PTCy, abatacept, and a short course of tacrolimus for GVHD prevention after haploidentical transplantation.

Reducing the incidence of graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (HSCT) is warranted. Posttransplant cyclophosphamide (PTCy) is the main agent used for GVHD prevention in this setting. It remains unknown whether costimulation blockade can be safely combined with PTCy and enhance its efficacy. We performed a phase 1b-2 clinical trial to examine the combination of PTCy, abatacept, and a short course of tacrolimus (CAST) after peripheral blood haploidentical HSCT. The primary end point was the incidence of grades 2-4 acute GVHD by day +120. The study enrolled 46 patients with a median age of 60 years (range, 18-74 years). The cumulative incidences of grades 2-4 and 3 or 4 acute GVHD were 17.4% (95% confidence interval [CI], 9.2-32.9) and 4.4% (95% CI, 1.1-17.1), respectively. With a median follow-up of 15.3 months, the cumulative incidence of 1-year treatment-related mortality was 4.4% (95% CI, 1.1-17.1). The estimated 1-year moderate-to-severe chronic GVHD rate, relapse rate, progression-free survival, overall survival, and GVHD- and relapse-free survival were 15.9% (95% CI, 8-31.7), 11.7% (95% CI, 5-27.2), 84.1% (95% CI, 73.8-95.7), 85.9% (95% CI, 75.9-97.2), and 66.1% (95% CI, 53.4-81.8), respectively. Toxicities were similar to those expected in patients receiving haploidentical HSCT. This clinical trial showed that the CAST regimen is safe and effective in reducing the rate of grades 2-4 acute GVHD after haploidentical peripheral blood HSCT. This trial was registered at www.clinicaltrials.gov as #NCT04503616.

How to Harness the Power of Social Media for Quality Drug Information in Infectious Diseases: Perspectives on Behalf of the Society of Infectious Diseases Pharmacists.

Clinicians, researchers, and the public frequently turn to digital channels and social media for up-to-the-minute information on novel therapeutics and vaccines. The value of credible infectious diseases drug information is more apparent in the setting of the coronavirus disease 2019 (COVID-19) pandemic. This viewpoint by the Society of Infectious Diseases Pharmacists (SIDP) provides guidance on utilizing social media platforms to optimize infectious diseases pharmacotherapy. It includes tips for all levels of users but primarily serves a guide for the infectious diseases clinician who has not yet joined social media. It compares various social media platforms and suggests which to begin with based on user needs, recommends efficient curation of social media content, and outlines a stepwise approach (shown below) to increasing engagement over time. This summary will hopefully spur further quality content and engagement regarding drug information from the infectious diseases social media network.

Time between diagnosis and achievement of virologic suppression in people living with HIV.

PURPOSE: Data support the individual and public health advantages of shortened time intervals between HIV diagnosis, initiation of antiretroviral therapy (ART), and virologic suppression. The time from HIV diagnosis to linkage to care, initiation of ART, and virologic suppression was evaluated in newly diagnosed, ART-naive individuals after structured programmatic changes were implemented to reduce time to virologic suppression (TVS). METHODS: The retrospective cohort included newly diagnosed, ART-naive adult patients receiving care in a Midwestern Ryan White Clinic. Study periods were between January 1, 2015, and December 31, 2015 (delayed treatment group) and January 1, 2017, and December 31, 2017 (rapid treatment group). Changes during the intervention time period were related to access to care and ART. The primary outcome of time from HIV diagnosis to virologic suppression was compared between the groups. Secondary outcomes included the time from diagnosis to linkage to care and the time to initiation of ART. RESULTS: Twenty-four and 35 individuals were included in the control and intervention groups, respectively. Median (interquartile range) time from diagnosis to viral suppression was 137 (77-318) days in the delayed treatment group vs 76.5 (51-151) days in the rapid treatment group (P = 0.021). Time from diagnosis to first clinic visit remained similar (median of 13.5 vs 15 days, P = 0.859), while time from first clinic visit to initiation of ART decreased significantly (median of 15 vs 0 days, P < 0.001). CONCLUSION: Time from first clinic visit to ART initiation was significantly shortened in this intervention and was the driving force to decreasing TVS. Additional research into barriers impacting time from diagnosis to linkage to care are needed to further shorten TVS.

Post-transplantation Cyclophosphamide: From HLA-Haploidentical to Matched-Related and Matched-Unrelated Donor Blood and Marrow Transplantation.

Following allogeneic blood and marrow transplantation (BMT), graft-versus-host disease (GvHD) continues to represent a significant cause of treatment failure, despite the routine use of conventional, mainly calcineurin inhibitor-based prophylaxis. Recently, post-transplant cyclophosphamide (PTCy) has emerged as a safe and efficacious alternative. First, omitting the need for ex vivo T-cell depletion in the setting of haploidentical transplantation, growing evidence supports PTCy role in GvHD prevention in matched-related and matched-unrelated transplants. Through improved understanding of GvHD pathophysiology and advancements in drug development, PTCy emerges as a unique opportunity to design calcineurin inhibitor-free strategies by integrating agents that target different stages of GvHD development.

Current Status and Future Directions in Graft-Versus-Host Disease Prevention Following Allogeneic Blood and Marrow Transplantation in Adults.

Graft-versus-host disease (GvHD) in its acute and chronic forms continues to represent a significant barrier to the success and wide-applicability of blood and marrow transplantation as a potentially curative treatment modality for a number of benign and malignant blood conditions. Presently, calcineurin inhibitor (CNI)-based regimens remain the most commonly used prevention strategy, although post-transplant cyclophosphamide is emerging as an alternative approach, and is providing a backbone for innovative CNI-free combinations. In this paper, we review the current strategies used for the prevention of GvHD, and highlight some of the developing and promising combinations.

Human Herpes Virus-6 Encephalitis Following Autologous Blood and Marrow Transplant.

Human herpesvirus-6 (HHV-6) is a highly prevalent virus that establishes lifelong latency in human hosts. Symptomatic HHV-6 reactivation rarely occurs in immunocompetent individuals and is best described in immunosuppressed patients such as recipients of bone marrow transplants (BMT). In that setting, HHV-6 reactivation has been associated with fever, rash, pneumonitis, encephalitis, and delayed engraftment. While these complications are well documented in allogeneic transplant, the clinical impact of such reactivation is not well known in autologous BMT. We described a case of HHV-6-associated encephalitis in a previously heavily treated patient with multiple myeloma (MM) following a second autologous BMT, and discuss the need for clinicians to be aware of the potential clinical impact of HHV-6 following autologous BMT in the era of immunomodulatory agents.

Antimicrobial Stewardship Interventions to Combat Antibiotic Resistance: an Update on Targeted Strategies.

PURPOSE OF REVIEW: Overutilization of antimicrobials is a known contributor to the development of antimicrobial resistance, which is a threat to global health. The goal of antimicrobial stewardship programs (ASPs) is to implement targeted interventions to reduce inappropriate antimicrobial prescribing and prevent development of antimicrobial resistance. We aim to review recently published literature focused on five categories of ASP interventions that have demonstrated success in optimizing appropriate antimicrobial use, improving patient outcomes, and fighting antimicrobial resistance. RECENT FINDINGS: In the past year, ASP interventions in the published literature have focused on minimizing duration of antimicrobial therapy for infectious syndromes, implementing novel methods for performing prospective audit and feedback, utilizing microbiology laboratory or rapid diagnostic tests to expedite diagnosis, leveraging clinical decision support and electronic medical record tools, and performing penicillin allergy assessment. While the majority of studies assessing ASP interventions do not assess changes in antimicrobial resistance, outcomes demonstrating improved appropriate antibiotic use have been used as a surrogate. Successful ASPs should seek to implement and evaluate novel interventions targeting improvement in antimicrobial prescribing. Such interventions are of critical importance to prevent further growth of antimicrobial resistance.

Comparison of Short-Course and Prolonged Antimicrobial Therapy in the Management of Intra-Abdominal Infections.

Background: Guidelines recommend an antimicrobial therapy duration of four to seven days for intra-abdominal infections (IAIs). Despite evidence that shorter treatments are appropriate for this disease state, longer durations frequently are utilized in clinical practice. This study compared the clinical outcomes of short course (SC) and prolonged course (PC) antimicrobial therapy for IAI. Methods: This was a noninterventional, retrospective, single-center study. Adults admitted with documented IAI who received antimicrobial treatment for ≥48 hours were included. Results: A total of 175 patients were enrolled, 73 patients receiving SC (≤7 days) and 102 patients receiving PC (>7 days) therapy. No significant differences were observed in the primary outcome of clinical cure (74% versus 67.6%; p = 0.367). Secondary outcomes including hospital length of stay (LOS) (5.5 versus 5.8 days; p = 0.372), intensive care unit (ICU) LOS (3 versus 5 days; p = 0.117), 28-day all-cause mortality rate (4.1% versus 2%; p = 0.651), and 30-day re-admission rate (19.2% versus 20.6%; p = 0.818) also were not significantly different. Conclusions: There was no significant difference in the rate of clinical cure between SC and PC antimicrobial therapy. These results further support guideline recommendations for a shorter duration of antimicrobial therapy in IAI.

Calcineurin and mTOR Inhibitor-Free Post-Transplantation Cyclophosphamide and Bortezomib Combination for Graft-versus-Host Disease Prevention after Peripheral Blood Allogeneic Hematopoietic Stem Cell Transplantation: A Phase I/II Study.

Graft-versus-host disease (GVHD) hampers the utility of allogeneic hematopoietic stem cell transplantation (AHSCT). The purpose of this study was to determine the feasibility, safety, and efficacy of a novel combination of post-transplantation cyclophosphamide (PTC) and bortezomib for the prevention of GVHD. Patients undergoing peripheral blood AHSCT for hematological malignancies after reduced-intensity conditioning with grafts from HLA-matched related or unrelated donors were enrolled in a phase I/II clinical trial. Patients received a fixed dose of PTC and an increasing dose of bortezomib in 3 cohorts, from .7 to 1 and then to 1.3 mg/m2, administered 6 hours after graft infusion and 72 hours thereafter, during phase I. The study was then extended at the higher dose in phase II for a total of 28 patients. No graft failure and no unexpected grade ≥3 nonhematologic toxicities were encountered. The median times to neutrophil and platelet engraftment were 16 and 27 days, respectively. Day +100 treatment-related mortality was 3.6% (95% confidence interval [CI], .2% to 15.7%). The cumulative incidences of grades II to IV and grades III and IV acute GVHD were 35.9% (95% CI, 18.6% to 53.6%) and 11.7% (95% CI, 2.8% to 27.5%), respectively. The incidence of chronic GVHD was 27% (95% CI, 11.4% to 45.3%). Progression-free survival, overall survival, and GVHD and relapse-free survival rates were 50% (95% CI, 30.6% to 66.6%), 50.8% (95% CI, 30.1% to 68.2%), and 37.7% (95% CI, 20.1% to 55.3%), respectively. Immune reconstitution, measured by CD3, CD4, and CD8 recovery, was prompt. The combination of PTC and bortezomib for the prevention of GVHD is feasible, safe, and yields promising results. The combination warrants further examination in a multi-institutional trial.

Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent fashion.

There is an abiding need for innovative approaches to the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Interest in prevention of GvHD by dendritic cell (DC) suppression has re-emerged since the introduction of proteasome inhibitors into clinical practice. Ixazomib is an orally bioavailable proteasome inhibitor with a rapid proteasome dissociation rate. We studied the effects of ixazomib on human DC maturation, viability, and cytokine production in vitro. We also determined the effects of ixazomib in a murine GvHD model. Although ixazomib suppressed naïve human DC maturation, it had only a limited effect on cell viability. Ixazomib decreased pro-inflammatory cytokine production of resting DCs. This effect was diminished or reversed when DCs were pre-stimulated. In vivo, ixazomib administered post-transplantation on days +1 and +4 or days -1, +2, and +5 ameliorated GvHD in comparison to the GvHD group. Although a fraction of mice treated according to the prolonged schedule died abruptly after the day +5 treatment, both schedules resulted in improved overall survival. When we examined the effects of ixazomib on splenic cells and serum cytokines, we found that ixazomib exerted complex schedule-dependent immunomodulatory effects. Our study provides a rationale for the potential use of ixazomib in the prevention of GvHD.

Post-Transplantation Cyclophosphamide and Ixazomib Combination Rescues Mice Subjected to Experimental Graft-versus-Host Disease and Is Superior to Either Agent Alone.

Lapses in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) warrant novel approaches. Such approaches include, among others, the use of post-transplantation cyclophosphamide (PTC) and proteasome inhibitors. Although PTC alone consistently produces low rates of chronic GVHD, the incidence of acute GVHD remains significant. Inversely, prolonged post-transplantation administration of proteasome inhibitors carries a risk of paradoxical aggravation of GVHD. We examined whether the combination of cyclophosphamide and ixazomib addresses the limitations of each of these agents when used alone to prevent GVHD in mice subjected to allogeneic HSCT across MHC barriers. We chose ixazomib, an orally bioavailable proteasome inhibitor, because of its favorable physiochemical characteristics. The combination of cyclophosphamide and ixazomib improved overall survival of mice in comparison to an untreated control group and to groups receiving either cyclophosphamide alone or ixazomib alone. Furthermore, cyclophosphamide prevented the surge of IL-1ß, GVHD aggravation, and sudden death associated with prolonged administration of ixazomib after HSCT. Finally, we demonstrated that although ixazomib was administered before cyclophosphamide, it did not impair the preferential depletion of proliferating as opposed to resting donor T cells. Our data suggest that the combination of cyclophosphamide and ixazomib for the prevention of GVHD after allogeneic HSCT is promising and merits further investigation in clinical trials.

Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation is the standard treatment for a variety of benign and malignant conditions. However, graft-versus-host disease (GvHD) continues to present a major barrier to the success and wide applicability of this procedure. Although current GvHD prevention and treatment regimens exclusively target T cells, bortezomib, a reversible proteasome inhibitor, possesses unique immune regulatory activities that span a wide variety of cellular processes of T and dendritic cells essential for the development of GvHD. Herein, we review the current understanding of the effects of bortezomib in vitro and in animal models and summarize the clinical data relevant to its use in the prevention and treatment of GvHD. We conclude with an outline of the remaining challenges and opportunities to optimize bortezomib's potential role in this setting.

Outcomes of Aminopenicillin Therapy for Vancomycin-Resistant Enterococcal Urinary Tract Infections.

Vancomycin-resistant urinary tract infections are often challenging to treat. This retrospective cohort study compared outcomes between patients treated for vancomycin-resistant enterococcal urinary tract infection with an aminopenicillin and those treated with a non-ß-lactam antibiotic. Inpatients treated with an enterococcus-active agent for their first symptomatic vancomycin-resistant enterococcal urinary tract infection between 1 January 2012 and 31 December 2013 were considered for inclusion. Patients with colonization, on hospice, or receiving comfort care only were excluded. The primary endpoint of clinical cure was defined as resolution of clinical symptoms, or symptom improvement to the extent that no additional antibacterial drug therapy was necessary, and lack of microbiologic persistence. Secondary endpoints of 30-day readmission or retreatment and 30-day all-cause mortality were also compared. A total of 316 urinary isolates were screened, and 61 patients with symptomatic urinary tract infection were included. Twenty (35%) of the 57 isolates tested were ampicillin susceptible. Thirty-one patients received an aminopenicillin, and 30 received a non-ß-lactam. Rates of clinical cure for aminopenicillin versus non-ß-lactam treatment were 26/31 (83.9%) and 22/30 (73.3%) (P = 0.315), respectively. Rates of 30-day readmission (6/31, or 19.4%, versus 9/30, or 30%, respectively; P = 0.334), 30-day retreatment (4/31, or 12.9%, versus 4/30, 13.3%, respectively; P = 0.960), and 30-day all-cause mortality (2/31, or 6.5%, versus 1/30, or 3.3%, respectively; P = 0.573) were also not significantly different between groups. Aminopenicillins may be a viable option for treating vancomycin-resistant urinary tract infection regardless of the organism's ampicillin susceptibility. Prospective validation with larger cohorts of patients should be considered.

Short Course of Post-Transplantation Cyclophosphamide and Bortezomib for Graft-versus-Host Disease Prevention after Allogeneic Peripheral Blood Stem Cell Transplantation Is Feasible and Yields Favorable Results: A Phase I Study.

An effective graft-versus-host disease (GVHD) preventative approach that preserves the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation (HSCT) remains elusive. Standard GVHD prophylactic regimens suppress T cells indiscriminately and are suboptimal. Conversely, post-transplantation high-dose cyclophosphamide selectively destroys proliferating alloreactive T cells, allows the expansion of regulatory T cells, and induces long-lasting clonal deletion of intrathymic antihost T cells. It has been successfully used to prevent GVHD after allogeneic HSCT. Bortezomib has antitumor activity on a variety of hematological malignancies and exhibits a number of favorable immunomodulatory effects that include inhibition of dendritic cells. Therefore, an approach that combines post-transplantation cyclophosphamide and bortezomib seems attractive. Herein, we report the results of a phase I study examining the feasibility and safety of high-dose post-transplantation cyclophosphamide in combination with bortezomib in patients undergoing allogeneic peripheral blood HSCT from matched siblings or unrelated donors after reduced-intensity conditioning. Cyclophosphamide was given at a fixed dose (50 mg/kg on days +3 and +4). Bortezomib dose was started at .7 mg/m2, escalated up to 1.3 mg/m2, and was administered on days 0 and +3. Patients receiving grafts from unrelated donors also received rabbit antithymocyte globulin. The combination was well tolerated and allowed prompt engraftment in all patients. The incidences of acute GVHD grades II to IV and grades III and IV were 20% and 6.7%, respectively. With a median follow-up of 9.1 months (range, 4.3 to 26.7), treatment-related mortality was 13.5% with predicted 2-year disease-free survival and overall survival of 55.7% and 68%, respectively. The study suggests that the combination of post-transplantation cyclophosphamide and bortezomib is feasible and may offer an effective and practical GVHD prophylactic regimen. The combination, therefore, merits further examination.

Post-transplant high-dose cyclophosphamide for the prevention of graft-versus-host disease.

Cyclophosphamide's lack of hematopoietic stem cell toxicity and its unique effects on the immune system have prompted several investigators to explore its potential for the prevention of graft-versus-host disease (GVHD). In haploidentical hematopoietic stem cell transplants, post-transplant cyclophosphamide together with standard prophylaxis reduces the incidence of GVHD to acceptable rates without the need for T cell depletion. In matched related and unrelated donor settings, cyclophosphamide alone has produced encouraging results. In particular, the low incidence of chronic GVHD is noteworthy. Here, we present a review of the current understanding of the mechanism of action of post-transplant cyclophosphamide and summarize the clinical data on its use for the prevention of GVHD.