Significant Difference In Cumulative Incidence Research Articles

Geriatric Nutritional Risk Index Is an Important Predictor of Survival in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Introduction:The body mass index (BMI) and geriatric nutritional risk index (GNRI) are nutrition-related risk assessment tool and has been used in various clinical settings. The relationship between BMI and the associated risk of hematopoietic stem cell transplantation (HSCT), such as relapse and non-relapse mortality (NRM), have been reported (Fuji S et al. BMT. 2014;49:1505). However, the relationship between GNRI and HSCT outcome remains inconclusive. We aimed to evaluate the association between GNRI and overall survival (OS), relapse, and NRM of patients who received allogenic HSCT for hematological malignancies. Methods:We retrospectively analyzed aged 16 years or older patients who underwent first allogeneic HSCT from January 2010 to December 2022 at the Jikei university hospital. The primary endpoints of this study was OS at 5 years. Secondary endpoints were NRM, the incidences of relapse, all-grade acute GVHD and chronic GVHD. Nutritional risk was evaluated both BMI and GNRI. Patients were classified into three groups based on pre-transplant BMI (underweight; BMI <18.5, overweight; BMI ≥25, and others as standard), and also classified into three groups based on pre-transplant GNRI (low-risk; GNRI>98, intermediate-risk; 92≤GNR≤98, and high-risk; GNR<92). GNRI was calculated as follows: (1.519 x serum albumin) + (41.7 x current body weight/ ideal body weight). Data on serum albumin level and body weight were collected at the beginning of conditioning regimen. Results:Two hundred and three patients who received allogeneic HSCT for hematological malignancies (acute myeloid leukemia; n=98, acute lymphoblastic leukemia; n=51, myelodysplastic syndrome; n=27, myeloproliferative neoplasms; n=8, chronic myeloid leukemia; n=18, and other leukemias; n=2) were evaluated. The median age was 52 years old (range 16-69). The median follow-up period of survivors was 1394 days (range 51-4420) after allogeneic HSCT. The donor sources consisted of 39 (19.2%) HLA-matched related donor, 50(24.6%) HLA-mismatched related donor, 26(12.8%) HLA-matched unrelated donor and 88(43.4%) HLA-mismatched unrelated donor. One hundred and nine patients (53.7%) received myeloablative conditioning regimens. Based on the BMI, underweight, standard, overweight were included 33 (16.3%), 139 (68.4%), and 31 (15.3%) patients, respectively. While, based on the GNRI, the low-risk, intermediate-risk and high-risk were divided into 105 (51.7%), 46 (22.8%), and 51 (25.2%) patients, respectively . The 5-year OS rates of standard, underweight, and overweight were 52.6%, 39.5%, and 62.1%, respectively (p=0.07). On the other hand, the 5-year OS of low-risk, intermediate-risk, and high-risk were 62.6%, 50.4%, and 33.2%, respectively (p=0.01). In addition, multivariate analysis showed high-risk group showed significantly lower OS (p=0.03). Five-year cumulative incidences (CI) of relapse in the standard, underweight, and overweight, were 46.4%, 45.4%, and 25.0%, respectively (p=0.11). However, multivariate analysis showed that CI of relapse ratio was significantly lower in overweight group (p=0.02). While, 5-year CI of relapse rates in the low-risk, intermediate-risk, and high-risk were 36.5%, 47.2%, and 52.5%, respectively (p=0.03). However, multivariate analysis showed that there were no significant differences in relapse among three risk groups (p=0.06). There were no significant differences in CI of NRM, acute GVHD and chronic GVHD either BMI or GNRI. Subgroup analysis in the patients who underwent HSCT in complete remission revealed that there was no significant difference in OS among the three BMI groups (p=0.11), as well as the three GNRI groups (p=0.06). For the patients in non-remission at the time of allogeneic HSCT, there was no significant difference in OS between the three groups in BMI; however, OS was shorter in the high-risk group in GNRI (p=0.01). Conclusions:In our study, OS of high-risk group defined by GNRI showed significantly poor , especially in non-remission patients. Although overweight defined by BMI did predict low CI of relapse, overweight did not predict OS. These results suggest that nutrition-related risk assessed by GNRI could be prognostic marker for survival in patients who received allogeneic HSCT.

CR1 Favors PTCy-haplo over UCB in Allogeneic Stem Cell Transplantation for Adult Patients with AL

[Introduction] HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCB) are alternative to HLA-matched hematopoietic stem cell transplantation (HSCT). However, advantage of PTCy-haplo versus UCB has not been determined in patients with acute lymphoblastic leukemia (ALL). Thus, we compared post-HSCT outcomes of PTCy-haplo and UCB in adult patients with ALL to determine patient subgroups who benefit from PTCy-haplo. [Methods] We analyzed data on adult patients (≥16 years) with ALL who underwent HSCT with PTCy-haplo or single-unit UCB between January 2013 and December 2021, using the Japanese nationwide registry database. Endpoints of the analysis included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse, non-relapse mortality (NRM), engraftments, acute and chronic graft-versus-host disease (GVHD), and infections. In addition to multivariate analysis, propensity score matching was performed as a sensitivity analysis. [Results] We analyzed 1999 patients (PTCy-haplo, 330; UCB, 1669). Median age at HSCT was 44.5 years (range, 16-73) in PTCy-haplo and 45 years (range, 16-74) in UCB group. The proportion of patients who underwent HSCT in the first complete remission (CR1) (PTCy-haplo, 50.3%; UCB, 48.8%) and median time from diagnosis to HSCT (PTCy-haplo, 7.8 months; UCB, 7.7 months) were comparable between the groups. Regarding conditioning, the proportion of those who received myeloablative conditioning (PTCy-haplo, 50.6%; UCB, 54.8%), or conditioning with total body irradiation (PTCy-haplo, 82.4%; UCB, 79.3%) were comparable between the groups. Multivariate analyses showed that PTCy-haplo recipients had comparable 3-year OS (54.1% vs. 52.3%; adjusted hazard ratio [aHR], 0.93; p = 0.51) and DFS (49.7% vs. 47.1%; aHR, 1.06; p = 0.60) with UCB recipients. PTCy-haplo recipients had a significantly higher 3-year relapse rate (32.2% vs. 26.4%; aHR, 1.47; p = 0.01), but had a significantly lower 3 -year NRM (18.1% vs. 26.5%; aHR, 0.70; p = 0.03) as compared to UCB along with significantly faster neutrophil (median, 16 days vs. 20 days) and platelet (median, 30 days vs. 42 days) engraftments, and lower incidence of viral, fungal and bacterial infections. There was no significant difference in cumulative incidence of acute GVHD (30.9% vs. 36.4%, grade II-IV at 100 days; p = 0.15), or chronic GVHD (22.5% vs. 20.9% at 3 years; p = 0.85) between the two groups. These comparable OS and DFS between the two groups were confirmed after minimizing differences in patient characteristics with propensity score matching analysis (Figure 1A). Then, to identify patient subgroups who benefit from PTCy-haplo rather than UCB transplant, we performed subgroup analyses of OS. Significantly favorable effects of PTCy-haplo over UCB were observed in patients with CR1 at HSCT (HR, 0.66; p = 0.03). Indeed, propensity score matching analysis showed that PTCy-haplo recipients had a significantly higher 3-year OS (76.4% vs. 67.6%; HR, 0.57; p = 0.01) and DFS (70.5% vs. 60.6%; HR, 0.66; p = 0.03) than UCB recipients, along with a significantly lower NRM (12.9% vs. 26.3%; HR, 0.39; p < 0.01), and a comparable relapse rate (16.6% vs. 13.1%; HR, 1.41; p = 0.25) with UCB. These results suggest that the low NRM in PTCy-haplo transplant outweighs potential concerns of relapse among patients transplanted in CR1 (Figure 1B). By contrast, in patients with ≥ 2 nd CR or non-CR at HSCT, survival benefits of PTCy-haplo were not observed. [Conclusions] Our results suggest that while both PTCy-haplo and UCB are suitable alternative donor sources for adult ALL patients without HLA-matched donors, in patients with CR1, selection of PTCy-haplo rather than UCB improves post-transplant prognosis.

Assessing the duration of EDSS improvement after a therapy start: A novel approach applied to the long-term extension of the PRISMS study.

In a chronic and progressive disease such as multiple sclerosis (MS), the improvement on Expanded Disability Status Scale (EDSS) can be a transient event. Therefore, estimating the prevalence of disability improvement over time, accounting both for improvement incidence and duration, is of interest. The aim of this study was to show the application of a simple estimator for the proportion of patients with sustained improvement over time using data from the long-term extension of the PRISMS trial. A total of 534 relapsing-remitting MS (RRMS) patients from the PRISMS trial were included. Patients with a baseline EDSS of 0 were excluded. Patients were randomized to placebo (n=178), subcutaneous interferon beta-1a (sc IFN β-1a) 22µg (n=181) or sc IFN β-1a 44µg (n=175). At Year 2, patients receiving placebo were re-randomized to sc IFN β-1a 22µg or 44µg (delayed sc IFN β-1a) while patients receiving sc IFN β-1a 22µg or 44µg continued their initial regimen. Patients were followed up for over 7 years post-randomization. Disability improvement was defined as a 1-point decrease in EDSS from baseline confirmed at 6 months. Prevalence of improvement was estimated as difference of Kaplan-Meier (KM) estimators while the cumulative incidence of improvement was calculated using the standard KM curves. No significant differences in cumulative incidence of EDSS improvement at 3 years between delayed sc IFN β-1a (20.3%) and sc IFN β-1a 22µg (20.8%; p=0.49) or 44µg (21.3%; p=0.33). When taking duration of improvement into account, the proportion of patients showing an improved condition after 3 years was 10.1% with delayed sc IFN β-1a, 11.3% with sc IFN β-1a 22µg (p=0.17) and 15.4% with sc IFN β-1a 44µg (p=0.037) that was substantially maintained over the long term. With the use of this new statistical methodology, it is possible to estimate the time to improvement as well as the duration of improvement, information that is better suited to describing a non-final outcome like disability improvement. In this case, early sc IFN β-1a 44µg initiation had a greater proportion of patients with a sustained disability improvement over a long period of follow-up as compared to patients who had initially been randomized to placebo. In contrast, no significant differences on the cumulative incidence of improvement were observed.

Predictors of Hepatotoxicity in Patients with Metastatic Solid Tumors Treated with Immune Checkpoint Inhibition (ICI) and Liver-Directed SBRT

Liver-metastasis-directed SBRT (LM-SBRT) alone provides durable local control for liver metastases with low rates of toxicity when adhering to established dose constraints. Whether these constraints are sufficient in the context of concurrent ICI is not established. To determine whether LM-SBRT contributes to hepatotoxic adverse events (HAE) in patients receiving ICI, we analyzed potential predictors of HAE in a prospectively evaluated cohort of clinical trial patients treated with both SBRT and ICI. Patients with metastatic solid tumors were included from three trials of multi-site SBRT with ICI given concurrently or shortly after SBRT provided they received all study treatments and were monitored for adverse events. ICI agents included pembrolizumab alone or dual agent ICI with nivolumab and either cabiralizumab, urelumab, or ipilimumab. LM-SBRT was delivered to 45 Gy in 3 fr with mean liver dose (MLD) limited to 16 Gy and <700 cc of liver receiving 17.1 Gy. HAE were defined using CTCAE 4.0 as: elevation of AST, ALT, bilirubin or alkaline phosphatase; autoimmune hepatitis; hepatic failure; or cholecystitis. HAE were included if rated at least possibly related to treatment by the trial monitoring committee. Cumulative incidence (CI) of HAE was modeled with death as a competing risk. Competing risks regression was performed using Fine-Gray modeling. Two hundred thirteen patients were evaluable. Median follow-up was 10 months. Median age was 61, 90 had liver metastases at treatment, 65 received SBRT to a liver lesion, 15 had underlying liver disease (cirrhosis or hepatic steatosis) and 13 patients had a primary liver cancer. Dual agent ICI was given to 97 patients. Table 1 shows CI at 6 months of grades 1-4 HAE in all patients, LM-SBRT patients and non-liver SBRT patients (NL-SBRT). None experienced grade 5 HAE. There was no significant difference in CI of any grade of HAE between LM-SBRT and NL-SBRT patients. This was also true when comparing LM-SBRT patients to NL-SBRT patients with <0.1 Gy MLD. ICI dose reduction or cessation due to HAE occurred in 4 patients, none of whom received LM-SBRT. On univariate analysis, underlying liver disease and dual agent ICI were significantly associated with grade 2+ HAE while age, LM-SBRT, MLD, primary liver cancer and presence of liver metastases at treatment were not. On multivariate analysis, underlying liver disease and dual agent ICI remained significantly associated with grade 2+ HAE (HR: 6.7, 95% CI 2.3 - 19.1; 4.7, 95% CI 1.7 - 13.0). LM-SBRT and MLD were not significant on MVA. LM-SBRT did not significantly increase the risk for hepatotoxicity in patients receiving ICI when respecting the above dose constraints. Risk for hepatotoxicity appears to be driven by dual agent ICI and underlying liver disease.

Genetic-Guided Oral P2Y12 Inhibitor Selection and Cumulative Ischemic Events After Percutaneous Coronary Intervention

BackgroundGenetic-guided P2Y12 inhibitor selection has been proposed to reduce ischemic events by identifying CYP2C19 loss-of-function (LOF) carriers at increased risk with clopidogrel treatment after percutaneous coronary intervention (PCI). A prespecified analysis of TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) evaluated the effect of genetic-guided P2Y12 inhibitor therapy on cumulative ischemic and bleeding events. ObjectivesHere, the authors detail a prespecified analysis of cumulative endpoints. The primary endpoint was cumulative incidence rate of ischemic events at 12 months. Cumulative incidence of major and minor bleeding was a secondary endpoint. Cox proportional hazards models as adapted by Wei, Lin, and Weissfeld were used to estimate the effect of this strategy on all observed events. MethodsThe TAILOR-PCI trial was a prospective trial including 5,302 post-PCI patients with acute and stable coronary artery disease (CAD) who were randomized to genetic-guided P2Y12 inhibitor or conventional clopidogrel therapy. In the genetic-guided group, LOF carriers were prescribed ticagrelor, whereas noncarriers received clopidogrel. TAILOR-PCI’s primary analysis was time to first event in LOF carriers. ResultsAmong 5,276 patients (median age 62 years; 25% women; 82% acute CAD; 18% stable CAD), 1,849 were LOF carriers (903 genetic-guided; 946 conventional therapy). The cumulative primary endpoint was significantly reduced in the genetic-guided group compared with the conventional therapy (HR: 0.61; 95% CI: 0.41-0.89; P = 0.011) with no significant difference in cumulative incidence of major or minor bleeding (HR: 1.36; 95% CI: 0.67-2.76; P = 0.39). ConclusionsAmong CYP2C19 LOF carriers undergoing PCI, a genetic-guided strategy resulted in a statistically significant reduction in cumulative ischemic events without a significant difference in bleeding. (Tailored Antiplatelet Therapy Following PCI [TAILOR-PCI]; NCT01742117)

Long-term morbidity of triplets according to their birth order; A population- based cohort study

The association between birth order and adverse perinatal outcome has been studies vastly in twin pregnancies. However, little is known regarding differences in long-term morbidity within triplets according to birth order. Hence, we opted to assess differences in long-term morbidities of triplets by their birth order. In a population-based retrospective cohort study, the incidence of long-term morbidity was compared between the triplet's siblings according to their birth order. Deliveries occurred between the years 1991 and 2021 in a tertiary medical center. The study groups were followed until 18 years of age for cardiovascular, respiratory, neurological and infectious- related morbidities. Kaplan-Meier survival curves were used to compare cumulative morbidity and Cox proportional hazards models were performed to control for confounders. The study included 117 triplet deliveries. No significant differences in cardiovascular, respiratory, neurological and infectious, morbidities were noted between the first, second and third sibling (Table). Likewise, no significant differences in cumulative incidence of long-term pediatric morbidities were noted between the siblings, using Kaplan-Meier survival analyses (Figure). In Cox proportional hazards models, controlling for weight and gender, birth order in triplet pregnancy did not exhibit an association with long-term morbidities of the offspring. Despite the known association between birth order in twins and adverse perinatal outcome, birth order in triplets does not seem to have an impact on the long-term morbidity of the offspring.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Racial, Ethnic and Socioeconomic Disparity in Outcomes of Patients with Chronic Graft-Versus-Host Disease: A CIBMTR Analysis

Introduction: Prior studies have demonstrated that racial/ethnic minority groups and patients with low socioeconomic status (SES) have worse overall survival (OS) after allogeneic hematopoietic stem cell transplant (allo-HCT). Whether the racial and SES disparity in outcomes persists and possibly may even be exacerbated in allo-HCT recipients with chronic graft-versus-host disease (cGVHD) is unknown. Certain aspects of cGVHD such as the need for long term care, prolonged immunosuppressive treatment, and close follow up for complications may exacerbate racial and SES disparities. In the current study, we analyzed the association of race/ethnicity and SES with the incidence of cGVHD and compared the long-term outcomes of allo-HCT survivors with cGVHD by race/ethnicity and SES. Methods: The study population comprised 14,825 adults with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), or myeloproliferative neoplasm (MPN) who received first allo-HCT between 2008-2018 in the United States. Residential ZIP code at the time of allo-HCT was used to estimate annual household income as the measure of SES. Patients with relapse of the primary disease prior to diagnosis of cGVHD were excluded. The incidence of cGVHD was calculated using the cumulative incidence estimator. Cox regression models were used to determine whether race/ethnicity and SES were associated with overall survival (OS), treatment related mortality (TRM) and relapse among patients with cGVHD. A stepwise backward variable selection was used to develop models for each outcome with a threshold of 0.05 for retention in the model. The main variable was then forced into the models. Interactions between the main variable and the adjusted covariates were tested at the significance level of 0.01. Results: Patients were reported to be Non-Hispanic White (W) (n=11,796), Non-Hispanic Black (B) (n=1,009), Hispanic (H) (n=1,325), and Asian (A) (n=695). A total of 5,600 relapse-free allo-HCT recipients developed cGVHD. There was no significant difference in cumulative incidence of cGVHD based on race/ethnicity (p=0.49, Table 1) or SES (p=0.44). In the multivariable analysis, we observed no significant differences in OS (p=0.15), TRM (p=0.11) and relapse (p=0.03) in patients with cGVHD based on race and ethnicity adjusted for patient-, disease- and transplant-related covariates. SES (household income, with or without adjustment for health insurance status) was significantly associated with OS (p<0.0001) and TRM (p=0.0006). More specifically, the highest quartile of household income (≥ $80,000) was associated with improved OS (HR 0.78, CI 0.71-0.86, p< 0.0001) and reduced TRM (HR 0.75, CI 0.66-0.86, p< 0.0001) compared with the lowest household income quartile (< $48,000) (Table 2). There was no association between the SES and relapse among patients with cGVHD (p=0.29). Conclusions: Our study highlights that low SES, regardless of race/ethnicity, has a negative impact on outcomes after diagnosis of cGVHD. Disparities in outcomes solely based on race/ethnicity were not evident among patients with cGVHD. Future studies are needed to determine if people with low SES and cGVHD have disproportionately worse outcomes than those with low SES without cGVHD. If they do, then optimizing the health care resources available to cGVHD patients with low SES may improve long-term outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 9454: Cardiovascular Risks of Chemo-Immunotherapy for Lung Cancer: A Population-Based Cohort Study

Introduction: Chemo-immunotherapy combinations have proven efficacious for treating advanced lung cancer. However, their cardiovascular risks are unclear. This study thus aimed to compare the cardiovascular risks between programmed cell death protein 1 (PD-1) inhibitors, and chemo-immunotherapy in Asian patients with lung cancer. Methods: This retrospective cohort study included patients aged at least 18 years old with lung cancer receiving any PD-1 inhibitor in Hong Kong during 2013-2021. Patients with non-concurrent use of PD-1 inhibitor and chemotherapy, use of tyrosine kinase inhibitor, other immunotherapy, or those with prior stroke, heart failure, or myocardial infarction were excluded. Treatment groups were defined as PD-1 inhibitor only, and concurrent use of PD-1 inhibitor and chemotherapy (chemo-immunotherapy). The endpoint was major adverse cardiovascular events (MACE), that was the first occurrence of cardiovascular death, heart failure, stroke, or myocardial infarction. Patients were followed up until the end of 2021. Inverse probability treatment weighting (IPTW) was used to minimise covariate imbalances. Results: Of the 1508 patients identified, 713 were analysed (538 male, mean age 66.2±10.6 years old, mean follow up 1.4±1.3 years); 333 received PD-1 inhibitors only, and 380 received chemo-immunotherapy. IPTW achieved good balance for all covariates. The observed incidence rate of MACE was 2.8 events per 100 person-year (95% confidence interval (CI) 1.6-4.8) for patients on PD-1 inhibitors, and 2.1 per 100 person-year (95% CI 1.2-3.8) for those on chemo-immunotherapy. The log-rank test showed no significant difference in cumulative incidence of MACE between treatment groups (p=0.641; Figure 1). Conclusions: MACE may be uncommon amongst patients with lung cancer receiving PD-1 inhibitors or chemo-immunotherapy. The associated risks of MACE may not be significantly different between PD-1 inhibitors and chemo-immunotherapy.

Hereditary angioedema is associated with an increased risk of venous thromboembolism

Hereditary angioedema is associated with an increased risk of venous thromboembolism

Analysis of Rates of Brain Metastases and Association With Breast Cancer Subtypes in Ontario, Canada

Approximately 1 in 7 patients with metastatic breast cancer (MBC) will receive radiotherapy for brain metastases (BRM). Significant differences in cumulative incidence of BRM by breast cancer subtype may inform future BRM screening protocols. To describe cumulative incidence of BRM among patients with de novo MBC. In this population-based cohort study, population health administrative databases in Ontario, Canada, held at the ICES were used to identify patients diagnosed with de novo MBC between 2009 and 2018. Given that a code for BRM does not exist within ICES, we analyzed the incidence of radiotherapy for BRM. The median (IQR) follow-up was 19.3 (6.2-39.5) months. A total of 100 747 patients with a new diagnosis of breast cancer between January 2009 and December 2018 were identified. Of these patients, 17 955 were excluded because they had previous or subsequent malignant neoplasms, 583 were excluded because they were younger than 18 years, 974 were excluded because there was an invalid Ontario Health Insurance Plan number or a date of death on or before the index date. Among 81 235 remaining patients, 3916 were identified as having de novo MBC. Treatment with radiotherapy for breast cancer BRM. Cumulative incidence of radiotherapy for BRM accounting for the competing risk of death, and time from MBC diagnosis to brain radiotherapy. Kaplan-Meier analyses were performed for time-to-event end points. Logistic regression was used to account for confounding variables. Among 3916 patients with MBC, 1215 (31.0%) had HR-positive/ERBB2 (formerly HER2)-negative cancer, 310 (7.9%) had ERBB2-positive/HR-positive cancer, 200 (5.1%) had ERBB2-positive/HR-negative cancer, 258 (6.6%) had TNBC, and the remaining 1933 patients (49.4%) had an unknown breast cancer subtype. The median (IQR) age at diagnosis was 63 (52-75). A total of 549 (14.0%) underwent stereotactic radiosurgery or whole brain radiotherapy for breast cancer BRM. Cumulative incidence of BRM was higher among patients with ERBB2-positive/HR-negative breast cancer (34.7%), ERBB2-positive/HR-positive breast cancer (28.1%), and triple-negative breast cancer (21.9%) compared to those with HR-positive/ERBB2-negative breast cancer (12.1%). The median (IQR) time from MBC diagnosis to brain radiotherapy ranged from 7.5 (2.3-17.4) months for patients with TNBC to 19.8 (12.2-35.1) months for those with ERBB2-positive/HR-positive breast cancer. Incidence and time to development of BRM vary significantly by breast cancer subtype. A better understanding of the biology of intracranial metastatic disease may help inform potential screening programs or preventative interventions.

Impact of digoxin utilization on clinical outcomes following left ventricular assist device implantation.

We aimed to assess the impact of digoxin use following left ventricular assist device (LVAD) implantation on clinical outcomes. Patients implanted with continuous flow LVADs at a single academic medical center and survived to initial hospital discharge were included in the analysis (n = 346). Clinical events were captured at a maximum of 2 years of follow up. Digoxin use was defined as 30-day continuous use post-LVAD. Negative binomial regression and Kaplan-Meier method were used to assess the association between digoxin use and clinical outcomes. Mean age of the cohort was 56 years (±13) and 23% (79/346) were female sex. Digoxin was used in 144 patients (41.6%) for a median of 268 days (IQR 154, 616). Digoxin use was associated with a significant reduction in cumulative incidence of gastrointestinal bleeding (GIB) (15% vs 26%, p = 0.004). After adjusting for age, hypertension, post-operative hemoglobin, RDW, potassium, and GFR, and use of angiotensin receptor/neprilysin inhibitor, there remained a significant 47% reduction in GIB incidence in patients treated with digoxin. There was no significant difference in cumulative incidence in right ventricular failure (RVF) between the two groups. There was no difference in overall 2-year survival between groups. Digoxin use was associated with reduction in GIB events, but not in RVF or mortality. Further studies are needed to confirm these findings and to investigate optimal timing and patient population.

Race/ethnicity and outcomes in hematopoietic stem cell transplantation (HCT) in myeloproliferative neoplasms (MPN): A single institutional study.

e19083 Background: Previous studies have demonstrated racial disparities in MPN outcomes, but there is no data regarding impact of race on outcomes of HCT in MPN. This is a retrospective study evaluating transplant related outcomes in Hispanics undergoing allogeneic HCT for MPN/MF in a large hospital in South Texas. Methods: A total of 45 patients who underwent HCT for MPN disorders from January 2008 to December 2020 at the Methodist Hospital, San Antonio were included. Race was self-reported by patients and obtained from electronic medical record along with other variables. Significance of variation in categorical outcomes were assessed with Chi-square tests. OS was estimated using the Kaplan-Meier method and compared between races using the log rank test. Results: This study analyzed 19 Non-Hispanic White (NHW) and 19 Hispanic (H) patients (7 patients were excluded due to unknown or other race). Patients primarily underwent transplantation for Myelofibrosis (n=19) followed by CMML (n=12) and MDS-MPN-U (n=7). There were no significant differences between NHW and H patients with regards to performance status, conditioning regimen, stem cell source and GvHD prophylaxis. However, H were younger at transplant with a median of 52 years (range 42-71) compared with 62 years (41-76) in NHW (p=0.50) and were more likely to have a haploidentical donor (47% vs 11%, p &lt; 0.001). There were no significant differences in time to neutrophil (median 22 days (range 15-560) versus 25 days (range 8-48 days), p=0.7) or platelet recovery (median 24 days (range 15-636) versus 25 days (range 6-102), p=0.9) in NHW vs H patients. There were no significant differences in cumulative incidence of grade 1-2 and grade 3-4 acute GvHD between NHW (50 and 50%) vs H (40 and 60%) patients (p=0.4 and p=0.5, respectively). There was significant difference in the cumulative incidence of chronic GvHD (68% NHW compared to 37% H, p=0.03). Median OS was 6.75 years in NHW and 2.67 years in H (p=0.08). The cumulative incidence of Relapse Mortality (RM) and non-RM were not statistically significant between NHW and H, however H had higher percentage of relapse related mortality at 5 years (5.3% vs 17.5%)(Table). Among the 5 NHW and 8 H non-relapse deaths, causes of death were similar among the two groups – the most common being infection (20% and 38%, respectively), acute and chronic (40% and 25%) GvHD and graft failure (0% and 25%). Conclusions: NHW and H had comparable relapse, non-relapse and survival rates likely due to similar access to treatment and follow-up within a single institution. Larger and prospective studies are needed to further elucidate this important topic.[Table: see text]

Randomized Trial of Tacrolimus and Methotrexate Versus Tacrolimus, Reduced Dose Methotrexate, and Mycophenolate Mofetil for Prevention of Graft-Versus-Host Disease after Myeloablative Related and Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Background: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). The combination of tacrolimus (Tac) and methotrexate (MTX) is a standard regimen for GVHD prophylaxis; however, it is associated with several toxicities and patients are often not able to complete the full MTX regimen. The combination of Tac, reduced dose (“mini”)-MTX, and mycophenolate mofetil (MMF) has been investigated with a well-tolerated toxicity profile and low incidence of GVHD, although comparison with standard dose MTX has not been done. We performed a randomized non-inferiority trial comparing Tac/MTX (Full-MTX) to Tac/mini-MTX/MMF (Mini-MTX) for prevention of GVHD after myeloablative related and unrelated donor HCT.Methods: Patients <70 years in age receiving first myeloablative allogeneic HCT using 8/8 HLA-matched related or unrelated donor were eligible; all diagnoses and both bone marrow and peripheral blood stem cell grafts were allowed. Full-MTX patients received MTX dose of 15 mg/m 2 day +1, and 10 mg/m 2 days +3, +6, and +11. Mini-MTX patients received doses of 5 mg/m 2 on days +1, +3, and +6 plus MMF 1000 mg BID. MTX and MMF doses were adjusted for body weight in pediatric recipients. Primary endpoints were incidence of acute GVHD, mucositis, and hematopoietic engraftment. Secondary endpoints included incidence of chronic GVHD, organ toxicity, infection, relapse, non-relapse mortality (NRM), and overall survival (OS). Based on our local incidence rates, 45 patients/arm were needed to detect a hazard ratio of at most 1.7 for acute GVHD (no difference between two arms) using a one-sided non-inferiority log-rank test with 5% significance and 80% power.Results: We enrolled 101 patients; 5 were excluded due to change in eligibility or withdrawal of consent prior to HCT. Analysis is based on 96 patients who were randomized to receive Full-MTX (N=49) or Mini-MTX (N=47). Patient characteristics are described in the Table, and were generally balanced between the two groups . All patients in the Mini-MTX arm received their 3 planned doses of MTX; in the Full-MTX arm, 71% received all 4 doses, 26% received 3 doses, and 1 patient received 2 doses of MTX. There was no significant difference in cumulative incidence of grade 2-4 acute GVHD by day 100 between arms (28% Mini-MTX vs 27% Full-MTX, P=0.41) (Figure 1); however, there was a trend toward higher grade 3-4 acute GVHD in Mini-MTX arm (13% vs 4%, P=0.07). Mini-MTX recipients had lower incidence of severe WHO grade 3-4 mucositis (57% vs 82%, P=0.010), shorter duration of mucositis (median 11 vs 18 days, P<0.001), and had faster engraftment of both neutrophils (median 15 vs 17 days, P<0.001) and platelets (median 23 vs 27 days, P=0.023), with resultant shorter hospital stay (median 27 vs 31 days, P<0.001). There were no significant differences between the two arms in any grade of chronic GVHD (36% vs 25%, P=0.09) or moderate-severe chronic GVHD at 1 year (23% vs 20%, P=0.14). There were also no differences in bacterial (P=0.18), viral (P=0.52) or fungal (P=0.74) infections. There were no significant differences in hepatotoxicity, but lower proportion of patients receiving Mini-MTX experienced nephrotoxicity (creatinine ≥3X upper limit of normal: 2% vs 26%, P<0.001). Mini-MTX recipients also had less respiratory failure in the first 6 months (6% versus 22%, P=0.026). There was no difference in relapse between arms (2-year incidence 22% vs 21%, P=0.89), although Mini-MTX was associated with lower NRM (11% vs 25% at 2 years) (Figure 2), and non-significant but higher OS (70% vs 52% at 2 years; P=0.06).Conclusions: Compared to Full-MTX, a Mini-MTX regimen that incorporates MMF was associated with no difference in acute or chronic GVHD incidence and a more favorable toxicity profile, with faster engraftment, less mucositis, less organ toxicity, and lower NRM. The combination of Tac/mini-MTX/MMF is an acceptable alternative to Tac/MTX after myeloablative related and unrelated donor HCT. [Display omitted] DisclosuresHamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Gerds: Imago: Research Funding; AbbVie: Consultancy; Constellation: Consultancy; Brystol Myers Squibb: Consultancy; Sierra Oncology: Consultancy; Incyte: Research Funding; PharmaEssentia: Consultancy; Novartis: Consultancy; Constellation: Research Funding; Krtos: Research Funding; CTI Biopharma: Research Funding; Accutate: Research Funding. Hill: Gentenech: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding. Copelan: Amgen: Consultancy. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy.

Impact of Choice of Platinum-Based Salvage Therapy on CNS Relapse in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Impact of Choice of Platinum-Based Salvage Therapy on CNS Relapse in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Pre-Transplant Minimal Residual Disease Determined By Multiparameter Flow Cytometry Is Better Than RQ-PCR to Predict the Outcomes of Ph+ALL Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

▪Acute lymphoblastic leukemia with the Philadelphia (Ph) chromosome (Ph+ALL) occurs in about 25-30% adult patient ALL. Though the appearance of tyrosine kinase inhibitors (TKIs) greatly improved the outcomes of this kind of leukemia, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still a radical approach for this kind of leukemia. Several previous studies had demonstrated that minimal residual disease prior to transplantation (pre-MRD) could predict the transplant outcomes, especially leukemia relapse. For Ph+ALL, multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (RQ-PCR) were used to monitor MRD. In this study, we compared the impact of pre-MRD determined by MFC and BCR/ABL expression on the outcomes of Ph+ALL who underwent allo-HSCT. Total 155 patients who received HLA-matched sibling donor transplantation (MSDT, n=49) and unmanipulated haploidentical HSCT (haplo-HSCT, n=106) were enrolled. Pre-MRD was determined using MFC (pre-MFC) and RQ-PCR-based BCR/ABL expression (pre-BCR/ABL). The results showed that patients received MSDT and haplo-HSCT could have the comparable clinical outcomes. When pre-MRD was evaluated by RQ-PCR, the patients with or without BCR/ABL expression in both MSDT and haplo-HSCT groups didn't show any significant difference in cumulative incidence of relapse (CIR), transplantation related mortality (TRM), leukemia-free survival (LFS) and overall survival (OS). In addition, we also divided patients into 5 groups based on pre-BCR/ABL level: group 1, BCR/ABL=0; group 2, 0<BCR/ABL<0.1%; group 3, 0.1%<BCR/ABL<1%; group 4, 1%<BCR/ABL<10%; group 5, BCR/ABL>10%. Through kaplan-meier analysis, it showed that only patients of group 5 would show the extremely higher CIR (75.0%) while there was no significant difference among the other four groups (group 1 vs. 2 vs. 3 vs. 4, 14.5% vs. 10.2% vs. 20.6% vs. 10.0%, P>0.05). However, when pre-MRD was determined by MFC, patients with negative pre-MFC had a lower 2-year CIR and a slight higher 2-year leukemia-free survival (LFS) than those with positive pre-MFC in whole crowd (CIR: 7.5% vs. 40.0%, P<0.001; LFS: 74.4% vs. 61.2%,P=0.119). For those pre-BCR/ABL positive patients, they were further stratified by pre-MFC in both MSDT and haplo-HSCT groups. Patients with pre-MFC prior to MSDT showed a higher 2-year CIR and lower 2-year LFS compared to those with negative MRD (CIR: 44.4% vs. 6.6%, P=0.002; LFS: 44.4% vs. 85.7%, P=0.019). In patients undergoing haplo-HSCT, the 2-year CIR in pre-MFC positive group was higher than that of pre-MFC negative group (32.4% vs. 5.9%, P=0.014), while the 2-year LFS was comparable between above two groups (62.9% vs. 73.8%, P=0.513). Multivariate analysis indicated that prolonged neutrophil engraftment (HR, 1.243; 95% CI, 1.073-1.440, P=0.004) and positive pre-MFC (HR, 5.492; 95% CI, 1.574-19.161; P=0.008) was associated with a higher CIR. The results indicated that, pre-transplant MRD determined by MFC was better than RQ-PCR-based BCR/ABL expression in predicting outcomes of Ph+ALL patients receiving allo-HSCT. DisclosuresNo relevant conflicts of interest to declare.

Incidence and Risk Factors of Hepatic Fibrosis in Psoriatic Patients Receiving Methotrexate with Concomitant Acitretin Therapy and Methotrexate Monotherapy.

BackgroundThe use of methotrexate-acitretin (MTX-ACI) combination therapy in treating psoriasis has been limited due to concerns related to hepatic fibrosis. However, in vitro evidence revealed a protective effect of acitretin in methotrexate (MTX)-induced liver fibrosis.ObjectiveThis study aimed to compare the real-life incidence of hepatic fibrosis in patients with psoriasis receiving MTX-ACI and MTX monotherapy and to investigate factors associated with hepatic fibrosis in MTX-exposed patients.MethodsA retrospective cohort study was conducted based on a real-life registry containing data on patients with psoriasis who were administered MTX-ACI or MTX between 2008 and 2019 and underwent transient elastography according to cumulative MTX dose of 1.0–1.5 g and/or 3.5–4.0 g. Time-to-event analysis was performed to determine the cumulative incidence, incidence rate, and factors potentially affecting the occurrence of hepatic fibrosis.ResultsOf the 160 patients, 32 (20%) were treated with MTX-ACI, and 128 (80%) with MTX alone. Four patients (12.5%) in MTX-ACI group and 21 (16.4%) in MTX group developed hepatic fibrosis (p = 0.59). There was no statistically significant difference in cumulative incidence (16% in MTX-ACI vs 17% in MTX, p = 0.89) and incidence rate (37 cases per 1000 person-year in MTX-ACI vs 23 cases per 1000 person-year in MTX; hazard ratio [HR] = 1.07; p = 0.90) of hepatic fibrosis between the two groups. Diabetes and obesity were identified as significant factors associated with hepatic fibrosis (adjusted HR = 2.40, 95% confidence interval [CI]: 1.05–5.51; p = 0.04 and adjusted HR = 3.28, 95% CI: 1.18–9.16; p = 0.02, respectively) regardless of the cumulative MTX dose.ConclusionThe incidence of hepatic fibrosis in a real-life clinical situation, determined by transient elastography in patients with psoriasis receiving MTX-ACI, was not increased compared to those receiving MTX monotherapy. Type 2 diabetes mellitus and obesity were identified as risk factors of hepatic fibrosis; hence, patients with these factors receiving long-term MTX therapy should be regularly monitored for this particular event.

Malignancies before and after Heart Transplantation - A Single-Centre Long-Term Outcome Study

PurposeHeart transplantation (HTx) has become the standard treatment for patients with end-stage heart disease. The aim of this study was to report our incidence and long-term outcome of malignancies after HTx.MethodsThe study is a single centre retrospective study of 664 patients, who underwent HTx at our centre between, 1985-2017. Data were retrieved from the Cancer Registry and the Birth and Death registry, both of which are obligatory national registries managed by the National Board of Health and Welfare.ResultsIn total, 231 malignancies were diagnosed in 138 patients (19.6%). The median follow-up time was 6.9 years (IQR 2.4-13.1). No patient was lost to follow-up. The overall risk of cancer following organ transplantation was 6.1-fold and 2.9-fold when excluding nonmelanoma skin cancer. The three most common malignancies were; nonmelanoma skin cancer, non-Hodgins lymphoma and lung cancer. There was no significant difference (p<0.79) in overall survival, 10 years after HTx, between those who had cancer before HTx and those who were cancer-free before HTx. Cumulative incidence for those who developed cancer post-transplant was analysed in a competing risk model showing cumulative incidence of cancer and mortality. There was no significant difference (p=0.22) in cumulative incidence of cancer as first event when transplantation was stratified into three time-eras (1985-2000, 2001-2010, 2011-2017). However, there was a significant difference in cumulative incidence of death as first event between those time-eras (p<0.001). Over time, survival has improved and despite that incidence of cancer have not increased.ConclusionNineteen percent of patients had experienced a malignancy after almost 7 years of median follow-up after HTx. We have shown an overall risk of cancer to be over 6-fold higher than among the general population, and almost 3-fold higher when non-melanoma skin cancer was excluded, after heart transplantation. Heart transplantation (HTx) has become the standard treatment for patients with end-stage heart disease. The aim of this study was to report our incidence and long-term outcome of malignancies after HTx. The study is a single centre retrospective study of 664 patients, who underwent HTx at our centre between, 1985-2017. Data were retrieved from the Cancer Registry and the Birth and Death registry, both of which are obligatory national registries managed by the National Board of Health and Welfare. In total, 231 malignancies were diagnosed in 138 patients (19.6%). The median follow-up time was 6.9 years (IQR 2.4-13.1). No patient was lost to follow-up. The overall risk of cancer following organ transplantation was 6.1-fold and 2.9-fold when excluding nonmelanoma skin cancer. The three most common malignancies were; nonmelanoma skin cancer, non-Hodgins lymphoma and lung cancer. There was no significant difference (p<0.79) in overall survival, 10 years after HTx, between those who had cancer before HTx and those who were cancer-free before HTx. Cumulative incidence for those who developed cancer post-transplant was analysed in a competing risk model showing cumulative incidence of cancer and mortality. There was no significant difference (p=0.22) in cumulative incidence of cancer as first event when transplantation was stratified into three time-eras (1985-2000, 2001-2010, 2011-2017). However, there was a significant difference in cumulative incidence of death as first event between those time-eras (p<0.001). Over time, survival has improved and despite that incidence of cancer have not increased. Nineteen percent of patients had experienced a malignancy after almost 7 years of median follow-up after HTx. We have shown an overall risk of cancer to be over 6-fold higher than among the general population, and almost 3-fold higher when non-melanoma skin cancer was excluded, after heart transplantation.

Long-term outcomes of thoracoscopic thymectomy for thymoma stage i-ii

To compare long-term outcomes of video-assisted thoracoscopic (VATS) and conventional open surgery in patients with early-stage (Masaoka stage I-II) thymic malignancies. Retrospective study included patients after VATS and open thymectomy for the period 2000-2019. Long-term outcomes were analyzed. VATS thymectomy was performed in 53 (54.1%) patients, open thymectomy - in 45 (45.9%) cases. Median follow-up period was 66.9 months. Overall 5-year survival was 89.8% and 97% in the Open and VATS groups, respectively (p=0.076). Disease-free survival rates were 79.6% and 86.6% (p=0.279), respectively. There was no significant difference in cumulative incidence of recurrence (13.3% vs 7.5%, p=0.505). Age <50 years and tumor size >5 cm were the independent risk factors of recurrence. VATS thymectomy is an effective approach ensuring similar long-term outcomes in patients with early stages of thymic malignancies.

Incidence and case fatality rate of COVID-19 in patients with inflammatory articular diseases.

To describe the incidence and fatality of coronavirus disease 2019 (COVID-19) and identify risk factors to fatality in patients with inflammatory articular diseases (IAD). This is a cross-sectional observational study of IAD patients and COVID-19 with controls matched for age, sex, and RT-PCR. A control group was used to compare the cumulative incidence (CI) and case fatality rate (CFR). The main outcomes of the study were CI and CFR. Other variables included comorbidities, treatments, and characteristics of the COVID-19. Multiple logistic regression analysis was performed to investigate risk factors for fatality in patients with IAD. Of the 1537 patients who fulfilled the inclusion criteria, 23/1537 (1.49%) had IAD 13 (0.8%) had rheumatoid arthritis (RA), 5 psoriatic arthritis (PsA) (0.3%) and 5 axial spondyloarthritis (0.3%). There were no significant differences in CI of COVID-19 and CFR in patients with IAD compared with COVID-19 patients without IAD. In RT-PCR positive patients, the CI of COVID-19 in PsA and AS was higher. Of the 23 IAD patients, 2 RA patients (8.6%) died. The patients did no show characteristics of the COVID-19 disease different from the population. In multivariate analysis, the factor associated with fatality in patients with IAD was older age (OR [95% CI], 1.1 [1.0-1.2]). COVID-19 CI, fatality rate and other features do not seem to be increased in IAD patients. Older age was associated with fatality in patients with IAD.

Decitabine Versus Hydroxyurea for Advanced Proliferative CMML: Results of the Emsco Randomized Phase 3 Dacota Trial

Decitabine Versus Hydroxyurea for Advanced Proliferative CMML: Results of the Emsco Randomized Phase 3 Dacota Trial