scholarly journals 702. Hepatic Safety Among Patients Treated with Anti-Fungal Triazole Agent Posaconazole: Characterization of Adverse events in a Manufacturer’s Safety Database

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S317-S317
Author(s):  
Yun-Ping Zhou ◽  
Rose O’Flynn ◽  
Hetty Waskin ◽  
Ronald W Leong ◽  
Walter Straus
Keyword(s):  
Adverse Events ◽  
Drug Exposure ◽  
Entire Group ◽  
Cell Transplant ◽  
Medical Conditions ◽  
Hepatocellular Injury ◽  
Hematopoietic Stem ◽  
Safety Database ◽  
Concomitant Medications ◽  
Anti Fungal

Abstract Background Second-generation triazoles including posaconazole are highly efficacious for the prophylaxis and salvage treatment of life-threatening invasive fungal diseases. All triazoles have been associated with hepatic adverse events (AEs), which may affect their clinical use; however, risk factors for those AEs are poorly defined. Methods Reports of hepatobiliary AEs for posaconazole from clinical trials and post-market use in our company’s global safety database were reviewed to characterize concomitant medical conditions and drug exposure. Results As of 2018, 444 cases of hepatic AEs were reported; 139 (31%) led to discontinuation of posaconazole. Most hepatic AEs had a time to onset >20 days (55.5%). The most frequent AEs reported (per Medical Dictionary for Regulatory Activities) were: Hyperbilirubinaemia (17%); Hepatotoxicity (13.5%); Hepatic function abnormal (11.5%); and Hepatocellular injury (11.3%). Most patients were adults (18–64 years old) (65%). Hematological malignancy (128 cases, 29%) and hematopoietic stem cell transplant (91 cases, 20%) were leading concurrent medical conditions. Notably, 75% of the cases reported exposure to other drugs (often multiple ones) with known risks for drug-induced liver injury (DILI, e.g., acetaminophen, cytarabine, cyclosporine). Among 139 cases in which posaconazole treatment was discontinued due to hepatic AEs, 6 of the 20 most frequently used co-medications (used by >4.5% of the cases) were classified by the FDA in its DILIRank as “Most-DILI-Concern” (resulting in drug withdrawal, or prominent labeling for severe DILI risk in boxed warning or warnings and precautions), and 7 were “Less-DILI-concern” drugs (DILI risk language in warnings and precautions or adverse reactions). Similarly, of the top 35 concomitant medications for the entire group, 9 are classified as “Most-DILI-Concern” and 12 are “Less-DILI Concern” drugs. Conclusion The use of concomitant medications with known risks for hepatic injury appears to be an important contributor to the development of hepatotoxicity in patients treated with posaconazole. Co-administration of these drugs with anti-fungal triazole agents such as posaconazole, when needed, will continue to be carefully monitored. Disclosures All authors: No reported disclosures.

scholarly journals Blinatumomab In pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis

2022 ◽  
Author(s):  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Noemi Mergen ◽  
Peter Bader ◽  
Sima Jeha ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Expanded Access ◽  
Molecular Abnormalities

The safety and efficacy of blinatumomab, a CD3/CD19-directed bispecific T-cell engager molecule, for treatment of pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) were examined in an open-label, single-arm, expanded access study (RIALTO). Children (>28 days, <18 years) with CD19+ R/R B-ALL received up to five cycles of blinatumomab by continuous infusion (cycle: 4 weeks on/2 weeks off). The primary endpoint was incidence of adverse events. Secondary endpoints included complete response (CR) and measurable residual disease (MRD) response within the first two cycles, relapse-free survival (RFS), overall survival (OS) and allogeneic hematopoietic stem cell transplant (alloHSCT) after treatment. At final data cutoff (1/10/20), 110 patients were enrolled (median age, 8.5 years; 88% ≥5% blasts at baseline). Blinatumomab treatment resulted in a low incidence of grade 3-4 cytokine release syndrome (n=2 [1.8%]) and neurologic events (n=4 [3.6%]). No blinatumomab-related fatal adverse events were reported. The probability of response was not affected by the presence of cytogenetic/molecular abnormalities. Median OS was 14.6 months (95%CI: 11.0─not estimable) and was significantly greater for MRD responders versus MRD non-responders (not estimable vs 9.3; HR 0.18, 95%CI: 0.08─0.39). One-year OS probability was higher for patients who received alloHSCT versus without alloHSCT post-blinatumomab (87% versus 29%). Median RFS for MRD responders (n=57) was 8.0 months (95%CI:3.4─10.1) versus 2.8 months (95%CI: 0.3─9.2) for MRD non-responders (n=10). Of patients achieving CR after 2 cycles, 73.5% (95%CI: 61.4%-83.5%) proceeded to alloHSCT. These findings support the use of blinatumomab as a safe and efficacious treatment for pediatric R/R B-ALL. (ClinicalTrials.gov identifier NCT02187354)

Vancomycin Resistant Enterococcus (VRE) Bloodstream Infections (BSI) in Patients with Hematological Malignancies: Is the Sick Getting Sicker?.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5373-5373
Author(s):  
Erik R. Dubberke ◽  
James Holland ◽  
Peter Georgantopolis ◽  
Kristan Augustin ◽  
John F. Dipersio ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Medical Condition ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Bloodstream Infections ◽  
Apache Ii ◽  
Apache Ii Score ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Anti Fungal

Abstract Patients with hematologic malignancies and hematopoietic stem cell transplant (HSCT) recipients are at high risk for bacterial BSI. Data describing the prognosis and outcomes of VRE BSI in this patient population is limited. We performed a retrospective chart review of all cases of VRE BSI occurring between February 1996 and December 2002 on the Leukemia/HSCT unit at Barnes-Jewish Hospital. 68 episodes of VRE BSI were observed in 60 patients with acute (53%) or chronic (8%) leukemia, NHL (22%), or other malignant hematologic disorders (17%).46 were autologous (13%), related (32%) and URD (32%) transplant recipients. Forty days prior to the VRE BSI, 70% were colonized with VRE, 95% had broad-spectrum antibiotic exposure and 42% had non-VRE BSI, 35% pneumonia, 22% CMV reactivation, 10% fungal infection. At the time of the VRE BSI, 42% of allograft recipients had active acute GVHD and 32% chronic GVHD. Only 57% were neutropenic, 52% had refractory/relapsed malignancy, and 60% had end organ dysfunction with a median APACHE II score of 17. VRE was easily eradicated from the bloodstream after initiation of anti-VRE therapy (median time to clearance 1 (range 1–9) day). 3 patients died within 48 hours of the VRE BSI from causes unrelated to the BSI. Median survival after VRE BSI was 19 days. Only 4 deaths were directly attributable to the VRE BSI. Age, ECOG PS ≥ 2 on admission, HSCT, pneumonia, mechanical ventilation, acute neurologic dysfunction, receipt of anti-fungal drugs, and low APACHE II score were significant factors associated with death by univariate analysis, while pneumonia, receipt of anti-fungal drugs, and low APACHE II score at the time of the VRE BSI remained significant after multivariate analysis. In summary, our analysis suggests that in patients with hematological malignancies, VRE does not have the microbiologic behavior of a virulent pathogen. VRE BSI may simply be a marker of these patients’s already existing critical medical condition.

scholarly journals Immunogenicity and safety of a live herpes zoster vaccine in hematopoietic stem cell transplant recipients

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
June Young Chun ◽  
Kichun Kim ◽  
Min Kyeong Lee ◽  
Chang Kyung Kang ◽  
Youngil Koh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Herpes Zoster ◽  
Adverse Events ◽  
Immune Responses ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Hematologic Malignancy ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Chemotherapy Group

Abstract Background Herpes zoster (HZ) infection of hematopoietic stem cell transplant (HSCT) patients is of clinical concern. Vaccination could help restore immunity to varicella zoster virus (VZV); however, temporal changes in immunogenicity and safety of live HZ vaccines after HSCT is still unclear. The aim of this study was to elucidate the temporal immunogenicity and safety of the HZ vaccine according to time since HSCT and to determine optimal timing of vaccination. Methods Live HZ vaccine was administered to patients 2–5 years or > 5 years post-HSCT. Control groups comprised patients with a hematologic malignancy who received cytotoxic chemotherapy and healthy volunteers. Humoral and cellular immunogenicity were measured using a glycoprotein enzyme-linked immunosorbent assay (gpELISA) and an interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assay. Vaccine-related adverse events were also monitored. Results Fifty-six patients with hematologic malignancy (41 in the HSCT group and 15 in the chemotherapy group) along with 30 healthy volunteers were enrolled. The geometric mean fold rises (GMFRs) in humoral immune responses of the 2–5 year and > 5 year HSCT groups, and the healthy volunteer group, were comparable and significantly higher than that of the chemotherapy group (3.15, 95% CI [1.96–5.07] vs 5.05, 95% CI [2.50–10.20] vs 2.97, 95% CI [2.30–3.83] vs 1.42, 95% CI [1.08–1.86]). The GMFR of cellular immune responses was highest in the HSCT 2–5 year group and lowest in the chemotherapy group. No subject suffered clinically significant adverse events or reactivation of VZV within the follow-up period. Conclusion Our findings demonstrate that a live HZ vaccine is immunogenic and safe when administered 2 years post-HSCT.

scholarly journals Risk Factors for CMV Viremia and Treatment-Associated Adverse Events among Pediatric Hematopoietic Stem Cell Transplant Recipients

2021 ◽  
Author(s):  
Sarah M Heston ◽  
Rebecca R Young ◽  
John S Tanaka ◽  
Kirsten Jenkins ◽  
Richard Vinesett ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Adverse Events ◽  
Hematopoietic Stem Cell ◽  
Treatment Strategies ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Antiviral Medications ◽  
Donor Source

Abstract Background Cytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HSCT). There are limited data on risk factors for CMV viremia and the safety of antiviral medications used to treat CMV in children. Methods We conducted a single-center retrospective study of children who underwent HSCT between 2000 and 2016. We used log-logistic regression to evaluate associations between clinical characteristics and CMV-free survival at 100 days after HSCT. We compared the incidences of laboratory-defined adverse events (AEs) during treatment with ganciclovir and foscarnet. Results Among 969 children, median (interquartile range) age was 6.5 (3.1, 11.5) years, and 80% underwent allogeneic HSCT. Two hundred forty-four (25%) children developed CMV viremia. Older age (OR=0.95; 95% CI: 0.92, 0.98), male sex (OR=0.71, 95% CI: 0.51, 0.99), non-Black non-white race (OR=0.56; 95% CI: 0.36, 0.87), umbilical cord blood donor source (OR=0.28; 95% CI: 0.08, 0.97), and CMV-seropositivity (R-/D+, OR=0.17, 95% CI: 0.07, 0.41; R+/D-, OR=0.14, 95% CI: 0.09, 0.21; R+/D+, OR=0.08, 95% CI: 0.04, 0.15) were associated with lower odds of 100-day CMV-free survival. Compared to foscarnet, ganciclovir was associated with lower incidences of thrombocytopenia (IRR: 0.38; 95% CI: 0.15, 0.97), electrolyte AEs (IRR: 0.42; 95% CI: 0.24, 0.75), endocrine AEs (IRR: 0.52; 95% CI: 0.34, 0.79), and renal AEs (IRR: 0.36; 95% CI: 0.19, 0.65). Conclusions CMV viremia occurred commonly among children after HSCT, and ganciclovir and foscarnet were associated with distinct toxicity profiles among children with CMV infection. These findings should be considered when developing CMV prevention and treatment strategies for children after HSCT.

A Randomized Placebo Controlled Phase II Trial of Prevention of Severe Oral Mucositis Using Single Dose Velafermin in Patients Receiving Myeloablative Therapy and Autologous Hematopoietic Stem Cell Transplant (AHSCT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 615-615 ◽  
Author(s):  
Michael W. Schuster ◽  
J. Mehta ◽  
E.K. Waller ◽  
R.M. Rifkin ◽  
I. Micallef ◽  
...  
Keyword(s):  
Stem Cell ◽  
Adverse Events ◽  
Oral Mucositis ◽  
Interim Analysis ◽  
Safety Information ◽  
Study Drug ◽  
Controlled Study ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Safety And Efficacy

Abstract Oral mucositis (OM) is a commonly occurring side effect in patients (pts) undergoing AHSCT. Velafermin, recombinant human fibroblast growth factor-20, is under investigation for the prevention of severe OM. Previous studies demonstrated that velafermin at 30 mcg/kg was well tolerated and was effective in reducing the incidence of severe mucositis. The primary objective of this multicenter, randomized, double-blind, placebo controlled study was to confirm safety and efficacy of 30 mcg/kg velafermin for prevention of severe OM incidence (grade 3/4 OM based on the WHO grading system). The secondary objective was to evaluate safety and efficacy of 10 and 60 mcg/kg doses to better define the therapeutic range. Pts were randomized to receive placebo or velafermin at 30, 10 or 60 mcg/kg in a 3:3:1:1 ratio 24–36 hrs after stem cell infusion. Randomization was stratified by study center and OM risk factors identified from the previous placebo controlled study in a similar population including conditioning regimen and body mass index (BMI ≥30). Pts with multiple myeloma or lymphoma (≥18 y.o.) receiving ≥2X106 /kg CD34+ cells following chemotherapy with or without Total Body Irradiation (TBI) were eligible. OM status and safety data were collected for 30 days post treatment while mortality and disease progression were followed for 1 yr. An interim analysis by a data monitoring committee (DMC) was planned to assess safety and efficacy after 50% of pts completed the 30 day treatment period. A total of 390 pts who received melphalan (200 mg/m2) (n=239), BEAM (n=129), TBI (n=15), or other (n=7) were randomized and 384 pts were treated. The study drug was well tolerated in general and no pts discontinued study due to drug-related adverse events. There were 93 serious adverse events (SAEs) in 78 (20%) pts and no drug-related death was reported. Five infusion-related SAEs were reported including vasovagal episode (2), syncope (2), and anaphylactoid reaction (1). All 5 episodes occurred on the day of study drug infusion and resolved on the same day with no sequelae. Based on review of the results from the interim analysis, which included safety and efficacy data from 200 pts, the DMC recommended that the study continue to completion as planned. The last pt has completed the 30 day study period. The un-blinded results of the OM efficacy endpoints from velafermin treated groups or placebo as well as 30-day safety information from all pts will be reported.

Gemtuzumab-Ozogamicin in Combination with Fludarabine, Cytarabine, Idarubicin (FLAI-GO) as Induction Therapy in CD33-Positive AML patients Younger Than 65 Years. Report of a Multicentric Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3998-3998
Author(s):  
Anna Candoni ◽  
Giovanni Martinelli ◽  
Cristina Papayannidis ◽  
Erica Simeone ◽  
Eleonora Toffoletti ◽  
...  
Keyword(s):  
Adverse Events ◽  
Safety Profile ◽  
Response Rate ◽  
Residual Disease ◽  
Target Therapy ◽  
Prospective Trial ◽  
Gemtuzumab Ozogamicin ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Induction Regimen

Abstract INTRODUCTION. The addition of Gemtuzumab-ozogamicin (GO) to an induction regimen including synergistic drugs, such as intermediate dose of cytarabine (Ara-C), idarubicin and fludarabine (FLAI), could reduce treatment failure in AML patients. Nevertheless, the role and safety of this antibody target-therapy in first-line chemotherapy in patients younger than 65 years has not yet been defined. PATIENTS and METHODS. The primary goal of this multicenter prospective trial (EUDRACT Number 2007-005248-26) was to evaluate the efficacy and the safety profile of FLAI plus GO as induction regimen. Sixty-eight consecutive AML patients were included from five Italian hematological centres. All patients were younger than 65 with a median age of 48 years and CD33 expression exceeded 20% in all cases. The M/F ratio was 37/31, and 54/68 (79%) of patients were poor-risk at diagnosis. The induction regimen (FLAI-GO) included fludarabine (30 mg/sqm) and Ara-C (2 g/sqm) on days 1–5, idarubicin (10 mg/sqm) on days 1, 3, and 5 and GO (3 mg/sqm) on day 6. Hematopoietic stem cell transplant (HSCT) was planned for all high risk AML patients in first complete remission (CR) after consolidation with intermediate doses of Ara-C and idarubicin (IDAC-IDA). Cytogenetic, multidrug-resistance phenotype, FLT3 mutation status, and WT1 quantitative expression analyses were performed at diagnosis in all patients. WT1 expression and cytogenetic (in positive cases) analyses were performed after induction to detect and follow Minimal Residual Disease. RESULTS. Patients were evaluated for response rate, treatment-related adverse events, overall survival and relapse free survival. After induction with FLAI-GO, CR rate was 86% (54 of 63 evaluable pts); one patient achieved partial remission and eight were resistant. There were only two cases of death during induction (DDI). After FLAI-GO, the mean value of WT1 dropped from 4540±2342 copies/104ABL to 180±277 copies/104ABL. The toxicity of FLAI-GO was acceptable; 58% of patients experienced transient and reversible GO infusion-related adverse events (especially fever and chills), but no cases of veno-occlusive disease occurred during CHT or after HSCT. After a median follow-up of 9 months (range 1–32), 60/68 (88%) patients are alive (57/60 in CR). The probability of 12 and 18 mths OS a was 91% and 78%, respectively. The probability of 12 and 18 mths RFS was 87 % and 78%, respectively. Allogeneic and autologus HSCT was performed in 30 (44%) and 8 (12%) patients. CONCLUSIONS. The preliminary results of this multicentric trial confirm that FLAI-GO is an effective and well tolerated induction regimen for CD33 positive AML patients younger than 65 years, with a high complete response rate, favourable safety profile and low DDI.

Adoptive Immune Cell Therapy for the Control of Fungal Infections in Hematopoietic Stem Cell Transplant Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4358-4358
Author(s):  
Lung-Ji Chang ◽  
Yin Liang ◽  
Lily Lien ◽  
Chun- Rong Tong ◽  
Lu-Jia Dong ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Fungal Infections ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Immune Effector ◽  
Effector Cells ◽  
Transplant Patients ◽  
Fungal Antigens ◽  
Anti Fungal

Abstract Similar to virus infections, fungal infections are commonly seen in immunosuppressed transplant patients and can be life-threatening. Invasive Aspergillosis and Candidiasis are principal fungal infections among hematopoietic stem cell transplant (HSCT) patients, but Aspergillosis and other molds are the leading cause of deaths by fungal infections in immunocompromised allogeneic HSCT patients. The most effective treatment for fungal infections is preemptive and empirical anti-fungal therapies using agents such as fluconazole and amphotericin B deoxycholate (AmB-D). However, the success rate of antifungal therapy is generally low (in the 30–40% range) and associated with high toxicity. Both diagnosis and treatment for fungal infections are expensive and often ineffective. While improved formulations of AmB-D, second-generation triazoles, and echinocandins may be tolerable, newer generations of anti-fungal agents are very expensive. In animal studies, it has been shown that Aspergillosis can be successfully treated using Aspergillus-specific cytotoxic T cells (CTLs). Therefore, it is conceivable that CTLs specific to fungal antigens are effective in controlling fungal infections in allogeneic HSCT patients. To explore anti-fungal immune cell therapy, we used two different approaches to generate fungus-specific immune cells: Trichoderma and Rhizopus fungal lysates as antigen source to pulse dendritic cells (DCs), and pooled antigenic peptides to pulse DCs. The antigen-primed DCs were then co-cultured with lymphocytes to generate antigen-specific immune effector cells. The ex vivo generated anti-fungal immune cells displayed antigen-specific effector functions as illustrated by intracellular IFN-γ and CD107a staining. Interestingly, the fungus-specific immune effector cells are mostly CD4 T cells for all three species of fungal antigens. In a pilot clinical study, patients were selected when diagnosed with invasive aspergillosis based on galactomannan and beta-glucan assays, radiographs, CT scans, and/or blood cultures, or after an extended unsuccessful anti-fungal treatment with non-tolerable organ toxicity. Early indications suggest that the infusion of anti-fungal immune cells is safe, with therapeutic efficacy based on objective clinical evidence and importantly, is cost-effective. Nevertheless, more effective diagnosis and surveillance tools are needed to document the effectiveness of our anti-fungal immune cell treatment.

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