ALBERT

Description: 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

Description: Background: B-cell Acute Lymphoblastic Leukemia (B-ALL) represents an aggressive malignancy but highly curable in children. Currently, pediatric collaborative clinical trials have reported survival rates that exceed 90%, and DNA ploidy by flow cytometry (FC) has been pointed for risk stratification and prognosis in these clinical trials. However, its generalized use remains controversial as few studies reported no impact in real-world populations. We aimed to evaluate prognostic value of DNA ploidy measured by FC in a large cohort of Peruvian children with B-ALL. Methods: We evaluated prospectively DNA-ploidy by FC in bone marrow diagnostic samples from newly diagnosed children (

Description: Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disease characterized by uncontrolled complement activation on the surface of PNH blood cells, which can lead to hemolytic anemia. Aplastic anemia is a closely related rare bone marrow disorder and commonly treated with immunosuppressive therapy (IST), such as cyclosporine and anti-thymocyte globulin. Previous research has shown that IST is effective when used concomitantly with eculizumab, regardless of the sequence of treatment initiation with IST or eculizumab. However, there are little available data in patients with PNH who may require concomitant ravulizumab and IST. Aims: To evaluate the efficacy and safety of concomitant ravulizumab and IST use in patients with PNH who received ravulizumab up to 52 weeks and those who switched to ravulizumab following the 26 weeks of treatment with eculizumab during the primary evaluation period, and to assess the transfusion requirements in these patients. Methods: Patient data from Study 301 (Lee JW, et al. Blood. 2019;133[6]:530-539; NCT02946463) were stratified by concomitant IST use during the primary evaluation period and extension period of this phase 3, multicenter, randomized, active-controlled, open-label, multicenter study. The study consisted of a 26-week primary evaluation period in which patients ≥18 years old with a documented diagnosis of PNH received either ravulizumab or eculizumab, followed by an extension period of up to 5 years, during which all patients received ravulizumab. Efficacy data were collected at the end of the primary evaluation period (through week 26) and through week 52 of the extension period. Data from week 52 were then compared with week 26 data to assess for maintenance of treatment response. Maintenance of treatment response is defined as patients who achieved the primary and secondary efficacy endpoints at both 26 weeks and 52 weeks. Safety variables were also assessed. Descriptive statistics are provided; no tests for differences between treatment groups were performed. Results: There were 246 patients receiving either ravulizumab or eculizumab in the 26-week primary evaluation period of Study 301, and 243 of these patients then received ravulizumab during the extension period. Of these patients, 28 received concomitant IST and 215 did not. Efficacy data are described in Table 1. For lactate dehydrogenase (LDH) normalization (LDH levels 〈 1x upper limit of normal; ULN), 50.0% of patients on IST maintained the treatment response from week 26 to week 52 vs 75.5% of patients without IST. Patients on IST had a numerically lower mean change in LDH levels compared with patients without IST at week 26, compared with baseline (Table 2). A total of 75.0% of patients taking IST maintained transfusion avoidance through 52 weeks compared with 89.9% of patients without IST, which may also be caused by an underlying coexisting condition such as bone marrow disease in patients who required IST. A similar proportion of patients on IST and without IST maintained stabilized hemoglobin levels through week 52 (avoidance of 〉2 g/dL decrease in hemoglobin levels from baseline in the absence of transfusion): 88.9% and 87.6%, respectively. Furthermore, a higher proportion of patients who were treated with IST also required transfusions: 53.3-61.5% of patients on IST vs 21.1-38.7% of patients without IST through week 26 and week 52. Similarly, patients treated with IST received, on average, more transfusions than patients without IST (Table 3). Safety results were similar between the IST and non-IST patient subgroups (Table 4). Conclusions: Despite a limited number of patients with available data for evaluating the effects of IST, concomitant use of ravulizumab and IST was effective and well tolerated in patients with PNH. Furthermore, patients treated with ravulizumab for the whole 52-week treatment period and did not receive concomitant IST had numerically fewer pRBC/whole blood transfusions compared with patients treated with IST. Disclosures Schrezenmeier: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Ptushkin:Alexion Pharmaceuticals Inc.: Honoraria. Notaro:Alexion Pharmaceuticals Inc.: Honoraria, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Okamoto:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Peffault De Latour:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: INTRODUCTION: Long-term survival of patients with chronic myeloid leukemia (CML) has significantly improved since the introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs). Several considerations about the side effects, risks and cost associated with the lifetime treatment, have led patients and physicians to explore the possibility of TKI discontinuation after achievement of a sustained deep molecular response (DMR), so-called treatment-free remission (TFR). Several clinical trials show that approximately half of patients who achieve a sustained DMR during TKI treatment maintain molecular remission after suspension of TKIs. There is currently no biomarker that reliably predicts TFR in CML, mainly due to different study designs that have generated inconsistent data. Thus, further investigations are needed to identify factors that consistently favor achievement of TFR. With the aim of developing a biomarker for TFR prediction we analyzed the phenotype of Natural Killer (NK) cells and their relation to successful TKI cessation. METHODS: This analysis was conducted as a substudy of the Argentina Stop Trial. Altogether, 50 consecutive chronic phase CML patients who participated in the clinical trial were recruited from 7 Argentinian centers. Peripheral blood samples were collected before stopping TKI treatment, at month 3, 12 and at any time when MR3.0 was lost. Freshly isolated mononuclear cells from 46 patients were immunophenotyped by staining with CD3, CD16, CD25, CD56, CD57, CD158, NKp30, NKp44, NKp46, NKG2A, NKG2C, NKG2D and PD-1 antibodies and NK cells subpopulations were analyzed by flow cytometry (BD FACS Canto™II). Molecular recurrence-free survival was estimated by the Kaplan-Meier method and compared within groups by the log-rank test. The cutoffs of the numerical variables were optimized according to the log-rank test. Quantitative variables were dichotomized according to receiver operating characteristics (ROC) curves in order to describe sensibility and specificity. Multivariate analysis was performed through Cox proportional hazards model. Main results are provided with hazard ratio (HR) at 6 months and 95% confidence intervals (95% CI). RESULTS: At the time of discontinuation the median proportion of NK cells (CD3-CD56+) among lymphocytes was significantly increased in patients compared with controls (15% vs 9%, P = 0.0016). A significant difference between molecular relapsed vs no-relapsed patients was observed when optimal cutoff (0.43) for CD56bright low and high was determined (at 6 months 74% vs 100% respectively, log rank test, p=0.023). At this time of follow up, no significant difference was observed for CD56dim NK cells. Phenotypic markers for adaptive-like NK cells were analyzed, however, no significant differences were observed between the non-relapsing and relapsing groups. Nevertheless, molecular non-relapsing patients had significantly higher frequencies of PD-1+ NK cells as compared with molecular relapsing patients (at 6 months 85% vs 64%, Log Rank test, P=0.009). Based on the ROC and Youden Index analysis, at 6 months the 1.2 cutoff shows an 80% specificity and 50% sensitivity. Moreover, after multivariable Cox proportional analysis, including age, time of treatment, deep molecular response time, Sokal risk, NK cells and PD-1+ NK cells, the last subpopulation was identified as an independent prognostic factor for molecular-relapse-free survival (Hazard ratio = 3.63; 95% CI 1.3 - 10.1; P=0.014). CONCLUSIONS: The clinical impact of NK cells in patients who have discontinued TKIs is controversial. The effects of TKIs against immune cells, including NK cell subsets, could depend on the type of TKIs; this aspect is particularly relevant in Argentinian treated patients real world, since many different copies of TKIs are routinely used in the clinical setting. Our study is the first, to our knowledge, to report a significant increase in PD-1 expression in NK cells at TKI cessation in patients who do not relapse. Accordingly to recent reports, PD-1 expression is more abundant on NK cells with an activated and more responsive phenotype and does not mark NK cells with an exhausted phenotype. To fully understand how PD-1 on NK cells modulates immune responses we are planning to carry out functional studies. In the future, we are also planning a comprehensive study of immune suppressors, including regulatory T cells and myeloid-derived suppressor cells. Disclosures Moiraghi: Novartis: Speakers Bureau; BMS: Speakers Bureau. Varela:Novartis: Consultancy, Speakers Bureau. Pavlovsky:Varifarma: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau. Pavlovsky:Pint Pharma: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: COVID-19 pandemic has raised several concerns regarding patients with hematologic and immune-mediated diseases. It can be assumed that Paroxysmal nocturnal hemoglobinuria (PNH), both classic hemolytic and associated with aplastic anemia, particularly on treatment with complement inhibitors, may be more susceptible and have higher morbidity and mortality rates from COVID-19 than the general population. Italy has been heavily affected from the COVID-19 outbreak with the peak of contagions at the end of March 2020. As of July, 23 2020 the cumulative incidence of COVID-19 in Italy was 0.4% (1 case every 246 residents) (ranging from 0.06% - 1/1621- in Calabria to 0.9% - 1/106 - in Lombardy). We conducted a survey on 126 patients with PNH (77 females/49 males, median age 48 years, range 19-86) among 7 reference Italian centers in order to evaluate the occurrence and clinical characteristics of COVID-19 infection from the outbreak until the time of writing. According to International PNH Interest Group (IPIG) classification, 95 patients suffered from classic hemolytic PNH, 24 had associated bone marrow failures (aplastic anemia or myelodysplastic syndrome), and 7 had subclinical PNH (clone size

Description: Introduction : The 20q deletion [del(20q)] is a recurrent chromosomal aberration in myelodysplastic syndromes (MDS) and, as a single abnormality, is associated according to the Revised International Prognostic Scoring System (IPSS-R) with a favorable outcome. However, the breakpoint of del(20q) is very heterogeneous and may cause deletion of the ASXL1 gene (20q11.21). This gene is an important epigenetic regulator of hematopoiesis and its mutations have been associated in MDS with a shorter overall survival (OS) and a lower response to azacitidine (AZA). Aim: To assess the incidence, prognostic value and impact on response to AZA of ASXL1 chromosomal alterations and genetic mutations in MDS patients with del(20q). Methods: We studied 153 patients diagnosed with MDS and del(20q) as a sole abnormality (n=93), with an additional chromosomal abnormality (n=27) or in a complex karyotype (n=33). Response to AZA therapy was assessed using the 2006 International Working Group (IWG) criteria. Analysis of ASXL1 chromosome alterations was performed by FISH (Empire Genomics probe). Samples with ASXL1 alterations by FISH were analyzed using the Agilent SurePrint G3 Human CGH 8x60K Microarray. Mutations of ASXL1 were detected by Sanger sequencing. SF3B1, SRSF2, U2AF1, DNMT3A, IDH1, IDH2, TP53, RUNX1, and SETBP1 mutations were screened by high-resolution melting and positives were confirmed by Sanger sequencing. An in vitro assay of the response to AZA in HAP1 and HAP1 ASXL1 knockout cell lines (Horizon) was also performed. The association of the clinical characteristics with the molecular findings was analyzed with the SPSS statistical program (v.20.0) and P values