Kurzfassung: Background and objective. Anthracycline-induced cardiotoxicity is a major issue in the treatment of elderly patients with diffuse large B-cell lymphoma (DLBCL). The use of non pegylated liposomal doxorubicin (Myocet®)has been associated with less cardiotoxicity as compared to conventional doxorubicin in breast cancer, but its benefit in DLBCL has been investigated mostly in retrospective and single-arm prospective studies. The objective of this study was to evaluate the benefit, in terms of cardiac toxicity, of the substitution of conventional doxorubicin as part of R-CHOP therapy by the non pegylated liposomal doxorubicin (Myocet®, R-COMP arm) in older patients (≥60 years) with de novo DLBCL or grade 3b follicular lymphoma (FL). Methods. This is a prospective randomized phase 2 trial (ClinicalTrials.gov Identifier: NCT02012088) of newly diagnosed patients with DLBCL or grade 3b FL ≥60 years old with baseline left ventricular ejection fraction (LVEF) 〉 55%. Patients were randomized to R-COMP or R-CHOP (in both cases every 21 days for a total of 6 cycles, with a dose of conventional doxorubicin or Myocet® of 50 mg/m2/cycle). The primary end-point was to evaluate the differences in subclinical cardiotoxicity between the two arms of treatment, defined by a decrease in LVEF to ≤ 55% at the end of treatment (measured by echocardiography at 1 and 4 months after the last cycle of chemotherapy). Secondary objectives were efficacy, safety and differences in the variations of cardiac biomarkers (troponin and N-terminal pro B-type natriuretic peptide [NT-proBNP]) through therapy in both arms of treatment. Results. Patient characteristics. A total of 91 patients from 15 Spanish hospitals were included, with a median age of 75 years (range 60-86), 49 (54%) were females. ECOG performance status was 2 in 15 (16%), stage III-IV in 68 (76%) and IPI 3-5 in 56 (63%). A total of 46 patients received R-COMP while 45 were treated with R-CHOP, without significant differences between arms regarding baseline characteristics. Subclinical cardio-toxicity: No differences between arms were observed in the number of patients with LVEF ≤55% determined at the end of treatment or at 4 months (6 [15%] in those treated with R-COMP and 5 [14%] in the R-CHOP arm, p=0.966). However, a higher number of patients in R-CHOP arm increased troponin levels at cycle 6 of treatment (17 out of 24 evaluable patients [71%] in R-COMP group vs. 25 out of 25 evaluable patients [100%] in R-CHOP group, p=0.004) or at the end-of-treatment visit (13 out of 21 evaluable patients [62%] in R-COMP group vs. 20 out of 23 evaluable patients [87%] in R-CHOP group, p=0.05). No differences between both groups were observed in variations of NT-proBNP levels through treatment period and follow-up. Serious adverse events (SAEs): With a median follow-up of 16 months (range 0.7-34), a total of 59 SAEs were reported in 37 patients (39 in 21 patients from R-COMP group and 20 in 16 patients from R-CHOP group), including 18 infections (12 in R-COMP and 6 in R-CHOP), and 14 episodes of febrile neutropenia (9 in R-COMP and 5 in R-CHOP). Four patients showed cardiovascular events: atrial fibrillation (n=1, R-COMP group), supraventricular tachycardia (n=2, R-CHOP group), and myocardial infarction (n=1, R-CHOP group). Efficacy: Overall response (OR) and complete remission (CR) were observed in 72 (96%) and 54 (72%) patients, respectively, without differences between R-COMP group (OR and CR rates of 97% and 72%) and R-CHOP group (OR and CR rates of 94% and 72%) (p=0.775). Conclusions. R-COMP is a feasible immunochemotherapy schedule for patients with de novo DLBCL older than 60 years. However, in our series, the use of non-pegylated doxorubicin instead of conventional doxorubicin was not associated with less decrease in LVEF measured by echocardiography, although the differences in troponin levels merits the need for further evaluation with a higher number of evaluable patients and longer follow-up. Disclosures Sancho: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees. González-Barca:Roche: Honoraria; Gilead: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Martín:Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sevier: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Kurzfassung: Introduction: Patients with Amyothrophyc Lateral Sclerosis (ALS) typically endure a progressive paralysis due to the continued loss of motoneurons that leads them to death in less than 5 years. No treatment has changed its natural history. Intraspinal injections of bone marrow mononuclear cells (MNC) have been able to ameliorate the course of ALS in murine models, acting as pumps of trophic factors that keep the motoneurons functional. We have designed a phase I/II clinical trial to check the feasibility of this approach in humans. Material and Methods: 10 patients were required for this study. Inclusion criteria required a medullar onset of the disease, a forced vital capacity (FVC) & gt;50% and under 90% desaturation time inferior to 2% of the sleeping time. Sixty mL of bone marrow were harvested under sedation. A ficoll procedure was performed in order to obtain the MNC, which were resuspended in 2 mL of saline. After laminectomy, the MNC were infused through a spinal needle in 2 injections 10 and 6 mm deep in the posterior tract of T3–T4 under electrophysiological surveillance. This level was chosen aiming the preservation of the lower intercostals function as a mean to stop the deterioration of the FVC, and thus prolong this patient’s survival. Patients are followed for 6 months before the infusion, to establish the individual evolution of the disease, and every three months for 1 year after the procedure. Results: 26 of 116 clinical histories submitted for revision to enter the trial initially met the inclusion criteria. Out of 26, 15 patients had to be excluded because they didn’t meet the inclusion criteria either in the first or subsequent visits prior to the procedure. Seven patients, 3 males and 4 females (median age 46 years, range 32 – 61) have been infused so far. All patients had received multiple prior medical treatments. Median time from diagnosis to cellular infusion was 20 months (range 15 – 47). We infused a total of 402 ×106 (240–602.8) MNC, including 3.16 ×106 (0.96–10.25) CD34+ cells. After ≥6 months of follow-up, assessment of the FVC’s evolution and the score points of the international ALS-FRS, Norris and MRC scales, revealed that of two rapidly evolving patients, one achieved stabilization of the progression and one was unaffected by the intervention. Five patients whose disease evolved more slowly also achieved stabilization of the functional scales or maintained basal FVC values (Fig. 1). Serial magnetic resonance image studies did not show any spinal cord damage. There were two severe adverse reactions (AE): 1 syncope secondary to constipation, and 1 admission due to a high tract respiratory infection with transient respiratory insufficiency in the patient in which the transplant was ineffective. Other AEs of WHO grade 1 or 2 and less than 2 months of duration were: constipation (7), intercostal pain (3), CSF hypotension (2) and lower limbs paresthesias (5, 1 of them persistent). After 6 months of follow-up, all patients had asymptomatic abolition of the somato-sensorial potentials of the posterior tract. Conclusions: The procedure was safe and feasible. No major complications or significant morbility was observed. Stabilization of the disease was achieved in 6 of the first 7 patients included in the protocol. The only unresponsive patient had developed bulbar involvement at the time of the infusion, an already known adverse prognostic factor for response to this type of cellular therapy. Figure Figure

Kurzfassung: Some clusters of children with a multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. We describe the epidemiological and clinical features of children with MIS-C in Spain. MIS-C is a potentially severe condition that presents in children with recent SARS-CoV-2 infection.

Kurzfassung: The use of non‐pegylated liposomal doxorubicin (Myocet ® ) in diffuse large B‐cell lymphoma (DLBCL) has been investigated in retrospective and single‐arm prospective studies. This was a prospective phase 2 trial of DLBCL patients ≥60 years old with left ventricular ejection fraction (LVEF) ≥55% randomized to standard R‐CHOP or investigational R‐COMP (with Myocet ® instead of conventional doxorubicin). The primary end point was to evaluate the differences in subclinical cardiotoxicity, defined as decrease in LVEF to 〈 55% at the end of treatment. Secondary objectives were efficacy, safety, and variations of troponin and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and LVEF along follow‐up. Ninety patients were included, 45 in each group. No differences were observed in the percentage of patients with LVEF 〈 55% at end of treatment (11% in R‐CHOP arm vs. 7% in R‐COMP arm, p  = 0.697) or at 4 months (10% vs. 6%, respectively, p  = 0.667) and 12 months (8% vs. 7%, respectively, p  = 1). However, a higher percentage of R‐CHOP compared with R‐COMP patients showed increased troponin levels in cycle 6 (100% vs. 63%, p  = 0.001) and at 1 month after treatment (88% vs. 56%, respectively, p  = 0.015). Cardiovascular adverse events were seen in five R‐CHOP patients (nine episodes, four grade ≥3) and in four R‐COMP patients (five episodes, all grade 1–2). No significant differences in efficacy were observed. In conclusion, R‐COMP is a feasible immunochemotherapy schedule for DLBCL patients ≥60 years, with similar efficacy to R‐CHOP. However, the use of non‐pegylated doxorubicin instead of conventional doxorubicin was not associated with less early cardiotoxicity, although some reduced cardiac safety signals were observed. Trial registration: ClinicalTrials.gov Identifier: NCT02012088.

Kurzfassung: Sickle cell disease (SCD) is an inherited autosomal recessive hemoglobin disorder caused by the presence of hemoglobin S, a mutant abnormal hemoglobin caused by a nucleotide change in codon 6 of the β-globin chain gene. SCD involves a chronic inflammatory state, exacerbated during vaso-occlusive crises, which leads to end-organ damage that occurs throughout the lifespan. SCD is associated with premature mortality in the first years of life. The process of sickling provokes asplenia in the first years of life with an increased risk of infection by encapsulated germs. These complications can be life-threatening and require early diagnosis and management. The most important interventions recommend an early diagnosis of SCD to ensure that affected newborns receive immediate care to reduce mortality and morbidity. The newborn screening program in the region of Murcia for SCD began in March 2016. We aimed to determine the incidence of sickle cell anemia and other structural hemoglobinopathies in the neonatal population of the region of Murcia, an area of high migratory stress, and to systematically assess the benefit of newborn screening for SCD, leading to earlier treatment, as well as to offer genetic counseling to all carriers. The prevalence of SCD in our region is similar to others in Spain, except for Catalonia and Madrid. The newborns with confirmed diagnoses of SCD received early attention, and all the carriers received genetic counseling.

Kurzfassung: Background: Clinical and analytical data on patients suffering from coronavirus disease-2019 (COVID-19) indicate that endothelial damage plays a key role in the pathophysiology of the disease and is responsible for the pulmonary complications and the thrombotic microangiopathy affecting multiple organs, which contribute directly to mortality (Ackerman et al. N Engl J Med 2020). Detection of biomarkers of endothelial injury in circulating blood may provide critical diagnostic and prognostic information on the disease course (Goshua et al. Lancet Haematology 2020). Endothelial injury is also a cornerstone of pathobiology in other septic and potentially life-threatening inflammatory syndromes. Objectives: To identify circulating markers of endothelial damage in COVID-19 patients, and compare their levels with those observed in other septic syndromes. Methods: Plasma samples from non-critically ill patients with confirmed COVID-19 pneumonia (positive nasopharyngeal swab and confirmatory radiological chest imaging) requiring admission (n=42) were collected during the first 36h of hospitalization. Endothelial damage was evaluated by measuring in plasma: i) markers of endothelial function and activation (sVCAM-1, VWF, ADAMTS-13 activity, Protein C and α2-antiplasmin as a marker of fibrinolysis); ii) heparan sulfate (HS) levels, as indicators of endothelial glycocalyx degradation and loss of endothelial barrier function; and iii) C5b9 deposits on endothelial cells in culture, and soluble C5b9 (sC5b9) levels, to measure complement activation. Circulating dsDNA was analyzed as an indicator of the presence of neutrophil extracellular traps (NETs). ELISA tests were used for sVCAM-1, Protein C, HS, and sC5b9 levels. ADAMTS-13 activity was evaluated by FRETS. VWF, Protein C, and α2-antiplasmin were measured at the Atellica COAG 360 (Siemens Healthineers). C5b9 deposits were assessed by immunofluorescence and dsDNA levels by Quant-iT PicoGreen assay kit. Results were compared with those obtained in healthy donors (controls, n=45), and patients with non-infectious systemic inflammatory response syndrome (NI-SIRS, n=8) and septic shock (SS, n=8). Results: Levels of sVCAM-1 were significantly higher in COVID-19 patients vs. controls, NI-SIRS and SS (159±12 vs. 79±4, 57±8 and 80±10 ng/mL, respectively, p & lt;0.005) (Mean±SDM). VWF was elevated in COVID-19 patients vs. controls (240±26 vs. 96±5%, p & lt;0.001), with similar values in NI-SIRS (271±40%), and significantly reduced vs. SS (476±43%, p & lt;0.001). HS levels in COVID-19 patients were twice those detected in controls (1669±174 vs. 839±36 ng/mL, p=0.001), but they did not differ from those in NI-SIRS (1372±368 ng/mL), and were significantly lower than in SS (3677±880 ng/mL, p & lt;0.001 vs COVID-19). Regarding complement activation, deposits of C5b9 on endothelial cells were significantly increased vs. controls (2-fold, p & lt;0.01), with no notable differences vs. NI-SIRS (3±1-fold) and significantly lower than in SS (8±2-fold, p & lt;0.001). Remarkably, sC5b9 levels were much more elevated in COVID-19 patients (1064±120 vs. 204±11 ng/mL, p & lt;0.001), and no significant differences were observed vs. NI-SIRS (902±160 ng/mL) or SS (958±180 ng/mL). Also of note, presence of NETs was significantly elevated in the plasma of COVID-19 patients vs. controls (16±1.3 vs. 2±0.3 ng/ml, p & lt;0.001), but similar to NI-SIRS (19±5 ng/mL) and clearly inferior to SS (33±6 ng/mL, p & lt;0.001) (Figure). Importantly and in contrast, ADAMTS-13 activity, Protein C, and α2-antiplasmin values were within the normal range in COVID-19 patients. Conclusions: Our data clearly demonstrate the presence of endothelial stress products in the circulating blood of non-critically ill COVID-19 patients. These biomarkers of endothelial injury are suggestive indicators of different aspects of the disease: specifically, release of acute phase reactants, degradation of the endothelial cell glycocalyx, and activation of the complement system. Furthermore, this profile of biomarkers in COVID-19 appears specific, with a differential behavior in comparison with septic shock, in which endothelial damage is also known to be critical. Additional studies are needed to validate these biomarkers as diagnostic and prognostic tools of the endothelial complications in COVID-19 patients, both in early disease and later, as well as supporting specific forms of therapeutic intervention. Figure Disclosures Carreras: Jazz Pharmaceuticals: Research Funding, Speakers Bureau; German Jose´ Carreras Leukaemia Foundation: Research Funding. Carlo-Stella:Boehringer Ingelheim and Sanofi: Consultancy; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Moraleda:Sandoz: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Other: Travel Expenses; Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Other: Travel Expenses. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Diaz-Ricart:German Jose Carreras Leukaemia Foundation: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding.

Kurzfassung: INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only curative strategy for relapsed/refractory T cell lymphoma (T-NHL). In the past ten years, there have been several improvements in conditioning regimens and graft versus host disease prophylaxis (GVHD), which have contributed to lower transplant-related mortality (TRM). Also, selective and low toxicity therapies, might improve response quality in some T-NHL Recently, haploidentical stem cell transplantation (Haplo) with post-transplant cyclophosphamide is a new option for those patients who do not have an HLA-identical sibling or a suitable unrelated donor, but also it has shortened the time for urgent cases. METHODS: This study analyzes overall outcomes of 211 consecutive patients diagnosed with T-NHL who received an alloSCT from 1995 to 2018 in GELTAMO/GETH centers. Previous therapies (chemotherapies and autologous stem cell transplantation) and baseline diagnostic parameters were recorded. RESULTS The median age at alloSCT was 47 years (range, 17-69). (see table 1). Forty-nine (23%) had primary extranodal disease. Disease status pre alloSCT was available in 202 patientes: 54% were in complete response (CR), 30% in partial response (PR) and 16% with stable/progressive disease (PD). Since 2013 BV was used as a bridge therapy in ≥ 3rd line in 25 patients with CD30+ tumor expression, it was effective in 20 (CR 68% (n=17), PR 12% (n=3) PD 16% (n=4), not assessed in 1 case). The use of BV was not associated with a better response probability pre alloSCT compared with other regimens used after third line and it did not impact on post alloSCT outcomes. Reduced intensity conditioning (RIC) was the most frequent (76%, n=156). (see table 2) GVHD prophylaxis were Methotrexate + CsaA or Tacrolimus (n=72, 35,8%), sirolimus-tacrolimus (n=37; 18,4%), Cy-post based (n=44, 21,9%; used in Haplo setting n= 29). The median follow-up of all cohort was 22.5 months (range, 0-280). The two year overall survival (OS) and disease free survival (DFS) were 60% (CI95%, 53-67%) and 76.7% (CI95%, 69.3-82.5%) (Figure 1A) We observed a significant improvement in alloSCT outcomes since 2011 (OS 〈 2011 51.4% vs ≥2011 64.8%, p=0,04).(Figure 1B) Disease status was the only pre alloSCT variable that impacts 2 years - OS: CR 72.8% (CI95%, 63-80.4%), PR 52%(38.7-63.7%), PD 43.8 (26.5-59.8%) (p=0.002) (Figure 1C). Forty-three (21%) cases relapsed after alloSCT. To analyze the impact of GVHD on OS and DFS we selected landmark time point at day +100 and +1 year after alloSCT for acute (aGVHD) and chronic GVHD (cGVHD) respectively, which allowed us to capture the majority of events that could interfere with the analysis. A landmark analysis (day +100) showed a 2 year OS for grade 3-4 aGVHD was 18% and for 1-2 aGVHD 54,6% (p 〈 0,001). The severity of aGVHD had no impact on DFS. Different grades of cGVHD did not impact OS nor DFS significantly. Cumulative incidence of acute GVHD at 90 days was 51.6% (CI95%, 43.9-58.2%) being 27% grade 3-4. Chronic GVHD at 6 months was 53.9% (46.1-60.5), 54% of cases were grade 3-4). The 2 years non relapse mortality (NRM) was 30.2% (CI95%, 23.3-36.5%); the main causes contributing to NRM were GVHD (40%) and infections (44%) Haploidentical (Haplo) alloSCT was introduced in 2012 (29 of 128). With a median follow up of 13 months (range, 0-60) we found that outcomes in terms of 1 year OS (Haplo 60.7% vs. others 67,5%), 1 year DFS (Haplo 74.8% vs. others 83.8%) and 1 year NRM (Haplo 29.7% vs. 26%) are similar to other alloSCT modalities (Figure 1D). Not additional analysis could be estimated due to the low number of population at risk for each category. CONCLUSION Overall outcomes of alloSCT for T-NHL have improved over time. Complete response pre alloSCT is the only determinant for OS. Haploidentical alloSCT is not significantly different from other approaches and should be considered as an alternative. Disclosures Sierra: Novartis: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria.

Kurzfassung: Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species–mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252.