Multicenter Study Of Adult Patients Research Articles

Liver dysfunction in adults with COVID-19 infection: A longitudinal study with transient elastography evaluation.

Abnormal liver biochemistry (ALB) is common among patients with COVID-19 infection due to various factors. It is uncertain if it persists after the acute infection. We aimed to investigate this. A multicenter study of adult patients hospitalized for COVID-19 infection, with at least a single abnormal liver function test, was conducted. Detailed laboratory and imaging tests, including transabdominal ultrasound and FibroScan, were performed at assessment and at 6-month follow-up after hospital discharge. From an initial cohort of 1246 patients who were hospitalized, 731 (58.7%) had ALB. A total of 174/731 patients fulfilled the inclusion criteria with the following characteristics: 48.9% patients had severe COVID-19; 62.1% had chronic liver disease (CLD); and 56.9% had metabolic-associated fatty liver disease (MAFLD). ALB was predominantly of a mixed pattern (67.8%). Among those (55.2%) who had liver injury (aspartate aminotransferase/alanine aminotransferase >3 times the upper limit of normal, or alkaline phosphatase/γ-glutamyl transferase/bilirubin >2 times the upper limit of normal), a mixed pattern was similarly predominant. Approximately 52.3% had normalization of the liver lunction test in the 6-month period post discharge. Patients with persistent ALB had significantly higher mean body mass index (BMI) and serum low-density lipoprotein (LDL), higher rates of MAFLD and CLD, higher mean liver stiffness measurement and continuous attenuated parameter score on FibroScan, and higher rates of liver injury on univariate analysis. Multivariate analysis was not statistically significant. Approximately 47.7% of COVID-19 patients were found to have persistent ALB up to 6 months following the acute infection, and it was associated with raised BMI, elevated serum LDL, increased rates of MAFLD and CLD, and higher rates of liver injury on univariate analysis, but not on multivariate analysis.

4-factor prothrombin complex concentrate is not inferior to andexanet alfa for the reversal or oral factor Xa inhibitors: An Eastern Association for the Surgery of Trauma multicenter study.

Andexanet Alfa (AA) is the only FDA approved reversal agent for apixaban and rivaroxaban (DOAC). There are no studies comparing its efficacy with 4-Factor Prothrombin Complex Concentrate (PCC). This study aimed to compare PCC to AA for DOAC reversal, hypothesizing non-inferiority of PCC. We performed a retrospective, non-inferiority multicenter study of adult patients admitted from July 1, 2018 to December 31, 2019 who had taken a DOAC within 12 hours of injury, were transfused red blood cells (RBCs) or had traumatic brain injury, and received AA or PCC. Primary outcome was PRBC unit transfusion. Secondary outcome with ICU length of stay. MICE imputation was used to account for missing data and zero-inflated poisson regression was used to account for an excess of zero units of RBC transfused. 2 Units difference in RBC transfusion was selected as non-inferior. Results: From 263 patients at 10 centers, 77 (29%) received PCC and 186 (71%) AA. Patients had similar transfusion rates across reversal treatment groups (23.7% AA vs 19.5% PCC) with median transfusion in both groups of 0 RBC. According to the Poisson component, PCC increases the amount of RBC transfusion by 1.02 times (95% CI: 0.79-1.33) compared to AA after adjusting for other covariates. The averaged amount of RBC transfusion (non-zero group) is 6.13. Multiplying this number by the estimated rate ratio, PCC is estimated to have an increase RBC transfusion by 0.123 (95% CI: 0.53-2.02) units compared to AA. PCC appears non-inferior to AA for reversal of DOACs for RBC transfusion in traumatically injured patients. Additional prospective, randomized trials are necessary to compare PCC and AA for the treatment of hemorrhage in injured patients on DOACs. Therapeutic/Care Management, Level III.

Real-World Clinical Experience of Dupilumab in the Treatment of Chronic Palmo-Plantar Eczema in Patients with Moderate-Severe Atopic Dermatitis: 52-Week Follow-Up.

Background: Hand-foot eczema (HFE) are special locations of dermatitis, which are often associated with atopic dermatitis (AD) and have a significant negative impact on the quality of life, demanding a clinically relevant improvement. Objectives: To evaluate the effectiveness and safety of dupilumab in the treatment of eczema localized in hands and/or feet in patients with moderate-to-severe AD. Methods: Retrospective multicenter study of adult patients with HFE treated with dupilumab for their AD. Patients with other concomitantly systemic immunosuppressive treatments did not undergo a washout period. The severity of palmar and/or plantar involvement was assessed using the Physician Global Assessment (PGA) scale on a scale of 0 ( = clear) to 5 ( = very severe). Eczema Area and Severity Index (EASI) and NRS-pruritus scales were also evaluated. One hundred percent of patients reached week 16, while 67/84 reached week 52 of follow-up. Results: A total of 84 patients were included 86.69% of patients showed a reduction in PGA-Hand, and 80.34% in PGA-Foot at week 52, EASI improvement was reached by 83.55% of patients at week 16 and 87.35% at week 52. Reduction of pruritus (≥4 points in NRS-pruritus scale) was 73.01% at week 16 and 80.67% at week 52. No differences in response to dupilumab were observed in the different subtypes of palmo-plantar dermatitis. Conclusions: The results obtained in our study suggest that dupilumab may be an effective and safe therapeutic option for the treatment of dermatitis localized in hands and/or feet.

Results of the compassionate program of inotuzumab ozogamicin for adult patients with relapsed or refractory acute lymphoblastic leukemia in Spain.

The prognosis of relapsed B cell precursor acute lymphoblastic leukemia (B-ALL) is poor and few patients can be successfully rescued with conventional therapies. Inotuzumab ozogamicin (IO), an antibody against the CD22 antigen linked to calicheamicin, has been approved as a rescue treatment in relapsed/refractory (R/R) B-ALL. This was an observational, retrospective, multicenter study of adult patients included in the Spanish program of compassionate use of IO in centers from the PETHEMA group (Programa Español de Tratamientos en Hematología). Thirty-four patients with a median age of 43 years (range, 19-73) were included. Twenty patients (59%) were refractory to the last treatment, IO treatment was given as ≥3rd salvage treatment in 25 patients (73%) and 20 patients (59%) received allogeneic hematopoietic stem cell transplantation before IO treatment. After a median of 2 cycles of IO, 64% of patients achieved complete response (CR)/complete response with incomplete recovery. The median response duration, progression-free survival and overall survival (OS) were 4.7 (95%CI, 2.4-7.0 months), 3.5 (95%CI, 1.0-5.0 months) and 4 months (95%CI, 1.9-6.1 months) respectively, with better OS for patients with relapsed B-ALL versus refractory disease (10.4 vs. 2.5 months, respectively) (p = .01). There was a trend for better OS for patients with first CR duration >12 months (7.2 months [95%CI, 3.2-11.2] vs. 3 months [95% CI, 1.8-4.2] respectively) (p = .054). There was no sinusoidal obstruction syndrome (SOS) event during IO treatment, but three patients (9%) developed grade 3-4 SOS during alloHSCT after IO treatment. Our study showed slightly inferior outcomes of the pivotal trial probably due to poorer risk factors and late onset of IO therapy of recruited patients. Our results support early use of IO in relapsed/refractory ALL patients.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: Classical Hodgkin lymphoma (cHL), the most common lymphoma in young adults, is a disease of poorly understood heterogeneity. The need for enriching tumor cells before assaying has limited the granularity of its molecular sub-classification. Although the cure rates of patients with cHL have increased over time, new biomarkers are still needed for more precise treatment decision-making in this complex patient population. Patients with cHL frequently have significant amounts of circulating tumor DNA (ctDNA), suggesting an alternative approach for studying this enigmatic tumor. Methods: IOSI-EMA003 (NCT03280394) is a prospective, observational, multi-center study of adult patients with newly diagnosed cHL aiming at: (i) identifying subgroups of patients with phenotype- and outcome-associated molecular signatures; (ii) testing and validating baseline ctDNA load as a prognostic biomarker; (iii) testing if ctDNA can be used as biomarker for the early identification of chemoresistance. Blood samples were collected at staging and disease response assessment. PET scans were centrally and blindly reviewed. ctDNA was analyzed by using deep targeted and low pass whole genome sequencing to measure ctDNA load, capture mutations and profile ctDNA fragmentation patterns. Single-cell RNA sequencing has been used to deconvolute the composition of the tumor microenvironment. Results: A total of 215 patients were enrolled. Based on ctDNA fragmentation patterns reflecting chromatin accessibility in the regulatory region of germinal center (GC) B-cell genes, we segregated cHL into two previously unknown subgroups that we named SNCD (for sub-nucleosomal cfDNA) and NCD (for nucleosomal cfDNA). We hypothesized that SNCD cHL stems from a cell that is closer to the GC B-cell differentiation stage than NCD cHL. SNCD cHL and NCD cHL differed in many aspects, including activation induced cytidine deaminase (AID)-hypermutation profile, neoantigen load, immune editing mechanism and response to chemotherapy and checkpoint inhibitors. Clinically, SNCD cHL displayed less sensitivity to both chemotherapy and anti-PD1 antibodies. Immune editing of SNCD cHL points loss of MHC-I, recruitment of Treg and upregulation of LAG3 as prominent immune checkpoint. High load of pre-treatment ctDNA nominated high-risk patients more accurately than clinico-radiological features. In addition, persistence of residual 18FDG avid lesions along with measurable ctDNA after two chemotherapy courses was a better proof of chemoresistance than the sole persistence of residual 18FDG avid lesions. Also, persistence of measurable ctDNA after the end of therapy invariably predicted progression. Conclusions: Collectively, our results provide a roadmap for cHL subtyping and for the clinical use of ctDNA as a biomarker to aid risk stratification and guide treatment decisions in a more personalized approach. Encore Abstract - previously submitted to ASCO 2023 The research was funded by: Research Advisory Board of the Ente Ospedaliero Cantonale, ABREOC 2019-22514, Bellinzona, Switzerland; European Research Council (ERC) Consolidator Grant CLLCLONE, ID: 772051; Swiss Cancer Research Foundation, ID 3746, 4395, 4660, 5257, Bern, Switzerland; Swiss National Science Foundation, ID 320030_169670/1, 310030_192439, 320036_179318, Berne, Switzerland; The Leukemia & Lymphoma Society, Translational Research Program, ID 6594-20, New York; AFRI, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; ASH Global Research Award, Washington DC, USA; Worldwide Cancer Research (ID: 10583); ISREC Foundation; Helmut Horten Foundation, Switzerland; Fondazione Fidinam, Lugano, Switzerland; Nelia & Amadeo Barletta Foundation, Lausanne, Switzerland; Fond’Action, Lausanne, Switzerland; Fondazione Jacob, Lugano, Switzerland; Fondazione Dr. Ettore Balli, Lugano, Switzerland; Fondazione Ticinese per la Ricerca sul Cancro, Bellinzona, Switzerland; Jacques & Gloria Gossweiler Foundation, Berne, Switzerland. Keywords: Diagnostic and Prognostic Biomarkers, Hodgkin lymphoma, Liquid biopsy Conflicts of interests pertinent to the abstract. M. C. Pirosa Educational grants: BeiGene A. Condoluci Honoraria: AbbVie, AstraZeneca and Janssen Research funding: Gilead and Pfizer A. Moccia Honoraria: Janssen and Takeda A. Stathis Honoraria: Eli Lilly, Bayer, Roche, Novartis, Janssen Oncology, AstraZeneca Research funding: ADC Therapeutics, Pfizer, Roche, Novartis, Bayer, Eli Lilly, MEI Pharma, Cellestia, Debiopharm Group, Merck/MSD, Abbvie, Amgen, AstraZeneca, Incyte, Loxo, and Philogen C. Carlo-Stella Consultant or advisory role: Celgene/Bristol-Myers Squibb, ADC Therapeutics, Karyopharm 767 Therapeutics, Roche, and Sanofi Honoraria: Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca, Incyte, Novartis, Takeda, ADC Therapeutics Research funding: ADC Therapeutics, Sanofi, Roche G. Gaidano Honoraria: Abbvie, Astra Zeneca, BeiGene, Incyte, Janssen E. Zucca Honoraria: BeiGene, BMS, Celltion Healthcare, Curis, Eli/Lilly, Incyte, Ipsen, Janssen, Kyte, Merck, Miltenyi, Roche Research funding: AstraZeneca, BMS, Incyte, Janssen, Merck, Roche Educational grants: Abbvie, BeiGene, Janssen and Roche D. Rossi Honoraria: AbbVie, AstraZeneca, BeiGene, BMS, Janssen Research funding: AbbVie, AstraZeneca, Janssen Educational grants: AstraZeneca and Janssen.

OMNIA-2: Phase I/II study of ANV419, an IL-2R-βγ targeted antibody-IL-2 fusion protein, in patients with relapsed or refractory multiple myeloma.

TPS8068 Background: ANV419 is a potent, selective IL-2Rβγ targeted antibody IL-2 fusion protein, designed to enable the delivery of high dose interleukin-2 (IL-2) to patients, in order to stimulate anti-tumour response and minimise toxicities. The ANV419-001 first-in-human study (NCT 04855929) demonstrated that ANV419 preferentially stimulates cytotoxic CD8+ T and natural killer (NK) cells over immunosuppressive regulatory T cells, with a significantly longer half-life than that of conventional IL-2. The safety and tolerability data from this study confirmed that ANV419 delivers high molar equivalents of IL-2 in a tolerable and convenient way. In patients with multiple myeloma, the critical role of NK cells has been well described. ANV419 is expected to promote antitumor response via the preferential stimulation of cytotoxic CD8+ T and NK cells. Methods: The OMNIA-2 study (ANV419-102; NCT 05641324) will evaluate safety and preliminary efficacy of ANV419 as monotherapy and in combination with daratumumab (dara), or lenalidomide with low dose dexamethasone (lena/dex), in patients with relapsed or refractory multiple myeloma. OMNIA-2 is a Phase I open-label, multi-center study in adult patients (n = 52) with symptomatic multiple myeloma who responded to previous treatment and received autologous stem cell transplant, or at least 2 lines of therapy including an immunomodulator, proteasome inhibitor, and/or dara. The study is conducted in 2 stages using a Bayesian Optimal Phase 2 approach. Stage 1 consists of a run-in phase with subsequent randomization to ANV419 243mcg/kg or ANV419 108mcg/kg for 8 weeks, followed by a second randomisation to ANV419 108mcg/kg in combination with lena/dex or dara for a further 8 weeks. Stage 2 follows a similar design as stage 1 and consists of a monotherapy run-in phase with either high or low dose ANV419, with a second randomisation to ANV419 108mcg/kg in combination with either lena/dex or dara, according to the safety and efficacy observed in Stage 1. ANV419 is administered intravenously over 15 to 20 minutes every two weeks. Lena, dex and dara are administered at their respective approved dosing regimens. Tumour response is determined using IMWG (2016) response criteria. AEs are assessed according to CTCAE V5.0. OMNIA-2 is being conducted in Denmark, France, Germany, Spain, Switzerland, UK and enrolment began in January 2023 and preliminary data are expected in Q1 2024. Clinical trial information: NCT05641324 .

Circulating tumor DNA of classical Hodgkin lymphoma.

7516 Background: Classical Hodgkin lymphoma (cHL) is the most common lymphoma in young adults. The morphologic peculiarity that makes cHL unique are the few tumor cells surrounded by a polytypic inflammatory microenvironment. It is also the cancer with the highest sensitivity to immune checkpoint inhibitors. But why is it so immunogenic and how it escapes the immune control at the same time have only been partially elucidated. Although cure rates of cHL have constantly increased over the years there is still a high need for identification of biomarkers for more precise treatment decisions. The need for enriching tumor cells before assaying has limited cHL biological studies. Patients with cHL have significant amounts of circulating tumor DNA (ctDNA), suggesting an alternative approach for studying this enigmatic tumor. Methods: IOSI-EMA003 (NCT03280394) is a prospective, observational, multi-center study of adult patients with previously untreated cHL aiming at: i) identifying subgroups of patients with phenotype- and outcome-associated molecular signatures; ii) testing and validating baseline ctDNA load as a prognostic biomarker; iii) testing if ctDNA can be used for the early identification of chemoresistance. Blood samples were collected at staging and disease response assessment. PET scans were centrally and blindly reviewed. ctDNA was analyzed by using deep targeted and shallow whole genome sequencing to measure ctDNA load, capture mutations and profile ctDNA fragmentation patterns. The composition of the tumor microenvironment of cHL was probed by single cell RNA-seq. Results: A total of 215 patients were enrolled. Based on ctDNA fragmentation patterns reflecting chromatin accessibility in the regulatory region of germinal center (GC) B-cell genes, we segregated cHL into two subgroups that we named SNCD (for sub-nucleosomal cfDNA) and NCD (for nucleosomal cfDNA). We hypothesized that SNCD cHL stems from a cell that is closer to the GC B-cell differentiation stage than NCD cHL. SNCD cHL and NCD cHL differed in many aspects, including activation induced cytidine deaminase (AID)-hypermutation profile, neoantigen load, immune editing mechanism and response to chemotherapy and checkpoint inhibitors. Clinically, SNCD cHL displayed less sensitivity to both chemotherapy and anti-PD1 antibodies. Immune editing of SNCD cHL points loss of MHC-I, recruitment of Treg and upregulation of LAG3 as prominent immune checkpoint. High load of pre-treatment ctDNA nominated high-risk patients more accurately than clinico-radiological features. In addition, persistence of residual 18FDG avid lesions and measurable ctDNA was a better proof of chemoresistance than the sole persistence of residual 18FDG avid lesions. Conclusions: Our results provide a roadmap for cHL subtyping and molecular classification. We also propose ctDNA as a quantifiable and radiation-free biomarker to be used in clinical trials testing a more personalized treatment approach. Clinical trial information: NCT03280394 .

Preliminary Safety and Efficacy from Apex, a Phase 2 Study of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Adults with Advanced Systemic Mastocytosis (AdvSM)

Background: Systemic mastocytosis (SM) is a rare disease characterized by the proliferation of mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of the KIT gene. Advanced SM (AdvSM) is an aggressive, life-threatening form of SM and includes three subtypes; aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and MC leukemia (MCL). Bezuclastinib is an oral, highly selective, and potent tyrosine kinase inhibitor (TKI) with specificity for mutations in KIT exons 9, 11, 17, and 18, including D816V, while sparing closely related kinases (e.g., PDGFRα, PDGFRβ, and CSF1R). Results from a phase 1/2 study in patients with advanced solid tumors coupled with preclinical data have led to the on-going evaluation of bezuclastinib in patients with AdvSM, the Apex study (NCT04996875). The primary objective of this study is to evaluate the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) profile of bezuclastinib in all AdvSM subtypes. Methods: Apex is a Phase 2, open-label, 2-part, multicenter study in adult patients with AdvSM per WHO diagnostic criteria, who have measurable SM-related organ damage according to modified IWG-MRT-ECNM consensus eligibility and response criteria (mIWG), and have a baseline serum tryptase of ≥20 ng/mL. Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the study. In Part 1, patients are randomized 1:1:1:1 to bezuclastinib 50, 100, or 200 mg BID, or 400 mg QD. Data from Part 1 will inform dose selection for Part 2. The primary efficacy endpoint for this study is overall response rate (complete response [CR], CR with incomplete hematologic recovery [CRh], partial response [PR] and clinical improvement [CI]) as assessed by a Central Response Review Committee and based on mIWG response criteria. Results: As of May 24, 2022, 11 mIWG evaluable patients with AdvSM (ASM: n=2, SM-AHN: n=8, and MCL: n=1) were randomized in Part 1 to 50mg BID (n=3), 100mg BID (n=3), 200mg BID (n=3), and 400mg QD (n=2). The majority of patients were male (82%) and treatment naïve (82%) with ECOG PS 0-1 (82%) and positive for KIT D816V (91%). Median (range) BM MC burden and serum tryptase at baseline were 30% (7-80%) and 182 ng/mL (68-1578 ng/mL), respectively. Bezuclastinib was well-tolerated across all dose levels. Treatment Emergent Adverse Events (TEAEs) reported in >1 patient included anemia (n=3), neutropenia (n=2), and thrombocytopenia (n=2), a majority of which were low-grade. One serious AE of hypersensitivity (mediator flare) was reported. Two patients had an AE-related dose reduction with one patient subsequently re-escalating to the randomized dose. Preliminary clinical activity data showed that all 11 patients experienced a >50% reduction in serum tryptase from baseline, 10/11 (91%) within the first week of treatment; 6 (55%) patients achieved a serum tryptase level <20 ng/mL, 4/6 within the first cycle of treatment. Among patients with available data after ≥2 cycles of treatment, all 8 achieved a median reduction of 68% in KIT D816V variant allele fraction (VAF) and ≥50% reduction in BM MC, with 6/8 (75%) achieving complete clearance of MC aggregates. There were no reported instances of cognitive effects or intracranial bleeding. Conclusion: Early data suggest that bezuclastinib is well-tolerated and is associated with encouraging early signs of clinical activity as demonstrated by meaningful reductions in serum tryptase, MC burden, and KIT D816V VAF. Enrollment is currently ongoing. Updated safety and clinical activity as well as initial clinical objective response data will be presented.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation from Different Donor Types in Primary Refractory Acute Myeloid Leukemia: A Report from the ALWP of the EBMT

Background Primary refractory acute myeloid leukemia (prAML) is a poor prognosis disease for which allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option currently available. We aimed to estimate outcomes in the recent period, to analyze how different donor types may have impacted survival outcomes and to identify the most relevant predictive factors for allo-HSCT in prAML. Methods We conducted a retrospective multicenter study of adult patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who received an allo-HSCT between 2015 and 2020 for prAML. We considered HSCT performed from matched sibling donors (MSD), 10/10 unrelated donors (UD 10/10), 9/10 unrelated donors (UD 9/10) and haploidentical donors. Primary endpoint was leukemia-free survival (LFS), secondary endpoints were overall survival (OS), relapse incidence (RI) and non-relapse mortality (NRM). A Cox proportional hazards model was used for multivariate analysis. Results We included 1574 patients. Median age was 56.9 years (range 18.1-77.9). Cytogenetic risk was intermediate in 855 (54.3%), adverse in 679 (43.2%) and favorable in 40 (2.5%) patients. Donor type was distributed as follows: MSD n = 521 (33.1%), UD 10/10 n = 540 (34.3%), UD 9/10 n = 153 (9.7%), haploidentical n = 360 (22.9%). Table 1 summarizes patient and transplant characteristics. Patients allografted from an MSD were younger, allografted faster after diagnosis, more often received myeloablative conditioning (MAC) (details in Table 1) and had less secondary AML. Use of post-transplant cyclophosphamide, and bone marrow as a stem cell source were more frequent in haploidentical transplants. LFS at 2 years was significantly lower in haploidentical transplants (27% [95%CI: 22-32.2]) compared to MSD (35.2% [95%CI: 30.6-39.9]), to UD 10/10 (37.6% [95%CI: 33.2-42.1]) and to UD 9/10 (35.2% [95%CI: 27.1-43.5]) (p=0.003). Haploidentical transplants also showed inferior OS at 2 years: 31.2% (95%CI: 25.8-36.8) compared to 40.9% (95%CI: 35.9-45.8) in MSD, to 45.7% (95%CI: 41.1-50.2) in UD 10/10 and to 43% (95%CI: 34.5-51.3) in UD 9/10 (p=0.001). In the UD 9/10 group we observed the lowest RI (33.5% [95%CI: 25.6-41.6], 46.7% [95%CI: 41.8-51.4] in MSD, 42.7% [95%CI: 38.2-47.1] in UD 10/10, 46.8% [95%CI: 41.1-52.3] in haploidentical) (p=0.013), and the highest NRM (31.2% [95%CI: 23.6-39.2], 18.1% [95%CI: 14.6-21.9] in MSD, 19.7% [95%CI: 16.3-23.3] in UD 10/10, 26.2% [95%CI: 21.6-31.1] in haploidentical) (p=0.001). Of note, LFS at 2 years was reduced for adverse cytogenetic risk (26.1% for adverse, 39.8% for intermediate and 51.9% for favorable risk) (p=0.001) and significantly differed between reduced intensity conditioning (RIC) and MAC (37.4% and 29.8%, respectively) (p=0.033). In multivariate analysis, factors predicting poor LFS were haploidentical donor (hazard ratio [HR] 1.22 [95%CI: 1.01-1.48], p=0.043), adverse cytogenetic risk (HR 1.73 [95%CI: 1.51-1.99], p<0.0001) and time from diagnosis to HSCT (HR 1.03 [95%CI: 1.01-1.06], p=0.009), whereas factors associated with a better LFS were RIC conditioning (HR 0.85 [95%CI: 0.73-0.98], p=0.025) and good Karnofsky performance status (KPS) ≥ 80 (HR 0.74 [95%CI: 0.62-0.88], p=0.0009). Haploidentical transplant correlated with lower OS (HR 1.3 [95%CI: 1.06-1.61], p=0.014) and higher NRM (HR 1.69 [95%CI: 1.18-2.41], p=0.004) and adverse cytogenetic risk was associated with higher RI (HR 1.9 [95%CI: 1.6-2.24], p<0.0001), higher NRM (HR 1.47 [95%CI: 1.15-1.87], p=0.002) and lower OS (HR 1.82 [95%CI: 1.57-2.11], p<0.0001). Moreover, increased age predicted higher NRM (HR 1.31 [95%CI: 1.17-1.47], p<0.0001) and lower OS (HR 1.09 [95%CI: 1.02-1.16], p=0.006). Conclusions Our study identified risk factors for survival outcomes in the challenging setting of allo-HSCT for prAML. The most relevant factors are adverse cytogenetic risk and haploidentical donor, both associated with worse outcomes. Of note, the group of haploidentical transplants presented the highest rate of bone marrow used as a stem cell source, with a possible impact on survival outcomes. Longer time from diagnosis to HSCT negatively impacted LFS, whereas use of RIC and KPS ≥ 80 showed a higher LFS. As concerns secondary endpoints, unrelated donors achieved better OS compared to other donors, and UD 9/10 showed the lowest RI at the expense of the highest NRM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Epidemiology of Complicated Urinary Tract Infections due to Enterobacterales Among Adult Patients Presenting in Emergency Departments Across the United States.

In this multicenter study of adult patients who presented to the emergency department with an Enterobacterales complicated urinary tract infection (cUTI), high rates of resistance and co-resistance to commonly used oral antibiotics (fluoroquinolones, trimethoprim-sulfamethoxazole, nitrofurantoin, and third-generation cephalosporins) were observed.

Ustekinumab Is Associated with Real-World Long-Term Effectiveness and Improved Health-Related Quality of Life in Crohn's Disease

BackgroundProspectively and systematically collected long-term real-world clinical data on ustekinumab (anti-interleukin-12/23) are still scarce.AimsTo assess the long-term effectiveness of ustekinumab in patients with active Crohn’s disease (CD).MethodsThis is a prospective multicenter study of adult patients with CD initiating ustekinumab according to recommended doses at 20 Swedish hospitals. The primary outcome was clinical remission (Harvey–Bradshaw Index (HBI) ≤ 4 points) at weeks 52 and 104. Secondary outcomes included clinical response (≥ 3-point-decrease in HBI among patients with initial HBI ≥ 5 points), treatment retention, and biomarkers (C-reactive protein (CRP), hemoglobin, fecal-calprotectin) at weeks 52 and 104 compared to baseline. We also reported Health-related Quality of Life (HRQoL) measures.ResultsOf 114 included patients, 107 (94%) had previously failed ≥ 1 and 58 (51%) ≥ 2 anti-tumor necrosis factor agents. Forty (35%) had failed anti-integrin agents. Ustekinumab retention rates at weeks 52 and 104 were 70% (n = 80/114) and 61% (n = 69/114), respectively. Clinical response was seen in 36% (n = 25/69) and 29% (n = 20/69) of the patients, and remission was achieved in 32% (n = 31/96) and 29% (n = 28/96) at weeks 52 and 104, respectively. Median HBI and CRP levels decreased significantly at both timepoints as compared to baseline. Significant improvements were also observed in HRQoL. Adverse events were reported in 11% (n = 13/114) of the patients, including five cases of severe adverse events. No malignancies were observed.ConclusionsIn this nationwide prospective real-world 104-week-follow-up study of adult patients with active CD, ustekinumab was associated with long-term clinical effectiveness and improvement in HRQoL measures when used in routine clinical care.

Outcomes by cannulation methods for venovenous extracorporeal membrane oxygenation during COVID-19: Amulticenter retrospective study.

In a multicenter, retrospective analysis of 435 patients with refractory COVID-19 placed on V-V ECMO, cannulation by a single, dual-lumen catheter with directed outflow to the pulmonary artery was associated with lower inpatient mortality.

Cross-cultural adaptation and validation of the Spanish version of the Orthognathic Quality of Life Questionnaire for patients with dentofacial deformities

ObjectiveThe aim of this study was to develop a Spanish version of the Orthognathic Quality of Life Questionnaire (OQLQ) that is conceptually equivalent to the original questionnaire, as well as acceptable, reliable, valid, and responsive for use in Chilean patients with dentofacial deformities. Material and methodsThe recommended standard methodology, with direct and back-translation, was used. A prospective longitudinal multicenter study of adult patients diagnosed with dentofacial deformity was carried out, self-administrating OQLQ, OHIP-14 (Oral Health Impact Profile), and SF-36 (Short Form 36 Health Survey) during the presurgery visit in order to examine construct validity. To evaluate reproducibility, questionnaires were re-administered 4 weeks later to subjects with a stable dental condition. Responsiveness was assessed among subjects followed up until 3 months after surgery. ResultsOf the 230 patients under presurgical orthodontic treatment included in the study, 216 completed the questionnaire, 142 formed the reliability sub-sample, and 30 were evaluated 3 months after surgery. Cronbach's alpha ranged from 0.78 to 0.94 and test–retest intraclass correlation coefficients ranged from 0.84 to 0.91 (p = 0.001) by dimension. The correlation matrix between OQLQ dimensions and SF-36 and OHIP-14 confirmed most of the associations previously hypothesized as moderate (rs > 0.4). Confirmatory factor analysis supported the same structure as the original instrument, considering four dimensions. Responsiveness was demonstrated by the large improvement observed in the global score 3 months after surgery: mean change ±SD = −15.1 ± 18.05 and standard response mean = −0.84 (p < 0.001). ConclusionsThe Spanish version of OQLQ has demonstrated good levels of reliability, validity, and responsiveness – similar to those of the original questionnaire.

Epidemiology of Invasive Pulmonary Aspergillosis Among Intubated Patients With COVID-19: A Prospective Study.

ABSTRACTBackgroundIn this study we evaluated the incidence of invasive pulmonary aspergillosis among intubated patients with critical coronavirus disease 2019 (COVID-19) and evaluated different case definitions of invasive aspergillosis.MethodsProspective, multicentre study on adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation. All included participants underwent screening protocol for invasive pulmonary aspergillosis with bronchoalveolar lavage galactomannan and cultures performed on admission at 7 days and in case of clinical deterioration. Cases were classified as coronavirus associated pulmonary aspergillosis (CAPA) according to previous consensus definitions. The new definition was compared with putative invasive pulmonary aspergillosis (PIPA).ResultsA total of 108 patients were enrolled. Probable CAPA was diagnosed in 30 (27.7%) of patients after a median of 4 (2-8) days from intensive care unit (ICU) admission. Kaplan-Meier curves showed a significant higher 30-day mortality rate from ICU admission among patients with either CAPA (44% vs 19%, p= 0.002) or PIPA (74% vs 26%, p<0.001) when compared with patients not fulfilling criteria for aspergillosis. The association between CAPA [OR 3.53 (95%CI 1.29-9.67), P=0.014] or PIPA [OR 11.60 (95%CI 3.24-41.29) p<0.001] with 30-day mortality from ICU admission was confirmed even after adjustment for confounders with a logistic regression model. Among patients with CAPA receiving voriconazole treatment (13 patients, 43%) A trend toward lower mortality (46% vs 59% p=0.30) and reduction of galactomannan index in consecutive samples was observed.ConclusionWe found a high incidence of CAPA among critically ill COVID-19 patients and that its occurrence seems to change the natural history of disease

Determinants of quality of life in patients with incurable cancer.

Optimizing quality of life (QoL) remains the central tenet of care in patients with incurable cancer; however, determinants of QoL are not clear. The objective of the current study was to examine which factors influence QoL in patients with incurable cancer. A multicenter study of adult patients with advanced cancer was conducted in Ireland and the United Kingdom between 2011 and 2016. Data were collected from patients at study entry and included patient demographics, Eastern Cooperative Oncology Group performance status (ECOG-PS), nutritional parameters (the percentage weight loss [%WL]), muscle parameters assessed using computed tomography images (skeletal muscle index and skeletal muscle attenuation), inflammatory markers (modified Glasgow Prognostic score [mGPS]), and QoL data (the European Organization for Research and Treatment Quality-of-Life Questionnaire C-30). The relation between clinical, nutritional, and inflammatory parameters with QoL was assessed using the Spearman rank correlation coefficient and multivariate binary logistic regression. Components of the European Organization for Research and Treatment Quality-of-Life Questionnaire C-30 (physical function, fatigue, and appetite loss) and summary QoL scores were mean-dichotomized for the logistic regression analyses. Data were available for 1027 patients (51% men; median age, 66years). Gastrointestinal cancer was most prevalent (40%), followed by lung cancer (26%) and breast cancer (9%). Distant metastatic disease was present in 87% of patients. The %WL, ECOG-PS, and mGPS were significantly correlated with deteriorating QoL functional and symptom scales (all P<.001). On multivariate regression analysis, >10% WL (odds ratio [OR], 2.69; 95% CI, 1.63-4.42), an ECOG-PS of 3 or 4 (OR, 14.33; 95% CI, 6.76-30.37), and an mGPS of 2 (OR, 1.58; 95% CI, 1.09-2.29) were independently associated with poorer summary QoL scores. These parameters were also independently associated with poorer physical function, fatigue, and appetite loss (all P<.05). Low skeletal muscle attenuation was independently associated with poorer physical functioning (OR, 1.67; 95% CI, 1.09-2.56), but muscle parameters were not independently associated with fatigue, appetite loss, or QoL summary scores. The current findings indicate that QoL is determined (at least in part) by WL, ECOG-PS, and the systemic inflammatory response in patients with advanced cancer. Identifying early predictors of poor QoL may allow the identification of patients who may benefit from early referral to palliative and supportive care, which has been shown to improve QoL.

P2.46: RESTORE project (improve underSTanding of small bOwel syndRomE in Argentina): First report of a prospective, observational, epidemiological, multicenter study of adult patients with Short Gut Syndrome in Argentina.

Introduction: There is no centralized registered information regarding patients (pts) suffering from Short Bowel Syndrome (SBS) in Argentina. Estimations based on other countries epidemiology predict an incidence of 8–10 new adult pts/year. In order to compile this information, we started a prospective multicenter observational and epidemiological registry for adults with SBS, independent from the etiology and the treatment proposed. We aim to present the first report of the RESTORE project. M-M: From 2015 to 2017, design, funding, Institutional Review Board and Ethical approvals were obtained. Since June 2017, 11 centers started activity. Data collection was made using case report forms; a monitor visited and supervised each center initiation and performance. The registered pts are followed at each center at weeks 4, 8, 12, 20 and 24, and yearly thereafter. Dead, intestinal adaptation and transplant have been considered as end-points of the study. The principal investigator developed a prospective database. Statistical analysis was done on SPSS v20.0. Results: 12 centers were initiated, 10 enrolled 42 pts; 33 pts were actively monitored and analyzed,12 pts completed 1 year of follow up (FU); 19 pts (57.6%) were female; mean age: 52.15 ± 15.4 years. Diagnoses in Figure 1. Mean intestinal length: 51.5 ± 42.4 cm. Anatomy type: T1: 22 pts; T2: 8 pts and T3: 3 pts; ileo-cecal valve was present in 11pts. Colon in 27 pts; Ostomies in 22 pts. Mean ostomy output: 1514 ± 1078 ml/day; Autologous GI tract Reconstruction Surgery (AGIRS) was done in 11 pts before enrollment. Meantime on parenteral nutrition (PN) before enrollment: 27.4 ± 37.18 months; PN and biochemical variables overtime are shown in Table 1; Espen Clinical Classification in Figure 1. Treatments proposed at first visit: PN+ Medical Rehabilitation: 20 pts (60%), AGIRS: 4 pts (12%); post-surgical teduglutide (TED): 8 pts (24%); transplant: 1 pt (3%); at the end of FU: 1pt was lost of FU; 4 pts adapted with AGIRS alone, or in combination with TED. One pt was transplanted and another pt. listed due to liver disease. The overall actuarial survival is 87%; sepsis was the main cause of death (3/4 pts). Conclusions: Although this report still has a limited number of centers, it has registered more SBS adult patients than expected according to theoretical estimations; reinforcing the importance of having registries to understand the behavior of SBS patients overtime and their outcome.

Assessment of procedural pain in French emergency departments: a multi-site, non-interventional, transverse study in patients with minor trauma injury

ABSTRACTObjective: To determine the mean number of procedural painful episodes per patient, and to retrieve information regarding diagnosis, therapeutic procedures and analgesic management, in patients visiting Emergency Departments (EDs) for minor trauma.Methods: This observational, non-interventional, multicenter study in adult patients was performed in 35 French EDs. All patients entering the EDs for minor trauma on a specified day between noon and 10 pm were registered; consenting patients were included in the study. Pain intensity was assessed using a verbal Numerical Rating Scale from 0 (no pain) to 10 (worst possible pain). An episode was described as painful if the difference in pain intensity between pain just before the procedure and maximal pain during the procedure was ≥2. Two independent nurses recorded data on 1 day in each center.Results: Overall, 909 patients were registered, 422 were included in the study, and complete data for 409 patients (1899 procedures) were available for analysis. The mean number of painful episodes per patient was 1.0 ± 1.3. Fifty-one percent of patients reported at least one painful procedure episode. Twenty-one percent of procedures were considered painful. Clinical examination was the procedure most often reported as painful. No preventive or curative analgesic treatment was reported in 95.1% of procedures.Conclusions: There is a need for improvement in routine pain assessment and, therefore, procedural pain management for ED patients. Specific protocols should be developed for procedural pain management, and teams should be trained especially for procedures usually not considered painful.

Usefulness of guideline recommendations for prognosis in patients with candidemia.

We aimed to analyze whether the lack of inclusion of specific recommendations for the management of candidemia is an independent risk factor for early and overall mortality. Multicenter study of adult patients with candidemia in 13 hospitals. We assessed the proportion of patients on whom nine specific ESCMID and IDSA guidelines recommendations had been applied, and analyzed its impact on mortality. 455 episodes of candidemia were documented. Patients who died within the first 48 hours were excluded. Sixty-two percent of patients received an appropriate antifungal treatment. Either echinocandin or amphotericin B therapy were administered in 43% of patients presenting septic shock and in 71% of those with neutropenia. Sixty-one percent of patients with breakthrough candidemia underwent a change in antifungal drug class. Venous catheters were removed in 79% of cases. Follow-up blood cultures were performed in 72% of cases. Ophthalmoscopy and echocardiogram were performed in 48% and 50% of patients, respectively. Length of treatment was appropriate in 78% of cases. Early (2-7 days) and overall (2-30 days) mortality were 8% and 27.7%, respectively. Inclusion of less than 50% of the specific recommendations was independently associated with a higher early (HR = 7.02, 95% CI: 2.97-16.57; P < .001) and overall mortality (HR = 3.55, 95% CI: 2.24-5.64; P < .001). In conclusion, ESCMID and IDSA guideline recommendations were not performed on a significant number of patients. Lack of inclusion of these recommendations proved to be an independent risk factor for early and overall mortality.

1790P - Correlation between fatigue evaluated with a visual analog scale (VAS) and quality of life (QoL) in cancer patients treated with biosimilar epoetin alfa for chemotherapy-induced anemia (CIA): The CIROCO study

Background: Anemia often occurs in cancer patients receiving chemotherapy. QoL can be affected by symptoms of anemia, fatigue being the most common. Evaluation of QoL with validated tools (eg EORTC QLQ C30) is time-consuming. Correlation between fatigue assessed with a VAS and QoL is unclear. Aim: To determine the correlation between fatigue assessed by a VAS and QoL in cancer patients treated with biosimilar epoetin alfa (Sandoz) for CIA. Methods: CIROCO is a non-interventional, prospective, multicenter study of adult patients (Full Analysis Set [FAS] population, n = 538) with ≥2 cycles of chemotherapy planned after study inclusion, with CIA and receiving biosimilar epoetin alfa. Data were collected on day of inclusion (T0), and after 2–3 (follow-up; T1) and 4–6 chemotherapy cycles (end of follow-up; T2). Patients and physicians separately assessed fatigue using a VAS (range 0–10); patients assessed QoL with the EORTC QLQ C30 questionnaire. Results: Data are reported for a subgroup of patients with solid tumors (FAS population, n = 434). Mean (SD) hemoglobin (Hb) at baseline was 9.7 (±0.8) g/dL. Mean (SD) increase in Hb was 1.2 (±1.4) g/dL between T0 and T1 and 0.4 (±1.5) g/dL between T1 and T2. In the safety population (n = 464), 151 (32.5%) had adverse events (AEs; n = 320), 64 patients (13.8%) had serious AEs (n = 144) and 14 patients (3%) experienced AEs considered related to study treatment (n = 25). In the FAS population, between T0 and T2, mean (SD) change in fatigue VAS score (patient-reported) was +5.2 (±92.6) % and mean (SD) change in QoL was 29.9 (±98.0) %. The Pearson correlation coefficient for fatigue VAS score and QoL was –0.4993 (p < 0.0001) at T0, –0.5726 (p < 0.0001) at T1, and –0.5681 (p < 0.0001) at T2. Using fatigue VAS, physician assessment of fatigue was consistent with patient perceptions at T0 (5.0±2.1 vs 5.3±2.2), T1 (4.3±2.2 vs 4.8±2.3) and T2 (4.2±2.3 vs 4.7±2.3). Conclusions: Biosimilar epoetin alfa was effective in this study, with improvements observed in Hb and QoL. A correlation was observed between reduced fatigue assessed with a VAS and improved QoL. Editorial acknowledgement: Tony Reardon, Spirit Medical Communications Ltd. Legal entity responsible for the study: Sandoz SAS. Funding: Sandoz SAS. Disclosure: N. Baize: Steering Committee member: CIROCO study. All other authors have declared no conflicts of interest.

Implications of Statin Use on Vasopressor Therapy in the Setting of Septic Shock.

Background: Pleiotropic anti-inflammatory and immunomodulatory effects of statins have been associated with improved outcomes in the critically ill population. Objective: To evaluate the implications of prior statin use on the duration of vasopressor therapy in the setting of septic shock. Methods: This was a retrospective, multicenter study of adult patients who were diagnosed with septic shock. Patients were included if they were treated with any vasopressor for greater than 6 hours from the time of admission. The primary outcome was to compare the duration of vasopressor therapy in patients with septic shock with and without previous statin exposure. Results: A total of 88 statin-exposed cases and 205 unexposed controls were included in the analysis. Despite 92% of statin-exposed patients being reinitiated on therapy within 24 hours, the duration of vasopressors did not differ between groups (44 hours, statin group vs 53 hours, control group, P = .51). There were also no mortality differences between the statin group and the controls (40% vs 47%, P = .27). Conclusions: Long-term statin exposure does not impact the duration of vasopressor therapy in septic shock. The lack of differences in clinical outcomes supports the concept that sepsis involves pro- and anti-inflammatory pathways as well as other nonimmunologic pathways. Results lend further credence to the recent conceptualization of sepsis, with complications leading to organ dysfunction caused not primarily due to inflammatory responses but by a dysregulated response to infection.