Genetic Variants in the UDP-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan

2004 ◽  
Vol 22 (8) ◽  
pp. 1382-1388 ◽  
Author(s):  
Federico Innocenti ◽  
Samir D. Undevia ◽  
Lalitha Iyer ◽  
Pei Xian Chen ◽  
Soma Das ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Total Bilirubin ◽  
Severe Neutropenia ◽  
Pharmacokinetic Data ◽  
Severe Toxicity ◽  
Genotype 3 ◽  
Count Nadir ◽  
Udp Glucuronosyltransferase

Purpose Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation. Patients and Methods Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m2 every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (−3279G>T, −3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped. Results The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P = .001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P = .02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean ± standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 ± 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 ± 0.03 mg/dL; P < .001). The −3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The −3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r2 = 0.51). Conclusion UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the −3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.

Fatal Neutropenia and Thrombocytopenia Associated with Ticlopidine

1994 ◽  
Vol 28 (11) ◽  
pp. 1236-1238 ◽  
Author(s):  
James A. Carlson ◽  
Jon E. Maesner
Keyword(s):  
Renal Function ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Impaired Renal Function ◽  
Healthcare Professionals ◽  
Severe Neutropenia ◽  
Gram Negative ◽  
Case Summary ◽  
First Case

OBJECTIVE: To report the first case of ticlopidine-associated neutropenia resulting in sepsis and death. CASE SUMMARY: An 83-year-old Filipino man was started on ticlopidine 250 mg bid. By the seventh week of therapy his absolute neutrophil count (ANC) had dropped to 2700 from 7600 × 106 cells/L. The ticlopidine was stopped. Six days later, he was admitted to the hospital. He died 18 hours later of gram-negative sepsis. DISCUSSION: Although ticlopidine therapy was discontinued four days after the patient's ANC was 2700 × 106 cells/L, the ANC dropped to and remained at 0 until his death eight days later. This may be associated with the patient's decreased clearance of ticlopidine given his age and impaired renal function. This is the first reported case of moderate or severe neutropenia in a nonwhite patient and the first reported case of sepsis and death caused by ticlopidine CONCLUSIONS: Healthcare professionals must be aware of the possibility of severe neutropenia and death caused by ticlopidine, even when the manufacturers' monitoring guidelines are followed.

scholarly journals Safety and efficacy of rifabutin among HIV/TB-coinfected children on lopinavir/ritonavir-based ART

2019 ◽  
Vol 74 (9) ◽  
pp. 2707-2715 ◽  
Author(s):  
Holly E Rawizza ◽  
Kristin M Darin ◽  
Regina Oladokun ◽  
Biobele Brown ◽  
Babatunde Ogunbosi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Treatment Options ◽  
Severe Neutropenia ◽  
Laboratory Monitoring ◽  
Safety And Efficacy ◽  
Cell Percentage ◽  
Grade 3 ◽  
Cd4 Cell

Abstract Background TB is the leading cause of death among HIV-infected children, yet treatment options for those who require PI-based ART are suboptimal. Rifabutin is the preferred rifamycin for adults on PI-based ART; only one study has evaluated its use among children on PIs and two of six children developed treatment-limiting neutropenia. Methods Since 2009, rifabutin has been available for HIV/TB-coinfected children requiring PI-based ART in the Harvard/APIN programme in Nigeria. We retrospectively analysed laboratory and clinical toxicities at baseline and during rifabutin therapy, and examined HIV/TB outcomes. Results Between 2009 and 2015, 48 children received rifabutin-containing TB therapy with PI (lopinavir/ritonavir)-based ART: 50% were female with a median (IQR) baseline age of 1.7 (0.9–5.0) years and a median (IQR) CD4+ cell percentage of 15% (9%–25%); 52% were ART experienced. Eighty-five percent completed the 6 month rifabutin course with resolution of TB symptoms and 79% were retained in care at 12 months. Adverse events (grade 1–4) were more common at baseline (27%) than during rifabutin treatment (15%) (P = 0.006). Absolute neutrophil count was lower during rifabutin compared with baseline (median = 1762 versus 2976 cells/mm3, respectively), but only one instance (2%) of grade 3 neutropenia occurred during rifabutin treatment. Conclusions With clinical and laboratory monitoring, our data suggest that rifabutin is a safe option for TB therapy among children on PI-based ART. By contrast with the only other study of this combination in children, severe neutropenia was rare. Furthermore, outcomes from this cohort suggest that rifabutin is effective, and a novel option for children who require PI-based ART. Additional study of rifabutin plus PIs in children is urgently needed.

GlycoPEGylated Filgrastim XM22 Fixed Dose Demonstrates Similar Activity in Comparison to Pegfilgrastim in Healthy Volunteers after Single Administration.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4082-4082
Author(s):  
Heinz Lubenau ◽  
Rolf Pokorny ◽  
Luis Lopez-Lazaro ◽  
Peter Bias ◽  
Bruce Wallin ◽  
...  
Keyword(s):  
Body Weight ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Cell Count ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Severe Neutropenia ◽  
Fixed Dose ◽  
Duration Of Action ◽  
Treatment Groups

Abstract XM22 is a glycoPEGylated recombinant human G-CSF that interacts with the G-CSF receptor by binding and activation. In pilot studies in non-neutropenic animals, XM22 demonstrated a similar PK/PD profile compared to pegfilgrastim. By its longer duration of action compared to filgrastim a once per cycle dosing as fixed dose in chemotherapy treated cancer patients for the reduction of duration of severe neutropenia and incidence of febrile neutropenia is intended. METHODS: A single center, randomized, single-blind study of XM22, administered as single fixed dose given by the s.c. route, was conducted to assess safety, pharmacokinetic profile and pharmacodynamic properties based on absolute neutrophil count (ANC) and CD34+ cell count. Male or female healthy volunteers were assigned to either XM22 6 mg or pegfilgrastim 6 mg fixed dose treatment. RESULTS: 36 healthy volunteers were enrolled in two treatment groups and completed 21 day follow-up. Injections were generally well-tolerated with no discontinuations due to adverse events or serious adverse events. Pharmacodynamic data were compared between the fixed doses of 6 mg XM22 and pegfilgrastim and in body weight strata within the treatment groups. Pharmacokinetic and antibody data will be presented. CONCLUSIONS: Single doses of 6 mg fixed dose of XM22 administered to healthy volunteers were generally well-tolerated with regard to the expected side effect profile and demonstrated increases in absolute neutrophil count and CD34+ cell count. These results supplement data from another study in healthy volunteers in which XM22 was administered in ascending single doses adjusted according to body-weight.

Predictive Role of the UGT1A1, UGT1A7, and UGT1A9 Genetic Variants and Their Haplotypes on the Outcome of Metastatic Colorectal Cancer Patients Treated With Fluorouracil, Leucovorin, and Irinotecan

2009 ◽  
Vol 27 (15) ◽  
pp. 2457-2465 ◽  
Author(s):  
Erika Cecchin ◽  
Federico Innocenti ◽  
Mario D'Andrea ◽  
Giuseppe Corona ◽  
Elena De Mattia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Objective Response ◽  
Area Under The Curve ◽  
Reference Sequence ◽  
Hematologic Toxicity ◽  
Pharmacokinetic Data ◽  
Severe Toxicity ◽  
Colorectal Cancer Patients

Purpose UGT1A1★28 is considered the main pharmacogenetic predictor of the toxicity outcome of irinotecan-treated patients. We evaluated the effect of other UGT1A variants and haplotypes involved in 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation on severe toxicity and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI). Patients and Methods In addition to UGT1A1★28, UGT1A1★60, UGT1A1★93, UGT1A7★3, and UGT1A9★22 were genotyped in 250 metastatic colorectal cancer patients, and associations with severe hematologic and nonhematologic toxicity, objective response, time to progression (TTP), and overall survival were evaluated. In a subset of 71 patients, pharmacokinetic data were also available. Results UGT1A7★3 was the only marker of severe hematologic toxicity after the first cycle (odds ratio [OR], 3.94; 95% CI, 1.05 to 14.82; P = .04) in a multivariate analysis. It was also associated with glucuronidation ratio (SN-38G area under the curve [AUC]/SN-38 AUC) and biliary index (irinotecan AUC) × (SN-38 AUC/SN-38G AUC). Haplotype I (all the reference sequence alleles but UGT1A9★22) was a predictor of severe hematologic toxicity during the entire course of therapy (OR, 0.39; 95% CI, 0.19 to 0.82; P = .01), together with sex (OR, 2.08; 95% CI, 1.01 to 4.28; P = .05). In addition to UGT1A1★28, haplotype II (all the variant alleles but UGT1A9★22) was associated with a response rate (OR, 8.61; 95% CI, 1.75 to 42.38; P = .01). UGT1A1★28 was the only marker associated with TTP. Conclusion We propose that UGT1A variants additional to UGT1A1★28 might improve the prediction of the outcome of colorectal cancer patients treated with FOLFIRI. A UGT1A haplotype-based approach might be an efficacious strategy to achieve treatment individualization of FOLFIRI.

scholarly journals Serum Total Bilirubin as a Predictive Factor for Severe Neutropenia in Lung Cancer Patients Treated with Cisplatin and Irinotecan

2007 ◽  
Vol 37 (5) ◽  
pp. 358-364 ◽  
Author(s):  
Yutaka Fujiwara ◽  
Ikuo Sekine ◽  
Yuichiro Ohe ◽  
Hideo Kunitoh ◽  
Noboru Yamamoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Predictive Factor ◽  
Total Bilirubin ◽  
Severe Neutropenia ◽  
Serum Total Bilirubin ◽  
Lung Cancer Patients

scholarly journals Absolute Neutrophil Count in the Peripheral Blood Predicts Prognosis in Lung Cancer Patients Treated with Anlotinib

2021 ◽  
Vol Volume 13 ◽  
pp. 3619-3627
Author(s):  
Rong Chen ◽  
Fang-Ying Lu ◽  
Bing Liu ◽  
Jingwen Huang ◽  
Min Zhou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Peripheral Blood ◽  
Lung Cancer Patients

scholarly journals Absolute Neutrophil Count and Mean Platelet Volume in the Blood as Biomarkers to Detect Lung Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-5 ◽  
Author(s):  
Xuming Zhu ◽  
Yan Chen ◽  
Yubao Cui
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Mean Platelet Volume ◽  
Healthy Subjects ◽  
Healthy Individuals ◽  
Weak Correlation ◽  
Platelet Volume ◽  
Lung Cancer Patients

Objective. Inflammation plays an extremely considerable role in the development and progression of malignancies. Absolute neutrophil count (ANC) and mean platelet volume (MPV) in blood are associated with various inflammatory conditions and resulted in independent prognostic factors for lung cancer. However, whether ANC and MPV can be diagnostic markers for lung cancer remains unknown. This retrospective study investigated the roles of ANC and MPV, either alone or combined, in diagnosing lung cancer. Methods. This study analyzed data from lung cancer patients and healthy individuals in Wuxi People’s Hospital Affiliated with Nanjing Medical University. The Mann–Whitney U-test was performed to compare differences between lung cancer patients and healthy individuals. Spearman’s correlation analysis was used to assess correlations. Receiver operating characteristic (ROC) curves were performed to determine diagnostic accuracy. Results. 209 patients diagnosed with lung cancer and 236 healthy subjects were enrolled in this study. Levels of ANC and MPV increased in lung cancer patients compared with healthy individuals (P<0.001). ANC had statistically significant negative weak correlation with albumin concentrations (r=‐0.154, P=0.026), and MPV had statistically significant negative weak correlation with total protein concentrations (r=‐0.153, P=0.027) in lung cancer patients. ANC and neutrophil-to-lymphocyte ratio had statistically significant positive correlation in both lung cancer patients (r=0.756, P<0.001) and healthy subjects (r=0.639, P<0.001). MPV and platelet-to-lymphocyte ratio had statistically significant negative weak correlation in both lung cancer patients (r=‐0.242, P<0.001) and healthy subjects (r=‐0.325, P<0.001). ANC had sensitivity (SEN) and specificity (SPE) of 0.512 and 0.809, respectively, and the area under the curve (AUC) with 95% confidence interval (95% CI) was 0.656 (0.603-0.710). SEN and SPE of MPV were 0.928 and 0.708, respectively, and the AUC (95% CI) was 0.913 (0.889-0.938). When ANC and MPV were combined, SEN and SPE became 0.842 and 0.835, respectively, and the AUC (95% CI) became 0.919 (0.895-0.943). Conclusions. Compared with ANC or MPV alone, the combination of ANC and MPV can improve diagnostic ability to distinguish lung cancer patients from healthy subjects.

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