Search

Letermovir, a novel anti‐cytomegalovirus (CMV) agent acts by inhibiting the viral terminase complex and is approved for primary prophylaxis in CMV seropositive patients post allogeneic hematopoietic cell transplantation (HCT). The favorable efficacy and safety profile make it an attractive option for use as secondary prophylaxis in patients at high‐risk for CMV reactivation. In this study, we report the efficacy and safety of letermovir secondary prophylaxis after at least one treated episode of CMV reactivation in a cohort of 39 high‐risk patients. Thirty two (82%) patients received anti‐thymocyte globulin (ATG), 27 (69%) received a combination of ATG and post‐transplant cyclophosphamide for graft‐versus‐host disease (GVHD) prophylaxis. Twenty one patients (54%) received CMV seronegative grafts. In addition, 18 (46%) patients had HLA mismatched unrelated or haploidentical donors while 18 (46%) had active GVHD requiring immunosuppression at the time of commencing secondary prophylaxis. Letermovir was initiated at a median of 47 days (range, 41–56) after HCT and was administered for a median duration of 77 days (range, 46–90). A single breakthrough CMV reactivation was noted in this high‐risk cohort. Four additional episodes of CMV reactivation occurred at a median of 28 days (range, 23–59 days) after discontinuation of secondary prophylaxis. The drug was well tolerated and 77% of the cohort completed the planned duration of secondary prophylaxis. None of the patients discontinued treatment due to treatment‐related adverse effects. In conclusion, letermovir is effective and well tolerated and may be considered for secondary prophylaxis in patients at high risk for CMV reactivation. Prospective studies are required to validate these findings. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) reactivation post‐allogeneic hematopoietic cell transplantation (post‐alloHCT) increases morbidity and mortality. We sought to determine the frequency of CMV seroconversion in patients pre‐alloHCT and to investigate the impact on posttransplant outcomes. We retrospectively investigated 752 adult patients who underwent alloHCT at our center from January 2015 to February 2020 before the adoption of letermovir prophylaxis. CMV serology was assessed at consult and pretransplant. The cohort was divided into four groups based on pretransplant CMV seroconversion: negative to positive (Group 1), positive to negative (Group 2), consistently negative (Group 3), and consistently positive (Group 4). Eighty‐nine patients (12%) had seroconverted from negative to positive, 17 (2%) from positive to negative, 151 (20%) were consistently seronegative, and 495 (66%) were consistently seropositive pretransplant. For the four CMV serostatus groups, cumulative incidence of CMV reactivation at 6 months posttransplant was 4.5%, 47.1%, 6.6%, and 76.6% for Groups 1, 2, 3, and 4, respectively (p < .0001). No differences between groups were seen regarding Grade III–IV acute graft‐versus‐host disease (GVHD) (p = .91), moderate/severe chronic GVHD (p = .41), or graft failure (p = .28). On multivariable analysis, there was no impact of CMV serostatus group on overall survival (p = .67), cumulative incidence of relapse (p = .83) or non‐relapse mortality. alloHCT patients who demonstrate CMV seroconversion pretransplant from negative to positive have a very low risk of CMV reactivation posttransplant. The observed seroconversion may be due to passive CMV immunity acquired through blood products. Quantitative CMV immunoglobulin G/immunoglobulin M pretransplant may help differentiate between true seroconversion and passively transmitted CMV immunoglobulin. [ABSTRACT FROM AUTHOR]

Measurable residual disease (MRD) monitoring independently predicts long-term outcomes in patients with acute myeloid leukemia (AML). Of the various modalities available, multiparameter flow cytometry–based MRD analysis is widely used and relevant for patients without molecular targets. In the transplant (HCT) setting, the presence of MRD pre-HCT is associated with adverse outcomes. MRD-negative remission status pre-HCT was also associated with longer overall (OS) and progression-free survival and a lower risk of relapse. We hypothesize that the combination of disease risk and MRD at the time of first complete remission (CR1) could identify patients according to the benefit gained from HCT, especially for intermediate-risk patients. We performed a retrospective analysis comparing the outcomes of HCT versus non-HCT therapies based on MRD status in AML patients who achieved CR1. Time-dependent analysis was applied considering time-to-HCT as a time-dependent covariate and compared HCT versus non-HCT outcomes according to MRD status at CR1. Among 336 patients assessed at CR1, 35.1% were MRD positive (MRDpos) post-induction. MRDpos patients benefitted from HCT with improved OS and relapse-free survival (RFS), while no benefit was observed in MRDneg patients. In adverse-risk patients, HCT improved OS (HR for OS 0.55; p = 0.05). In intermediate-risk patients, HCT benefit was not significant for OS and RFS. Intermediate-risk MRDpos patients were found to have benefit from HCT with improved OS (HR 0.45, p = 0.04), RFS (HR 0.46, p = 0.02), and CIR (HR 0.41, p = 0.02). Our data underscore the benefit of HCT in adverse risk and MRDpos intermediate-risk AML patients. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR) T cell therapy is associated with high risk of adverse events. Glucocorticoids (GCs) are cornerstone in the management of high-grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Given the potentially deleterious effects of GCs on CAR T cells anti-tumor activity, increasing our understanding of GCs impact on CAR T cells is crucial. Methods: Using several CAR T cells i.e., CD19, mesothelin (MSLN)-CD28 and MSLN-41BB CAR T cells (M28z and MBBz), we compared phenotypical, functional, changes and anti-tumor activity between i) transduced CD19 CAR T cells with untransduced T cells, ii) M28z with MBBz CAR T cells induced by Dexamethasone (Dx) or Methylprednisolone (MP) exposures. Results: Higher levels of GC receptor were found in less differentiated CAR T cells. Overall, Dx and MP showed a similar impact on CAR T cells. Compared to untreated condition, GCs exposure increased the expression of PD-1 and TIM-3 and reduced the expression of LAG3 and function of T cells and CAR T cells. GC exposures induced more exhausted (LAG3 + PD1 + TIM3 +) and dysfunctional (CD107a-INFγ-TNF-IL2-) untransduced T cells in comparison to CD19 CAR T cells. GC exposure impaired more CD4 + than CD8 + CD19 CAR T cells. GC exposures increased more PD-1 expression associated with reduced proliferative capacity and function of M28z as compared to MBBz CAR T cells. CAR T cells anti-tumor activity was greatly affected by repeated GC exposure but partly recovered within 48h after GCs withdrawal. Conclusions: In summary, GCs impacted phenotype and function of untransduced and CAR T cell with different magnitude. The nature of the CAR costimulatory domain influenced the magnitude of CAR T cell response to GCs. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) is associated with morbidity and mortality following allogeneic hematopoietic cell transplantation (alloHCT). Letermovir is a novel antiviral agent that prevents CMV reactivation in alloHCT patients, with limited data regarding influence on post‐alloHCT outcomes. Methods: We retrospectively examined 273 alloHCT recipients, 158 in the non‐letermovir cohort (NLC), and 115 in the cohort using letermovir prophylaxis (LC). Patients that received letermovir were CMV‐seropositive and met criteria for high risk of CMV reactivation. Results: Median start of letermovir was 21 days post‐alloHCT, median duration of prophylaxis was 86 days. Letermovir prophylaxis demonstrated a statistically significant reduction in first CMV reactivation (at 200 days post 63.9% in the NLC vs. 35.7% in the LC; p <.001). On univariate analysis at 1 year, overall survival (OS) for NLC was 79.6% and 79.5% for LC (p =.54). Non relapse mortality (NRM) at 1 year for NLC was 12% and 12.3% for LC (p =.69). Cumulative incidence of relapse (CIR) at 1 year was 13.9% for NLC versus 17.1 for the LC (p =.27). On multivariable analysis, there was no significant difference between the two cohorts for OS, NRM, and CIR. Conclusions: Letermovir prophylaxis started at day +21 post‐alloHCT reduced CMV reactivation, with no impact on posttransplant outcomes. [ABSTRACT FROM AUTHOR]