scholarly journals Oral Minocycline As Systemic Therapy for Uncomplicated Venous Access Device-Related Bloodstream Infection with Coagulase-Negative Staphylococci in Patients after Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4859-4859
Author(s):  
Firas Bayoudh ◽  
Julie Descy ◽  
Corentin Fontaine ◽  
Frederic Baron ◽  
Evelyne Willems ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Systemic Therapy ◽  
Hematopoietic Cell Transplantation ◽  
Venous Access ◽  
Blood Cultures ◽  
Hematopoietic Cell ◽  
Coagulase Negative Staphylococci ◽  
Access Device ◽  
Venous Access Device

Abstract Venous access device-related bloodstream infections (VAD-BSIs) with coagulase-negative staphylococci (CoNS) are common complications after allogeneic hematopoietic cell transplantation (alloHCT). So far, the standard systemic antimicrobial therapy for uncomplicated VAD-BSIs with methicillin-resistant CoNS consisted of intravenous (IV) vancomycin (vanco). This approach requires hospitalization, necessitates new competent venous access, exposes patients to potential (mainly renal) toxicity and increases the risk of commensal flora dysbiosis with selection of vanco-resistant enterococci. Patients after alloHCT are particularly at risk of iatrogenic and nosocomial complications. In addition, repeated hospitalizations can impact autonomy and quality of life and are associated with significant costs. Minocycline (mino) is an oral antimicrobial agent that has strong in vitro effects on most Gram positive bacteria and potential anti-biofilm activity, and can be used in the clinic for some CoNS infections. Our infectious disease specialists proposed that systemic therapy with oral mino could be used for the management of uncomplicated VAD-BSIs, primarily when the reference treatment with IV vanco was not possible (renal failure or allergy) or when hospitalization was refused by patients. We retrospectively analyzed the results of this mino-based approach. From January 2012 to December 2020, we treated 24 uncomplicated VAD-BSIs with CoNS in 23 alloHCT patients aged 17-72y with oral mino. Uncomplicated VAD-BSIs were defined as 2 or more blood cultures positive for the same CoNS drawn consecutively peripherally and through the VAD, in patients without signs of sepsis, cellulitis or suppurative thrombophlebitis and without endovascular implant or orthopedic material. VAD were implantable ports (n=17), tunneled catheter (n=1) or PICC-lines (n=6). Pathogens were S. epidermidis (n= 21) or S. haemolyticus (n=3). CoNS were in vitro susceptible to mino according to EUCAST guidelines (with MIC <= 0.5mg/L, predominantly). Mino was administered at a dose of 100 mg BID for 7-14 days. For 8 VAD-BSIs, patients were initially treated with IV vanco for the first 1-3 days followed by oral mino, while 16 VAD-SIBs were managed with oral mino alone. VAD management consisted of catheter removal (for tunneled and PICC-lines, n=7) or antibiotic locks with vanco (n=15) or gentamicin (n=2) administered at least every other day for 14 days (for ports). Overall, clearance of bacteremia (as assessed by negativity of surveillance peripheral blood cultures with the same CoNS drawn between d+3 and +30 after initiation of systemic therapy) was achieved in all but 1 patient (with port, treated with mino alone) who had persistent bacteremia at day +9. No complication such as suppurative thrombophlebitis, endocarditis or metastatic foci of infection was observed in any patient during the 3-month period after initiation of treatment. Among the 17 patients for whom VAD salvage was attempted, VAD decontamination was successful in 10 cases while 4 patients experienced persistently positive VAD-derived blood cultures during the early (d+3 to +14) surveillance period and 3 patients experienced delayed relapse of VAD-BSIs with the same CoNS 1-3 months later (with 1 patient with cellulitis). All these events led to VAD removal. Treatment with mino was well tolerated with the exception of mild skin rash in one patient. Our results in this retrospective cohort suggest that oral mino can be a promising alternative to standard IV vanco for systemic therapy in VAD-BSIs with CoNS and that a strategy combining oral mino and antibiotic locks may salvage VAD in approximately half of the cases. This remains to be confirmed in prospective studies. Disclosures No relevant conflicts of interest to declare.

Abstract 135: Endothelial Dysfunction in Acute Graft-versus-host Disease After Allogeneic Hematopoietic Cell Transplantation. In vitro Evidence of the Protective Effect of Defibrotide

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Enrique Mir ◽  
Marta Palomo ◽  
Enric Carreras ◽  
Maribel Diaz-Ricart ◽  
Montse Rovira ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Protective Effect ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Endothelial Damage ◽  
Hematopoietic Cell ◽  
Graft Versus Host ◽  
Acute Graft

Acute Graft-Versus-Host Disease (aGVHD) is the most common early complication after allogeneic Hematopoietic Cell Transplantation (allo-HCT). We demonstrated endothelial dysfunction (ED) in association with allo-HCT. According to this data, aGVHD has been linked to an inflammatory process that may affect the endothelium. To investigate the differential degree of endothelial damage in patients developing or not aGVHD, to identify potential biomarkers, and to explore the protective effect of defibrotide (DF) in this scenario. DF has orphan designation for GVHD prevention. Patients blood samples were collected before allo-HCT, at day 0, and every week till day 28 after HCT. Plasma proteins (sTNFR1, sVCAM-1, VWF and ADAMTS-13) were measured as biomarkers of ED in individual samples from patients developing (GVHD, n=24), or not (NoGVHD, n=13), aGVHD. In in vitro assays, endothelial cells (EC) in culture were exposed to media containing pooled sera from patients to evaluate changes in the: a) expression of VCAM-1 and ICAM-1 on cell surfaces; b) presence of VWF on the extracellular matrix (ECM) and c) reactivity of the ECM towards platelets, under flow. The effect of DF was explored in the in vitro experiments by previous exposure of the EC (for 24h) followed by continuous incubation (100 μg/ml, added every 24h). Levels of sTNFRI, sVCAM-1 and VWF in samples from group GVHD were significantly higher than in NoGVHD (increases of 100, 37 and 150% respectively, at diagnose, p<0.01). ADAMTS-13 activity and VWF levels were inversely related. In in vitro studies, cell surface expression of VCAM-1 and ICAM-1, presence of VWF and platelet adhesion on the ECM in response to GVHD samples were always superior (increases vs NoGVHD of 80, 40, 100 and 21%, respectively, at diagnose). In vitro exposure of EC to DF attenuated signs of endothelial injury reducing significantly (p<0.05) the expression of VCAM-1, ICAM-1 and VWF (reductions of 22, 30 and 30%, respectively) in the GVHD condition. Our results demonstrate endothelial damage in association with aGVHD, as evidenced by elevated plasma levels of several biomarkers. The in vitro approach showed a marked proinflammatory and prothrombotic phenotype in association with aGVHD, which could be significantly prevented by defibrotide.

scholarly journals Bacterial substitution of coagulase-negative staphylococci for streptococci on the oral mucosa after hematopoietic cell transplantation

2010 ◽  
Vol 19 (7) ◽  
pp. 995-1000 ◽  
Author(s):  
Yoshihiko Soga ◽  
Yoshinobu Maeda ◽  
Fumihiko Ishimaru ◽  
Mitsune Tanimoto ◽  
Hiroshi Maeda ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Oral Mucosa ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Coagulase Negative Staphylococci

Alloanatigenic Reactions after Hematopoietic Cell Transplantation Induce Genomic Alterations in Epithelial Cells as Shown in Human Studies and in an In Vitro Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3213-3213
Author(s):  
Alexandros Spyridonidis ◽  
Philipp Faber ◽  
Loizos Petrikkos ◽  
Jurgen Finke
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Protein Translation ◽  
Hematopoietic Cell ◽  
Hygromycin B ◽  
Hygromycin Resistance ◽  
Hacat Cells ◽  
Genomic Alterations ◽  
Allogeneic Hct

Abstract Previous studies from our group demonstrated frequent genomic alterations measured by microsatellite instability (MSI) in non-neoplastic epithelial tissues of patients who underwent allogeneic hematopoietic cell transplantation (HCT) (Blood2006;107:3389–3396). These genomic alterations were found only after allogeneic but not after autologous HCT, and therefore we hypothesized that an “allogeneic” effect is substantially involved in the mutation process. We extended our previous analyses by examining 210 bucall swabs obtained from 70 patients between day (d+) 26 and d+3514 after allogeneic HCT for the presence of MSI. MSI analysis was performed by PCR and denaturing capillary electrophoresis at three tetranucleotide (THO-1, SEE33, D14S120) and three mononucleotide microsatellite (ZP3, BAT26, SRY) loci. MSI was found in the buccal smears of 38% allografted patients (median time of occurence 322 days). In a prospective trial, in which patients were followed from time before transplantation until d+365, 5 out of 14 (35%) patients exhibited MSI after transplantation although all of them showed stable microsatellites before transplantation. We are currently pefroming statistical analyses in order to identify which clinical factors influence the presence of MSI and we will present the data in the meeting. To test the hypothesis that an “alloantigenic” effect is responsible for th induction of MSI, we developed a model system in which keratinocyte (HaCaT) cells were transfected with a palsmid vector which carries a G418 (neo) selectable marker and a microsatellite repeat (CA) that places the sequence for Hygromycin Resistance (HygR) out of frame for protein translation. In this reporter system, DNA slippage mutations can restore the HygR reading frame and become detectable by hygromycin treatment as hygromycin resistant (HygR+) colonies. Pools of stably transfected (neo+) HaCaT cells were treated with supernatant (SN) of major histocompatibility complex nonmatched mixed lymphocyte cultures (MLC) and assayed for HygR+ colonies 48h later. Cells transfected with a control, in-frame hygromycin B gene construct (p12) were used as positive controls. Using this system, we found that HaCaT cells aquire hygromycin resistance after treatment with supernatatant from MLC. Treatment of cells with hydrogen hyperoxid which has been shown in a E. Coli system to induce MSI (PNAS1998, 95:12468–12473) generated HygR+ colonies at a >80% lower frequency than the SN-MLC treatment. Control p12 transfected cells were grown with high efficiency in the presence of hygromycin B. In summary, our in vivo data confirm our previous results and provide evidence of genomic alterations after allogeneic HCT and our in vitro data are compatible with the hypothesis that an “alloantigenic” factor is the driving force in producing detectable MSI in the allografted patients. Elucidating the ultimate mechanisms underlying the genomic instability following allogeneic HCT may prove to be of major therapeutic value.

scholarly journals Epidemiology and Real-World Treatment of Chronic Graft-Versus-Host Disease Post Allogeneic Hematopoietic Cell Transplantation: A US Claims Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2109-2109
Author(s):  
Carlos R. Bachier ◽  
Sanjay K. Aggarwal ◽  
Kalin Hennegan ◽  
Andrew Milgroom ◽  
Kevin Francis ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Real World ◽  
Systemic Therapy ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Outpatient Visits ◽  
Line Of Therapy

Background Chronic Graft-Versus-Host Disease (cGVHD) is a complication of hematopoietic cell transplantation (HCT). While the clinical outcomes of cGVHD are well documented, few studies have assessed its treatment practices in the real-world. The objectives of this study are to quantify the prevalence of cGVHD, to examine provider prescribing patterns, and to evaluate the healthcare cost and resource utilization (HCRU) in a real-world US cGVHD population. Methods This study analyzed de-identified claims from the Medicare FFS 5% sample for beneficiaries enrolled from 2013-2016 and Pharmetrics commercial 2013-2018 databases to identify cGVHD in allogenic HCT patients. cGVHD was identified based on ICD-9/10 diagnosis codes for cGVHD or unspecified GVHD with a first diagnosis >180 days post HCT, or subsequent unspecified GVHD diagnosis >12 months post index diagnosis. Chronic GVHD prevalence was estimated by calculating age-adjusted prevalence rates within the Medicare and Pharmetrics sample populations and applying rates to the total US patient subpopulations as determined by CMS and Census data. Prevalence estimates were based on the last complete year of both Medicare FFS and Pharmetrics data (2016). Longitudinal and Line of Therapy (LOT) analyses were based on data from 2013-2018. A new LOT was defined as starting with the addition of systemic therapy to a patient's cGVHD regimen, regardless of prior lines of therapy or prior treatment. Treatments that stopped and restarted within 60 days were considered continuous treatment. Healthcare costs were calculated by adding the inpatient, outpatient, and pharmacy insurer and beneficiary paid amounts for the commercially insured population. Total HCRU was assessed using the number of inpatient and outpatient visits following the initial cGVHD diagnosis. Results In 2016, the projected prevalence of cGVHD in the US based on the Medicare FFS and Pharmetrics commercial databases was 14,017 individual patients. Within 3 years post allogeneic HCT, 42% of patients developed cGVHD; 66% of cGVHD patients had a prior diagnosis of acute GVHD. The majority of cGVHD patients received at least one systemic therapy; 71% and 47% of cGVHD patients progressed to a second and third LOT, respectively (Table 1). Of patients that received a second and third LOT, the average time from diagnosis to the second and third LOT was approximately 7 months and 10 months, respectively. Over 80% of cGVHD patients received systemic corticosteroid therapy for the treatment of cGVHD within 12 months post diagnosis, and 41% of cGVHD patients were receiving a corticosteroid within the 30 days prior to diagnosis. Within the 12 months post cGVHD diagnosis, most patients received a corticosteroid or a corticosteroid combination as a first LOT (57%), which decreased slightly as patients progressed to second and third line of therapy (49% and 48%, respectively). A total of 25 unique therapeutic agents and over 150 combinations were used in second and third LOT. While newer agents, such as ibrutinib and ruxolitinib, are continuing to increase in utilization among cGVHD patients, these therapies are only used among 1% (ibrutinib) and 1-3% (ruxolitinib) of patients through their first three lines of therapy in the patients captured in Pharmetrics commercial database through June 2018. In the 12 months post diagnosis, cGVHD patients had an average of 21.0 GVHD-related inpatient and outpatient visits (2.8 inpatient and 18.2 outpatient visits). In 2016 the average total annual cost per commercially insured cGVHD patient was $291,357. Conclusion A significant proportion of allogenic HCT patients continue to develop cGVHD, and despite advances in the understanding of cGVHD, corticosteroids remain the mainstay of therapy. However, most cGVHD patients are not adequately managed with first line corticosteroids, and many patients are cycling through several therapies, likely in part due to lack of efficacy and toxicity associated with currently available treatments. Real-world utilization of systemic therapies is highly variable, particularly for patients who progress beyond the first LOT, which highlights the need for evidence-based treatment approaches. cGVHD is a highly burdensome complication of allogenic HCT, and safer, more effective treatments are needed as many patients are not currently well managed on available therapies. Disclosures Bachier: Viracyte: Consultancy; Kadmon Corporation, LLC: Consultancy; Sanofi: Speakers Bureau. Aggarwal:Kadmon Corporation, LLC: Employment, Equity Ownership. Hennegan:Kadmon Corporation, LLC: Consultancy. Milgroom:Kadmon Corporation, LLC: Consultancy. Francis:Kadmon Corporation, LLC: Consultancy. Rotta:Jazz: Speakers Bureau; Kadmon Corporation, LLC: Consultancy.

Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1828-1836 ◽  
Author(s):  
Alan M. Hanash ◽  
Robert B. Levy
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Disease Recurrence ◽  
Hematopoietic Cell ◽  
Allogeneic Bone ◽  
Hematopoietic Stem

AbstractAllogeneic bone marrow transplantation (BMT) is a potentially curative treatment for both inherited and acquired diseases of the hematopoietic compartment; however, its wider use is limited by the frequent and severe outcome of graft-versus-host disease (GVHD). Unfortunately, efforts to reduce GVHD by removing donor T cells have resulted in poor engraftment and elevated disease recurrence. Alternative cell populations capable of supporting allogeneic hematopoietic stem/progenitor cell engraftment without inducing GVHD could increase numbers of potential recipients while broadening the pool of acceptable donors. Although unfractionated CD4+ T cells have not been shown to be an efficient facilitating population, CD4+CD25+ regulatory cells (T-reg's) were examined for their capacity to support allogeneic hematopoietic engraftment. In a murine fully major histocompatibility complex (MHC)-mismatched BMT model, cotransplantation of donor B6 T-reg's into sublethally conditioned BALB/c recipients supported significantly greater lineage-committed and multipotential donor progenitors in recipient spleens 1 week after transplantation and significantly increased long-term multilineage donor chimerism. Donor engraftment occurred without GVHD-related weight loss or lethality and was associated with tolerance to donor and host antigens by in vitro and in vivo analyses. Donor CD4+CD25+ T cells may therefore represent a potential alternative to unfractionated T cells for promotion of allogeneic engraftment in clinical hematopoietic cell transplantation. (Blood. 2005;105:1828-1836)

scholarly journals KIR3DL1/HLA-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation

2017 ◽  
Vol 35 (20) ◽  
pp. 2268-2278 ◽  
Author(s):  
Jeanette E. Boudreau ◽  
Fabio Giglio ◽  
Ted A. Gooley ◽  
Philip A. Stevenson ◽  
Jean-Benoît Le Luduec ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Acute Myelogenous Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Nk Cell ◽  
High Risk Group ◽  
Hematopoietic Cell ◽  
Myelogenous Leukemia ◽  
Target Cells ◽  
Acute Myelogenous

Purpose Disease relapse remains a major challenge to successful outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Donor natural killer (NK) cell alloreactivity in HCT can control leukemic relapse, but capturing alloreactivity in HLA-matched HCT has been elusive. HLA expression on leukemia cells—upregulated in the post-HCT environment—signals for NK cell inhibition via inhibitory killer immunoglobulin-like (KIR) receptors and interrupts their antitumor activity. We hypothesized that varied strengths of inhibition among subtypes of the ubiquitous KIR3DL1 and its cognate ligand, HLA-B, would titrate NK reactivity against acute myelogenous leukemia (AML). Patients and Methods By using an algorithm that was based on polymorphism-driven expression levels and specificities, we predicted and tested inhibitory and cytotoxic NK potential on the basis of KIR3DL1/HLA-B subtype combinations in vitro and evaluated their impact in 1,328 patients with AML who underwent HCT from 9/10 or 10/10 HLA-matched unrelated donors. Results Segregated by KIR3DL1 subtype, NK cells demonstrated reproducible patterns of strong, weak, or noninhibition by target cells with defined HLA-B subtypes, which translated into discrete cytotoxic hierarchies against AML. In patients, KIR3DL1 and HLA-B subtype combinations that were predictive of weak inhibition or noninhibition were associated with significantly lower relapse (hazard ratio [HR], 0.72; P = .004) and overall mortality (HR, 0.84; P = .030) compared with strong inhibition combinations. The greatest effects were evident in the high-risk group of patients with all KIR ligands (relapse: HR, 0.54; P < .001; and mortality: HR, 0.74; P < .008). Beneficial effects of weak and noninhibiting KIR3DL1 and HLA-B subtype combinations were separate from and additive to the benefit of donor activating KIR2DS1. Conclusion Consideration of KIR3DL1-mediated inhibition in donor selection for HLA-matched HCT may achieve superior graft versus leukemia effects, lower risk for relapse, and an increase in survival among patients with AML.

Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2004-2013 ◽  
Author(s):  
Ginna G. Laport ◽  
Bruce L. Levine ◽  
Edward A. Stadtmauer ◽  
Stephen J. Schuster ◽  
Selina M. Luger ◽  
...  
Keyword(s):  
T Cells ◽  
Hodgkin Lymphoma ◽  
Cell Transplantation ◽  
Adoptive Transfer ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Non Hodgkin Lymphoma ◽  
Cytokine Activation

Abstract We explored the feasibility and toxicity of administering escalating doses of anti-CD3/CD28 ex vivo costimulated T cells as a therapeutic adjunct for patients with relapsed, refractory, or chemotherapy-resistant, aggressive non-Hodgkin lymphoma (NHL) following high-dose chemotherapy and CD34+-selected hematopoietic cell transplantation (HCT). Sixteen patients had infusions on day 14 after HCT of autologous T cells that had been stimulated using beads coated with anti-CD3 and anti-CD28 monoclonal antibodies. At baseline, the subjects had severe quantitative and functional T-cell impairments. The culture procedure partially reversed impaired cytokine responsiveness in T cells in vitro and in vivo. Transient dose-dependent infusion toxicities were observed. There was a rapid reconstitution of lymphocytes; however, there were persistent defects in CD4 T cells. Most interestingly, 5 patients had a delayed lymphocytosis between day 30 and day 120 after HCT. Maximal clinical responses included 5 patients with a complete response (CR), 7 patients with a partial response (PR), and 4 patients with stable disease. At a median follow-up of 33 months (range, 26-60 months), 5 patients are alive with stable or relapsed disease and 3 patients remain in CR. In conclusion, this phase 1 trial demonstrates that adoptive transfer of autologous costimulated T cells (1) is feasible in heavily pretreated patients with advanced NHL, (2) is associated with a rapid recovery of lymphocyte counts, (3) reverses cytokine activation deficits in vitro, and (4) is associated with delayed lymphocytosis in a subset of patients.

scholarly journals Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1702
Author(s):  
Jessica Stokes ◽  
Megan S. Molina ◽  
Emely A. Hoffman ◽  
Richard J. Simpson ◽  
Emmanuel Katsanis
Keyword(s):  
Cell Transplantation ◽  
Hematological Malignancies ◽  
Hematopoietic Cell Transplantation ◽  
Suppressor Cells ◽  
Hematopoietic Cell ◽  
Murine Models ◽  
Immunomodulatory Effects ◽  
Potential Applications ◽  
Flt3 Expression

Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with significant changes to key immunological cell populations, including T-cells, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently underway investigating new potential applications of BEN in the setting of allogeneic HCT.

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