Median Day Of Onset Research Articles

Characterizing immune checkpoint inhibitor-related cutaneous adverse reactions: A comprehensive analysis of FDA adverse event reporting system (FAERS) database

BackgroundThe increasing adoption of immune checkpoint inhibitors (ICIs) in clinical settings highlights their efficacy in treating diverse conditions, while also emphasizing the potential for common cutaneous adverse reactions to arise. The aim of this study is to investigate a multitude of impacting factors and determinants among patients presenting with ICI-associated cutaneous adverse reactions. MethodsWe conducted a comprehensive analysis of ICI-associated cutaneous adverse reactions using data from the FAERS. Our study spans from January 1, 2015, to March 31, 2023, focusing on ICIs, including anti-PD-1, anti-PD-L1, and anti-CTLA-4 agents. FindingsAmong the 334,293 reported irAR, 17,431 were identified as cutaneous adverse reactions (ARs). Predominant cutaneous ARs included rash (21.01 %), pruritus (11.22 %), and pemphigoid (3.90 %). Stevens-Johnson syndrome emerged as the most reported severe cutaneous adverse reaction (SCAR) (2.08 %). Anti-CTLA-4 agents exhibited higher cutaneous toxicity compared to anti-PD-1 and anti-PD-L1 agents. Anti-PD-1 agents demonstrated an elevated mortality rate. The combined use of ICIs with chemotherapy amplified the risk of SCAR and mortality. Targeted therapy was a risk factor for cutaneous ARs but was associated with reduced mortality. The median onset day for cutaneous toxicity was 21 days, while for SCAR, it was 23 days. Weight and age were identified as predictors of SCAR, cutaneous toxicity, and mortality. Skin cancer increased skin toxicity, while lung cancer heightened SCAR formation. The number of administered ICIs positively correlated with SCAR, skin toxicity, and mortality. InterpretationThis study highlights the significance of early identification and effective management of cutaneous toxicities, along with personalized follow-up care, as essential strategies for minimizing risks and preventing treatment disruptions.

Addition of IL-6 and phosphate to the m-EASIX score and detection of ICANS and CRS progression.

e14511 Background: Cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS) can be severe complications of CAR-T infusion. Both syndromes have been associated with endothelial dysfunction which prompted prior use of a modified version of the Endothelial Activation and Stress Index (m-EASIX) to predict the occurrence of severe grades of ICANS and CRS. Recent studies have linked low phosphorous (P) levels to both syndromes, and IL-6 is a known mediator of both. Our study aimed to enhance early prediction of CRS and ICANS by integrating both P and IL-6 into the m-EASIX score. Methods: This retrospective study included 44 patients (26 male and 18 female) ranging from 42 to 86 years old with non-Hodgkin's lymphoma presenting to the University of Arizona Cancer Center for CAR-T treatment. P, CRP, IL-6, and LDH were recorded up to 7 days before and 14 days after CAR-T infusion. All platelet levels were recorded the day of infusion. Variations of the m-EASIX score as outlined in table 1 were then calculated. The values of P were cubed to ensure relative differences in P had proportional consistency to differences in other values. The scores were then used to generate ROC curves for the occurrence of CRS, ICANS, and the progression of CRS to grade ≥2 with CI generated through the Wilson/Brown method. Results: Of the 44 patients, 21 developed CRS alone, 12 developed ICANS+CRS, and 11 developed neither. 18 patients had progression of CRS to grade ≥2. The median day of onset for CRS, ICANS, and progression of CRS to grade ≥2 was 2, 5, and 4 days respectively. Day 3 post infusion yielded the highest values of area under the curve (AUC) with each variation of the m-EASIX score statistically significant with a p<0.001 as represented in table 1. The addition of P and IL-6 to the m-EASIX score increased AUC, sensitivity, and specificity for the occurrence of CRS, ICANS, and progression of CRS to grade ≥2. Conclusions: The inclusion of P and IL-6 in the m-EASIX score improved the sensitivity and specificity of detecting CRS, CRS progression, and the development of ICANS on the 3rd day post infusion. Larger scale studies investigating the efficacy of inclusion of P and IL-6 in the m-EASIX score in guiding early interventions to mitigate complications associated with CAR-T therapy are necessary. [Table: see text]

Acute graft versus host disease 1976-2020: reduced incidence and predictive factors.

We studied the incidence of acute graft versus host disease (GvHD) and its outcome in three consecutive time frames (year <2000; 2000-2010; >2010), in 3,120 patients allografted in two transplant Centers between 1976 and 2020. The median age increased over the three periods from 32 to 42 to 54 years (p < 0.00001). The median day of onset of GvHD in the three periods was day +14, day +16, and day +30, respectively (p < 0.0001). The cumulative incidence (CI) of GvHD grades II-IV in the three periods was 47, 24, and 16%, respectively (p < 0.00001). The CI of GvHD grades III-IV was 13, 5, and 4% (p < 0.001). In multivariate analysis, significant predictive factors for GvHD II-IV, on top of year of transplant, were anti-thymocyte globulin (ATG) (RR 0.67, p > 0.001); post-transplant cyclophosphamide (PTCY) (RR 0.41, p < 0.001), a family mismatched donor (RR 1.31, p = 0.03) a matched unrelated donor (RR 2.1, p < 0.001), an unrelated mismatched donor (RR1.8, p = 0.001), donor age above 40 years (RR 1.27, p < 0.001), hematological malignancy-as compared to aplastic anemia (RR 2.3, p < 0.001). When selecting only GvHD grade II, in a multivariate analysis, there was a significant reduction of transplant-related mortality (TRM) for patients grafted in 2001-2010 (RR 0.62, p < 0.0001) and for patients grafted in 2011-2020 (RR 0.35, p < 0.0001) as compared to grafts before the year 2000. A similar reduction in time was seen for patients with GvHD grades III-IV. The overall TRM in the three periods was 30, 22, and 16% (p < 0.0001) and survival was 47, 51, and 58% (p < 0.0001). Relapse risk was unchanged. In conclusion, we showed improved prevention of acute GvHD with time, together with a significant delay in the onset of the disease. Treatment of GvHD has also improved over time, as suggested by both reduced TRM and improved survival in more recent transplant periods.

Acinetobacter baumannii Bloodstream Infections: A Nationwide Study in Israel.

Acinetobacter baumannii (Ab) bloodstream infections (BSIs) are a major public health concern and associated with high mortality. We describe the nationwide incidence, antimicrobial resistance, and mortality of Ab-BSI in Israel using laboratory-based BSI surveillance data from January 2018 to December 2019. During the study period, there were 971 Ab-BSI events (508 in 2018 and 463 in 2019), with an average annual incidence of 8.08/100,000 population. The median age of patients was 72 (IQR 62-83), and 56.4% were males. Two-thirds of Ab-BSI events were hospital-onset (HO), with median day of onset 16 (IQR 9-30). HO-BSI incidence was 0.62/10,000 patient-days (rate per 10,000 patient-days: 2.78, 1.17, and 0.2 for intensive care, medical, and surgical wards, respectively). Carbapenem susceptibility was 23.4%; 41.4% and 14.9% in community and HO events, respectively. The 14-day, 30-day, and 1-year mortality were 51.2%, 59.3%, and 81.4%, respectively. Carbapenem-resistant Ab-BSI were associated with a significantly higher 14-day, 30-day, and 1-year mortality (p < 0.001 for all). In the multivariable model, age (aHR 1.02) and carbapenem resistance (aHR 3.21) were independent predictors of 30-day mortality. In conclusion, Ab-BSIs pose a significant burden with high mortality, especially associated with antimicrobial resistance. Attention should be focused on prevention and improving treatment.

CMV infection is a risk factor for hemorrhagic cystitis after hematopoietic stem cell transplantation.

Hemorrhagic cystitis (HC) is a common complication after transplantation. The purpose of this study was to examine the incidence and risk factors for HC after hematopoietic stem cell transplantation (HSCT). The records of patients who underwent allogenic HSCT from January 2012 to December 2018 at our institution were retrospectively reviewed. Cox proportional regression and Kaplan-Meier analyses were performed to determine independent risk factors for HC. The statistical analysis was performed in May 2020. A total of 173 patients underwent HSCT, and 53 (30.6%) developed grade 2 or 3 HC cystitis at a median of 37days (range - 5 to 98days) after transplantation. Thirty-two patients developed moderate (grade 2) cystitis and 21 severe (grade 3) cystitis. Of the 173 patients, 61 developed acute graft-versus-host disease (GVHD) (median onset day 24) and 79 experienced cytomegalovirus (CMV) reactivation (median onset day 35). The relative risk (RR) of developing a CMV infection for patients with acute GVHD was 2.77 times that of patients without acute GVHD (P < 0.001). CMV infection was the only independent variable significantly associated with HC in both univariate and multivariate analyses. The estimated hazard ratio (HR) of CMV infection for the development of HC was 5.57 (95% confidence interval [CI]: 2.52 to 12.33, P < 0.001). CMV infection is an independent risk factor for the development of HC after HSCT, and acute GVHD is a risk factor for CMV reactivation. Decreasing the frequency of GVHD after HSCT may result in a lower frequency of HC.

Troubles neurocognitifs et traitement par CAR-T cells

Anti-CD19 CAR T cell therapy is approved for patients with relapsing B-cell lymphoma with ≥ 2 prior systemic therapies and, in recent years, has transformed the care of patients with relapsed and refractory hematologic malignancies. This impressive efficacy is associated with significant toxicity and sometimes life-threatening toxicities, the most prevalent being a cytokine release syndrome (CRS) and neurotoxicity (NT). In a real-life French cohort ( n = 84), sixty-seven patients (80%) developed CRS (grade 1–2 in 63 patients and grade 3–4 in 4 patients). Thirty-six patients (43%) also developed neurotoxicity: grade 1–2 CTCAEv5.0 in 23 patients (64%), and grade 3–4 in 13 patients (36%). Median day of onset of neurological symptoms was day 7 (range: 0–20). Neurotoxicity was associated with CRS in 100% of cases. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. We did not find evidence for mid-term cognitive deterioration after CAR-T cells. The pattern of neurotoxicity in patients treated for B-cell lymphoma identified cognitive disorders and, to a minor degree, movement and cerebellar disorders, as the hallmark of neurotoxicity linked to CAR T-cell therapy. Although sometimes severe, neurotoxicity is almost always reversible.

Abstract 72: Prevalence, course, and predictive factors of water and electrolyte disturbances (WEDs) following transsphenoidal pituitary surgery (TSS) in patients with pituitary adenoma

Background: TSS is commonly associated with various WEDs in postoperative period, which can lead to prolonged hospital stay, readmission and rarely be life threatening. There is scarcity of prospective studies regarding various factors which could predict occurrence of these disturbances.Aims and Objectives: To prospectively study the prevalence, presentation and clinical course of WEDs following TSS in patients with pituitary adenoma and assess potential risk factors for these disturbances.Results: Forty patients (median age 45.5 years, 60% male) harbored 25 clinically hormone inactive and 15 hormone secreting pituitary adenoma. Postoperative WEDs occurred in 45 % of the patients; in 22.5 % as transient diabetes insipidus (DI) %, in 5 % as biphasic response, in 5% as isolated SIADH, in 12.5% as persistent DI. Median day of onset of DI was day 2 and remission was day 4. Median day of onset of SIADH was day 5 and remission was day 9. Younger age and greater adenoma volume were associated with increased risk of DI.Conclusion: WEDs are common following TSS. Diabetes insipidus was more common than SIADH.

Nosocomial Fever in General Medical Wards: A Prospective Cohort Study of Clinical Characteristics and Outcomes.

PurposeNosocomial fever (NF) is a common sign of healthcare-associated infection; however, infection is not always followed up. We studied the etiology, clinical characteristics, and outcomes of nosocomial fever in hospitalized patients.Patients and MethodsBetween October 2019 and December 2020, we enrolled subjects from general medical wards who developed fever ≥48 hours after hospital admission or who were admitted with fever, defervesced, and then developed a fever ≥7 days later that was unrelated to the cause for admission. Subjects with NF underwent a comprehensive clinical evaluation and laboratory investigations.ResultsEighty-six cases of NF were identified and completely followed, the mean age was 69.29 years, and 35 were male. Fifty-seven were from infectious etiologies, 28 from non-infectious etiologies, and one case was unable to be determined. Hospital-associated pneumonia (47.4%) and urinary tract infection (22.8%) were the most common infectious causes, and malignancy (17.8%) and large hematoma (14.3%) were the most common non-infectious causes. The median day of onset of NF following hospitalization was 12 (4.7–21.2) days. Acute physiology and chronic health evaluation II (APACHE II) score (14.70 vs 11.97, p = 0.02), sequential organ failure assessment (SOFA) scores (4 vs 2, p < 0.01), pertinent clinical findings (82.5% vs 42.9%, p < 0.01), blood urea nitrogen (BUN) (37.30 vs 21.10, p = 0.03) and creatinine (1.41 vs 0.97, p = 0.05) levels, and abnormal chest radiography (45.6% vs 3.6%, p < 0.01) had significant differences between infectious and non-infectious etiologies. Twenty-three subjects (26.7%) died. The presence of end-stage renal disease (ESRD) [OR 19.49 (1.77–214.18), p = 0.015], SOFA score >6 [OR 5.18 (1.04–25.90), p = 0.045], and abnormal chest radiography [OR 3.45 (1.16–10.29), p = 0.026] were significantly associated with mortality.ConclusionNosocomial infections, malignancy, and hematoma were the leading causes of NF. Severity scores, clinical findings, renal function tests, and chest radiography were distinguishing features between infectious and non-infectious etiologies. ESRD, high SOFA scores, and abnormal chest radiography were associated with mortality.

High Incidence of CMV Reactivation after Haploidentical Donor Hematopoietic Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide, and Its Impact on Transplant Outcomes

Haploidentical donor hematopoietic cell transplantation (HaploHCT) using high-dose post-transplant cyclophosphamide (PTCy) has been increasingly used in patients with hematologic disorders with promising results. However, limited data is available on the incidence, pattern, and risk factors for cytomegalovirus (CMV) reactivation after HaploHCT with PTCy. Furthermore, the impact of CMV reactivation on HaploHCT outcomes has not been well understood in these patients. In this retrospective study we evaluated 119 consecutive patients undergoing HaploHCT for hematological diseases using PTCy between January 2008 and December 2016 at City of Hope under the IRB approved protocol. CMV reactivation was monitored by our institutional PCR assay (quantitative detection limit: 500gc/ml, qualitative limit: 250gc/ml) at least once a week for 100 days post-HCT, with preemptive anti-CMV therapy for positive PCR according to the institutional guidelines.The median age of the cohort was 43 years (range: 2 to 71 years); 47 patients were female and 72 were male. CMV serostatus of donor/recipient was D-R- in 7, D+R- in 6, D-R+ in 23, and D+R+ in 82 patients. Patients received fully ablative (n=46) or reduced-intensity/non-myeloablative conditioning (n=73) followed by peripheral blood stem cell (n=81) or bone marrow (n=38) graft from sibling (n=42) or non-sibling Haplo donor (n=77). Graft versus host disease (GVHD) prophylaxis was PTCy plus tacrolimus/mycophenolate mofetil. Diagnoses of these patients were acute leukemia (n=80), bone marrow failure (n=15), lymphoma (n=11), chronic leukemia (n=6), hemoglobinopathies (n=5), and multiple myeloma (n=2). The HCT-comorbidity index was more than 2 in 42% (n=50) of the patients.Cumulative incidence (CI) of CMV reactivation for the entire cohort was 69.2% (95%CI: 59.8-76.8%) at 100-days, with the median time to reactivation at 35 days (Figure 1a). While for seropositive recipients (n=105), cumulative incidence of CMV reactivation was 76.5% (95%CI: 66.9-83.6%) with the median onset at 33 days. The median CMV PCR values at onset was 624 gc/ml (range: <500 - 9,930) while the median peak PCR value during the 100-day period was 2965 gc/ml (range: <500 - 221,125). The median duration of CMV reactivation was 21 days and 28% (n=33) of patients had recurrent CMV reactivation during the first 100 days post-HCT. In our cohort there was no patient who developed CMV disease.In univariate analyses the only significant risk factor for CMV reactivation was recipient serostatus (HR=0.06, 95%CI: 0.01 to 0.40 for R- compared to R+, p<0.001) (Figure 1b). Acute GVHD (aGVHD) was not associated with CMV reactivation when analyzed as a time-dependent variable partly due to lower incidence and later onset of aGVHD (100 days incidence: 36.7%; median onset day was not reached, range= 18 to 88) than CMV reactivations (median: 33 days, range= 7 to 54).We then evaluated the impact of CMV reactivation in a landmark analysis of 101 patients who were relapse free for 100 days. The median follow up duration in this subgroup was 12.3 months (range: 3.4 to 99.1). In univariate analysis, CMV reactivation was not associated with overall survival (OS), relapse-free survival (RFS), relapse incidence, or non-relapse mortality (NRM). Similarly, the high-peak CMV reactivation or prolonged CMV reactivation (total duration or total episodes) was not predictive of poor outcomes in this cohort. Interestingly, the risk of chronic GVHD was greater in patients who had no CMV reactivation than those who developed prolonged/recurrent CMV reactivations (56.0% vs. 20.5%, p= 0.048, Figure 2).In conclusion, HaploHCT with PTCy was associated with a high rate of CMV reactivations in seropositive recipients. However, due to pre-emptive therapy approach, CMV reactivation did not translate into higher rate of CMV disease. Despite many patients requiring a long course of preemptive anti-CMV therapy, there was no obvious association between CMV reactivation and survival outcomes. The observed association between CMV reactivation and reduced risk of chronic GVHD warrant further clinical and correlative immunologic studies. [Display omitted] DisclosuresNademanee:seattle Genetics: Speakers Bureau.

Prospective Study of High Dose Foscarnet Prophylaxis for HHV-6 Related CNS Diseases in Cord Blood Transplantation for Adult Patients

Background: Umbilical cord blood transplant (UCBT) recipients showed higher incidence of HHV-6 related CNS diseases (HHV-6 RCD) than those of bone marrow (BM) or peripheral blood (PB). It causes short-term memory impairment or disorientation, which sometimes become irreversible, and convulsions in severe cases, resulted in high non-relapse mortality. We reported previously that in the group given higher doses of prophylactic Foscarnet (FCV) (≥60mg/kg), the incidence of HHV-6 RCD was reduced (Asano-Mori Y, et al. ASH 2013). We thus conducted a prospective study to assess efficacy of higher dose (120mg/kg) of prophylactic FCV to further reduce the incidence and to improve outcome of HHV-6 RCD.Patients and Methods: The study was started since May 2014 and was finished on September 2015. The protocol was approved by local IRB and UCBT recipients who gave written informed consent were included. FCV 120 mg/kg was administered prophylactically from day 7 to day 50 post UCBT.. FCV dose was adjusted according to renal function. The incidence of HHV-6 RCD, types of manifestation and severity of the symptoms, treatment response, and prognosis were evaluated.Results: Among 113 who were included in this study, 9 failed to start FCV from day 7 due to early death or renal impairment, 37 were switched to other drugs at some point before day 50 for reasons such as renal impairment or viral infections other than HHV-6 (23 changed to GCV, 10 to ACV, and 4 to CDV), and 67 received planned dose of FCV. Fifteen developed HHV-6 RCD (12 HHV-6 limbic encephalitis (LE) and 3 myelitis). The cumulative incidence of HHV-6 RCD was 11.5%. No significant risk factors before transplant associated with the development of HHV-6 RCD were identified. Six out of 22 who developed severe pre-engraftment immune reactions (PIR) developed HHV-6 RCD. PIR was shown to be a significant risk factor for HHV-6 RCD development when it was treated as a time-dependent covariate. The median onset day was day 40, and 4 out of 15 patients developed after the cessation of FCV. Only one of 12 encephalitis patients developed convulsions. The median number of copies of HHV-6 in the cerebrospinal fluid at onset was 40,400/µL. HHV-6 viral load in peripheral blood was examined on the same day of CSF examination in 13 and was not detected in 7. Six patients were treated with FCV and GCV in combination, 4 received increased dose of FCV, and 1 was switched from FCV to GCV. Two out of 4 patients who developed after the prophylactic administration of FCV resumed FCV, and the remaining 2 resumed GCV. The virus became undetectable in all 13 evaluable patients by follow-up CSF examination after treatment. The median day of viral disappearance from CSF was 19 days (8-34 days) after diagnosis. All but 2 who were unevaluable due to other complications, had their symptoms improved without sequalae. The median time from treatment intervention to symptomatic improvement was 28 days. The OS after 1 year from HHV6 encephalitis myelitis group was 46.2%, and there was no significant difference in the prognosis as 47.3% OS after 1 year from non-onset group when time-dependent co-analysis was performed (HR 1.88, 95%CI;0.49-2.84, p=0.69). Analysis of OS for 67 patients who were able to undergo preventative FCV administration and other group showed 53.2% and 38.3% respectively in 1 year, revealing a trend in which OS appeared to become higher as a result of continued prophylaxis.Conclusion: There was no difference in the incidence of HHV-6 RCD compared to the previous report even after prophylactic administration of high dose 120 mg/kg of FCV. However, there were few severely ill individuals, most of their symptoms improved due to antiviral treatment without significant sequalae. DisclosuresNo relevant conflicts of interest to declare.

Clinical Characteristics, Management, and Outcome of the First 19 Patients With Pneumonia Due to the 2019 Novel Coronavirus Disease Treated in an Intensive Care Unit in the Republic of Cyprus.

BackgroundThe widespread reach of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its consequences have severely affected the consistency of healthcare systems around the world and caused millions of deaths to date. Understanding the coronavirus disease 2019 (COVID-19) manifestation, progression, and management is crucial for the healthcare personnel caring for COVID-19 patients within the intensive care unit (ICU), as well as for the patients' health progression.MethodsA prospective observational study was used to investigate the progression of critically ill COVID-19 positive patients who were admitted to the ICU of Nicosia General Hospital from March 10 to May 1, 2020. All patients over the age of 18 were included in the study; their data were anonymously collected using the institution’s electronic medical record system and analyzed in Microsoft Excel (Microsoft Corporation, Redmond, WA). Pregnant women, children, and prisoners were excluded.ResultsDuring the study period, a total of 19 patients with a positive result on a reverse-transcriptase polymerase chain reaction (RT-PCR) were included in the study; 74% were men and their mean age was 64 years. Sixty-three percent of the patients were obese, 53% had a history of confirmed hypertension, 68% were admitted with severe respiratory failure, and all of them required invasive mechanical ventilation. Patients were categorized into four groups of ventilation based on the H or L ventilation phenotype in association with co-morbidities. Prone position in the first mechanical ventilation days was found to be more advantageous in L than H phenotype patients, 68% required vasopressor support, and 42% developed acute kidney injury (AKI) during their ICU stay. Diarrhea was with a median day of onset of eight days. Lactate levels above 2 mmol/L in the first four days of admission were correlated with a negative outcome. Nine patients (47%) were successfully discharged from the ICU while 10 (53%) died during their stay.ConclusionIn critically ill patients, male gender and obesity are significant risk factors for ICU admission due to COVID-19, and early prone position, mechanical ventilation, and low positive end-expiratory pressures (PEEP) values may be beneficial, especially in the L phenotype category patients. Patients' ventilation phenotype during ICU admission and hospitalization seemed to determine the outcome.Clinical improvement might have been higher and possibly ICU mortality lower if remdesivir was available. Hydroxychloroquine did not seem to improve patient outcomes, a consistent find, as suggested by other studies; on the contrary, it may have contributed to increased mortality rates.

Description of symptom course in a telemedicine monitoring clinic for acute symptomatic COVID-19: a retrospective cohort study

ObjectiveDescribe the disease course in a cohort of outpatients with COVID-19 and evaluate factors predicting duration of symptoms.DesignRetrospective cohort study.SettingTelemedicine clinic at a large medical system in Atlanta, Georgia.Participants337 patients...

Dynamic Detection of Delayed Cerebral Ischemia

Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage negatively impacts long-term recovery but is often detected too late to prevent damage. We aim to develop hourly risk scores using routinely collected clinical data to detect DCI. A DCI classification model was trained using vital sign measurements (heart rate, blood pressure, respiratory rate, and oxygen saturation) and demographics routinely collected for clinical care. Twenty-two time-varying physiological measures were computed including mean, SD, and cross-correlation of heart rate time series with each of the other vitals. Classification was achieved using an ensemble approach with L2-regularized logistic regression, random forest, and support vector machines models. Classifier performance was determined by area under the receiver operating characteristic curves and confusion matrices. Hourly DCI risk scores were generated as the posterior probability at time t using the Ensemble classifier on cohorts recruited at 2 external institutions (n=38 and 40). Three hundred ten patients were included in the training model (median, 54 years old [interquartile range, 45-65]; 80.2% women, 28.4% Hunt and Hess scale 4-5, 38.7% Modified Fisher Scale 3-4); 101 (33%) developed DCI with a median onset day 6 (interquartile range, 5-8). Classification accuracy before DCI onset was 0.83 (interquartile range, 0.76-0.83) area under the receiver operating characteristic curve. Risk scores applied to external institution datasets correctly predicted 64% and 91% of DCI events as early as 12 hours before clinical detection, with 2.7 and 1.6 true alerts for every false alert. An hourly risk score for DCI derived from routine vital signs may have the potential to alert clinicians to DCI, which could reduce neurological injury.

Real World Experience of Etanercept in Steroid Refractory Acute Graft Versus Host Disease from a Tertiary Cancer Centre in India

Introduction Acute graft versus host disease (aGVHD) is an important complication of allogeneic hematopoietic stem cell transplant (AHSCT). Steroid refractory (SR) aGVHD is seen in about 40- 50% of patients with no recommended standard of care. We report our experience with etanercept (ETA) as the initial agent in SR aGVHD. Materials and Methods We retrospectively analysed 43 AHSCT patients from 2010 to 2019 who received ETA as initial agent for SR aGVHD amongst 311 patients who underwent AHSCT in the same period. Patients received myeloablative (MAC) or reduced intensity conditioning (RIC). The transplants were from matched sibling donor (MSD), matched unrelated donor (MUD) and haploidentical donor (Haplo). GVHD prophylaxis was calcineurin inhibitor (CNI) plus methotrexate (MTX)/ mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide (PTCy) with CNI and MMF. aGVHD was graded as per the modified Glucksberg criteria. Additionally, all aGVHD episodes were also classified as per the Minnesota Scoring into High Risk (HR) and Standard Risk (sr) GVHD. First line treatment of aGVHD Grade II-IV was systemic steroids with methylprednisolone 1-2 mg/kg/day. SR aGVHD was defined as per standard criteria. ETA was started as 25 mg (0.4 mg/kg in children) subcutaneously every 72 hours initially and was tapered gradually depending on response. Response of SR aGVHD to ETA was defined as follows:Complete response (CR) was the complete resolution of aGVHD manifestations in all organs. Partial response (PR) was improvement in GVHD stage in at least 1 of the initially involved organs without CR and worsening in any other organs. Very good partial response (VGPR) was improvement in GVHD in all initial organs, with maximum stage I involvement in 1 or more organs (except upper gut). No response (NR)/Progression/Failure of therapy was defined as same grade or progression of GVHD in any organ or the addition of further GVHD therapy beyond ETA. Death prior to 1st response assessment was taken as NR. Response assessment was done at 3 time points - Day 14, Day 28 and Day 56 after initiation of ETA. Reduction of initial systemic steroid dose by ≥30% from baseline on day 28 after start of ETA was analysed as a subgroup to assess outcomes of patients. Results The characteristics of all 43 patients are shown in Table 1. ETA was required in a total of 45 episodes in 43 patients. The overall grade of GVHD and organs involved at the start of first line treatment are as in Table 2. The median day of onset of acute GVHD was 58 days (range 8-738 days). The median day of start of ETA was 86 days (range 16-74 days). The median number of days steroid was given prior to start of ETA was 7 days. The median number of ETA doses given were 11 (range 2-25). Response assessment on the predetermined time points are as in Table 2. The response rates (CR+VGPR+PR) at Day 14, Day 28 and Day 56 were 62%, 69% and 64% respectively. The organ specific response rates (CR+VGPR+PR) were 70% for lower gut, 67% for skin and 50% for liver. A third line agent for aGVHD was added in 10 patients, which included ruxolitinib, cyclosporine, mycophenolate mofetil, basiliximab or low dose weekly cyclophosphamide. The median OS of the whole cohort of SR aGVHD was 5.2 months. The median OS of the responders (CR+PR+VGPR) at Day 28 from ETA start was 6.8 months versus 2.8 months (p=0.0003) in non-responders (Fig 1). The median OS of sr group of Minnesota Grading was 24 months versus 10 months in HR group (p=0.085) (Fig 2). Patients, in whom reduction in the systemic steroid dose ≥ 30% at Day 28 from start of ETA was possible, had a significantly better median OS (9.5 months versus 3.5 months; p=0.000021) (Fig 3). In multivariate analysis, steroid dose reduction on day 28 of start of ETA was the most significant factor (p=0.008; hazard ratio 3.33; CI 1.3-8.1) CMV reactivation was seen in 64% of the patients. Fungal infections in 51% and bacterial infections in 78% patients after start of ETA. The causes of death were infection in 25 (58%) patients, refractory GVHD in 8 (18%), combination of GVHD and infection in 2 (5%) and relapse in 4 (9%) patients. Conclusion ETA used as initial agent has shown acceptable response rates for SR aGVHD in our cohort, especially for lower gut and skin. However, infections were the major cause for mortality for this cohort and early tapering of systemic steroids may be the key to improving outcomes. Disclosures No relevant conflicts of interest to declare.

Graft factors as determinants of postoperative delirium after liver transplantation

Post-operative delirium (POD) is a frequent complication after surgery, occurring in 15–20% of patients. POD is associated with a higher complications rate and mortality. Literature on POD after liver transplantation (LT) is limited, with the few available studies reporting an incidence of 10–47%. The aim of this study was analyzing pattern, risk factors and clinical impact of POD after LT. Data on donor and recipient characteristics, postoperative course and POD of consecutive adult LT recipients from March 2016 to May 2018 were prospectively collected and retrospectively analyzed. Risk factors for POD were analyzed using univariable logistic regression and Lasso regression. Kaplan–Meier method was used for survival analysis. 309 patients underwent LT during study period; 3 were excluded due to perioperative death. Incidence of POD was 13.4% (n = 41). The median day of onset was 5th (IQR [4–7]) with a median duration of 4 days (IQR [3–7]). Several risk factors, related to the severity of liver disease and graft characteristics, were identified. Graft macrovesicular steatosis was the only factor independently associated with POD at multivariable analysis (OR 1.27, CI 1.09–1.51, p = 0.003). POD was associated with a higher rate of severe postoperative complications and longer intensive care unit and hospital stay, but did not significantly impact on patient and graft survival. Incidence of POD after LT is comparable to that observed after general surgery and graft factors are strongly associated with its onset. These results help identifying a subset of patients to be considered for preventive interventions.

PCN62 Investigation of Diseases Incidence after Administration of Immune Check Inhibitors in LUNG Cancer Based on Claims DATA in JAPAN

Immune check inhibitors (iri) are currently one of the main drug treatment for lung cancer. However, it has been reported that immune-related adverse events unique to iri often occur. The purpose of this study was to investigate the number of irAE cases and the distribution of days of irAE onset in lung cancer based on Claims Data in Japan. We used data from 12346 patients(M:9500,F:2846) who received iri were used from Medical Data Vision data, mainly at DPC(Diagnosis Procedure Combination) hospitals. Using the three digits of the ICD10 code, the disease that first appeared after iri administration was extracted. The diseases targeted were relatively high incidence, interstitial lung disease(J84), thyroid dysfunction(E03, 05, 06, 07), and tuberculosis(A16), pituitary disorders(E22, E23) and type 1 diabetes(E10) that were added to the package insert after release. The number of patients expressing the disease and the average value and median of the number of days until expression of disease were calculated. The results of the major irAEs are as follows: Interstitial pneumonia(J84:1049 cases(8.4% occurrence rate), average onset day 161.19 days(median onset day 91 days)), thyroid dysfunction(E03:1335(10.81%), 96.56(45), E05:321(2.6), 96.56(45), E06:219(1.77), 101.05(63), E07:242(1.96), 113.88(51)). Diseases that have been added to the package insert as serious side effects are as follows: Tuberculosis (A16:54(0.44), 215.81(129)), type 1 diabetes(E10:46(0.37), 190.2(137)), pituitary abnormality(E22:47(0.38), 209.17(139), E23:176(1.43), 185.9(144.5)). Approximately 10% of cases of interstitial pneumonia and hypothyroidism were observed as in previous reports. In particular, thyroid dysfunction was observed relatively earlier from the median date of onset, suggesting that it is necessary to watch closely immediately after iri administration. With regard to tuberculosis, type 1 diabetes, and pituitary abnormalities, the incidence rate was 1% or less, and the timing of occurrence was various.

ACUTE GRAFT Versus Host Disease 1990-2017: Reduced Incidence and Predictive Factors

Alessandra Di Francesco1 , Anna Maria Raiola2 , Alida Dominietto2 , Carmen Di Grazia2, Francesca Gualandi2, Maria Teresa Van Lint2, Patrizia Chiusolo1, 3, Luca Laurenti1, 3, Federica Sora'1, 3, Sabrina Giammarco1 , Elisabetta Metafuni1 , Emanuele Angelucci2 , and Andrea Bacigalupo ,3 1Istituto di Ematologia, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma Italy 2IRCCS Policlinico San Martino, Genova, Italy 3Universita' Cattolica del Sacro Cuore, Roma, Italy; Background: Acute Graft versus Host Disease (GvHD) is a major complication of allogeneic HSCT, and prophylaxis has significantly changed in time . Aim of th study: we wanted to determine the cumulative incidence of GvHD and its outcome, in 3 periods :&lt;2000; 2000-2010; &gt;2010, together with predicting factors. Methods: we analyzed 3126 patients allografted in 2 transplant Centers between 1976 and 2018. Median age increased over the 3 periods from 32 (1-66) to 42 years (9-71) to 50 years (range13-74) (&lt;0.00001). Results GvHD timing : The median day of onset of GvHD before year 2000 was day +14 (2-90), between 2001 and 2010 it was day +19 (2-98) and beyond year 2010 it was day +33 (2-98) (p&lt;0.0001). There were 237 patients developing GvHD before day 14 before year 2000, 71 patients between 2001 and 2010 and only 8 patients beyond 2010 (p&lt;0-0001). GvHD cumulative incidence. The cumulative incidence (CI) of GvHD grade II-IV was 47% before 2000, 24% between 2000 and 2010, and 16% after 2010 (p&lt;0.00001). The CI of GvHD grade III-IV was 13%, 5%, 4% respectively in the three periods (p&lt;0.001). Survival at 5 years of patients with GvHD grade II has remained unchanged in the 3 periods (52%, 44%, 55%, respectively , p=0.2); survival of patients with GvHD grade III-IV has improved from 15%, to 30% and 23% respectively (p=0.003). GvHD and donor type. The incidence of GvHD grade II-IV in HLA identical siblings (SIBS) was 25%, 19% and 14% in the 3 periods (p=0.0005), and for alternative donors, these figures were 43%, 34%, 21% (p&lt;0.00001). Transplant related mortality (TRM). The CI of TRM for patients with grade II GvHD has not changed significantly (27%, 25%, 20%, p=0.1) whereas TRM for patients with GvHD grade III-IV has been reduced from 70% (&lt;2000) to 49% (2001-2010) to 26% beyond year 2010 (p=0.002). Multivariate analysis on survival for patients with grade II GvHD . Significant predictors of survival, for patients with GvHD grade II, were the day of onset of acute GvHD (&lt;/&gt;day 14), advanced phase of the disease, transplant year before year 2000, patients age over 60, and a donor other than an HLA identical sibling. When adding together these negative predictors , the 5 year survival was 28% for patients with 3-5 negative predictors, as compared to 56% for patients with 0-2 negative predictors Conclusions. We show a very significant reduction of the CI of GvHD with time, together with a very significant delay of the onset of the disease. TRM has been reduced in patients with grade III-IV GvHD, less so in patients with GvHD grade II. In the latter significant clinical predictors may allow the identification of patients at high risk, eligible for treatment protocols. Disclosures No relevant conflicts of interest to declare.

Tocilizumab for Prophylaxis of Cytokine Release Syndrome after Outpatient-Based Haploidentical T-Cell Replete Peripheral Blood Stem Cell Transplantation

Introduction Cytokine release syndrome (CRS) is a common and potentially severe toxicity associated with haploidentical peripheral blood hematopoietic stem cell transplantation (Haplo-HSCT). CRS is characterized by immune activation and a high level of circulating inflammatory cytokines, particularly interleukin-6 (IL-6). While tocilizumab, an IL-6 receptor-targeted monoclonal antibody has been effectively used to treat CRS in the context of immunotherapy, it has not been evaluated during the acute Haplo-HSCT period. We hypothesized that prophylactic tocilizumab can prevent CRS after Haplo-HSCT. We report the results of a pilot trial to evaluate its use. Methods Patients ≥18 years undergoing Haplo-HSCT of peripheral blood in a single center with any underlying diagnosis were included. The conditioning was myeloablative and was administered as follows: cyclophosphamide 350 mg / m2 and fludarabine 25 mg / m2 (days -5-3) or rabbit antithymocyte globulin (2.5 mg / kg days -4, -3), plus melphalan 200 mg / m2 PO (days -2-1). Prophylaxis of graft versus host disease (GVHD) consisted of cyclophosphamide (50 mg / kg / day, days +3 and +4), cyclosporine and mycophenolate mofetil on day +5. The cells were infused on day 0. Tocilizumab was administered on day -1 in a single dose of 4 mg / kg IV. CRS was rated according to Lee et al. The primary outcome included the incidence and severity of CRS, the adverse effects associated with tocilizumab, hospitalization and graft rates and the incidence of GVHD. Results Ten patients have enrolled, with an average age of 26 years (range 19-32). The underlying diagnoses were acute lymphoblastic leukemia (n = 7), acute myeloid leukemia (n = 1) and non-Hodgkin lymphoma (n = 2). There were no infusion reactions associated with tocilizumab. Six patients (60%) developed CRS, all grades 1-2, with a median day of onset on day +2 (range 1-3) and a median fever duration of 2 days (range 2-3), often accompanied by nausea, diarrhea, dehydration and transaminitis. All patients were hospitalized; hospitalization was not related to CRS in three patients. 4 patients are alive without relapse (40%), 2 patients alive with relapse (20%), 3 patients died due to transplant-related mortality (30%), one patient dies from relapse (10%). No graft failure occurred and mixed chimerism was observed in a patient. Acute GVHD with steroid response has been diagnosed in 2 cases (20%, grade I / II). The median follow-up is 8.3 months (range 0-20). Conclusion What we observe about the prophylactic use of tocilizumab for Haplo-HSCT of peripheral blood is that its administration is feasible, Grades 1-2 CRS was observed in 60% of patients, grades 3-4 were not observed, however the use of tocilizumab did not prevent hospitalizations. More feasibility data is required before starting a definitive randomized trial to evaluate the use of tocilizumab for Haplo-HSCT peripheral blood. Disclosures Gomez-Almaguer: Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. OffLabel Disclosure: Tocilizumab for Prophylaxis of Cytokine Release Syndrome

1089P - Invasive fungal diseases in patients with Hodgkin’s lymphoma before and after allogeneic hematopoietic stem cell transplantation

BackgroundThis study focuses on epidemiology of IFD before and after allo-HSCT in children and adults with Hodgkin’s lymphoma (HL). MethodsSingle center prospective observational study included 86 patients with classical r/r HL who received allo-HSCT from 2002 to 2018. The median age was 27 (13-49) y.o., children (<18 yo) – 13% (n=11). Allo-HSCT from MUD was performed in 45,4% (n=39), MRD – 24,4% (n=21), MMUD – 15,1% (n=13), haplo – 15,1% (n=13), with RIC (100%) and predominantly PTCY-based GvHD prophylaxis (71%). Primary antifungal prophylaxis was flu in 85%, secondary – vori (100%). EORTC/MSG 2008 criteria for diagnosis and response to therapy were used. Median follow-up time was 12 months [1-71]. ResultsIncidence of IFD before allo-HSCT was 12,8% (n=11). Antifungal therapy before allo-HSCT was used in 81,8% pts with median duration – 2 months. Complete response to antifungal therapy was in 45,4% pts, partial response or stabilization – 36,4%, and 18,2% pts had an “active IFD”. Cumulative incidence of relapse or progression of IA after allo-HSCT was 18,2% with the median 49day [19-79] after HSCT, which were successfully treated with vori in post HSCT period. Incidence of IFD after allo-HSCT for naïve patients was 17,6% (n=13/74). Etiology of IFD after allo-HSCT was IA – 69%, invasive candidiasis – 15%, mucormycosis – 8% and 8% combined IFD caused by Asp. fumigatus + Rhizopus stolonifer. The median day of onset of IFD after allo-HSCT was day+ 114 [1-489]. Antifungal therapy was used in all patients: vori – 59%, mica– 17%, posa – 8%, L-AmB – 8% and combination L-AmB with caspo – 8%. Overall survival (OS) at 12 weeks from the diagnosis of IFD after allo-HSCT was 80%. The 2-year OS in children and adult with HL after allo-HSCT was 73,3%. Development of IFD after allo-HSCT do not decrease the 2-year OS rate (69,2% vs 74%, p=0,77, figure 1a). The impact of prior IFD on 2-year OS in allo-HSCT recipients was not statistically significant in all group (63,6% vs 74,7%, p=0,47, figure 1b), and separately in children and adults. ConclusionsIncidence of IFD before allo-HSCT was 12,8%. Incidence of IFD after allo-HSCT was 17,6%. Despite the high incidence IFD before or after allo-HSCT didn’t influence the outcome in children and adults with Hodgkin lymphoma. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Invasive candidiasis in children after hematopoietic stem cell transplantation

Invasive fungal disease due to Candida spp. – Invasive candidiasis/candidaemia, is a life-threatening complication in immunosuppressed patients. The publications on epidemiology of invasive candidiasis (IC) in children after hematopoietic stem cell transplantation (HSCT) is limited. The purpose of the study was to study the epidemiology of IC in children after HSCT for the 7 years in Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation. In 2009–2016 yy have been performed 754 HSCT in children: 494 allogeneic and 260 autologous. The study was approved by the Independent Ethics Committee of the Raisa Gorbacheva Memorial Research Institute of Children's Oncology, Hematology and Transplantation. A retrospective study included 22 cases of invasive candidiasis in after HSCT. EORTC/MSG 2008 criteria were used for the diagnosis of proven invasive candidiasis as well as to evaluate response to therapy. Incidence of IC was 2.9%: allo-HSCT – 3% (n = 15), auto-HSCT – 2,7% (n = 7). The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. The etiology: Candida parapsilosis – 50%, Candida albicans – 27%, Candida krusei – 14%, Candida tropicalis – 5%, Candida dubliniensis – 4%. The most frequent underlying diseases was acute leukemia – 45% (n = 10). The median age was 8 y.o. (3 month–18 years). The median day of onset of IC after allo-HSCT was 63 days (4–243), auto-HSCT – 12 days (3–20). Febrile fever was the main clinical symptom; septic syndrome develops in 32% cases. Antifungal therapy was with echinocandins – 23%, lipid ampho B – 27%, triazole (fluconazole, voriconazole) – 32%, without therapy (due to early mortality) – 18%. Overall survival (OS) at 30 days from diagnosis invasive candidiasis was 50%. The central venous catheter (CVC) removal was the only factor significantly improved OS (70% vs 33%, p = 0,035). Incidence of Invasive candidiasis in children after hematopoietic stem cell transplantation was 2.9%. The main etiology agent was Candida parapsilosis. Invasive candidiasis infections most often affect leukemia patients, after allo-HSCT developed later than auto-HSCT. Overall survival at 30 days from the diagnosis was 50%. Removing of CVC improved overall survival in children with invasive candida infections after HSCT