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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]

Introduction: Prediction of outcomes following allogeneic hematopoietic cell transplantation (HCT) remains a major challenge. Machine learning (ML) is a computational procedure that may facilitate the generation of HCT prediction models. We sought to investigate the prognostic potential of multiple ML algorithms when applied to a large single-center allogeneic HCT database. Methods: Our registry included 2,697 patients that underwent allogeneic HCT from January 1976 to December 2017. 45 pretransplant baseline variables were included in the predictive assessment of each ML algorithm on overall survival (OS) as determined by area under the curve (AUC). Pretransplant variables used in the EBMT ML study (Shouval et al., 2015) were used as a benchmark for comparison. Results: On the entire dataset, the random forest (RF) algorithm performed best (AUC 0.71 ± 0.04) compared to the second-best model, logistic regression (LR) (AUC = 0.69 ± 0.04) (p < 0.001). Both algorithms demonstrated improved AUC scores using all 45 variables compared to the limited variables examined by the EBMT study. Survival at 100 days post-HCT using RF on the full dataset discriminated patients into different prognostic groups with different 2-year OS (p < 0.0001). We then examined the ML methods that allow for significant individual variable identification, including LR and RF, and identified matched related donors (HR = 0.49, p < 0.0001), increasing TBI dose (HR = 1.60, p = 0.006), increasing recipient age (HR = 1.92, p < 0.0001), higher baseline Hb (HR = 0.59, p = 0.0002), and increased baseline FEV1 (HR = 0.73, p = 0.02), among others. Conclusion: The application of multiple ML techniques on single-center allogeneic HCT databases warrants further investigation and may provide a useful tool to identify variables with prognostic potential. [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]

Background: Pre-transplant pulmonary function testing (PFT) is essential before allogeneic hematopoietic stem cell transplant (HCT), yet the optimal cutoff value for affecting transplant outcomes remains poorly defined. Study Design: Retrospective analysis of pre-HCT PFT data from 605 consecutive patients at the Princess Margaret Cancer Centre between January 1, 2004 and December 31, 2013 used binary recursive partitioning to identify cutoff values for overall survival (OS) as an endpoint of transplant outcomes. These values were compared to HCT comorbidity index (HCT-CI) FEV1 cutoffs for OS, cumulative incidence of relapse and non-relapse mortality. Results: FEV1 ≥ 81% was the identified cutoff point. The OS rate at 3 years showed 49.8% (FEV1 ≥ 81%) vs. 36.6% (<81%, p < .001). For HCT-CI cutoffs, the OS rate at 3 years for FEV1 ≥ 80%, 66%-80% and =65% were 49.0%, 38.1% and 37.6% (p = .011), respectively. Multivariate analysis confirmed that FEV1 ≥ 81% predicted reduced mortality (HR 0.682, p = .001). Subgroup analysis showed both FEV1 ≥ 81% and FEV1 by HCT-CI cutoffs may stratify patients according to OS and NRM risk in subgroups receiving myeloablative, but not reduced intensity conditioning. Conclusion: FEV1 ≥ 81% can predict OS and NRM in our cohort and is potentially simpler when risk stratifying patients undergoing allogeneic HCT, particularly those receiving myeloablative conditioning. [ABSTRACT FROM AUTHOR]

Introduction: The literature comparing outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) for acute myeloid leukemia (AML) is conflicting. Methods: We retrospectively analyzed 451 patients who underwent allogenic hematopoietic cell transplantation (alloHCT) for AML in complete remission (CR) with either RIC (n = 331) or MAC (n = 120) with the use of dual T‐cell depletion as graft‐versus‐host disease (GVHD) prophylaxis. Results: Univariate analysis demonstrated nonrelapse mortality (NRM) at 2 years was 19.1% for MAC and 22.5% for RIC (p =.44). Two‐year cumulative incidence of relapse (CIR) was 19.8% for MAC and 24.5% for RIC (p =.15). Two‐year overall survival (OS) was 61% and 53% for MAC and RIC, respectively (p =.02). Two‐year graft‐versus‐host disease relapse‐free survival (GRFS) was 40.8% for MAC and 33.7% for RIC (p =.30). A propensity score‐matched analysis was done matching patients for age, HLA match, in vivo T‐cell depletion, and Disease Risk Index (DRI). Two‐year OS was 67% for MAC, 66% for RIC (p =.95). A subgroup analysis identified that matched related donor transplants benefit from MAC with OS at 2 years 82.6% versus 57.3% for RIC (p =.006). Conclusions: In the matched‐related donor setting, MAC regimens may offer superior survival. Overall, for our cohort of predominantly in vivo T‐cell depleted patients the outcomes of MAC and RIC were similar. [ABSTRACT FROM AUTHOR]

Comment & Response B To the Editor b A recent study[1] showed pretransplant persistence of I FLT3 i internal tandem duplication ( I FLT3 i -ITD) and I NPM1 i variants in adults with acute myeloid leukemia (AML) to be an effective predictor of posttransplant relapse. DNA sequencing to detect residual disease in adults with acute myeloid leukemia prior to hematopoietic cell transplant. [Extracted from the article]

Background: Inconclusive cytogenetic analysis (IC) at baseline has been reported as a predictor of poor prognosis in patients with acute myeloid leukemia (AML). The mutational profile in this group of patients, and its impact on outcomes have not been reported. Methods: We retrospectively analyzed adult patients (≥18 years) with newly diagnosed AML treated with intensive induction chemotherapy between 2015 and 2019. Patients with any documented cytogenetic abnormalities were excluded. Targeted next generation sequencing (NGS) was performed in all patients. Baseline characteristics, mutation profile, and outcomes were compared between patients with normal cytogenetics(NC) and those with IC. Results: Sixty‐one patients (males 39.3%; median age 59 years) had IC at diagnosis. The proportion of patients with mutations in genes with proven prognostic impact were not different between AML patients with IC and NC. AML patients with NC were more likely to harbor the prognostically favorable NPM1mut/FLT3‐ITDwt mutational combination conferring "favorable" risk status. As a result, a larger proportion of patients in the IC group underwent allogeneic hematopoietic stem cell transplantation (allo HCT; 54.1% vs. 39.6%; p =.02). The 2‐year RFS (55.9% vs. 58.5%; p =.29) and OS (61.9% vs. 66.9%; p =.48) were similar in IC and NC patients. There was no difference in survival of patients who underwent allo HCT when compared with patients who did not (p =.99). Conclusions: Inconclusive cytogenetic analysis may not be an independent prognostic indicator in AML. In such patients, molecular abnormalities detected through NGS or whole genome sequencing are more likely to be informative. [ABSTRACT FROM AUTHOR]