ALBERT

Description: The incidence of neural tube defects (NTDs) declined by about 40 % in Canada with the introduction of a national folic acid (FA) fortification program. Despite the fact that few Canadians currently exhibit fol...

Description: Introduction: While hematopoietic stem cell transplantation (HSCT) has great therapeutic potential, intensive conditioning regimens and variability in time to stem cell engraftment result in a period of pancytopenia and immunosuppression in which patients are vulnerable to infection. Bloodstream infections (BSIs) occur in 20-45% of inpatient autologous and allogeneic transplant patients, leading to prolonged hospitalization and increased mortality. One method of infection prevention is daily application of the antiseptic chlorhexidine gluconate (CHG). Daily CHG bathing, either with a CHG wash or with application of CHG-impregnated cloths, has been shown to reduce the incidence of all-cause hospital-acquired BSIs in critically ill patients, such as those in the ICU, though very few studies include HSCT patients. Methods: We conducted an observational cohort study to assess the impact of daily CHG bathing on the rate of BSIs among adults undergoing inpatient HSCT at the Duke University Medical Center. Patients were included if they were admitted for pre-transplant conditioning and inpatient monitoring for allogeneic or autologous HSCT from January 2016 through December 2018. CHG bathing was instituted in January 2017 for all patients admitted to the inpatient HSCT unit using 2% CHG-impregnated cloths (SAGE™), providing one year of data with no CHG bathing and two years of data with bathing. Patients were tracked from admission until unit discharge, transfer, or first infection. Laboratory-confirmed bloodstream infections (LCBI), central-line associated bloodstream infections (CLABSI), and mucosal barrier injury laboratory-confirmed bloodstream infections (MBI-LCBI) were determined per CDC/NHSN definitions. An additional variable of "clinically-significant infection" was recorded; this included both laboratory-confirmed BSIs and infections deemed significant by the treatment team but that did not meet CDC/NHSN criteria. For example, patients that were febrile, hypotensive, and treated with antibiotics, but with only one positive culture of a common commensal were deemed to have a clinically-significant BSI. Because not all patients adhered to CHG, patients were grouped into four categories by rate of daily CHG usage: High (〉75%), Medium (50-75%), Low (1-49%), and None (0%). Baseline characteristics and clinical outcomes between groups were compared via ANOVA, Chi-squared test, or Cochran-Armitage two-sided trend test. Multivariate analysis using the Fine-Grey subdistribution hazard model was conducted to compare time to all infection variables, accounting for the effects of CHG usage, antibiotic prophylaxis regimen, and type of transplant. Results: We evaluated 192 patients hospitalized for HSCT, including 118 (62%) allogeneic transplants and 74 (38%) autologous transplants. Of these, 25 (13%) had high CHG usage, 33 (17%) medium, 45 (23%) low, and 89 (46%) none. Demographics and transplant characteristics were evenly matched between the CHG usage groups with the exception that high usage groups were more likely to receive levofloxacin for antibiotic prophylaxis (p=0.003). Increased CHG usage was significantly associated with decreased incidence of clinically-significant infection (p=0.006), CLABSI (p=0.04), and MBI-LCBI (p=0.002) (Table 1). Multivariate analysis did not demonstrate a significant contribution of antibiotic prophylaxis regimen. No significant difference was found between CHG usage groups in median days to stem cell engraftment, incidence of febrile neutropenia or C. difficile infection, or rashes requiring medical treatment. There were no rashes attributable to CHG usage. Among patients who were VRE rectal swab negative on admission, there was a significant trend toward lower rates of VRE acquisition with increasing CHG usage (High CHG 13.6% vs No CHG 25.3%, p=0.02). Discussion: Increased CHG usage is associated with a significant trend toward lower rates of clinically-significant infection, CLABSI, MBI-LCBI, and VRE colonization in adult inpatients undergoing HSCT. Effects are most strongly seen at 〉75% daily CHG usage. There were no adverse effects due to CHG application. The significant decrease in MBI-LCBI with topical CHG suggests an interaction between the skin microbial environment and enteric organisms. Therefore, further research exploring the effects of CHG on the skin and gut microbiota is warranted. Disclosures Gasparetto: BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Horwitz:Abbvie Inc: Membership on an entity's Board of Directors or advisory committees. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding. Sung:Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding.

Description: BACKGROUND: Interleukin-15 (IL-15) is a member of the 4-α helix bundle family of cytokines. Administration of single-agent IL-15 to patients with cancer produced substantial increases and activation of natural killer (NK) cells and CD8+ T cells, but no clinical responses. Subsequent studies showed that IL-15 enhances the efficacy of anti-tumor monoclonal antibodies that work through antibody-dependent cell cytotoxicity, a process mediated by NK cells. In the MET-1 xenograft mouse model, the combination of IL-15 and the anti-CD52 antibody alemtuzumab led to significantly more durable responses than each agent by itself. Here we report the final results of the phase I trial of IL-15 and alemtuzumab in patients with relapsed and refractory T-cell lymphoma (NCT02689453). METHODS: In this phase I single-center trial IL-15 was given subcutaneously 5 days per week for 2 weeks in a standard 3+3 dose escalation scheme (DL1: 0.5μg/kg, DL2: 1μg/kg, DL3: 2μg/kg), followed by alemtuzumab 30mg intravenously three times weekly for 4 weeks. Primary endpoints were type and frequency of adverse events and the maximum tolerated dose of IL-15. RESULTS: A total of eleven patients (pts) were treated at DL1 (3), DL2 (4) and DL3 (4). Seven pts had acute adult T-cell leukemia (ATL), two had chronic ATL, and two had peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). There were no dose-limiting toxicities through the maximum planned dose of 2μg/kg/day. Two pts both with acute subtype ATL were unable to complete treatment due to rapidly progressive disease early in their treatment course, but there was no evidence tumor simulation or expansion of circulating ATL cell numbers during the period of IL-15 administration Hematologic AEs included lymphopenia (all 11 pts, 7 with grade 3/4), neutropenia (8 pts, 2 with grade 3), anemia (10 pts, 1 with grade 3), and thrombocytopenia (4 pts, 1 with grade 3). The most common non-hematologic AEs were infusion-related reactions experienced by 10 of the 11 pts during alemtuzumab infusion, and urticaria (4, pts, 2 with grade 3, both of whom at MTD). Two pts had incidental findings of a catheter-associated thrombus and pulmonary emboli, necessitating institution of prophylactic anticoagulation for subsequent pts after which no additional thromboembolic events were seen. Infectious adverse events included one case each of CMV reactivation without end-org involvement, HSV reactivation, Zoster, bacterial sinusitis, and cellulitis (in a patient with ATL and skin involvement), all grade 2. There was no evidence of graft versus host disease in two pts with previous allogeneic stem cell transplantation, and there were no serious adverse events attributable to IL-15. Administration of IL-15 resulted in a median 2.1-fold increase (range 1.2-3.4) in absolute lymphocyte count, 2.5-fold (1-5.9) increase in the number of circulating CD8+ T cells, and 7.2-fold (1.1-17.1) increase in NK cells across all dose levels (Figure 1A). At the MTD, the median ALC, CD8+ T cell, and NK cell increases were 2, 2.1, and 15.3-fold respectively. The overall response rate was 45% with 2/11 complete responses (CR) and 3/11 partial responses (PR) (Figure 1B). Notably, all pts with leukemic disease attained CR in the blood (Figure 1C), with varying response in other compartments. A patient with acute ATL had a CR at first restaging but developed central nervous system relapse after four weeks; this remained the only site of disease until the patient's death 8 months later. A patient with PTCL-NOS had a delayed response, with a PR at 3 and CR at 5 months which was ongoing at 12-month follow-up. Two pts with chronic ATL had PRs which lasted 10 and 4 months, and a patient with acute ATL had a PR at first restaging which was ongoing at the end of treatment. In all pts, response was correlated with normalization of serum LDH and soluble CD25. Analysis of peripheral blood mononuclear cells from responders and non-responders using single-cell RNA-seq is under way and will be presented. CONCLUSION: Combination of IL-15 and alemtuzumab was safe at all dose levels administered with no evidence of treatment related disease stimulation. The contribution of IL-15 to the known clinical efficacy of alemtuzumab in relapsed/refractory T-cell malignancies needs to be assessed in a randomized trial. Further evaluation of IL-15 in the post-allogeneic transplant setting, particularly prior to donor lymphocyte infusion, is also planned. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: alemtuzumab for T-cell lymphoma