Kunze, Katie L.

Abstract Introduction: Donor T cell chimerism is tested frequently early after allogeneic hematopoietic cell transplantation (HCT). However, the predictive ability of testing this early after HCT, i.e. at day +30 or day +60, has not been well described, outside of smaller single center studies. Herein, we evaluate the correlation of early donor T cell chimerism with clinical outcomes of overall survival (OS) and relapse in patients undergoing HCT for various hematological malignancies. Methods: We identified patients who received HCT with 8/8 matched unrelated donors at our center between 2007 and 2016 and obtained the clinical data retrospectively. Chimerism studies were included for patients who had testing done at day+30 and/ or day +60. Chimerism is tested using PCR based technique. Due to limited variability in chimerism levels <100% donor chimerism, a cut-off of 100% was used for analysis. Hence, patients were divided into those who achieved full donor chimerism in CD3 fraction (100%) and those in whom CD3 donor chimerism was < 100% at the respective time points. Clinical outcomes evaluate for this abstract were OS and time to relapse. Univariate and multivariate Cox proportional hazard regression models were used using variables of interest, the later adjusted for age at HCT, use of ATG, conditioning regimen and disease risk index (DRI). Results: Baseline patient and HCT data: There were 209 patients who met the selection criteria of which 4 died within 30 days from HCT and hence, were not included in the analysis. Among the 205, 87 (42%) were women and median age at HCT was 55 (range, 18 - 74) years. The hematological malignancy diagnosis was acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS) in 112 (55%), acute lymphoblastic leukemia (ALL) in 35 (17%), chronic leukemias in 13 (6%), lymphomas in 13 (6%) and myeloproliferative neoplasm in 20 (10%); with DRI being very high in 9 (5%), high in 53 (27%), intermediate in 120 (60%) and low in 17 (9%) patients. Myeloablative conditioning was used in 81 (40%) and reduced intensity conditioning in 124 (60%). Graft versus host disease prophylaxis used was calcineurin inhibitor with methotrexate of mycophenolate in all patients while anti-thymocyte globulin was used in 125 (61%) patients. All patients received a peripheral blood graft. Outcomes: Median follow-up for all included patients was 615 (range, 30 - 3147) days. At day +30, 138 patients had achieved 100% donor CD3 chimerism of 189 patients in whom this data was available (73%) while at day +60, 131 (76%) out of 173 had 100% donor CD3 chimerism. In the univariate model, CD3 donor chimerism level at day +30 as well as day +60, was not predictive of OS (HR 1.5, 95% CI 0.82 - 2.9; p = 0.18 for day +30, HR 1.8, 95% CI 0.81 - 4.0, p = 0.15 for day +60). As for time to relapse, CD3 chimerism did not significantly affect the risk of relapse at these time points (HR 0.43, 95% CI 0.17 - 1.1, p = 0.08 for day +30; HR 0.55, 95% CI 0.18 - 1.6, p = 0.28 for day +60). In the multivariate model also, after adjustment as described above, CD3 at day +30 or at day +60 was not significantly associated with the risk of OS or time to relapse (Figure 1). Kaplan Meier curves for OS for CD3 chimerism at day +30 and day +60 are shown in Figure 2. Conclusions: In this study, T cell chimerism as early as day +30 or day +60 does not seem to predict OS or relapse in patients undergoing HCT for various hematological malignancies. Given the limitations of a smaller retrospective design, this must be validated in a larger study, possibly using registry data. If these findings are indeed confirmed, then the practice of testing chimerism early and frequently, that adds additional expense to the overall cost of HCT, must be reconsidered. Disclosures Palmer: Novartis: Research Funding.

Abstract Introduction - Allogenic hematopoietic cell transplantation (HCT) remains potential curative treatment for hematologic malignancies. Anti-thymocyte globulin (ATG) is an immunoglobulin directed to human T lymphocytes, and may decrease the risk of chronic graft versus host disease (cGVHD). Use of ATG has been associated with higher incidence of disease relapse and infection. While the optimal dosing of ATG has not been well established, higher doses (≥ 7.5 mg/kg) have a stronger association with infection and disease relapse. Our institution utilizes low dose rabbit ATG at 2.5 mg/kg for in-vivo T-cell depletion. In this retrospective study we evaluated outcomes in patients receiving low dose ATG to those not undergoing in-vivo T-cell depletion with the hypothesis that low dose ATG protects against cGVHD without impacting infectious complications or relapse. Patients and Methods - We evaluated all patients with 8/8 HLA Matched unrelated Donors (MUD) undergoing HCT between 2007 and 2016. Patients were divided in to two cohorts, those receiving low dose ATG to those that did not. Both cohorts received standard GVHD prophylaxis with calcineurin inhibition plus methotrexate or mycophenolate. The primary outcome was overall survival (OS). Secondary outcomes included relapse free survival (RFS), EBV reactivation, CMV reactivation, CMV disease, invasive fungal infection, incidence of acute GVHD (aGVHD) grades III-IV, and moderate to severe cGVHD. A subset analysis was performed to assess relapse free survival (RFS) in patients with myeloid malignancies. Descriptive statistics were utilized for baseline characteristics; and a series of univariate and multivariant Cox proportional hazard regression models were conducted for outcomes of interest. A Kaplan-Meier (K-M) survival curve was used to depict probability of survival by ATG cohort. Results - We identified 209 patients, with 129 (62%) in ATG group and 80 (38%) in non-ATG group. At baseline, there were no differences in the age at transplant, sex, ABO incompatibility, or performance status. The ATG cohort had fewer low disease risk index (DRI) patients and more patients with intermediate or high DRI (2.4%, 64.6%, 28.3% vs 18.4%, 51.3%, 23.7% respectively), and Fisher's Exact test showed that this difference between ATG groups was statistically significant, p = <0.001. The ATG cohort also had significantly different rates of myeloablative (MA) conditioning regimens from the non-ATG cohort with fewer receiving MA (31% vs 53% p < 0.01). No statistically significant differences in OS were observed between the two ATG cohorts at up to 5 years post-transplant (p=0.35; Fig. 1). The primary predictor of OS was DRI very high vs low [HR 6.0 (2-18) p < 0.01]. The ATG exposed cohort had significantly lower risk of cGVHD [HR 0.17 (0.08-0.37) p = <0.001]. There was no difference in risk of death from relapse, incidence of EBV or CMV reactivation, CMV disease, invasive fungal infection, or grade III-IV acute GVHD. Low dose ATG was not associated with inferior RFS, including in subset analysis of patients with myeloid malignancies [HR 0.85 (0.5-1.4) p = 0.549]. Conclusions - Our study shows no significant difference in survival or death from relapse for patients who receive ATG. Importantly, patients receiving ATG had a lower rate of cGVHD with no increased rates of infectious complications. Low dose ATG did not appear to increase the risk of relapse, even when considering only myeloid malignancies. These findings suggest that low dose ATG can improve cGVHD with no impact on survival, relapse, or infectious complications. Additional prospective trials using low dose ATG compared to no ATG are warranted. Disclosures Palmer: Novartis: Research Funding.

Background: The treatment of heart failure with reduced ejection fraction has been the subject of numerous randomized controlled trials involving medications and cardiac implantable electronic device therapies. As newer effective pharmacological therapies suggest significant reductions in all-cause mortality, the role of additional device therapy in heart failure with reduced ejection fraction deserves further scrutiny. Methods: A systematic review and network meta-analysis on the effect of medication and device therapies in heart failure with reduced ejection fraction on all-cause mortality was performed. Randomized controlled trials published between January 1980 and July 2017 were identified using Medline, EMBASE, and Cochrane Controlled Register of Trials databases. Pcnetmeta package in R was used to calculate treatment arm–based estimated rates, rate ratios, and probability ranks with 95% credible intervals. Results: Combination therapy of ACE (angiotensin-converting enzyme) inhibitors or ARBs (angiotensin receptor blockers) with β-blockers (BBs) alone or in addition to implantable cardiac defibrillators or cardiac resynchronization therapy with defibrillators demonstrated a significant reduction of all-cause mortality when compared with placebo. By probability rank, implantable cardiac defibrillator+ACE inhibitor or ARB+BB+mineralocorticoid receptor antagonist, implantable cardiac defibrillator+ACE inhibitor or ARB+BB, and angiotensin receptor-neprilysin inhibitor+BB+mineralocorticoid receptor antagonist combination therapies have the highest probability of being ranked the best treatment. There was no significant difference in the rate of mortality when comparing angiotensin receptor-neprilysin inhibitor+BB+mineralocorticoid receptor antagonist to implantable cardiac defibrillator+optimal pharmacological combination therapy. Conclusions: BB and renin-angiotensin system blockers alone or in combination with defibrillator device therapy have robust evidence for a reduction in mortality compared with placebo. The comparative efficacy of pharmacological therapy with angiotensin receptor-neprilysin inhibitors and device therapy deserves further investigation.