Single-agent Prophylaxis Research Articles

Safety and Efficacy of Orca-Q with Haploidentical Donors for the Treatment of Advanced Hematologic Malignancies without the Use of Post-Transplant Cyclophosphamide

Srour, Salhotra, Lowsky and Abedi contributed equally as authors BACKGROUND Allogeneic stem cell transplantation (SCT) can be curative for several high-risk hematologic malignancies, but access was previously limited to patients with a fully matched donor. The introduction of post-transplant cyclophosphamide (PTCy) GvHD prophylaxis has increased the use of haploidentical donors (haplo) for patients who lack an HLA-matched donor. However, clinical outcomes associated with PTCy-based regimens remain challenging due to increased relapse rates (particularly in the setting of reduced intensity conditioning) and the adverse event profile including higher incidence of mucositis, cytokine release syndrome (CRS), delayed engraftment & T cell reconstitution, infections, early cardiotoxicity events and death from organ failure (Dulery 2021, Abboud 2021, Nagler 2022, Hoover 2022, Bolaños-Meade 2023). Additionally, the incidence of chronic GvHD after haplo SCT with PTCy is 24 - 33% at 1 year in various historical cohorts. Orca-Q -an investigational precision engineered cell therapy biologic- represents an alternative strategy which may be administered with single agent prophylaxis and does not require PTCy. The cellular composition of Orca-Q includes enriched CD34+ stem cells, combined with specific T-cell subsets, and is intended to reconstitute the blood and immune systems. METHODS Adult patients with high-risk hematologic malignancies eligible for MAC SCT were enrolled on the haplo donor dose expansion arm of a multicenter phase1 study of Orca-Q (NCT03802695). Haplo was defined as ≥ 4/8 but < 7/8 matched related donor at HLA-A, -B, -C, and -DRB1 typed using DNA-based high-resolution. Patients received MAC conditioning and single agent GVHD prophylaxis with tacrolimus (starting on day -1 and taper day +60). Orca-Q was manufactured centrally at Orca Bio Manufacturing Site in Sacramento, CA from G-CSF mobilized peripheral blood apheresis. RESULTS Orca-Q was successfully manufactured and delivered to all subjects with a vein-to-vein time (time between end of donor apheresis to start of recipient's Orca-T infusion) of < 72 hours. A total of 33 patients (21 AML, 10 ALL, 2 CML) were included. Median age was 43 (range, 21 - 63) years, 73% were male. Median follow-up was 375 (range, 73 - 1384) days. Sixteen patients received TBI-based MAC; 17 received busulfan-based MAC (Table). All patients engrafted with median time of 12.0 (range, 8 - 25) and 15.5 (range, 8 - 79) days for neutrophil and platelet engraftment, respectively. Two patients had secondary graft failure. Two patients had Grade 1 CRS; 1 patient had Grade 2 CRS. Grade 2+ aGvHD through Day 180+ occurred in 15% of patients. Grade 3-4 acute GvHD (aGvHD) was rare with only 1 event of grade 3 aGvHD and no grade 4 aGvHD. No patients had moderate-to-severe cGvHD. Estimated incidence of CTCAE grade 2 and > grade 3 infections were 9% and 15% at 1 year, respectively. 5 patients died (2 from relapsed disease) during the study period. NRM was 9% at 1 year. The 1-year relapse-free survival, GvHD-and-relapse free survival (Figure), and overall survival at 1 year was 82%. CONCLUSIONS Our findings reveal promising safety and efficacy outcomes using Orca-Q cell therapy for haplo-SCT despite the use of MAC with only single-agent tacrolimus, and without PTCy. With median follow-up of approximately 1 year, no patients experienced moderate or severe cGvHD, the low AE profile in the haplo setting remains favorable, and 1 year GvHD-free, relapse-free survival of 83% is very encouraging. This phase 1 study continues to enroll patients across the US. REFERENCES Abboud R, Wan F, Mariotti J, et al. Bone Marrow Transplant. 2021;56(11):2763-2770. Bolaños-Meade GM, Hamadani M, Wu J. N Engl J Med. 2023; 388(25):2338-2348. Duléry R, Mohty R, Labopin M, et al. JACC CardioOncol. 2021; 3(2):250-259. Hoover A, O'Leary D, Cao Q, et al. Blood. 2022; 140 (Supplement 1):282-283 Nagler A, Tsirigotis P. Bone Marrow Transplant. 2022; 57(11):1640-1641.

Orca-Q Demonstrates Favorable GvHD-and-Relapse-Free Survival in Haploidentical Transplants without Post-Transplant Cyclophosphamide

^Salhotra, Srour, Lowsky and Abedi contributed equally Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) can be curative for a variety of malignant and nonmalignant disorders, but until recent years, access has been limited to patients with HLA-matched donors. The increased utilization of post-transplant cyclophosphamide (PTCy) has enabled patients to receive alloHSCT with haploidentical (haplo) related donors; however, high rates of cGVHD following myeloablative conditioning (MAC) regimens and high rates of relapse following reduced intensity conditioning regimens have been observed with this approach. Thus, GVHD-and-relapse free survival (GRFS) rates in this population at 1-year post-transplant remain low. Haplo alloHSCT with PTCy is also associated with high incidence of cytokine release syndrome (CRS) and infections. Orca-Q -an investigational precision engineered cell therapy- represents an alternative strategy which may be administered with single agent prophylaxis and does not require PTCy. The cellular composition of Orca-Q consists of enriched CD34+ stem cells combined with specific T- cell subsets and is intended to reconstitute the blood and immune systems. Orca-Q is hypothesized to reduce GVHD, relapse, and serious infections. Methods: Adult patients (18 to 65 years) with high-risk hematologic malignancies undergoing myeloablative conditioning (MAC) alloHSCT were enrolled between January 2019 to July 2022 on the haplo donor dose expansion arm of a multicenter phase 1 study of Orca-Q (NCT03802695). Haplo was defined as ≥ 4/8 but < 7/8 matched related donor at HLA-A, -B, -C, and -DRB1 typed using DNA-based high-resolution. Patients received only single agent tacrolimus (starting on day -1 and taper day +60 if no GVHD) as GVHD prophylaxis. PTCy was not permitted. The Orca-Q drug product was manufactured centrally at Orca Bio Manufacturing Site in Sacramento, CA from G-CSF mobilized peripheral blood apheresis. Results: The Orca-Q drug product was successfully manufactured and delivered to all subjects with a vein-to-vein time of less than 72 hours. A total of 21 patients (11 AML, 8 ALL, 2 CML in blast crisis) with > 30 days of follow up were included in this analysis. All were 4/8 HLA match at HLA-A, -B, C, and DRB1. Median age of subjects was 44 years (range 21 - 63) and median follow-up was 333 days (range 39 - 1020). Disease risk index (DRI) score was available in 20 showing 2 very high, 3 high, 13 intermediate, and 2 low risk categories. The M:F ratio was 12:9. Patients received either TBI (n=13) or non-TBI (n=8) based MAC regimens. 2 patients had Gr 1 CRS (CTCAE v5). Median neutrophil and platelet engraftment times were 13 days (range 8 - 25) and 16 days (range 12 - 25), respectively. 1 secondary engraftment failure was observed. The estimated incidence of BMT CTN MOP3 infections was 27% at 1 year. The estimated incidence of gr 2-4 aGVHD at 6 months was 14% which compares favorably with literature reports of 21% to 63% for gr 2-4 aGVHD in patients undergoing haplo transplant with PTCy-based prophylaxis.[1-5] Likewise, gr 3-4 aGVHD was rare with Orca-Q with only 1 case of gr 3 aGVHD and no gr 4 aGVHD. Of the 16 patients who had at least 3 months follow up, only 1 developed mild cGVHD. No patients had moderate-to-severe cGVHD, a notable improvement compared to historic rates of 24% to 31% for moderate-to-severe cGVHD with PTCy, despite the fact that Orca-Q patients receive only single agent GVHD prophylaxis.[1-4] 2 patients experienced disease relapse and there was a total of 5 deaths (2 due to relapse, 1 Aspergillus pulmonary infection, 1 respiratory failure associated with renal failure, and 1 COVID infection). GVHD-and-relapse free survival (GRFS) was 71% at 1 year with Orca-Q (Figure 1) which compares favorably to a GRFS of 46% reported by Sanz in the context of MAC haplo alloHSCT with PTCy.[2] Conclusions: Initial Orca-Q data demonstrates good clinical outcomes with single agent tacrolimus and no PTCy or MMF. Patients treated with Orca-Q experienced a low adverse event profile, low incidence and severity of both aGVHD and cGVHD, and improved GRFS rates, offering a potential new treatment option for patients undergoing haplo alloHSCT. This phase 1 study of Orca-Q continues to enroll patients with haplo donors across the US. References (1) Gooptu, M., et al. (2) Sanz, J., et al. (3) Wagner, J.E., et al. (4) Baker, M., et al. (5) Bashey, A., et al. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Antibiotic Prophylaxis for the Prevention of Infectious Complications following Prostate Biopsy: A Systematic Review and Meta-Analysis.

Infectious complications following prostate biopsy are increasing and fluoroquinolone prophylaxis has recently been banned by the European Commission. In this systematic review we summarize the evidence for different antibiotic prophylaxis regimens. We searched MEDLINE®, Embase® and Cochrane Database for randomized controlled trials (inception to October 2019) assessing antimicrobial interventions in prostate biopsy. Primary outcome was infectious complications. Exclusion criteria were simultaneous interfering interventions. GRADE (Grading of Recommendations, Assessment, Development and Evaluations) was used to assess the certainty of evidence. Protocol was registered with PROSPERO (CRD42015026354). Overall 59 randomized controlled trials (14,153 participants) and 7 different antimicrobial interventions were included. Antibiotic prophylaxis reduced infectious complications compared to no prophylaxis (RR 0.56, 95% CI 0.40-0.77, p=0.0005, I2=15%, participants 1,753, studies 11). A short-term prophylaxis (single shot to 3 days) was inferior to a long-term prophylaxis (1 to 7 days) with fluoroquinolone (RR 1.89, 95% CI 1.37-2.61, p=0.0001, I2=0%, participants 3,999, studies 17). Fosfomycin trometamol was an alternative to fluoroquinolone with reduced rates of infectious complications (RR 0.49, 95 CI 0.27-0.87, p=0.02, I2=54%, participants 1,239, studies 3). Empiric prophylaxis was inferior to targeted prophylaxis (RR 1.81, 95% CI 1.28-2.55, p=0.0008, I2=48%, participants 1,511, studies 6). Standard prophylaxis was inferior to augmented prophylaxis (using multiple rather than single agent) using a fixed model (RR 2.10, 95% CI 1.53-2.88, p <0.0001, I2=71%, participants 2,597, studies 9), but not using a random model (p=0.07). No difference was observed in infectious complications based on route or timing of antimicrobial prophylaxis. The certainty of evidence was rated as low/very low. In countries where fluoroquinolones are allowed as antibiotic prophylaxis, a minimum of a full 1-day administration as well as targeted therapy in case of fluoroquinolone resistance is recommended. In countries with a ban on fluoroquinolones, fosfomycin is a good alternative, as is augmented prophylaxis, although no established standard combination exists to date.

Cost-Effectiveness of Antibiotic Prophylaxis Strategies for Transrectal Prostate Biopsy in an Era of Increasing Antimicrobial Resistance

ObjectivesTo determine the optimal antibiotic prophylaxis strategy for transrectal prostate biopsy (TRPB) as a function of the local antibiotic resistance profile. MethodsWe developed a decision-analytic model to assess the cost-effectiveness of four antibiotic prophylaxis strategies: ciprofloxacin alone, ceftriaxone alone, ciprofloxacin and ceftriaxone in combination, and directed prophylaxis selection based on susceptibility testing. We used a payer’s perspective and estimated the health care costs and quality-adjusted life-years (QALYs) associated with each strategy for a cohort of 66-year-old men undergoing TRPB. Costs and benefits were discounted at 3% annually. Base-case resistance prevalence was 29% to ciprofloxacin and 7% to ceftriaxone, reflecting susceptibility patterns observed at the Minneapolis Veterans Affairs Health Care System. Resistance levels were varied in sensitivity analysis. ResultsIn the base case, single-agent prophylaxis strategies were dominated. Directed prophylaxis strategy was the optimal strategy at a willingness-to-pay threshold of $50,000/QALY gained. Relative to the directed prophylaxis strategy, the incremental cost-effectiveness ratio of the combination strategy was $123,333/QALY gained over the lifetime time horizon. In sensitivity analysis, single-agent prophylaxis strategies were preferred only at extreme levels of resistance. ConclusionsDirected or combination prophylaxis strategies were optimal for a wide range of resistance levels. Facilities using single-agent antibiotic prophylaxis strategies before TRPB should re-evaluate their strategies unless extremely low levels of antimicrobial resistance are documented.

Risk of surgical site infection, acute kidney injury, and Clostridium difficile infection following antibiotic prophylaxis with vancomycin plus a beta-lactam versus either drug alone: A national propensity-score-adjusted retrospective cohort study.

BackgroundThe optimal regimen for perioperative antimicrobial prophylaxis is controversial. Use of combination prophylaxis with a beta-lactam plus vancomycin is increasing; however, the relative risks and benefits associated with this strategy are unknown. Thus, we sought to compare postoperative outcomes following administration of 2 antimicrobials versus a single agent for the prevention of surgical site infections (SSIs). Potential harms associated with combination regimens, including acute kidney injury (AKI) and Clostridium difficile infection (CDI), were also considered.Methods and findingsUsing a multicenter, national Veterans Affairs (VA) cohort, all patients who underwent cardiac, orthopedic joint replacement, vascular, colorectal, and hysterectomy procedures during the period from 1 October 2008 to 30 September 2013 and who received planned manual review of perioperative antimicrobial prophylaxis regimen and manual review for the 30-day incidence of SSI were included. Using a propensity-adjusted log-binomial regression model stratified by type of surgical procedure, the association between receipt of 2 antimicrobials (vancomycin plus a beta-lactam) versus either single agent alone (vancomycin or a beta-lactam) and SSI was evaluated. Measures of association were adjusted for age, diabetes, smoking, American Society of Anesthesiologists score, preoperative methicillin-resistant Staphylococcus aureus (MRSA) status, and receipt of mupirocin. The 7-day incidence of postoperative AKI and 90-day incidence of CDI were also measured. In all, 70,101 procedures (52,504 beta-lactam only, 5,089 vancomycin only, and 12,508 combination) with 2,466 (3.5%) SSIs from 109 medical centers were included. Among cardiac surgery patients, combination prophylaxis was associated with a lower incidence of SSI (66/6,953, 0.95%) than single-agent prophylaxis (190/12,834, 1.48%; crude risk ratio [RR] 0.64, 95% CI 0.49, 0.85; adjusted RR 0.61, 95% CI 0.46, 0.83). After adjusting for SSI risk, no association between receipt of combination prophylaxis and SSI was found for the other types of surgeries evaluated, including orthopedic joint replacement procedures. In MRSA-colonized patients undergoing cardiac surgery, SSI occurred in 8/346 (2.3%) patients who received combination prophylaxis versus 4/100 (4.0%) patients who received vancomycin alone (crude RR 0.58, 95% CI 0.18, 1.88). Among MRSA-negative and -unknown cardiac surgery patients, SSIs occurred in 58/6,607 (0.9%) patients receiving combination prophylaxis versus 146/10,215 (1.4%) patients who received a beta-lactam alone (crude RR 0.61, 95% CI 0.45, 0.83). Based on these associations, the number needed to treat to prevent 1 SSI in MRSA-colonized patients is estimated to be 53, compared to 176 in non-MRSA patients. CDI incidence was similar in both exposure groups. Across all types of surgical procedures, risk of AKI was increased in the combination antimicrobial prophylaxis group (2,971/12,508 [23.8%] receiving combination versus 1,058/5,089 [20.8%] receiving vancomycin alone versus 7,314/52,504 [13.9%] receiving beta-lactam alone). We found a significant association between absolute risk of AKI and receipt of combination regimens across all types of procedures. If the observed association is causal, the number needed to harm for severe AKI following cardiac surgery would be 167. The major limitation of our investigation is that it is an observational study in a predominantly male population, which may limit generalizability and lead to unmeasured confounding.ConclusionsThere are benefits but also unintended consequences of antimicrobial and infection prevention strategies aimed at “getting to zero” healthcare-associated infections. In our study, combination prophylaxis was associated with both benefits (reduction in SSIs following cardiac surgical procedures) and harms (increase in postoperative AKI). In cardiac surgery patients, the difference in risk–benefit profile by MRSA status suggests that MRSA-screening-directed prophylaxis may optimize benefits while minimizing harms in this selected population. More information about long-term outcomes and patient and societal preferences regarding risk of SSI versus risk of AKI is needed to improve clinical decision-making.

Randomized double blind trial of ciprofloxacin prophylaxis during induction treatment in childhood acute lymphoblastic leukemia in the WK-ALL protocol in Indonesia.

ObjectivesToxic death is a big problem in the treatment of childhood acute lymphoblastic leukemia (ALL), especially in low-income countries. Studies of ciprofloxacin as single agent prophylaxis vary widely in success rate. We conducted a double-blind, randomized study to test the effects of ciprofloxacin monotherapy as prophylaxis for sepsis and death in induction treatment of the Indonesian childhood ALL protocol.MethodsPatients were randomized to the ciprofloxacin arm (n = 58) and to the placebo arm (n = 52). Oral ciprofloxacin monotherapy or oral placebo was administered twice a day. All events during induction were recorded: toxic death, abandonment, resistant disease, and complete remission rate.ResultsOf 110 patients enrolled in this study, 79 (71.8%) achieved CR. In comparison to the placebo arm, the ciprofloxacin arm had lower nadir of absolute neutrophil count during induction with median of 62 (range: 5–884) versus 270 (range: 14–25,480) × 109 cells/L (P < 0.01), greater risks for experiencing fever (50.0% versus 32.7%, P = 0.07), clinical sepsis (50.0% versus 38.5%, P = 0.22), and death (18.9% versus 5.8%, P = 0.05).ConclusionIn our setting, a reduced intensity protocol in a low-income situation, the data warn against using ciprofloxacin prophylaxis during induction treatment. A lower nadir of neutrophil count and higher mortality were found in the ciprofloxacin group.

Single-Infusion of Donor Early Apoptotic Cells (ApoCell) As Prophylaxis of Graft-Versus-Host Disease in Myeloablative HLA-Matched Allogeneic Bone Marrow Transplantati

Abstract 4176Because of its potent immunomodulatory effect together with presumably high safety profile, apoptotic cells infusion (ApoCell) was tested in addition to cyclosporine and methotrexate, as prophylaxis of graft-versus-host disease (GVHD) in HLA-matched myeloablative allogeneic bone marrow transplantation (alloBMT) from a related donor. We conducted a phase I//IIa clinical trial where we treated 13 patients (median age, 37 years; range, 20–59 years) with advanced hematologic malignancies (7 patients with ALL, 5 patients with AML (4 patients with MDS that transformed to AML and one patient with AML de novo), and 1 patient with CML that received conventional myeloablation with 35, or 70, or 140, or 210×106 cell/kg of donor ApoCell, on day -1 of transplantation. Ten serious adverse effects were reported with all being not related (seven) or unlikely to be related (3) to ApoCell infusion. Out of hundreds adverse effects, only three were reported as possibly related to ApoCell infusion (with no definite or probable adverse effects). The non-relapse mortality at day 100 and 180 after transplantation was the same, 7.7%. The overall survival at 100 and 180 days after transplantation was 92% and 85%, respectively. The incidences of acute grades II through IV GVHD for all 13 patients and for the two higher doses were 23% and 0% (six patients), respectively. Biomarker ratio levels including tumor necrosis factor receptor I (TNFR1), hepatocyte growth factor (HGF), interleukin 2 receptor alpha (IL-2Ra), and interleukin 7 (IL-7), supported the clinical data. These results suggest that single-infusion high-dose donor early apoptotic cells in HLA-matched myeloablative alloBMT is a safe and potentially effective single-agent prophylaxis of acute GVHD occurring after myeloablative conditioning (clinicaltrials.gov no. NCT00524784). Disclosures:Mevorach:Enlivex: Consultancy, Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Reiner:Enlivex: Employment.

OC-113 Prevention of post-ERCP acute pancreatitis: complete systematic review

IntroductionPost-ERCP acute pancreatitis (post-ERCP-AP) occurs in ∼5% of patients undergoing ERCP, severe in ∼1%. Despite multiple trials, optimal prophylaxis remains undetermined. We sought to clarify the effectiveness of prophylactic interventions...

Low Incidence of Severe Mucositis After Myeloablative, HLA-Matched Bone Marrow Transplantation and High Dose, Post-Transplantation Cyclophosphamide

Abstract 893▪▪This icon denotes a clinically relevant abstract Background:Oral mucositis is a debilitating and frequently encountered consequence of high-intensity chemotherapy used prior to and after bone marrow transplantation (BMT). It is associated with increased acute oral pain, use of total parenteral nutrition (TPN) and intravenous narcotic analgesics, length of hospital stay, incidence and severity of graft-versus-host disease (GVHD), risk of severe infections, and mortality. Important contributors to the duration and severity of mucositis include certain agents used in the conditioning regimen and as GVHD prophylaxis, especially methotrexate (MTX). High dose post-transplantation cyclophosphamide (PT/Cy) has been shown to be effective as a single-agent prophylaxis of GVHD after HLA-matched BMT. Due to the reduced toxicity profile of Cy compared to MTX, we sought to characterize mucositis among patients receiving PT/Cy, and to compare it to historical controls receiving cyclosporine A (CsA) and MTX as GVHD prophylaxis. Methods:We performed a retrospective record review of 142 consecutive patients treated at our institution between June 2004 and October 2009 who received a standard regimen of busulfan (Bu) 4 mg/kg/day orally or 3.2 mg/kg/day IV from days −6 to −3, Cy 50 mg/kg/day IV on days −2 and −1, and T cell-replete bone marrow from HLA-matched siblings (n = 79) or unrelated donors (n = 63) on day 0. GVHD prophylaxis consisted of PT/Cy 50 mg/kg/day IV on days +3 and +4. We also examined a historical control group of 15 patients treated between 2002 and 2005, who also received myeloablative conditioning with BuCy, but subsequently received CsA/MTX (15 mg/m2 IV on day 1, 10 mg/m2 IV on days 3, 6, and 11), instead of PT/Cy, for GVHD prophylaxis. Mucositis was graded on a scale from 0 to 4, where 0 connotes normal oral mucosa; 1 indicates the presence of erythema only; 2 and 3 reflect ulcerations and/or white patches covering <25% and >25% of the oral mucosa, respectively; and 4 represents hemorrhagic ulcerations. Mucositis assessments were documented daily for at least 28 days following the start of conditioning. Results:Recipients of PT/Cy experienced a significantly lower incidence of severe (grades 3–4) mucositis than did recipients of CsA/MTX (25.3% vs. 93.3%, Fisher’s exact test, p < 0.001). The peak mucositis severity among recipients of PT/Cy was 2.2, compared to 3.4 for patients receiving CsA/MTX (Mann-Whitney, p < 0.0001). The mean duration of severe mucositis among PT/Cy recipients was 4.2 days. Incidences of total parenteral nutrition (TPN) use and IV narcotics administration via patient-controlled analgesia (PCA) were 8.4% and 41.5%, respectively, among patients receiving PT/Cy. The total number of days of TPN and PCA use were 9.5 and 8.7, respectively. Among patients using PCA, the average cumulative dose of IV narcotics administered was 950.1 milligrams of morphine equivalents (MME). Patients receiving PT/Cy experienced a mean maximum oral pain rating of 4.5. The 100-day cumulative incidences of grades II–IV and grades III–IV GVHD in the PT/Cy cohort were 46% and 13%, respectively. Comparative data for duration of severe mucositis, use of PCA and TPN, severity of oral pain, and cumulative incidence of GVHD in the group of patients treated with CsA/MTX is currently being collected; however, all of the mucositis-associated clinical outcomes described above compare favorably with those reported in previously published studies. Conclusions:The incidence and severity of mucositis among patients receiving myeloablative, HLA-matched BMT with high dose PT/Cy are low compared to those of historical patients treated with CsA/MTX for GVHD prophylaxis. Measures of TPN use, PCA use, oral pain, and GVHD compare favorably with previous reports. Thus, GVHD prophylaxis with high dose cyclophopshamide can significantly reduce mucositis and may impact associated clinical sequelae after transplant. Disclosures:Off Label Use: Post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis. Jones:Accentia Biopharmaceuticals: Patents & Royalties. Luznik:Otsuka Pharmaceuticals: Research Funding. Fuchs:Accentia Biopharmaceuticals: Patents & Royalties.

Critical Role of CD4+Foxp3+ T Cells In Gvhd Prevention with High-Dose Posttransplant Cyclophosphamide (Cy).

AbstractAbstract 3749Regulatory T cells (Tregs) contribute to the maintenance of self-tolerance and have been shown to ameliorate acute GVHD both in murine models and in the clinical setting. However, translation of results and mechanistic insights from animal models to the clinic is difficult due to inherent incongruities in the use of post-grafting immunosuppression for prevention of GVHD. Administration of high-dose cyclophosphamide (Cy) in mouse models of allogeneic bone marrow transplantation (BMT) and its identical use as a short course single agent prophylaxis for GVHD in a HLA-matched setting provides an ideal model for studying the interaction between postgrafting immunosuppression and Tregs. We explored the hypothesis that Tregs play a critical role in prevention of GVHD in a MHC-matched mouse model of alloBMT using C57Bl/6-Foxp3-DTR mice (H-2b, CD45.2+) as donors, in which Foxp3+ Tregs can be selectively depleted in vivo by administration of diptheria toxin (DT; 2 doses on days 0 and +1). Donor mice were further crossed with those expressing luciferase (luc+) so that the in vivo expansion and engraftment of transplanted T cells could be noninvasively tracked by bioluminescent imaging (BLI) in addition to standard metrics of GVHD severity. We transplanted 1.2×107 splenocytes (or purified conventional T cells) from C57Bl/6-luc+-Foxp3-DTR mice (H-2b, CD45.2+) plus 1×107 bone marrow (BM) cells from B6-Ly5.2 (H-2b, CD45.1+) donors into myeloablatively conditioned allogeneic Balb/b recipients (H-2b, CD45.2+, 775 cGy) to induce acute GVHD. BLI on day 4 post-BMT revealed a significantly higher bioluminescent signal (photons/second/mouse) in animals treated with DT compared to PBS recipients (p < 0.001). Treatment of chimeras with Cy on day+3 led to a significantly reduced expansion of alloreactive luc+ T cells on days 4, 7, 14 and 21 (p < 0.05; Cy vs DT-treated chimeras and controls). Conversely, BLI of chimeras that received DT on days 0 and +1 followed by Cy on day +3 demonstrated a moderate increase in proliferation of donor derived luc+ T-cells in comparison to Cy recipients suggesting that the depletion of CD4+Foxp3+ Tregs early after transplant was detrimental to the protective action of the drug. Clinical severity of GVHD was significantly increased in chimeras with depleted Foxp3+ Tregs (P < 0.05, compared to PBS-treated chimeras), while Cy administration completely prevented manifestation of GVHD (P< 0.01, Cy vs PBS- and DT-treated chimeras). Consistent with BLI findings, depletion of Foxp3+ Tregs early after transplant abrogated the protective effect of Cy on GVHD, reflected in increased morbidity and mortality. To determine the effect of Cy on Foxp3 expression, in vitro experiments were conducted with CD4+Foxp3-GFPneg T cells co-cultured with allogeneic DCs and treated with mafosfamide. While exposure to increasing doses of the drug (2.5 and 12.5 μg/ml) caused a proportionally higher cell kill, the surviving T cells showed a marked induction of GFP expression in comparison to cells in the untreated culture. Taken together, these results suggest that Tregs are critical for prevention of GVHD in the context of GVHD prophylaxis with single agent high-dose Cy and that this approach besides limiting alloreactive T cell expansion may also foster conversion of naïve peripheral CD4+ T cells into CD4+Foxp3+ Tregs. Disclosures:No relevant conflicts of interest to declare.

High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease

AbstractBecause of its potent immunosuppressive yet stem cell–sparing activity, high-dose cyclophosphamide was tested as sole prophylaxis of graft-versus-host disease (GVHD) after myeloablative allogeneic bone marrow transplantation (alloBMT). We treated 117 patients (median age, 50 years; range, 21-66 years) with advanced hematologic malignancies; 78 had human leukocyte antigen (HLA)–matched related donors and 39 had HLA-matched unrelated donors. All patients received conventional myeloablation with busulfan/cyclophosphamide (BuCy) and T cell–replete bone marrow followed by 50 mg/kg/d of cyclophosphamide on days 3 and 4 after transplantation. The incidences of acute grades II through IV and grades III through IV GVHD for all patients were 43% and 10%, respectively. The nonrelapse mortality at day 100 and 2 years after transplantation were 9% and 17%, respectively. The actuarial overall survival and event-free survivals at 2 years after transplantation were 55% and 39%, respectively, for all patients and 63% and 54%, respectively, for patients who underwent transplantation while in remission. With a median follow-up of 26.3 months among surviving patients, the cumulative incidence of chronic GVHD is 10%. These results suggest that high-dose posttransplantation cyclophosphamide is an effective single-agent prophylaxis of acute and chronic GVHD after BuCy conditioning and HLA-matched BMT (clinicaltrials.gov no. NCT00134017).

Should Methotrexate plus Calcineurin Inhibitors Be Considered Standard of Care for Prophylaxis of acute Graft-versus-Host Disease?

In a rapidly developing field, one can always anticipate that different interpretations of similar data will coexist. Stem cell transplanters can be a contentious lot, especially in the absence of controlled randomized trials. Thus, although improvements in the basic understanding of acute graft-versus-host disease (aGVHD) has led to many testable hypotheses in the management of GVHD, there remains little consensus regarding the most effective and least toxic approach to GVHD prevention. In the 1980s, the comparison would have been between cyclosporine-based regimens and ex vivo T cell depletion (TCD). Although ex vivo TCD is still used in some settings, pharmacologic-based therapy and in vivo TCD with serotherapy now predominate. This review is meant to highlight the advantages and disadvantages of the "standard of care" and assess the prospects for future regimens that may be more effective.

Influence of Broad-Spectrum Antibiotic Prophylaxis on Intracranial Pressure Monitor Infections and Subsequent Infectious Complications in Head-Injured Patients

The benefit of antibiotic prophylaxis for intracranial pressure (ICP) monitors remains controversial, and clinical practice varies widely. Whether any antibiotic coverage, particularly broad-spectrum coverage, reduces monitor-related infections remains unproved, and exposure to antibiotics may affect the susceptibility patterns of pathogens producing subsequent infectious complications. Despite the lack of data supporting its use, our level I trauma center had a long-standing ICP monitor prophylaxis protocol that provided broad-spectrum coverage that included ceftriaxone. In April 2002, a protocol change was instituted that substituted cefazolin for ceftriaxone as single-agent prophylaxis for ICP monitors. Broader-spectrum antibiotic prophylaxis does not reduce ICP monitor-related infections but is associated with acquisition of more drug-resistant infections than narrow-spectrum prophylaxis. To evaluate the influence of broad- versus narrow-spectrum prophylaxis, a three year period encompassing each practice was selected. All injured patients with ICP monitors placed between January 1, 2001, and December 31, 2003 (n = 279), were identified using the Vanderbilt trauma database. Antibiotic prophylaxis for ICP monitors was determined using the hospital financial database to identify all antibiotics given to individual patients and subsequent chart review to identify those antibiotics given solely for ICP prophylaxis. A total of 119 patients received narrow-spectrum (either cefazolin or vancomycin; n = 100) or no (n = 19) prophylaxis, whereas 160 received broad-spectrum prophylaxis (ceftriaxone or ciprofloxacin). The two groups did not differ with respect to baseline demographics, type of ICP monitor, or duration of monitor placement. Infectious complications were determined by continuous infection surveillance utilizing standard U.S. Centers for Disease Control and Prevention National Nosocomial Infection Surveillance System (CDC-NNIS) definitions and maintained in a contemporary database. The influence of broad-spectrum antibiotic prophylaxis on both ICP monitor infections and subsequent infections outside the central nervous system (CNS) was determined. Nine patients (3.2%) developed CNS infections; two of 119 patients (1.7%) who received narrow-spectrum or no prophylaxis versus seven of 160 patients (4.4%) who received broad-spectrum prophylaxis (p = NS). Only the duration of monitor placement and Injury Severity Score were associated with the infection rate. In the total population, 185 infections occurred in 93 patients (33%). Infection rates did not differ between patients who received narrow-spectrum or no prophylaxis (32%) and those who received broad-spectrum prophylaxis (34%). However, patients who received broad-spectrum prophylaxis acquired gram-negative infections with significantly greater antibiotic resistance. Broad-spectrum antibiotic prophylaxis of ICP monitors does not reduce CNS infections, but is associated with a shift to resistant gram-negative pathogens in subsequent infectious complications. Thus, broad-spectrum antibiotic prophylaxis of ICP monitors should be eliminated or minimized unless data from randomized trials prove its utility.

Dolasetron versus Ondansetron as Single-Agent Prophylaxis for Patients at Increased Risk for Postoperative Nausea and Vomiting: A Prospective, Double-Blind, Randomized Trial

This study identified 100 ambulatory surgery patients receiving general anesthesia who were at increased risk for postoperative nausea and vomiting (PONV) and randomly assigned them to receive single-agent prophylaxis (12.5 mg of dolasetron or 4 mg of ondansetron) 15 to 30 minutes before the end of surgery. Data were collected in the postanesthesia care unit, and patients completed a questionnaire 24 hours after surgery. No statistically significant difference existed between study groups in demographic features, history of PONV, history of motion sickness, or type and duration of surgery and anesthesia. No statistically significant difference existed in satisfaction with the medication used for PONV prophylaxis (dolasetron, 70.9 of 100 mm; ondansetron, 67.9 of 100 mm; p = 0.69). No statistically significant difference existed in satisfaction with the overall surgical experience (dolasetron, 87.9 of 100 mm; ondansetron, 85.3 of 100 mm; p = 0.36). Costminimization strategies should be considered without fear of substandard care or increased patient dissatisfaction.

Hemodynamic effects of spinal anesthesia and simultaneous intravenous bolus of combined phenylephrine and ephedrine versus ephedrine for cesarean delivery

Hypotension following spinal anesthesia for cesarean delivery can produce adverse maternal symptoms and neonatal acid-base effects. Single-agent prophylaxis, most notably with ephedrine, does not reliably prevent spinal anesthesia-induced hypotension; recently, however, the prophylactic use of phenylephrine with ephedrine as an infusion was observed to be effective. We postulated that this combination, when given as an intravenous bolus for prophylaxis and rescue treatment, could be similarly effective. Forty-three term parturients were randomized to receive a bolus of ephedrine 10 mg +/- phenylephrine 40 microg (groups E and EP, respectively) simultaneously with spinal anesthesia. Hypotension was defined as a systolic blood pressure below 100 mmHg or a decrease of 20% from a baseline value. Rescue boluses comprised of ephedrine 5 mg +/- phenylephrine 20 microg. For groups E and EP, respectively, the incidence of hypotension was 80% vs. 95% (P=0.339), with the mean number of rescue boluses being 3.85+/-3.7 and 3.05+/-1.7 and the mean umbilical artery pH being 7.246+/-0.081 vs. 7.244+/-0.106. All comparisons were not significant (NS). The combination of ephedrine and phenylephrine given as an intravenous bolus at the doses selected is not superior to ephedrine alone in preventing or treating hypotension in healthy parturients undergoing cesarean delivery.

New perspectives in antibiotic prophylaxis for intra-abdominal surgery

Effective management of intra-abdominal infections requires a combination of preoperative preparation, antibiotic prophylaxis and appropriate surgical technique. Antibacterial prophylaxis should provide coverage of all likely pathogens, including aerobic and anaerobic organisms. Whereas antibacterial combination therapy is appropriate in certain situations, single-agent prophylaxis is appropriate for the majority of patients and ampicillin/sulbactam, with its broad-spectrum anti-aerobic/anti-anaerobic activity, is an attractive prophylactic option. Surgery involving the gastrointestinal tract provides a special challenge by virtue of its high, predominantly anaerobic, bacterial load. However, the requirement for prophylaxis varies depending upon the precise site of intervention. Biliary tract surgery requires prophylaxis in high-risk patients only, whereas hepatobiliary or pancreatic surgery requires prophylaxis in all patients. Gastroduodenal operations require prophylaxis in the presence of risk factors, such as abnormal gastric acidity or bleeding. Colorectal procedures present a high risk of anaerobic infection and sepsis, and require adequate prophylaxis combined with a thorough preoperative preparation designed to reduce considerably the bacterial load of the bowel. Where peritonitis does follow intra-abdominal surgery, patients should receive antibacterial therapy commensurate with the risk of serious infection. A small proportion of patients will be at risk of severe infection and will require triple-agent therapy. However, most patients are likely to develop mild-to-moderate infections only and can be treated with a single, broad-spectrum antibiotic agent, such as ampicillin/sulbactam, a beta-lactam/beta-lactamase inhibitor.

A National Survey of Antimicrobial Prophylaxis in Adult Cardiac Surgery Across Canada

To characterize national and regional patterns of antimicrobial prophylaxis in adult cardiac surgery across Canada. Retrospective, cross-sectional analysis. Thirty-three adult cardiac surgical centres across Canada. A one-page questionnaire collecting information regarding institutional demographics and antimicrobial prophylaxis regimens for adult cardiac surgical procedures was mailed to all adult surgical centres across Canada. If a response was not received within one month, a second survey was mailed, followed by a telephone reminder within two weeks of the second mailing. The Overall response rate was 100%. Prophylactic antimicrobials were used in all the adult cardiac centres; single-agent prophylaxis was used in 97% (32 of 33) of centres; Single-dose antimicrobial prophylaxis was used in only 3% (one of 33) of centres. Preoperative and postoperative antimicrobial prophylaxis regimens varied both between provinces and within provinces across Canada. Cefazolin was the antimicrobial used in 88% (38 of 43) and 87% (33 of 38) of the reported pre-operative and post-operative prophylaxis regimens, respectively. Antimicrobial prophylaxis was initiated in the operating room 72% (26 of 36) of the time and intra-operative supplemental antimicrobial doses were administered for cardiac procedures longer than a median of 4 hours (range 4 to 8 hr). Overall, the median duration of antimicrobial prophylaxis was 36 hours (range 8 to 96 hr). Despite the availability of various published guidelines, our survey identified several areas for improvement with respect to antimicrobial prophylaxis in adult cardiac surgery across Canada.

Preliminary Results of a Survey of the Use of Antimicrobial Agents as Prophylaxis in Orthopedic Surgery

An epidemiological survey of the use of antimicrobial prophylaxis in Italian hospitals was carried out under the auspices of the Journal of Chemotherapy. Out of 500 Italian orthopedic centers queried, 225 agreed to participate in this study. A total of 136,321 surgical procedures were reported in the 166 centers reporting complete answers on type of surgery. They comprised hip and knee prosthesis (13.9%), spine surgery (4%), hip endoprosthesis (5.2%), osteosynthesis (26.9%), arthroscopy (24.4%), and others (25.5%). Perioperative antimicrobial prophylaxis was used in 75% of operations (ranging from 57.1% to 99.4% in arthroscopy and joint prosthesis, respectively). Short term (<24 h) antimicrobial prophylaxis was performed in 38.4% of the 206 centers answering this question correctly. 61.1% of centers employed single agent prophylaxis and 70.8% of these prescriptions were betalactam antibiotics. Bacteriological analysis revealed Gram-positive isolates in 73.3% of cases. Methicillin resistance was present in 45% of 915 tested strains. Out of 4221 patients with high risk of infectious complications (joint prosthesis surgery) given antimicrobial prophylaxis in 46 centers, the percentage of surgical wound infections was overall 2.1%, while that of non-surgical wound infections was 3.6%. The total infection rate was decreased by about half in association with long-term (>24 h) as compared to short-term (<24 h) antibiotic treatment (3.7% vs 7.6%, respectively), and with use of antibiotic drug combinations vs single antibiotic drugs (3.9 vs 6.6%, respectively). The incidence of surgical-site infection was not decreased by extending the chemoprophylaxis for more than the first 24 h after surgery, while it was reduced from 2.5 to 1.4% by use of combination antibiotic therapy.

Profilassi Antimicrobica della Infezione Chirurgica in Ortopedia. Risultati della Indagine Epidemiologica Promossa per l’Italia dal Journal of Chemotherapy

SummaryAn epidemiological survey of the use of antimicrobial prophylaxis in Italian hospitals was carried out under the auspices of the Journal of Chemotherapy. Out of 500 Italian orthopedic centers requested, 225 have participated in this study. A total of 136,321 surgical procedures were reported in the 166 centers reporting complete answers on type of surgery. They comprised hip and knee prosthesis (13.9%), spine surgery (4%), hip endoprosthesis (5.2%), osteosynthesis (26.9%), arthroscopy (24.4%), and others (25.5%). Perioperative antimicrobial prophylaxis was used in 75% of operations (ranging from 57.1% to 99.4% in arthroscopy and joint prosthesis, respectively). Short term (<24 h) antimicrobial prophylaxis was performed in 38.4% of the 206 Centers answering this question correctly. 61.1% of Centers employed single agent prophylaxis. 70.8% of these prescriptions were betalactam antibiotics. Bacteriological analysis of the wound in 86 Centers (total number of isolates 2013) revealed the presence of Gram-positive isolates in 73.7% of cases. Methicillin resistance was expressed in 45% of 915 tested strains. Out of 4221 patients with high risk of infectious complications (joint prosthesis surgery) given antimicrobial prophylaxis in 46 Centers, the percentage of surgical wound infections was overall 2.1%, while that of non-surgical wound infections was 3.6%. A decrease in the total infection rate by about half was associated with long-term (>24 h) as compared to short-term (<24h) antibiotic treatment (3.7 vs 7.6%, respectively), and with the use of antibiotic drug combinations vs single antibiotic drugs (3.9 vs 6.6%, respectively). The incidence of surgicalsite infection is not decreased by extending the chemoprophylaxis for more than the first 24 h after surgery, while it is reduced from 2.5 to 1.4% by use of combination antibiotic therapy.

Use of fluoroquinolones as prophylactic agents in patients with neutropenia.

The use of fluorinated quinolone antibiotics to selectively decontaminate the gastrointestinal tract is a reasonable alternative to prevent infection in neutropenic patients. The fluoroquinolones represent ideal antibiotics with which to achieve the principles of selective decontamination by allowing colonization of anaerobes to inhibit the adherence, colonization and proliferation of potentially pathogenic aerobic flora. This report describes the prophylactic use of fluoroquinolones in neutropenic patients. The majority of studies of fluoroquinolone prophylaxis in neutropenic patients have shown a reduction in documented Gram-negative bacterial infections. However, Gram-positive infections, particularly those with viridans streptococci, present a major impediment to the use of single agent prophylaxis with a quinolone. Prophylaxis with fluoroquinolones in neutropenic patients was found to be advantageous, but it must be balanced against the risk of Gram-positive infections and the potential for antibiotic resistance.