Background Clostridiodes difficile infections (CDI) are a significant cause of morbidity in the early transplant period, with reported incidences in hematopoietic cell transplant (HCT) recipients as high as 33%. Previously published data from our center found that 650 of 781 (83.2%) HCTs performed from 2010 to 2013 had a stool sample submitted for CD testing in the peritransplant setting. Testing identified 86 (13.2%) cases with CDI (12% in autologous and 17.5% in allogeneic HCT recipients), the majority being diagnosed within a week after transplantation. In December of 2018, Infection Control at Emory University Hospital implemented a HCT-unit CD screening policy for all patients upon admission. This review was aimed to assess the effects the new screening policy had on healthcare-facility onset (HO) CDI rates in our transplant population. Methods This is a retrospective review of autologous and allogeneic HCT recipients admitted from January 1, 2019 to July 31, 2019. All HCT patients admitted during this time period were included. Per the CD screening policy, PCR based testing of stool samples would be performed for all patients within 3 calendar days of admission. Patients with positive screens that later develop symptoms of CDI were classified as community-onset (CO), whereas patients with negative or absent screening tests were considered HO if subsequently had positive testing. If positive screened patients developed CDI and had been hospitalized at our facility within the past 4 weeks then they were classified as community-onset healthcare facility-associated (CO-HCFA). Results A total of 210 patients were admitted for transplant during the time frame (155 autologous and 55 allogeneic). The median age was 57.6 years and 55.2% were male. One-hundred forty-three (68.1%) patients were screened within 3 calendar days of admission. Screening identified 20 (14%) positive screens with 15 being autologous HCT. There were 16 additional positive tests identified on days 4 through 30 with 10 being autologous HCT. The 36 cases were classified as 6.2% (13) HO, 8.1% (17) CO and 2.9% (6) CO-HCFA. Conclusion CD screening upon transplant admission allowed our facility to more clearly define the epidemiology of CDIs on our transplant unit. By identifying patients colonized with CD, our faculty reduced the number of CDI that would have historically been classified as HO. As only 68.1% of transplant recipients were screened upon admission, the opportunity exists to improve identification of colonized patients. A full analysis of CDI screening for all patients admitted to the transplant unit, which includes patients receiving chemotherapy and transplant readmissions, is planned for a later date.
Background: Busulfan (Bu) and cyclophosphamide are widely used in conditioning regimens before hematopoietic cell transplantation. Increased relapse rates and graft rejection have previously been reported with low Bu area-under-the-curve (AUC) micromol∗min/L, and sinusoidal obstruction syndrome is associated with high AUCs. This has lead to strategies to adjust Bu dosing to achieve a target AUC. Previous studies have suggested that a 0.8 mg/kg dose of IV Bu would achieve an AUC similar to that of 1 mg/kg of oral Bu. PK monitoring of IV Bu at our institution demonstrated that 0.8 mg/kg often failed to achieve our target AUC of 1150–1350. Fifteen AML/MDS patients receiving 0.8 mg/kg had a mean AUC of 1059 (822–1653), with 12 AUCs < 1150. Subsequently, our routine starting dose of IV Bu was changed to 0.9 mg/kg. Methods: We performed a retrospective review of AML and MDS patients from an IRB approved HIPAA compliant database established for the collection and analysis of Bu PK. Data from two groups of Bu patients treated between 1998 and 2008 were analyzed. Fifty-eight patients were treated with oral Bu (1 mg/kg) and fifty-eight patients were treated with IV Bu (0.9 mg/kg). Bu AUC was determined for the first dose and adjustments were made on subsequent doses to target an AUC of 1150–1350. Results: Median age for IV and oral Bu patients was 42 (18–68) and 47 (23–67), respectively (p = 0.0049). The mean terminal half-life (T½) was 186 minutes (131–253) for IV Bu and 181 minutes (110–305) for oral Bu (p = NS). Mean AUCs were 1115 (777–1569) for IV Bu patients and 1260 (654–2019) for oral Bu (p = 0.0094). Seventeen (29.3%) patients in each group achieved AUCs within our target of 1150–1350. Thirty-four (58.6%) IV Bu patients had AUCs < 1150 compared to twenty (34.5%) oral Bu patients (p = 0.0092). Eight (13.8%) IV Bu patients had AUCs >1350 compared to twenty-one (36.2%) oral Bu patients (p = 0.0053). Conclusions: While first dose PK analysis showed similar T½ for IV and oral Bu, the AUCs achieved with 0.9 mg/kg IV Bu are lower than with 1mg/kg oral Bu dosing. First-dose AUC from recipients of IV Bu had a lower variance than AUC from recipients of oral Bu. Despite changing our starting IV Bu dosing from 0.8 mg/kg to 0.9 mg/kg, the majority of patients still require therapeutic drug monitoring with dose adjustments to obtain our desired target AUC of 1150–1350.
Introduction: Multiple myeloma (MM) is a plasma cell disorder characterized by bone marrow suppression, skeletal complications, renal dysfunction and often a long course involving multiple different treatments. Over the past decade, novel treatment modalities have resulted in significant improvements in progression-free and overall survival. Histone deacetylase inhibitor(s) (HDACi) appear to offer an alternative therapeutic avenue in the treatment for MM likely through their impact on HDAC-6 function, and possibly through epigenetic effects as well. Panobinostat, a novel pan-HDAC (Pan-Dac) inhibitor, is of particular interest due to its broad HDAC inhibition, selectivity toward malignant cells and oral bioavailability.Areas covered: In this review, the authors discuss the potential therapeutic benefits of panobinostat, in the treatment of MM. Topics covered include pleiotropic effects of HDAC modulation in MM, pharmacokinetics and pharmacodynamics of panobinostat, as well as available data demonstrating clinical efficacy and safety from clinical trials.Expert opinion: Panobinostat is a novel Pan-Dac inhibitor with a number of different mechanisms of action related to its impact on myeloma. Data in combination with bortezomib suggests significant improvement in progression-free survival when compared with control treatment, as well as the ability to overcome bortezomib resistance. These factors suggest that the addition of panobinostat to our current treatment paradigm will offer new and important treatment options for our patients in all phases of myeloma treatment.
Graft-versus-host disease (GVHD) is a common complication associated with allogeneic hematopoietic stem cell transplants (HSCT). Tacrolimus plays an integral role in GVHD prophylaxis. At Emory Healthcare, the daily intravenous dose has been 0.03 mg/kg/day based on ideal body weight. Over the last two decades, our target tacrolimus levels have gradually changed from 10 - 40 ng/mL to 6 - 12 ng/mL. However, our dosing has remained unchanged. Due to results of a prior evaluation demonstrating that the majority of our patients required dose reductions based on drug levels, we implemented a 48 hour loading dose of 0.03 mg/kg/day followed by a 0.02 mg/kg/day maintenance dose. We have now performed an evaluation to assess the impact of this tacrolimus dosing strategy compared to the previously studied cohort. A retrospective chart review was conducted in allogeneic HSCT patients who received intravenous tacrolimus from May 2008 to March 2009. Data collected included height, weight, tacrolimus doses on days - 2 through day + 10, and tacrolimus levels on days 0 through day + 10. This group was compared to the previously studied cohort receiving the standard 0.03 mg/kg dose as a control. A total of 22 patients were studied. The control group of 14 patients demonstrated an average dose adjustment of 54% (25% - 96%) on days 5, 7, and 10. The study group remained at an approximate average dose of 0.02 mg/kg/day for an average of 99% (50% - 200%) of the maintenance dose. Compared with the control group which had 100% of patients achieving levels > 12 ng/mL during days 1 through 10, the study group resulted in approximately 36% of patients with supratherapeutic levels. The control group had 50% of patients with levels < 6 ng/mL compared to 54% in the study group. This medication use evaluation showed that a 48 hour load of 0.03 mg/kg/day followed by a 0.02 mg/kg/day maintenance dose of tacrolimus demonstrated potential to optimize tacrolimus therapy. When compared to the control group, the study group exhibited fewer patients with supratherapeutic levels with no difference in the number of patients with levels < 6 ng/mL. The dosing strategy implemented at Emory Healthcare has resulted in a greater number of patients with tacrolimus levels within the desired range.
High dose IV melphalan is widely used in preparative regimens for hematopoietic cell transplantation. Package insert recommendations state to prepare doses to a concentration of
Individuals who are immunocompromised, including patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL), often mount ineffective antibody responses after SARS-CoV-2 vaccination 1-3 and remain at a high risk of severe Several monoclonal antibodies against the SARS-CoV-2 spike protein have been developed for prophylaxis or treatment against infection.5 AZD7442 is a combination of 2 such antibodies (tixagevimab and cilgavimab) with a half-life of ~90 days. 6It received emergency use authorization (EUA) for use as preexposure prophylaxis in patients who are immunocompromised based on the PROVENT trial, which showed a reduced risk of symptomatic infection among patients deemed at risk of inadequate vaccine response or increased viral exposure.7 However, only 7.2% of the participants had cancer, and 3.2% received immunosuppressive therapy.Importantly, PROVENT was conducted before the emergence of the B.1.1.529(Omicron) variant. Uing purified antibodies and/or pseudoviruses, some studies showed that many antibody formulations developed against the original SARS-CoV-2, including AZD7442, lost significant in vitro activity against Omicron variants.8 Additionally, sera from patients who received AZD7442 blocked the binding between the wild-type spike receptor binding domain (RBD) and plates coated with its receptor ACE2 but had minimal efficacy at blocking the binding between Omicron BA.1 RBD and ACE2.9 Reduced efficacy against Omicron variants was observed in patients treated with half-dose AZD7442, 10 and ~10% of AZD7442-treated kidney transplant recipients developed COVID-19 afterwards, with 35.9% of them requiring hospitalization.11 Although these reports raise concerns that AZD7442 has limited efficacy against Omicron variants, the neutralizing activity of full dose AZD7442 against live, contemporary Omicron variants after administration to patients who are immunocompromised remains unknown.We measured the antibody binding and neutralizing activities of plasma from AZD7442-treated patients with NHL/CLL for several live SARS-CoV-2 variants, including Omicron BA.2.75, BA.5, BQ.1.1,and XBB, which are currently in circulation.Adult patients with NHL/CLL at the Winship Cancer Institute of Emory University who received AZD7442 in accordance with the EUA fact sheet were enrolled in this prospective observational study approved by the institutional review board of Emory University.As such, patients received either a dose of 150 mg of each antibody followed by a repeat dose within 3 months or a single dose of 300 mg of each antibody.Blood was drawn after providing written informed consent, and antibody binding and live virus neutralization activities were measured as described previously 1,12 and in the supplemental Material.
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