Fatal Neutropenia and Thrombocytopenia Associated with Ticlopidine

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.

Download Full-text

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

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz219 ◽

2019 ◽

Vol 74 (9) ◽

pp. 2707-2715 ◽

Cited By ~ 4

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.

Download Full-text

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

Blood ◽

10.1182/blood.v110.11.4082.4082 ◽

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.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2004.07.173 ◽

2004 ◽

Vol 22 (8) ◽

pp. 1382-1388 ◽

Cited By ~ 714

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.

Download Full-text

Quantitative Relationship Between AUEC of Absolute Neutrophil Count and Duration of Severe Neutropenia for G-CSF in Breast Cancer Patients

Clinical Pharmacology & Therapeutics ◽

10.1002/cpt.991 ◽

2018 ◽

Vol 104 (4) ◽

pp. 742-748 ◽

Cited By ~ 4

Author(s):

Liang Li ◽

Lian Ma ◽

Sarah J. Schrieber ◽

Nam Atiqur Rahman ◽

Albert Deisseroth ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Absolute Neutrophil Count ◽

Neutrophil Count ◽

Quantitative Relationship ◽

Severe Neutropenia ◽

Breast Cancer Patients

Download Full-text

Meta-analysis and indirect treatment comparison of lipegfilgrastim with pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia-related events

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155217714859 ◽

2017 ◽

Vol 24 (6) ◽

pp. 412-423 ◽

Cited By ~ 9

Author(s):

T Christopher Bond ◽

Erika Szabo ◽

Susan Gabriel ◽

Jean Klastersky ◽

Omar Tomey ◽

...

Keyword(s):

Febrile Neutropenia ◽

Risk Ratio ◽

Absolute Neutrophil Count ◽

Neutrophil Count ◽

Bone Pain ◽

Meta Analysis ◽

Severe Neutropenia ◽

Random Effects Models ◽

Treatment Comparison ◽

Indirect Treatment

Background Granulocyte colony-stimulating factors are effective at reducing the risk and duration of neutropenia. The current meta-analysis compared the neutropenia-related efficacy and safety of lipegfilgrastim to those of pegfilgrastim and filgrastim. Methods Embase was searched for trials examining the efficacy/safety of lipegfilgrastim, pegfilgrastim, or filgrastim. Outcomes included febrile neutropenia, severe neutropenia, duration of severe neutropenia, time to recovery of absolute neutrophil count, and incidence of bone pain. Direct comparisons were made using random-effects models. No trials directly compared lipegfilgrastim and filgrastim. Indirect comparisons were made between lipegfilgrastim and filgrastim with pegfilgrastim as the common comparator. Results This meta-analysis included a total of 5769 patients from 24 studies. Over all cycles, lipegfilgrastim showed a lower, nonsignificant risk of febrile neutropenia compared with pegfilgrastim. Lipegfilgrastim has a lower risk of febrile neutropenia versus filgrastim but was also not statistically significant. The risk ratio for severe neutropenia in cycle 1 was 0.80, a 20% reduction in favor of lipegfilgrastim. For cycles 2–4, the risk ratio was 0.53 (0.35, 0.79) for lipegfilgrastim versus pegfilgrastim. The risk of severe neutropenia in cycles 2–4 was also significantly lower for lipegfilgrastim (risk ratio 0.45, 0.27, 0.75, respectively). No significant differences were found for febrile neutropenia and severe neutropenia in cycle 1. However, in cycles 2–4, lipegfilgrastim was associated with significant and clinically meaningful reductions in risk of severe neutropenia versus either pegfilgrastim or filgrastim. Conclusions Compared with pegfilgrastim or filgrastim, lipegfilgrastim has a statistically significantly lower absolute neutrophil count recovery time; however, differences in duration of severe neutropenia and bone pain were nonsignificant.

Download Full-text

Severe Neutropenia in Patients with Chronic Hepatitis C Not on Antiviral Therapy At the Memphis Veteran's Affairs Medical Center

Blood ◽

10.1182/blood.v118.21.4733.4733 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4733-4733

Author(s):

Vivien Sheehan ◽

Bradford Waters ◽

Alva B. Weir

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Antiviral Therapy ◽

Chronic Hepatitis C ◽

Absolute Neutrophil Count ◽

Neutrophil Count ◽

Medical Center ◽

Severe Neutropenia ◽

Significant Difference ◽

Veteran's Affairs

Abstract Abstract 4733 Abstract: We reviewed the records of 685 patients evaluated for treatment of chronic hepatitis C virus (HCV) at the Veteran's Affairs Medical Center in Memphis, TN in 2010. We identified six cases of severe neutropenia (defined as an absolute neutrophil count <500 x103/dL), in the absence of medications known to cause neutropenia such as interferon. None had concomitant HIV infections. Bone marrow biopsies were performed in three of the six patients and were negative for malignancy or abnormal myelopoesis. In this case series report, we compare laboratory parameters and clinical histories of these six patients to a similar cohort of chronic hepatitis C patients with at least one documented absolute neutrophil count (ANC) between 1000 x103/dL and 1500 × 103/dL. The two groups differed only in ANC and frequency of anti-nuclear antibody positivity. There was no significant difference in race, MELD scores, viral load, viral type, hemoglobin levels or platelet levels. Neither group suffered serious systemic infections. There was no evidence that the severe neutropenia was related to portal hypertension or splenomegaly. In our series, patients with severe neutropenia in the setting of chronic HCV had a benign course that did not lead to severe infections and responded to granulocyte colony stimulating factor. This opens the question of whether these patients may be candidates for antiviral therapy. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

GlycoPEGylated Filgrastim XM22 Demonstrates Dose-Dependent Activity in Comparison to Pegfilgrastim in a Dose-Escalating Study in Healthy Volunteers after Body-Weight Dependent Single Dose.

Blood ◽

10.1182/blood.v110.11.4081.4081 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4081-4081

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 ◽

Dose Dependent

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. Because of its longer duration of action compared to filgrastim, XM22 is intended to be dosed once per cycle for the reduction of duration of severe neutropenia and incidence of febrile neutropenia in cancer patients undergoing chemotherapy. METHODS: A single center, randomized, single-blind study of XM22, administered as single escalating body-weight (bw) dependent doses 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 one of 3 XM22 dose groups, at 25 μg/kg bw dose (n=8), at 50 μg/kg bw (n=15), and 100 μg/kg bw (n=15) compared to 100 μg/kg bw pegfilgrastim (n=15). RESULTS: 53 healthy volunteers were enrolled in the three dose groups and completed 21 day follow-up. Injections were generally well-tolerated with no discontinuations due to adverse events or serious adverse events. XM22 at a dose of 100 μg/kg bw exhibited a PK profile with increased bioavailability and extended half life compared to the same dose of pegfilgrastim. ANC area over baseline effect curve (AOBEC) and CD34+ AOBEC were higher after treatment with XM22 100 μg/kg bw (6818.55 hr*neut./nl and 7340.16 hr*cell count/μl geometric mean respectively) compared to the same dose of pegfilgrastim. Antibody data will be presented. CONCLUSIONS: Single body-weight dependent doses up to 100 mg/kg of XM22 administered to healthy volunteers were generally well-tolerated with regard to the expected side effect profile and demonstrated dose-dependent increases in absolute neutrophil count and CD34+ cell count. These data supplement results from another study in healthy volunteers in which XM22 was administered as a fixed dose.

Download Full-text