La Caixa Research Articles

Validation of New International Prognostic Scores, Including Baseline Peripheral Blood Variables, in Patients with Diffuse Large B-Cell Lymphoma and HIV Infection Treated with R-CHOP and Combined Antiretroviral Therapy. Retrospective Study from Spanish Lymphoma Group Geltamo

Validation of New International Prognostic Scores, Including Baseline Peripheral Blood Variables, in Patients with Diffuse Large B-Cell Lymphoma and HIV Infection Treated with R-CHOP and Combined Antiretroviral Therapy. Retrospective Study from Spanish Lymphoma Group Geltamo

Ponatinib and Chemotherapy in Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Final Results of Ponalfil Clinical Trial

Background and objective. The combination of HyperCVAD and ponatinib resulted in a high molecular response rate and survival in adults with Ph+ ALL, suggesting improved outcome compared with combinations of chemotherapy with first- or second-generation tyrosine kinase inhibitors (TKI) (Jabbour E, et al, Lancet Haematol. 2018;5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same chemotherapy as that of the ALL Ph08 trial that used imatinib as TKI (Ribera JM et al. Cancer 2019;125:2810-17). Final results of this trial are reported.Patients and method. PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin, prednisone) followed by consolidation (high-dose methotrexate, high-dose ARA-C, mercaptopurine, etoposide) and allogeneic hematopoietic stem cell transplantation (alloHSCT). Ponatinib was scheduled after alloHSCT only for patients (pts) with persistence/reappearance of MRD. Response to therapy (complete morphological [CR], molecular [complete -CMR- or major -MMR-] after induction and before alloHSCT) (assessed by centralized BCR-ABL1/ABL1 ratio), disease-free survival (DFS), overall survival [OS]) and toxicity were analyzed. The following genetic studies were performed: 1. Additional gene abnormalities (Copy Number Alteration [CNA] analysis by SNP array Affymetrix 750K), 2. ABL1 mutation status at diagnosis (Sanger sequencing), 3. T315I mutation at diagnosis (allele-specific PCR). A propensity score comparison with the results of the ALL Ph08 trial was performed.Results. Median age was 49 (19-59) years (y), and 13/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score was <2 in 90% of pts. Median WBC count was 6.4 x10 9/L (0.6-359.3), Hb 90 g/L (63-145), platelets 38 x10 9/L (11-206). Immunologic phenotype was common in 26 cases, with p190 isoform in 20 pts (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained in 30/30 pts, CMR in 14/30 (47%), MMR in 5/30 (17%) and no molecular response in 11/30 (37%). Two pts withdrew the trial during induction (thrombosis of central retina artery and severe intestinal infection, one case each). Consolidation was given to 28 pts, 2 pts withdrew the trial (physician's decision and lack of molecular response, one case each) and 26 pts received alloHSCT (20 in CMR, 6 in MMR). No relapses before HSCT were detected. One pt died by severe GVHD and two withdrew the trial (grade IV hepatic toxicity:1, protocol deviation after molecular relapse:1). One pt relapsed in BM after HSCT. Ponatinib was given after HSCT in 4/26 pts and dasatinib in 1/26 due to MRD reappearance, and 1/26 received dasatinib in CMR because of refusal to receive CNS prophylaxis, whereas 20/26 pts did not receive any TKI therapy after HSCT. Twenty-nine pts are alive (median follow-up 2.3y, range 1.3-4). 2y DFS and OS probabilities were 97% (91%-100%) and 97% (91%-100%) (Figure 1).Among 7/16 pts without CMR after consolidation and genetic material available, 4 showed IKZF1 deletion (IKZF1 plus in 2), 1 showed CDKN2A/B and PAX5 deletion and 2 did not show any CNA. Among 5/19 pts with molecular relapse, 3 showed IKZF1 deletion (1 being IKZF1 plus), and 2 pts did not show any CNA. No ABL1 mutations or T315I mutation at diagnosis were found.Propensity score with 1:1 matching identified 30 pts in each cohort (variables: age, gender, ECOG, WBC, CNS involvement, cytogenetic risk and BCR/ABL isoform). 2y DFS rates for PONALFIL and ALL Ph08 trials were 97% and 62%, (p=0.005), and 2y OS rates were 97% and 66% (p=0.001) (Figure 2).107 adverse events (AE) were registered in 20 pts (21 severe in 11 pts), prompting to withdrawn of the trial in 3 (thrombosis of central retina artery, severe bowel infection, grade IV hepatic toxicity). The most frequent AE were hematologic (28%), gastrointestinal (14%), hepatic (11%), infections (7%), and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina).Conclusions. The results of the PONALFIL trial show a high antileukemic efficacy with acceptable toxicity profile and compare favorably with the same chemotherapy schedule and imatinib.Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and “La Caixa” Foundation.Figure 1. OS (A) and DFS (B). PONALFIL.Figure 2. OS (A) and DFS (B). PONALFIL vs. ALL Ph08. [Display omitted] DisclosuresRibera: AMGEN: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Esteve: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Novartis: Research Funding; Jazz: Consultancy; Astellas: Consultancy. Mercadal: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Honoraria, Speakers Bureau. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. OffLabel Disclosure:This trial includes Ponatinib in off-label indication.

Sociodemographic, clinical, and immunological factors associated with SARS-CoV-2 diagnosis and severe COVID-19 outcomes in people living with HIV: a retrospective cohort study.

BackgroundFactors affecting outcomes of SARS-CoV-2 infection in people living with HIV are unclear. We assessed the factors associated with SARS-CoV-2 diagnosis and severe outcomes among people living with HIV.MethodsWe did a retrospective cohort study using data from the PISCIS cohort of people with HIV in Catalonia (Spain) between March 1 and Dec 15, 2020. We linked PISCIS data with integrated health-care, clinical, and surveillance registries through the Public Data Analysis for Health Research and Innovation Program of Catalonia (PADRIS) to obtain data on SARS-CoV-2 diagnosis, chronic comorbidities, as well as clinical and mortality outcomes. Participants were aged at least 16 years in care at 16 hospitals in Catalonia. Factors associated with SARS-CoV-2 diagnoses and severe outcomes were assessed using univariable and multivariable Cox regression models. We estimated the effect of immunosuppression on severe outcomes (hospital admission for >24 h with dyspnoea, tachypnoea, hypoxaemia, asphyxia, or hyperventilation; or death) using Kaplan-Meier survival analysis.FindingsWe linked 20 847 (72·8%) of 28 666 participants in the PISCIS cohort with PADRIS data; 13 142 people had HIV. 749 (5·7%) people with HIV were diagnosed with SARS-CoV-2: their median age was 43·5 years (IQR 37·0–52·7), 131 (17·5%) were female, and 618 (82·5%) were male. 103 people with HIV (13·8%) were hospitalised, seven (0·9%) admitted to intensive care, and 13 (1·7%) died. SARS-CoV-2 diagnosis was more common among migrants (adjusted hazard ratio 1·55, 95% CI 1·31–1·83), men who have sex with men (1·42, 1·09–1·86), and those with four or more chronic comorbidities (1·46, 1·09–1·97). Age at least 75 years (5·2, 1·8–15·3), non-Spanish origin (2·1, 1·3–3·4), and neuropsychiatric (1·69, 1·07–2·69), autoimmune disease (1·92, 1·14–3·23), respiratory disease (1·84, 1·09–3·09), and metabolic disease (2·59, 1·59–4·23) chronic comorbidities were associated with increased risk of severe outcomes. A Kaplan-Meier estimator showed differences in the risk of severe outcomes according to CD4 cell count in patients with detectable HIV RNA (p=0·039) but no differences were observed in patients with undetectable HIV RNA (p=0·15).InterpretationPeople living with HIV with detectable HIV viraemia, chronic comorbidities, and some subpopulations could be at increased risk of severe outcomes from COVID-19. These groups should be prioritised in clinical management and SARS-CoV-2 vaccination programmes.FundingFundació “la Caixa”.TranslationsFor the Catalan, Spanish and Russian translations of the Summary see Supplementary Materials section.

CMR analysis of the cardioprotective effects of chronic statin therapy prior to first STEMI: a propensity score analysis

Abstract Background In addition to their lipid-lowering properties, statins possess cardioprotective effects. However, the impact of the latter on acute cardioprotection and adverse left ventricular (LV) remodelling following ST-elevation myocardial infarction (STEMI) have not been investigated through cardiac magnetic resonance (CMR) analysis to date. Purpose To investigate the cardioprotective effects of chronic oral statin treatment prior to first STEMI. Methods The study included 1236 patients with a first STEMI and a CMR performed during the index admission. Among them, 923 underwent a second CMR at 6 months follow-up. The effects of chronic oral statin treatment prior to STEMI on acute infarct size (IS) as a percentage of LV mass, LV ejection fraction (LVEF), microvascular obstruction (MVO), and changes in LV end-diastolic volume (EDVi) and end-systolic volume indexes (ESVi)] at 6 months were evaluated. A propensity score to receive treatment prior to STEMI with statins was calculated based on the inverse probability of treatment weighting (IPTW) from the following parameters: age on admission, sex, smoking status, type 2 diabetes, hypertension, family history of coronary artery disease, current co-treatments (ACEis/ARBs and/or beta-blockers), heart rate (HR), blood pressure (BP) and creatinine levels on admission, and pre-PCI TIMI flow in the culprit artery. Results were stratified according to a symptom-to-balloon time (S2Bt) ≤ or &amp;gt;3 hours. Results The study population's median age was 59 years (IQR 50–68), 16.3% were women; 18.9% were receiving treatment with statins prior to STEMI (table 1). Despite no effect on MVO occurrence (OR: 0.81 [0.60; 1.09], p=0.166), prior treatment with statins was associated with a reduction in IS (18.43% [16.67; 20.19] vs 21.50% [20.67; 22.34], p=0.002), particularly among subjects with ≤3 hours of S2Bt. Accordingly, prior treatment with statins conferred a benefit in mean baseline LVEF (50.23% [48.73; 51.73] vs 48.15% [47.43; 48.87], p=0.014). At 6 months, treatment with statins prior to STEMI blunted the changes in EDVi and ESVi, but only among patients with ≤3 hours of S2Bt (table 2). In addition, a reduction in the probability of adverse LV remodelling, defined as an increase in ESVi &amp;gt;10%, was observed in statin pre-treated patients (OR: 0.67 [0.45; 0.99], p=0.043). Conclusion Treatment with statins before STEMI is associated with improved indexes of cardioprotection as assessed by CMR, particularly among subjects with S2Bt ≤3 hours. Those effects seem to have an impact in limiting adverse LV remodelling as early as 6 months follow-up, and a greater than 10% change in ESVi. These findings warrant further and prospective evaluation of the potential cardioprotective effects of chronic oral statin treatment prior to STEMI. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): This study was partially funded by several grants from Fundaciό La Marato TV3 (2015 30 31 32), Instituto de Salud Carlos III (FIS15/00531) and La Caixa Banking Foundation (HR17-00527).

Cardiac remodeling in fetuses conceived by ARTs: fresh versus frozen embryo transfer.

Do fetuses from frozen embryo transfer (FET) present signs of cardiac remodeling and suboptimal function similar to those observed in fetuses from fresh embryo transfer (ET)? Fetuses from both fresh ET and FET present signs of fetal cardiac remodeling and suboptimal function, with more pronounced changes after fresh ET as compared to FET. Our group and others have previously demonstrated that fetuses and children conceived by ARTs present cardiac remodeling and suboptimal function. These fetuses show dilated atria, more globular and thicker ventricles, reduced longitudinal motion, and impaired relaxation. Cardiac changes were already present in utero and persisted after birth. Most of the ART fetuses included in previous publications were from fresh ET. However, singletons from FET have different perinatal outcomes compared to those from fresh ET. There are no previous studies comparing cardiac morphology and function between fetuses following fresh and FET. This is a prospective cohort study of 300 singleton pregnancies recruited from 2017 to 2020, including 100 spontaneously conceived (SC) pregnancies, 100 fetuses conceived by IVF with FET, and 100 fetuses conceived by IVF with fresh ET. Fetal structural and functional echocardiography was performed in all pregnancies. Pregnancies conceived by IVF were recruited from a single assisted reproduction center, ensuring homogeneity in IVF stimulation protocols, endometrial preparation for FET, laboratory procedures, and embryo culture conditions. SC pregnancies from fertile couples were selected from the general population and matched to IVF pregnancies by maternal age. Epidemiological and perinatal outcomes were collected in all cases. Fetal echocardiography was performed at 28-33 weeks of pregnancy to assess cardiac structure and function in all pregnancies. All echocardiographic comparisons were adjusted by maternal age, nulliparity, birthweight centile, preeclampsia, and prematurity. Parental age, ethnicity, body mass index and smoking were similar among the study groups. Median gestational age at echocardiography and estimated fetal weight were similar in all study groups. Both fresh ET and FET groups showed similar fetal echocardiographic changes, with more pronounced features in the fresh ET as compared to FET pregnancies. Fetuses conceived by IVF showed larger atria (right atria-to-heart ratio: fresh ET mean 18.1% (SD 3.2) vs FET 18.0% (3.9) vs SC 17.3% (3.2); linear tendency P-value <0.001), more globular ventricles (right ventricular sphericity index: fresh ET 1.62 (0.29) vs FET 1.61 (0.25) vs SC 1.68 (0.26); <0.001) and thicker myocardial walls (relative wall thickness: fresh ET 0.79 (0.21) vs FET 0.74 (0.22) vs SC 0.65 (0.25); <0.001) as compared to SC pregnancies. Both fresh ET and FET groups also had signs of suboptimal systolic and diastolic function, with reduced tricuspid annular systolic peak velocity (fresh ET 7.17 cm/s (1.22) vs FET 7.41 cm/s (1.19) vs SC 7.58 cm/s (1.32); <0.001) and increased left myocardial performance index (fresh ET 0.53 (0.08) vs FET 0.53 (0.08) vs SC 0.50 (0.09); <0.001) as compared to SC pregnancies. The cardiac changes reported here are subclinical, with most cardiovascular indexes lying within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with the long-term cardiovascular disease remains to be proven. The observed milder fetal cardiac features in FET fetuses cannot condition the choice of this technique and must be considered together with the global perinatal results related to these gestations. The identification of cardiac remodeling in fetuses conceived by IVF with fresh ET and FET represents an opportunity for early detection. Future studies are warranted to study the potential long-term consequences of these findings. This project has been partially funded with support from the Erasmus + Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects the views only of the author, and the Commission cannot be held responsible for any use, which may be made of the information contained therein. Additionally, the research leading to these results has received funding from 'la Caixa' Foundation under grant agreement LCF/PR/GN18/10310003, the Instituto de Salud Carlos III (PI15/00130, PI17/00675, PI18/00073) integrated into the Plan Nacional de I + D+I and cofinanced by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER) 'Una manera de hacer Europa', Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and AGAUR 2017 SGR grant n° 1531. The authors declare no conflicts of interest. N/A.

Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study

Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome. We did a multicentre cohort study, including adults with Down syndrome (≥18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively; NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses. Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia; ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3·6 years (SD 1·6, range 0·6-9·2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0·83 (95% CI 0·76-0·91) in the prodromal group and 0·94 (0·90-0·97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1·04-fold risk of clinical progression (95% CI 1·01-1·07; p=0·0034). Plasma NfL concentrations showed an annual increase of 3·0% (95% CI 0·4-5·8) per year in the asymptomatic non-progressors group, 11·5% (4·9-18·5) per year in the asymptomatic progressors group, and 16·0% (8·4-24·0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24·3% (15·3-34·1). Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials. AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit, and NHS National Institute of Health Research Applied Research Collaborations East of England, UK.

Ebv-Mir-BART11-3p, Ebv-Mir-BART9 and Ebv-Mir-BART10 Are Present in the Plasma of HIV-Infected Subjects with Lymphoma and Are Potential Lymphoma Biomarkers

Epstein Barr virus (EBV) has been implicated in the lymphomagenesis, particularly of HIV-related lymphomas. EBV-infected cells are able to share miRNAs with other cells via exosomes and certain EBV-miRNAs were found in cells not infected with the virus but from patients with increased levels of EBV copies in plasma such as HIV-infected individuals. Thus, EBV-miRNAs might be detected in the plasma and might be relevant for the diagnosis and follow-up of HIV-related lymphomas.This case-control study included a group of 26 HIV-infected patients with lymphoma that responded to treatment and a control-group of HIV-infected subjetcs without lymphoma matched for age, gender, CD4-lymphocyte counts, plasma HIV viremia and time from HIV infection. We evaluated the presence of 43 EBV-miRNAs in frozen plasma samples from patients with lymphoma at diagnosis (Dx-group, N=26), one year before diagnosis (Pre-group, N=15) and complete response (CR-group, N=26). RNA was extracted from 200µl of plasma using Trizol LS (Ambion, Carlsbad, CA) and cel-miR-39 was used as spike-in. The detection of EBV-miRNAs was assessed by QRT-PCR in a BioMark™ HD System of Fluidigm (San Francisco, CA) using TaqMan® microRNA assays and TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA). The following clinical and biological parameters were collected from records: age, gender, ECOG score, extranodal and bulky disease, B symptoms, Ann-Arbor stage, serum lactate dehydrogenase (LDH) and beta2-microglobulin, International Prognostic Index (IPI), HCV and HBV serology, history of opportunistic infection and of AIDS-defining illnesses, onset of combination antiretroviral therapy, CD4-lymphocyte counts, plasma HIV viremia. McNemar's and Wilcoxon tests were used for paired comparisons between groups. P-values of less than .05 were considered statistically significant.Overall, 30 EBV-miRNAs were detected in the Dx-group whereas only 8 EBV-miRNAs where found in the control-group and 19 in the CR-group. EBV-miRNAs were detected more frequently in the Dx-group (17 out of 26) than in the control-group (7 out of 26) (P =.002) and in the CR-group (11 out of 26) (P=.02). The presence of 6 EBV-miRNAs (ebv-miR-BART11-3p, ebv-miR-BART9, ebv-miR-BART10, ebv-miR-BART15, ebv-miR-BART31, and ebv-miR-BART19) could be associated with the lymphoma condition, since they were detected significantly different in the Dx-group and the control-group (Figure 1). Importantly, 3 of those EBV-miRNAs (ebv-miRBART11-3p, ebv-miR-BART9 and ebv-miRBART10) were found to be significantly less frequent in the CR group, reinforcing the idea that they could be derived from lymphoma cells and be used as biomarkers for diagnosis and follow up of HIV-related lymphoma. EBV-miRNAs cannot be used as early biomarkers of lymphoma in HIV-infected patients because none of the 3 EBV-miRNAs associated with lymphoma was significantly found in samples before diagnosis. The detection in plasma of ebv-miR-BART11-3p, ebv-miR-BART10 or ebv-miR-BART9 was not associated with having tumor cells infected with EBV (Figure 1). Only the detection of ebv-miR-BART9 was associated with detectable EBV loads [7/14 (50%) vs. 1/12 (8.3%), P=.036] (Figure 1). The following were the statistically significant associations between the presence of the 3 potential EBV-miRNA lymphoma biomarkers and the clinical-biological features studied. The presence of ebv-miR-BART10 in plasma was associated with IPI>2 [8/14 (57.1%) vs. 1/9 (11.1%), P=.004] and ECOG>2 [8/14 (57.1%) vs. 1/11 (9.1%), P=.011]. Also, more patients with ebv-miR-BART11-3p expression in plasma had ECOG>2 than patients without it [7/13 (53.8%) vs. 1/12 (8.3%), P=.030].Ebv-miR-BART11-3p, ebv-miR-BART9 and ebv-miR-BART10 can be detected in the plasma of patients with HIV-related lymphoma, independently of the presence of EBV in tumor cells or of EBV plasma viremia. They are potential biomarkers of lymphoma to be used in the diagnosis and follow up of HIV-infected subjects with the advantage of being easily determined by QRT-PCR employing noninvasive procedures.This work was supported in part by 2014 SGR225 (GRE) from CERCA Programme/Generalitat de Catalunya, and by funds from Josep Carreras International Foundation, “la Caixa” Foundation, DKMS, and Celgene Spain. [Display omitted] DisclosuresBaptista:DKMS: Research Funding; la Caixa Foundation: Research Funding; Carreras International Foundation: Research Funding; CERCA Programme/Generalitat de Catalunya: Research Funding; Celgene Spain: Research Funding. Sancho:Roche: Honoraria; Laboratorios Servier: Consultancy; Mundipharma: Honoraria; Kern Pharma: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Ribera:Celgene: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Amgen Inc.: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; Roche: Honoraria. Navarro:Celgene Spain: Research Funding; DKMS: Research Funding; la Caixa Foundation: Research Funding; Josep Carreras International Foundation: Research Funding; CERCA Programme/Generalitat de Catalunya: Research Funding.

Usefulness of a Sequencing Panel in Myeloproliferative Neoplasms Lacking Mutations in Driver Genes

Background : Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders characterized by proliferation in one or more cell lineages. Driver mutations are major diagnostic criteria in 2016 World Health Organization Classification. Moreover, variants in a group of genes that are not unique to MPN are associated with prognosis or leukemic transformation.Aim : To assess the utility of a sequencing panel targeting regions in MPN without driver mutations.Methodology : This study included 48 patients: 21 JAK2 negative polycythemia vera (PV) and 27 triple-negative patients (24 essential thrombocytemia, ET and 3 primary myelofibrosis, PMF).Targeted deep sequencing (TDS) was performed on DNA either from peripheral blood or from bone marrow samples. Libraries were prepared using a custom amplicon based panel (HEAT-Seq Choice Target Enrichment System, Roche), targeting selected regions of 17 genes that have recurrent somatic mutations in MPN (Table 1). TDS was performed on Illumina MiSeq instruments at a mean coverage of 850x. Data were analyzed using an in-house bioinformatic pipeline. Variants were filtered according to variant type, location, and population frequency (< 1%).ResultsSubgroup of PV patientsOf the 21 patients diagnosed with JAK2 negative PV, 19 did not present any variant in the 17 analyzed genes. One patient presented IDH1 R132H variant at low variant allele frequency (VAF= 4.58%), in contrast, the other patient presented nonsynonymous TET2 variant at VAF= 47%.Subgroup of triple-negative ET and PMF casesIn this cohort 5/27 (18.5%) patients (all with ET diagnosis) harbored some variant. One presented noncanonical MPL S204P variant (VAF= 12.04%). The second patient presented a nonsynonymous DNMT3A variant (VAF= 17.54%). Moreover, 3 patients presented variants in TET2 gene: 2 nonsynonymous variants and one a frameshift deletion (VAFs= 47, 52 and 37%, respectively).Preliminary overall survival analysis did not show any differences between mutated and nonmutated patients, according to analyzed genes.ConclusionsOur panel has proven usefulness to detect variants at low and high VAFs, which is important for accurate diagnosis of MPN, as one patient was misclassified as triple-negative when in fact it harbors a noncanonical MPL variant outside the exon 10.One of the limitations of the study is the small number of patients; we are now increasing the series in order to study the prognostic impact accurately.Acknowledgments : 2014 SGR225 (GRE) Generalitat de Catalunya, Fundació Internacional Josep Carreras and “la Caixa” Foundation, IGTP Genomic Core Facility. Probes and reagents provided by Roche Sequencing Solutions, Inc. (Pleasanton, CA, USA). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Use of Bortezomib-Containing Regimens in the Frontline Treatment of Patients with Plasmablastic Lymphoma: A Multicenter Retrospective Analysis

▪Introduction: Plasmablastic lymphoma (PBL) is a rare and aggressive CD20-negative lymphoma with plasmacytic differentiation associated with poor outcomes. Multiple studies have shown a high relapse rate and median survival times of 12-18 months. Several case reports and small case series have suggested an increased response rate in PBL patients treated with bortezomib alone or in combination with chemotherapy. Due to its rarity, prospective studies in PBL patients are unlikely to be performed. Based on this, we decided to evaluate the potential therapeutic value of frontline bortezomib-containing regimens in patients with PBL.Methods: We performed an international retrospective multicenter study looking for patients with a pathological diagnosis of PBL who received therapy with bortezomib-containing regimens in the frontline setting. Clinical (i.e. age, sex, HIV infection, stage, ECOG performance status, LDH level and CD 4 count) and pathological characteristics (i.e. expression of CD20, CD38, CD138, ki67, EBER, HHV8, ALK, and MYC rearrangement) were gathered and are presented descriptively. Kaplan-Meier overall (OS) curves were estimated.Results: Nineteen patients with a diagnosis of PBL and treated with bortezomib-containing regimens as frontline were included in our analysis. The median age at diagnosis was 51 years (range 31-77 years). Fifteen patients (79%) were men. ECOG performance status >=2 was seen in 8 patients (42%). LDH was elevated in 9 patients (47%). Stage III or IV was reported in 13 (68%). Seventeen patients (89%) had extranodal involvement. Extranodal sites included the gastrointestinal tract (n=5), bone marrow (n=4), skeletal bone (n=3), lungs (n=2), head & neck (n=2), kidney (n=2), testicles (n=2) and subcutaneous tissue (n=1). Eight patients (42%) were infected by HIV. Among HIV-infected patients, the median CD4+ count was 91 cells/mm3 (range 33-422 cells/mm3). Pathologically, all cases were negative for CD20 expression and positive for CD38 or CD138 expression. Median Ki67 expression was 90% (20-100%). MYC gene rearrangements were identified in 8 of 10 (80%) samples tested. EBER was identified in 9 of 14 (64%)o of samples tested. HHV-8 LANA was identified in 1 of 10 (10%) samples tested. ALK expression was negative in 7 of 7 (0%) samples tested. With regard to treatment, 10 patients (53%) received bortezomib-EPOCH, 2 patients (11%) received bortezomib-CHOP, 2 patients (11%) received VCD, 2 patients (11%) received VAD, 2 patients (11%) received VD, and 1 patient (5%) received alternating VCD and VAD. Complete response was seen in 11 patients (58%), partial response in 3 (16%) and no response in 5 (26%). Only 2 patients received ASCT in first remission. Eleven patients (58%) experienced relapsed disease, including one of the patients who achieved CR and underwent ASCT. Salvage therapy was provided to only 4 patients and included daratumumab-ICE, rituximab-ICE, DHAP and etoposide-cyclophosphamide and prednisone. With a median follow-up of 33 months, the median OS was not reached. The 3-year OS rate was 59% (95% CI 33-78%; see Figure). When evaluating the 12 patients who received bortezomib + CHOP or EPOCH, the CR rate was 75%, the relapse rate was 25%, and the 3-year OS rate was 64% (95% CI 30-85%). The most common adverse events (Grade 3 or higher) included infections, febrile neutropenia, neuropathy and thrombocytopenia.Conclusion: Our study suggests that bortezomib-containing regimens are feasible and effective as frontline treatment in patients with PBL. Our results suggest a high response rate as well as 3-year OS rate of approximately 60%, in contrast with the previously reported median OS time of 12-18 months. Prospective studies are needed to confirm the therapeutic role of frontline bortezomib-containing regimens in PBL. [Display omitted] DisclosuresCartron:Sanofi, BMS, Jansen, celgene, Roche, Gilead: Equity Ownership; Celgene: Consultancy, Employment; Roche: Consultancy, Equity Ownership, Honoraria, Research Funding. Lansigan:Spectrum Pharmaceuticals: Consultancy, Research Funding; Seattle Genetics: Consultancy. Navarro:Celgene Spain: Research Funding; DKMS: Research Funding; la Caixa Foundation: Research Funding; Josep Carreras International Foundation: Research Funding; CERCA Programme/Generalitat de Catalunya: Research Funding. Reagan:Teva: Membership on an entity's Board of Directors or advisory committees. Castillo:Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Millennium: Research Funding; Pharmacyclics: Consultancy, Research Funding.

"Antibody of Unknown Significance" (AUS): The Issue of Interpreting Antibody Test Results.

"Antibody of Unknown Significance" (AUS): The Issue of Interpreting Antibody Test Results.

The Impact of Prioritisation and Dosing Intervals on the Effects of COVID-19 Vaccination in Europe: An Agent-Based Cohort Model

Background: Different strategies are being explored to maximise the effect of COVID-19 vaccination in Europe. We studied the impact of different population prioritisation and dose intervals on infections, hospitalisations, mortality, and public health restrictions.Method: An agent-based model was built to quantify the impact of different vaccination strategies over 6 months. Input parameters were derived from recent phase 3 trials and official European figures. We explored the prioritisation of vulnerable people, care-home staff and residents, and contagious groups and dose intervals from 3 to 12 weeks.Findings: Prioritising vulnerable people, rather than the most contagious groups, led to higher COVID-19 prevalence, but clear reductions in mortality, hospital admissions, and restrictions. At a realistic vaccination speed of ≤0·1% population/day, separating doses by 12 (instead of 3) weeks reduced hospitalisations, mortality, and restrictions for vaccines with similar first- and second-dose efficacy (e.g., the Oxford-AstraZeneca and Moderna vaccines), but not for those with lower first-dose efficacy (e.g., the Pfizer/BioNTech vaccine).Interpretation: Mass vaccination should dramatically reduce the effect of COVID-19 on Europe’s health and economy. Early vaccination of vulnerable populations will reduce mortality, hospitalisations, and public health restrictions compared to prioritisation of the most contagious groups. The choice of interval between doses should be based on expected vaccine availability and first-dose efficacy, with 12-week intervals preferred over shorter intervals in most realistic scenarios.Funding Statement: The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). DPA is funded through a NIHR Senior Research Fellowship (Grant number SRF-2018-11-ST2-004). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the department of Health. CP research is partially funded by Ministerio de Ciencia e Innovación, Gobierno de España through the grant PGC2018-095456-B-I00. MC is funded by La Caixa Foundation (ID 100010434), under agreement LCF/PR/GN17/50300003.Declaration of Interests: Dr. Prats reports grants from Ministerio de Ciencia e Innovación, Gobierno de España (PGC2018-095456-B-I00), during the conduct of the study; other from European Commission, DG-CONNECT (CNECT/LUX/2020/LVP/0085, LC-01591965), outside the submitted work. Dr. Prieto-Alhambra reports grants and other from AMGEN, grants, non-financial support and other from UCB Biopharma, grants from Les Laboratoires Servier, outside the submitted work; and HTA Funding Committee membership. Janssen, on behalf of IMI-funded EHDEN and EMIF consortiums, and Synapse Management Partners have supported training programmes organised by DPA's department and open for external participants. Dr. CATALÀ reports grants from Ministerio de Ciencia e Innovación, Gobierno de España (PGC2018-095456-B- I00), grants from La Caixa Foundation (ID 100010434), under agreement LCF/PR/GN17/50300003, during the conduct of the study; other from European Commission, DG-CONNECT (CNECT/LUX/2020/LVP/0085, LC-01591965), outside the submitted work. Ms. Li has nothing to disclose.Ethics Approval Statement: Only public aggregated data was used for this study. The use of such data does not require ethics approval.

Use of Neuromuscular Blocking Agents in Mechanically Ventilated Patients with COVID-19: A Propensity Score Analysis

Background: Neuromuscular blocking agents (NMBA) have been previously used in patients with acute respiratory distress syndrome (ARDS). It is unknown if NMBA are useful in COVID-19 patients who require invasive mechanical ventilation (IMV).Methods: We investigated use of NMBA in COVID-19 patients on IMV from February 1 to November 24, 2020, in 147 hospitals across 6 continents, comprising the COVID-19 Critical Care Consortium. We performed propensity score (PS) matched Cox proportional hazards analysis to appraise the impact of NMBA use for ≥2 days, continuously or discontinuously (treatment), vs. no use of NMBA or only upon commencement of IMV (control) on 28-day intensive care unit (ICU) mortality.Findings: 1548 (72%) patients received any NMBA therapy; 1165 (54%) of patients were stratified in the treatment group, with a median (IQR) time from ICU admission to commencement of NMBA therapy of 0 (0-2) days. The median (IQR) duration of NMBA therapy was 3 (2-6) days (N=1548). Upon commencement of IMV, patients who received NMBA therapy had a lower mean (±SD) PaO2/FiO2 (139±75 vs 157±93; PInterpretation: Use of NMBA is common in COVID-19 patients on IMV and associated with a 2.2-fold increase in risk of 28-day mortality. Until further randomised evidence is available, NMBA should be applied cautiously in routine clinical practice.Funding Statement: University of Queensland, Wesley Medical Research, The Prince Charles Hospital Foundation, The Health Research Board of Ireland; Biomedicine international training research programme for excellent clinician-scientists; European Union’s research and innovation programme (Horizon 2020); la Caixa Foundation. Finally, Carol Hodgson is funded by a National Health and Medical Research Council Grant.Declaration of Interests: Dr. Li Bassi received research support from Fisher & Paykel outside the submitted work. Dr. Dalton has consulting from Innovative ECMO Concepts, Abiomed and Instrumentation Labs , none which affect the current work. Dr. Brodie receives research support from ALung Technologies and he has been on the medical advisory boards for Baxter, Abiomed, Xenios and Hemovent. Dr. Fan reports personal fees from ALung Technologies, Baxter, Fresenius Medical Care, Getinge, and MC3Cardiopulmonary outside the submitted work. Dr. Laffey reports consulting fees from Baxter and Cala Medical, both outside the submitted work. Dr Nichol is supported by a health Research Board of Ireland award (CTN-2014-012). Dr. Fraser receives research support from Fisher & Paykel outside the submitted work. Remaining authors do not have any competing interest to declare. Ethics Approval Statement: Participating hospitals obtained local ethics committee approval and a waiver of informed consent was granted in all cases.De-identified patient data were collected and stored via the REDCap (Vanderbilt/NIH/NCATS UL1 TR000445 v.10.0.23) electronic data capture tool, hosted at the University of Oxford, United Kingdom and University of Queensland.

The Emergence of COVID-19 Associated Mucormycosis: Analysis of Cases From 18 Countries

Coronavirus disease 2019 (COVID-19)–associated mucormycosis (CAM) has recently been increasingly reported, particularly among patients with uncontrolled diabetes. Patients with diabetes and hyperglycemia often display an inflammatory state that may be potentiated by the activation of antiviral immunity to SARS-CoV-2, and thus may favor secondary infections. We analyze 80 published and unpublished cases of CAM, with a predominance (42/80) of cases from India. Uncontrolled diabetes mellitus as well as systemic corticosteroid treatment represented major comorbid predisposing factors and rhino-orbital cerebral mucormycosis was the most frequent presentation of disease. Mortality was high at 49%, driven particularly by those with pulmonary or disseminated mucormycosis and those with cerebral involvement. Furthermore, a significant proportion of surviving patients suffered life-changing morbidities (loss of vision in 46% of survivors). Our review indicates that CAM may be a relevant complication of severe COVID-19, particularly in those with uncontrolled diabetes. Funding: Martin Hoenigl received funding from Astellas for two investigator initiated studies (ISR005824 and ISR005838), and was supported by the National Institutes of Health, Grant UL1TR001442. Agostinho Carvalho was supported by the Fundação para a Ciência e a Tecnologia (FCT) (UIDB/50026/2020 and UIDP/50026/2020), the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000039), the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 847507, and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003.Declaration of Interest: MH received research funding from Gilead, Pfizer, Astellas, Scynexis and NIH. JPG received speaker and expert advice fees from Pfizer and Gilead. NK has received research grants or honoraria as a speaker or advisor from Astellas, Gilead, MSD, and Pfizer, outside the submitted work. KL received consultancy fees from SMB Laboratoires Brussels, MSD and Gilead, travel support from Pfizer, speaker fees from FUJIFILM WAKO, Pfizer and Gilead, a service fee from Thermo fisher Scientific. OAC is supported by the German Federal Ministry of Research and Education, is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388 and has received research grants from, is an advisor to, or received lecture honoraria from Actelion, Allecra Therapeutics, Al-Jazeera Pharmaceuticals, Amplyx, Astellas, Basilea, Biosys, Cidara, Da Volterra, Entasis, F2G, Gilead, Grupo Biotoscana, Immunic, IQVIA, Janssen, Matinas, Medicines Company, MedPace, Melinta Therapeutics, Menarini, Merck/MSD, Mylan, Nabriva, Noxxon, Octapharma, Paratek, Pfizer, PSI, Roche Diagnostics, Scynexis, and Shionogi. PLW performed diagnostic evaluations and received meeting sponsorship from Bruker, Dynamiker, and Launch Diagnostics; Speakers fees, expert advice fees and meeting sponsorship from Gilead; and speaker and expert advice fees 489 from F2G and speaker fees MSD and Pfizer. Is a founding member of the European Aspergillus PCR Initiative. ACh received funding support from educational grant of Pfizer, MSD Pharmaceutical Ltd, and Gilead. All other authors no conflicts.Ethical Approval: MISSING

Frequency, Clinical Characteristics and Outcome of Adult Patients with Acute Lymphoblastic Leukemia (ALL) and COVID-19 in Spain: Results of a Survey from Pethema and Geth Groups

Introduction and objective. SARS-CoV-2 pandemic has deeply impacted in Spain. In cancer patients (pts) the lethality has been higher than in normal population, but, little is known on the impact in adults with ALL. Our objective was to analyze the frequency, clinical characteristics and outcome of adult ALL patients infected by SARS-CoV-2.Methods. Between March 1, 2020 and May 31, 2020 (the period of the peak of COVID-19 infection in Spain) two registries from the PETHEMA (Programa Español de Tratamientos en Hematologia) and GETH (Grupo Español de Trasplante Hematopoyético y Terapia Celular) groups were activated to recruit adult patients with ALL and COVID-19 infection confirmed by PCR. The PETHEMA registry was based on ASH proposal (www.ashresearchcollaborative.org/covid-19-registry) and the GETH registry was specifically performed for hematological diseases and COVID-19 infection. Both registries were merged for this study. Eighty-four Spanish centers were contacted and weekly reminds were sent until May 19, 2020. The demographic and clinical characteristics of ALL and COVID-19 infection, the comorbidities, the treatment and outcome were collected. The study was closed for follow in July 10, 2020.Results. Fifty-six of 84 centers answered the survey and 28 patients with ALL and COVID-19 infection were identified in 17 of them, especially on March (n=11) and April (n=15). Median age was 46 (range 20-78) yrs. and 19 were aged over 40 yrs. Fifteen pts were male, 1 was active smoker and 9 showed one or more comorbidities (chronic liver disease [n=2] diabetes [n=1], hypertension [n=5], cardiopathy [n=2], prior malignancy [n=1] and hypogammaglobulinemia [n=1]). ALL was of B-cell precursors in 18 pts (Ph+ in 6) and T in 10. Twenty-six pts were on treatment of LAL (induction [n=10], consolidation [n=3], maintenance [n=1], HSCT [n=5], rescue [n=6], and palliative [n=1]). Eight patients were previously submitted to allogeneic HSCT, CAR T [n=1] or immunotherapy with monoclonal antibodies (inotuzumab, n=4) and 21 were receiving immunosuppressive drugs (corticosteroids in 11, fludarabine in 4, among others). Eleven pts showed neutropenia <0.5x109/L and 18 lymphocytopenia <0.5x109/L. Median value of C reactive protein was 28.7 mg/L (0.9-311.7) and D-dimer 690 ng/mL (120-31,200). The main clinical characteristics of COVID-19 infection were: fever (n=18), cough (n=16), shortness of breath (n=9) and asthenia (n=11) and 5 pts were asymptomatic. The most frequency therapies were hydroxychloroquine/chloroquine (n=23), combined or not with lopinavir/ritonavir. Tocilizumab was given to 8 pts. Twelve pts required oxygen supply and 7 required ICU support (median stay 16 [1-47] days). COVID-19 was solved in 18 pts, although 5 pts showed PCR+ persistence (median 25 [16-91] days) after resolution of symptoms. The treatment of ALL was stopped/modified in 11 pts. Nine pts dead (COVID-19 [n=6], COVID-19 and ALL progression [n=2] and COVID-19 andPseudomonassepsis [n=1]). A trend for higher mortality was observed in patients with neutropenia <0.5x109/L and in those with lymphocytopenia <0.5x109/L.Conclusion. The frequency of adult patients with ALL and COVID-19 infection can be considered high, given the low incidence of adult ALL. COVID-19 infection was frequent in patients with advanced age and on ALL therapy. The frequency of severe COVID-19 infection and the mortality were high.Supported in part by 2017 SGR288 (GRC) Generalitat de Catalunya and “la Caixa” Foundation.DisclosuresRibera:Pfizer, Amgen, Ariad, Novartis:Consultancy, Speakers Bureau;Pfizer, Amgen:Research Funding.Barba:Amgen, Celgene, Novartis, Pfizer:Speakers Bureau;Amgen, Celgene, Gilead, Jazz Pharmaceuticals, Novartis, Pfizer, Shire:Consultancy.

Outcome of Adults with Relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL) Included in Minimal Residual Disease (MRD)-Oriented Trials

Introduction and objective. Despite a high complete remission (CR) rate obtained with frontline therapy most adults with T-ALL eventually relapse. Although promising therapies are emerging, salvage options for T-ALL are currently limited. Little is known about outcome of patients (pts) with relapsed T-ALL (R T-ALL) treated with contemporary MRD-oriented trials. Our goal was to analyze the outcome of pts with R T-ALL included in two successive MRD-oriented trials (ALL-AR-03 and ALL-HR-11) from the Spanish PETHEMA Group. Methods. Retrospective study of R T-ALL adults diagnosed between 2003 and 2019 and included in the protocols ALL-AR-03 (NCT00853008) and ALL-HR-11 (NCT01540812). The clinical characteristics at baseline and at relapse, salvage therapies and outcomes (CR and OS) were analyzed and a study of prognostic factors for OS was performed. Results Forty-nine patients were identified (ALL-AR-03 [n=27], ALL-HR-11 [n=22]). Median age (range) at diagnosis was 29 (16-58) yrs, 38 males (78%), CNS involvement 6 (12%), mediastinal mass 30 (61%), WBC count 40.8 x109/L (0.6-351.0), early T-cell precursor 11 (23%), pre-T 8 (16%), cortical 16 (33%), mature 9 (18%), T unspecified 5 (10%). Post-induction-1 MRD level ≥0.1%: 14/42 (33%), ≥0.01%: 17/39 (44%). Nine pts (18%) required 2nd induction therapy (resistant disease after induction-1 [n=5], MRD≥0.1% after induction-1 [n=4]). Allogeneic HSCT in CR1: 8 pts. Interval CR1-relapse: 11.2 [0.1-36.7] months. Relapse was located in BM (n=20, 41%), BM+extramedullary (n=16, 33%) and extramedullary (n=13, 26%). CNS at relapse was involved in 18 pts (37%, isolated in 8 cases). Median number of rescue lineages was 2 (range 1-5). The most frequent first salvage schedules were FLAG-Ida (n=24, 49%), HyperCVAD (n=8, 16%) and nelarabine (n=4, 8%) (other schedules in 13 pts). Second CR was attained in 21/48 pts (44%). The patients with poor morphologic and/or poor MRD response after Induction-1 in first line therapy (n=9) did not respond to first salvage therapy (0/9 vs. 21/39, p=0.003). AlloHSCT was performed in 19 pts (15 in CR2) (HLA-identical sibling: 9, URD: 9, haploidentical: 1, myeloablative conditioning: 16). Thirty-nine pts died (progression: 27, toxicity of rescue regimens: 7, TRM: 5) and 9/10 alive patients were submitted to HSCT (the remaining is on rescue therapy). Median OS (95%CI) was 6.1 (4.9-7.2) months, 5yr OS probability 21% (9%-33%) (Figure 1). By multivariable analysis, only the CR after first salvage regimen emerged as favorable prognostic factor for OS (HR 3.110, 95%CI: 1.579-6.124) (Figure 2). Conclusion. This study shows poor outcome of adults with R T-ALL, with CR to first salvage therapy of 44% and a median OS of 6 months. Poor early response to first line therapy correlated with poor response to salvage-1. The only independent predictor for better survival was CR to first salvage regimen. This study highlights the unmet need for novel effective therapies for T-ALL. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation; ISCIII (PI19/01828), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future". Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Barba:Amgen, Celgene, Gilead, Jazz Pharmaceuticals, Novartis, Pfizer, Shire: Consultancy; Amgen, Celgene, Novartis, Pfizer: Speakers Bureau. Tormo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Giménez Conca:AbbVie: Honoraria, Speakers Bureau.

Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Results of Ponalfil Clinical Trial after Completion of Recruitment

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was &amp;lt;2 in 86% of pts. Median of WBC count was 6.4 (0.6-359.3) x109/L, Hb 90 (63-145) g/L, platelets 38 (11-206) x109/L. The immunologic phenotype was common in 26 cases, with molecular isoform p190 in 20 patients (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained 26/26 patients (100%) (4 are still on induction therapy), with CMR in 11/26 cases (42%), MMR in 6/26 (23%) and no molecular response in 9/26 (35%)).Two patients withdrew the trial (thrombosis of the central retina artery and severe intestinal infection, one case each). Consolidation was given to 24 patients, 2/24 are receiving consolidation and 22 patients received allogeneic HSCT (14 in CMR, 6 in MMR, 2 without molecular response). No relapses before HSCT were detected. No transplant-related mortality was observed to date, but 1 patient withdrew the trial by severe GVHD. Ponatinib was given after HSCT in 4 pts due to loss of molecular response. Three pts relapsed after HSCT, one of them after documented loss of molecular response. All pts are alive (median follow-up of 4.5 months, range 0.5-26.2.2). The EFS probability at 30 months was 91% (79%, 100%) (Figure 1). One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

Nanocrystal–Molecular Hybrids for the Photocatalytic Oxidation of Water

The authors acknowledge financial support from BIST Ignite project SOLHYCAT. N.G.B. and V.P. acknowledge financial support from the Spanish MCIU (RTI2018-099965-B-I00, AEI/FEDER, UE) and Generalitat de Catalunya (2017-SGR-1431). A.L. acknowledges support from MINECO, FEDER, and AGAUR (PID2019-111617RB-I00, 2017-SGR-1631). N.G.B. acknowledges financial support from MINECO through the Ramon y Cajal program (RYC-2012- 10991). M.V. thanks “la Caixa” Foundation for the INPhINIT fellowship program. ICN2 is supported by the Severo Ochoa program from Spanish MINECO (grant no. SEV-2017-0706), and ICN2 and ICIQ are funded by the CERCA Program from Generalitat de Catalunya.

ALL-257: Unraveling IKZF1 Deletion Therapeutic Vulnerabilities in Adult B-Cell Precursor Acute Lymphoblastic Leukemia

Context IKZF1 (Ikaros) deletion has been proposed as a poor prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP ALL) in children and adults. Objective To analyze the frequency and prognostic impact of IKZF1 deletions in adult BCP ALL patients. To identify the IKZF1 gene expression signature to find patients with different deletion isoforms and therapeutic opportunities. Patients and methods MLPA or SNP array samples of 151 (109 Ph-negative and 42 Ph+) adult BCP ALL patients treated with MRD-oriented protocols from the PETHEMA Group. RNAseq was performed in 48 of them (27 Ph-negative and 21 Ph+). Results Median age was 40 [15–72] years. Ph+ patients showed older age (52 [20;72] vs. 36 [15;68] years, p 1.5 in RNAseq data analysis, we identified a robust IKZF1 deletion gene expression profile. This resulted in 119 significantly upregulated genes after multi-comparison adjustment (i.e. CCND1, LAMA3, SLC2A9, SNAI1, LDHC, CD34, ID3, CDH2, MAF) and 39 downregulated genes (i.e. ROBO1, HES6, KREMEN1, DHCR24, ABHD15). Downregulated genes were involved in Slit/Robo/EMT, Notch, Wnt/beta-catenin, and glucose and fatty acid metabolism pathways, while upregulated genes were involved in focal adhesion, ROS homeostasis, histone modification, anaerobic metabolism, stem cell quiescence, and IL-6/STAT pathways. A significant number of dysregulated gene targets of chemotherapeutic agents (retinoic acid, doxorubicin, cisplatin, gemcitabine) and targeted therapies, such as FAKi, ERKi, BCL2i, mTORi, JAKi, BRKi, EGFRi and CDKi, were identified. Conclusions Adult BCP ALL patients with IKZF1 partial gene deletions showed poor prognosis. Gene expression analysis enables the identification of potentially targetable lesions. Funding Supported in part by a grant from the Instituto de Salud Carlos III, Ministerio de Economia y Competividad, Spain (PI14/01971); 2017 SGR288 (GRC) Generalitat de Catalunya; and support from CERCA Programme/Generalitat de Catalunya, Fundacio Internacional Josep Carreras. The research leading to this invention has received funding from “la Caixa” Foundation.

Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study

SummaryBackgroundAlzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome.MethodsWe did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1–42 and 1–40 and their ratio (Aβ1–42/1–40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate.FindingsBetween Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ1–42/1–40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5–54·1), and Alzheimer's disease dementia at 53·7 years (49·5–57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90–100% in the seventh decade of life.InterpretationAlzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments.FundingInstituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.

Eating a Weekly Serving of Walnuts Relates to Beneficial Brain Imaging Phenotypes in a Cohort at Increased Risk of Alzheimer’s Disease

Abstract Objectives There is increasing evidence on the brain benefits of nut consumption. Magnetic resonance imaging (MRI) enables the detection of brain changes associated with neurodegenerative and vascular diseases. In middle-aged cognitively unimpaired subjects at increased risk of Alzheimer's disease (AD), we searched for cross-sectional associations between nut consumption and MRI-assessed brain phenotypes, including white matter hyperintensities (WMH, a marker of cerebral small vessel disease that confers increased risk of AD and stroke) and topographic patterns of gray matter volume (GMv). Methods We performed high-resolution structural MRI in 382 participants from the ALFA study (ALzheimer and FAmilies) cohort, which is enriched by family history of sporadic AD and APOE-ε4 carriership, the most prevalent genetic risk factor for AD. We assessed nut consumption by a food-frequency questionnaire containing five items related to nuts. WMH volume was normalized by intracranial volume (TIV) and rank-transformed. For WMH, we conducted univariate models with two factors: nut consumption (&amp;lt;1 and ≥1 serving/week) and being APOE-ε4 homozygote (yes/no), and their interaction, adjusting for age, gender, hypertension, hypercholesterolemia, and adherence to Mediterranean Diet. We also explored whether nut consumption related to differences in GMv using a voxel-based morphometry analysis corrected by age, gender, number of APOE-ε4 alleles, hypertension, hypercholesterolemia, adherence to Mediterranean Diet, and TIV. Results 187 participants reported nut consumption of ≥1 serving/week, 148 of whom disclosed walnut consumption. Nut (or walnut) consumption of ≥1 serving/week related to a significantly lower WMH volume (P ≤ 0.035, both). We found no statistically significant nut × APOE-ε4 interactions. Participants reporting consumption of ≥1 walnut serving/week showed significantly greater GMv in areas including the anterior/middle cingulate cortex, which is relevant for cognition and has been associated with successful aging. Conclusions Nut (in particular walnut) consumption relates to beneficial phenotypes of both cerebral vasculature and regional GMv. Funding Sources Instituto de Salud Carlos III, Spain; “la Caixa” Foundation; California Walnut Commission.