrate that HRD is a valid biomarker for PARP inhibitors in Chinese ovarian cancer patients.

Real world outcomes in advanced urothelial cancer and the role of neutrophil to lymphocyte ratio.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16020-e16020
Author(s):  
Steven Yip ◽  
Jeenan Kaiser ◽  
Haocheng Li ◽  
Scott A. North ◽  
Daniel Yick Chin Heng ◽  
...  
Keyword(s):  
Real World ◽  
Cox Regression ◽  
Response Rates ◽  
Neutrophil To Lymphocyte Ratio ◽  
Second Line ◽  
First Line ◽  
Cox Regression Analysis ◽  
Lymphocyte Ratio ◽  
Line Setting

e16020 Background: Advanced urothelial carcinoma (UC) patients have a poor prognosis. In the first and second line UC treatment setting, we investigated real world outcomes and evaluated the prognostic role of the neutrophil to lymphocyte ratio (NLR). Methods: A retrospective analysis was performed on advanced UC patients treated with systemic therapy. Overall response rates (ORR), time to treatment failure (TTF) and overall survival (OS) were calculated. Cox regression analysis was performed to examine the association between baseline NLR (low NLR<3 vs high NLR≥3) and TTF and OS. Results: We evaluated 233 advanced UC patients. In the first line setting, the ORR was 25%. Median TTF and OS were 6.9 mo and 9 mo, respectively. Low baseline NLR was significantly associated with improved 8.3 mo median TTF, versus 5.8 mo for high NLR patients (p=0.05). Low NLR was significantly correlated with a longer median OS of 13.1 mo, in comparison to 8.2 mo in patients with high NLR (p=0.007). In the second line, an ORR of 22%, a median TTF of 4.1 mo and a median OS of 8 mo were observed. Low NLR in the second line was significantly associated with improved median TTF at 7.9 mo, versus 3.6 mo for patients with high NLR (p=0.03). Second line low NLR was also significantly associated with a longer median OS of 12.2 mo, in comparison to 6.8 mo in patients with high NLR (p=0.003). Conclusions: In this real world analysis of advanced UC patients, first line outcomes were lower than expected, while response rates in the second line compared favorably to the literature, suggesting a highly selected patient population actually receives second line treatment. A low baseline NLR in the first and second line is associated with improved TTF and OS and warrants further prospective evaluation. [Table: see text]

Intensification of Mercaptopurine/Methotrexate Maintenance Chemotherapy May Increase the Risk of Relapse for Some Children With Acute Lymphoblastic Leukemia

2003 ◽  
Vol 21 (7) ◽  
pp. 1332-1339 ◽  
Author(s):  
Kjeld Schmiegelow ◽  
Olle Björk ◽  
Anders Glomstein ◽  
Göran Gustafsson ◽  
Niels Keiding ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Tpmt Activity ◽  
Control Group ◽  
Cox Regression Analysis ◽  
Cell Counts ◽  
Increased Risk ◽  
Risk Of Relapse

Purpose: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). Patients and Methods: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). Results: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P = .00003), high WBC at diagnosis (P = .03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P = .002), and high average neutrophil counts during maintenance therapy (P = .0009), with a significant interaction between sex and randomization group (P = .0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P = .001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P < .0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P = .03; boys 19.3 v 18.0 U/mL, P = .04). Conclusion: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

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