Abstract: Introduction: Diffuse large B-cell lymphoma (DLBCL) is one of the most common malignant neoplasms in elderly patients, potentially curable when optimum treatment is administered. The combination of rituximab with CHOP chemotherapy (R-CHOP) is considered standard for these patients, but randomized studies published to date are limited to the range of age from 60 to 80 years, so that in patients over this age treatment election is not so clear, usually opting for palliative treatment or a "full" treatment at a reduced dose. This retrospective study is primarily aimed to analyze the influence of the type of treatment and comorbidity scales in overall survival (OS) of a large series of patients 〉 80 years with aggressive B-cell lymphoma. Methods: Eligible patients were aged ≥ 80 years, diagnosed of DLBCL, follicular lymphoma grade 3B or transformed lymphoma. The main patient characteristics were obtained retrospectively from the medical records, including a complete geriatric assessment (CGA, "comprehensive geriatric assessment") and the Charlson comorbidity index. The Ethics Committee of the University Hospital of Salamanca approved the study. Results: 288 patients from 19 GELTAMO hospitals were registered in the study, of which 234 (60% women) were evaluable and have been included in this preliminary analysis. The median age was 84 years (80-94) and the vast majority (94%) were DLBCL. According to the Charlson index, 65% of patients were low-intermediate risk, and according to CGA, 63% of patients were considered "fit". A higher proportion (60% v 44%, p = 0.03) of patients with low or intermediate comorbidity index were treated with a curative intent (CHOP +/- rituximab), as compared with patients with high or very high index. With a median follow up of 41 (range 9-142) months, the median OS was 11.5 months (33% estimated at 3 years). The median OS for patients treated with R-CHOP-like (N=96) was 35.3 months, significantly better (p 〈 0.001) than those achieved with CHOP-like (n=23, 7.9 months), R-CVP (n=20, 6.9 months) or cyclophosphamide- prednisone +/- vincristine (n=69, 6.2 months). Charlson comorbidity index and CGA scale also had a significant influence on OS (median of 14.6 vs. 6.1 months for patients with low or intermediate versus high or very high risk, p = 0.006; and 18 vs 6.6 months for patients "fit" versus "non-fit", p = 0.006). In the multivariate analysis, treatment with R-CHOP-like (RR = 0.4; 95% CI: 0.3-0.6) and IPI 〈 3 (RR = 0.4; 95% CI: 0.3-0.6) had an independent positive influence on OS. Conclusions: In patients over 80 years with DLBCL, treatment with R-CHOP-like was associated with the best results in terms of OS. Therefore, its administration must be considered whenever possible. Disclosures Sancho: CELLTRION, Inc.: Research Funding.

Abstract: Abstract 2468 Introduction: Pim kinases are a family of oncogenic kinases that has been demonstrated to play a role in B-cell development and lymphomagenesis, and proposed as Chronic Lymphocytic Leukemia (CLL) therapeutic target. An increased expression of PIM1 and PIM2 has been found in subsets of CLL and other B-cell lymphoma types. In order to further explore PIM inhibition as a rational therapeutic target, we decided to test a new pan-Pim kinase inhibitor, ETP-39010, developed by the Experimental Therapeutics Programme at the CNIO. Materials and methods: Blood samples from 16 CLL patients were collected by the Tumor Bank Unit at the CNIO. Samples were processed in order to separate B cells (RosetteSep® Human B cell enrichment Cocktail, Stem cell Technologies). Sensitivity to the compound was analyzed by EC50 calculations using the Cell Titer Glo® commercial kit from Promega. Gene expression data were normalized and preprocessed using GEPAS utility available at http://gepas.bioinfo.cipf.es/. Differentially expressed genes and pathways were obtained using T-Rex (GEPAS) or GSEA (http://www.broadinstitute.org/gsea/) bioinformatic tools respectively. Apoptosis was measured by Annexin V/ PI staining and cell cycle was studied by PI staining using flow cytometry. Results: A significant variability in ETP-39010 sensitivity was found in this series of B-CLL samples, with EC50 values ranging from 1,3 nM to 22,6 nM, consistently with the heterogeneous PIM expression levels observed in CLL cases. A higher sensitivity to the compound was identified in samples with markers of unfavorable outcome, such as ZAP70 positivity (p 〈 0.05) or unmutated IGHV (p=0.09). The series was divided into sensitive and resistant samples according to the EC50 value (above or below the median of the series). Gene expression studies showed that sensitive samples expressed higher levels of LPL, another prognosis marker that has been shown to be related with IGVH somatic mutation load. Pharmacodynamic studies demonstrated that ETP-39010 was able to induce apoptosis in sensitive CLL samples, without cell cycle changes. Furthermore, treatment with ETP-39010 was related with the downregulation of genes involved in protein metabolic processes, transport, signal transduction and cellular biosynthetic processes (T-Rex and Babelomics analysis), as well as to downregulation of several pathways related to metabolism (GSEA analysis). Conclusion: Inhibition of PIM kinases by ETP-39010 induces apoptosis in CLL samples. An increased sensitivity to PIM inhibition has been found in CLL cases with unfavourable prognostic markers, such as unmutated immunoglobulin heavy chain (IGHV) and increased expression of ZAP70 and LPL, pointing out PIM kinases as a potential therapeutic target for unmutated CLL. Disclosures: Garcia-Marco: ROCHE: Consultancy, Honoraria, Research Funding.

Abstract: Abstract 3827 Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological disorders in which diagnosis, risk stratification, and treatment selection are based on morphological and cytogenetic studies in bone marrow (BM) samples. MDS are characterized by several recurrent chromosomal abnormalities, most of them unbalanced, with a widely variable prognosis. The assessment of these genomic defects is essential for a correct risk stratification of these patients. However, conventional cytogenetic (CC) techniques are not sufficient for the study of all MDS patients, because of the high proportion of normal karyotypes (40–50%) and unsuccessful cytogenetics (10%) (defined as the absence of mitosis). Array-based comparative genomic hybridization (aCGH) technology allows the screening of copy number changes among the whole genome in one single experiment and offers a higher resolution than conventional cytogenetics. Aims: To assess the potential application of aCGH in the clinical diagnosis of MDS as complementary tool to conventional cytogenetics. Patients and Methods: The study cohort comprises a total of 263 patients: MDS (203) and MDS/MPN (60) patients that have been previously studied by CC and FISH. Among the whole series, 33 (12.5%) patients had no successful cytogenetic results due to the absence of mitosis. In the remaining 230 patients with evaluable metaphases, 42 (16%) had an aberrant, while 188 (71.5%) presented a normal karyotype. Within this last group, 141 had ≥20 good-quality metaphases evaluated, 37 had 10–20 metaphases studied, and 10 patients had ≤10 successful metaphases. Copy number changes were analysed in all patients included in the study using NimbleGen Human CGH 12×135K Whole-Genome Tiling Array (Roche NimbleGen). Sex-matched human commercial DNA samples were used as reference. Data were analysed using the segMNT algorithm in NimbleScanv2.6 Software. Subsequently all genomic abnormalities found by aCGH analysis were confirmed by FISH. Results: Using aCGH methodology, copy number changes (greater than 600 bp) were detected in 54 patients of the global series: 4.3% of the normal karyotype patients, 88.1% of cases with abnormal cytogenetics, and 27.3% of patients with unsuccessful cytogenetics. Overall a high correlation (94.3%) between the cytogenetic changes observed by CC and CGH arrays was observed. Thus aCGH analysis revealed the same genomic abnormalities showed by CC in 88.1% of patients. In the remaining 11.9% genomic results were discordant between aCGH and CC, because of the presence of balanced translocations, not assessable by aCGH, and clonal cell populations below 30%. Furthermore, additional genomic abnormalities (n=36) not detected by CC were found by aCGH. The most frequent aberrations were losses affecting chromosomes 5 (33%), 7/7q (17%), 20q (14%), and Y (14%), as well as gains involving chromosome 8 (14%). Interestingly, other abnormalities, mainly losses, were found in chromosomes 4, 12, and 17. Focusing on the 188 patients with normal karyotype by CC, the aCGH profiling results were concordant with cytogenetics in 98% of those patients with ≥20 metaphases studied and in 92% of those with 10–20 metaphases. However, only 80% of those patients with ≤10 successful metaphases and no changes by CC displayed no copy number changes by aCGH. The most frequent abnormality found by aCGH among these normal karyotype cases was the presence of 5q deletion (2%), while other chromosomes affected were 7, 8, 11, 12 and 20. All these abnormalities were confirmed by FISH. Regarding the patients with unsuccessful cytogenetics, 72.7% of cases displayed a normal aCGH profile, while 27.3% showed at least one genomic imbalance The most frequent genomic aberrations were losses in 4q (6%), 5q (12%) and 7q (9%), and gain of chromosome 8 (6%). In addition, three of these cases showed a complex karyotype, showing more than 5 abnormalities. Conclusion: The use of aCGH karyotyping in the diagnosis of MDS could be used as a complementary technique to conventional karyotyping in the evaluation of MDS patients. Mainly in patients with unsuccessful cytogenetics and those with normal karyotype and 〈 20 good-quality metaphases evaluated. Disclosures: Hernández: Celgene: Research Funding.

Abstract: Abstract 2470 Introduction: Impaired apoptosis is a hallmark of CLL cells, in association with overexpression of antiapoptotic Bcl-2 family members, including Bcl-2 and Mcl-1. Several compounds and antisense molecules that interfere with the Bcl-2 family have been proposed for the therapy of CLL, and some are already at clinical trials. These studies have shown that high levels of Mcl-1 may explain resistance to some of these compounds. Moreover, Mcl-1 has been related to BCR signaling and prolonged survival of CLL cells, while MCL-1 expression is an adverse prognosis marker. Previous gene expression studies from our laboratory have shown a heterogeneous expression of the different members of the Bcl-2 family, with subsets of cases showing increased expression. TW-37 is a novel Bcl-2 family small molecule inhibitor that derives from the natural compound gossypol and binds to the BH3-binding groove of Bcl-2, Bcl-XL and interestingly also Mcl-1.Therefore, we aimed at studying the sensitivity of primary CLL samples to TW-37. Materials and Methods: Forty-three peripheral blood samples were collected at diagnosis by the Tumor Bank unit at CNIO and processed in order to obtain either peripheral blood mononuclear cells (PBMCs) or purified B cells. Sensitivity to the compound was analyzed by EC50 calculations using the Cell Titer Glo® commercial kit from Promega. Mcl-1 antibody used was purchased from Santa Cruz (S-19). Expression profiling (Agilent microarray) were normalized and preprocessed using GEPAS utility available at http://gepas.bioinfo.cipf.es/. Apoptosis was measured by AnnexinV/ PI staining using flow cytometry. Results: The small molecule Bcl-2 inhibitor TW-37 was tested in a first series of PBMC CLL primary samples. EC50 values in the low nanomolar range (from 32.82 to 753.1 nM) were obtained. CLL cases with 17p loss showed a lower TW-37 sensitivity. When cases with 17p deletions were excluded from the study, there was a tendency of unmutated-CLL cases to be more sensitive to TW-37 (p= 0.07; n=23). TW-37 was tested on a second series of purified B cells and an inverse correlation between Mcl-1 protein levels and response to TW-37 (Pearson= −0.5; n=9) was observed. Consistently with what is known on the mechanism of action of the compound, TW-37 induced apoptosis in sensitive samples in a time and dose dependent manner. Using gene expression analysis, we identified a group of genes with higher expression in TW-37 resistant samples. This group included GADD45B, CXCL17, VAV2 and PKCQ (BCR signaling) and PIK3CB (p100β subunit of PI3K). Conclusion: CLL samples with p53 pathway integrity were sensitive to Bcl-2-family inhibition using the TW-37 compound. This drug induced apoptosis in a time and dose dependent manner. Sensitivity was associated with naive IGHV genes, and higher levels of expression of Mcl-1, a potential biomarker of TW-37 sensitivity. Moreover, resistance to this compound seems to be related to differential expression of a gene signature that includes CXCL17, VAV2 and PKCQ; this signature might reflect the influence of the microenvironment and/or an exacerbated BCR activation. Disclosures: Garcia-Marco: ROCHE: Consultancy, Honoraria, Research Funding.

Abstract: Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of approximately 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform (NanoString Technologies, Seattle, WA) that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways, and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma [AITL]; PTCL with T follicular helper [TFH] phenotype; PTCL not otherwise specified [NOS]) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers, and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells, and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH, and PTCL-NOS. The main differences among the 3 nodal PTCL classes involved the RHOAG17V mutations (P & lt; .0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these 3 categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL.

Abstract: SARS-CoV-2 infection can impact survival of patients with acute myeloid leukemia (AML). International experts recommend considering delaying or stopping AML treatment, test patients who need intensive induction and s prioritizing outpatient treatment. However there is little published evidence in AML. Objective To analyze the clinical futures and outcome of SARS-CoV-2 infection in AML patients. Methods and patients Observational multicenter study between March and May 2020; 117 patients reported from 47 Spanish centers, but 13 had no PCR or antibody test documented, finally including 104 patients from 45 hospitals. Results The median age was 68 years, men (56.7% vs 43.3%), and the median time from AML diagnosis to SARS-CoV-2 was 4 months. The mean of comorbidities was 1.2, high blood pressure (40.4%), heart disease (17.3%), diabetes (13.5%), smoking (8.8%), chronic obstructive pulmonary disease or emphysema (7.7%), renal failure (6.7%) and liver dysfunction (1.9%). Cytogenetic risk was low in 16.9%, intermediate in 57.1% and high in 26.0%; 55.7% had active disease, 39.2% complete remission and 5.1% partial response. 29.4% were off-therapy and 70.6% under antileukemic treatment at the time of SARS-CoV-2: induction chemotherapy (25.3%), hypomethylating (19.3%), clinical trial (17.0%), consolidation chemotherapy (14.8%), venetoclax (3.4%), FLT3 inhibitors (3.4%) and/or maintenance (1.1%). Overall 3.7% were newly diagnosed (no prior therapy), 77.8% had received one line of treatment, 14.8% two and 3.7% four. 15.4% had prior allogeneic transplantation. Only 4.0% of the patients were asymptomatic, while the main signs and symptoms were fever (77.8%), pneumonia (75.0%), cough (65.3%), dyspnea (52.0%), diarrhea (20.4%), nausea and/or vomiting (12.2%), rhinorrhea (10.2%) and headache (7.4%). Analytical parameters were: neutrophils 3112 cells/µL (1900-7300), lymphocytes 1090 cells/µL (1000-3000), interleukin 6 118 pg/mL (0-100), ferritin 4505 ng/mL (15-150) and D-dimer 2823 ng/mL (20-500), with liver enzymes altered in 23.9% of cases. 84.2% received specific treatment for coronavirus infection: chloroquine or hydroxychloroquine (82.2%), lopinavir/ritonavir (54.0%), corticosteroids (39.6%), azithromycin (33.0%), tocilizumab (15.8%), plasma convalescent (3.0%), clinical trial medication (3.0%), remdesivir (2.0%) and/or anakinra (1.0%). The course was mild in 14.7% (no hospitalization), moderate in 32.0% and severe in 53.3%. The implementation of intensive measures was assessed in 48.2%(14.9% admitted to the ICU and the remaining 33.3% rejected). The mean time to negativization was 20.5 days, duration of symptoms 17.6 days and the hospital stay 11.1 days. In 48.1% of the cases treatment for AML was maintained, in 26.6% delayed and in 25.3% modified due to coronavirus disease.47.5% died, establishing an association between mortality and age over 60 years (58.3% vs 36.4%, p=0.043), ≥2 lines of treatment (72.7% vs 44.3%, p=0.020), active disease (62.5% vs 29.4%, p=0.002) and pneumonia (61.2% versus 22.7%, p=0.002). Overall 47.5% overcame the infection, and in 5.0% SARS-CoV-2 genetic material was still detected at the time of analysis. A non-significant lower mortality rate was observed among: previous transplantation (45.7% vs 64.3%, p=0.19), neutrophil & gt;1900 cells/µL (41.1% vs 60.0%, p=0.09), lymphocyte & gt;1000 cells/µL (42.9% vs 63.6%, p = 0.09) and hydroxychloroquine/chloroquine plus azithromycin (35.3% vs 60.0%, p=0.10). Conclusions SARS-CoV-2 infection produces high mortality among AML patients. Mortality was correlated with age, active disease and pneumonia. Disclosures Martinez-Lopez: Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Research Funding.

Abstract: BACKGROUND Current treatment choices are based on generalized outcome data from clinical trials, but not all MM patients respond the same and a considerable percentage of them do not achieve a desirable treatment endpoint. Contradictory results based on the rate of descent of the monoclonal component (M-component) to predict long-term outcome have been published, but no to identify patients with insufficient response to a therapeutic regimen. The ability to identify treatment early on resistance could accelerate the introduction of another (and more effective) line of therapy. AIM Develop and validate a rule based on the rate of descent of the M-component, to predict the probability of disease resistance to reach a complete remission (CR) in MM patients. METHODS Three studies were conducted: exploratory, confirmatory, and clinical validation. A total of 87 patients treated between July 2014 and September 2018, were included for the first two. Patients who were unable to complete the planned treatment due to toxicity or comorbidities, and those treated for palliative purposes only, were excluded. A therapeutic regimen was considered to be effective if CR was achieved with it. Conversely, a therapeutic regimen was considered to be ineffective if disease progression was observed during treatment, or if CR was not achieved with it. The percentage of the daily decrease in the M-component achieved by each treatment cycle is calculated dividing the percentage of the decrease during the cycle by the number of days elapsed (n.nn% /day). Timing between measurement of the M-component do not differed more than 15% from the scheduled cycle time. In the exploratory study using the receiver operating characteristic (ROC) curve through SPSS v24, the ability to discriminate between effective and ineffective therapeutic regimen was investigated in 99 cycles, to identify the optimal cutoff, and to desing a rule; followed by a confirmatory study of the rule in 52 cycles different from those of the first study. A third clinical validation study was carried out with 62 patients, 31 with treatment guided by response speed rule (RSR-guided) and 31 not (unguided). RESULTS In the exploratory study it was observed that the area under the ROC curve was 0.971 (CI 95%: 0.93 - 1.00) (p & lt;0.001) to predict ineffective therapeutic regimen. The optimal threshold was 1.405% /day. The test was considered positive for therapeutic ineffectiveness if ≤1,40% /day. Sensitivity 95.0% (CI 95%: 88.0 - 99.0), specificity 94.7% (CI 95%: 74.0 - 99.8). It was estimated that the false positive results arose due to the occasional lack of adherence of the patient to oral treatment. Also, we have observed that the first therapeutic cycle usually produces a greater decrease in the M component than the successive cycles, and this was the reason for false negative results. Thus, the Response Speed Rule (RSR) was defined as a descent of ≤ 1.40% /day in two successive cycles, and & gt; 1.40% /day in a first cycle it does not indicate efficacy. In the confirmatory study it was observed for the RSR a sensitivity 100% (CI 95%: 92 - 100), specificity 100% (CI 95%: 66 - 100), reliability 100% (CI 95%: 93 - 100). In the clinical validation study the most common treatments in 1st, 2nd, and 3rd line were VBCMP/VBAD, VCD, and KRd for candidates, and VCD, Rd, DRd or KRd in non-candidates respectively. No significant differences were observed in the type of treatment used between RSR-guided and unguided patients. The median (months) to reach the CR in the RSR-guided patients was lower (8.5 vs 12.1 months; p = 0.003). RS-guided patients need fewer cycles to achieve CR (5.29 vs. 10.84; p = 0.002). The CR rate at 18 months was 94.3% (CI 95%: 84.1 - 100) and 74.2% (CI 95%: 58.4 - 90.0) for RSR-guided and unguided patients respectively, although in unguided patients the rate rose to 96.8% (CI 95%: 90.4 - 100.0) continuing treatment until 30 months. No significant differences were found in the number of lines for CR (1.96 vs 2.42; p = 0.054). CONCLUSIONS The Response Speed Rule (RSR), defined as a speed of M-component descent of ≤ 1.40% /day in two successive cycles, predicted with great accuracy the current ineffectiveness of a therapeutic regimen to deliver CR. During the clinical validation of this cutoff, it was shown that CR is achieved in less time and with fewer cycles using RSR. This is a simple metric that can be used broadly and accelerate the introduction of another (and more effective) line of therapy. Figure Disclosures No relevant conflicts of interest to declare.

Abstract: Background: Although great strides were made in the management of MM, our best chances to eradicate this malignancy may lie in preventing its progression.Most current models to predict risk of transformation in SMM are commonly established at diagnosis and not reevaluated over time, because some parameters such as tumor burden or genetic abnormalities require invasive bone marrow (BM) aspirates. It could be hypothesized that periodic monitoring of tumor biomarkers is needed to improve risk-stratification of SMM patients, and so would be new minimally-invasive methods that can replace those performed in BM samples. Such methods should also monitor immune profiles, to identify patients with stable tumor burden/genetics but at risk of progression due to lost immune surveillance. Aim: Determine the level of concordance between the tumor/immune landscape in BM vs peripheral blood (PB) of SMM patients, as well as to evaluate immune profiles together with circulating tumor cell (CTC) numbers and genetic alterations every 6 months in PB, as minimally-invasive methods for identification of SMM patients at risk of developing active MM. Methods: 300 patients are planned to be enrolled in the iMMunocell study that includes 24 sites across 8 European countries. PB samples are collected every 6 months during three years for next-generation flow (NGF) cytometry monitoring of CTCs and immune profiles. Additionally, CTCs and various immune cells are FACSorted to evaluate, every 6 months, their molecular profile in SMM patients with stable vs progressive disease. BM samples are taken at baseline and every 12 months according to patients' choice, in which the same methods described previously for PB are performed. An interim analysis was preplanned to the moment when 150 patients were enrolled. Results: A total of 170 SMM patients were enrolled and we report here data on the first 150. Thus far, 18/150 (12%) patients progressed to MM and according to 20/20/20 criteria, 1 had low, 7 intermediate and 10 had high risk SMM. Only 7/18 cases who progressed had & gt;20% BM plasma cells (PC) by morphology. CTCs were detectable in 107/150 (71%) patients at baseline (median of 0.001% [0% - 0.42%] and 0.03 [0 - 21] CTCs/µL of PB). There was no correlation (or only modestly-significant) between the percentage of CTCs and BMPC by morphology (r=0.156, p=0.065) or flow cytometry (r=0.293, p=0.02). Median CTC counts were 0.02, 0.03 and 0.11 in SMM patients with low, intermediate and high risk disease according to 20/20/20 criteria, respectively (p=0.002). Median CTC numbers were significantly different between cases with stable vs progressive disease (0.02 vs 0.11, p=0.005). As compared to those with ≤1 CTC/µL of PB, patients with & gt;1 CTC/uL showed significantly higher risk of transformation (8% vs 47%, p & lt;0.001) with a median time to progression of 6 months. In addition to the 150 PB samples analyzed at baseline, another 139 specimens were processed at 6, 12 and 18 months. The fluctuation in CTC numbers every 6 months was generally low (median, 0.03 CTCs/uL; IQR, 0.003 - 0.12), though in 10% of patient-samples the absolute variation was & gt;0.5 CTCs/uL. Data on the genetic landscape of CTCs analyzed every 6 months from baseline to disease progression will be shown at the meeting. Immune monitoring in patient-paired PB and BM samples at baseline (n=50) uncovered that 48 of 74 innate and adaptive immune cell types measured by multidimensional flow cytometry had similar distribution. Furthermore, we found significant differences in the distribution of three CD8 T cell subsets defined by differential expression of CD28, CD127, PD1, TIGIT, in PB of SMM patients with stable vs progressive disease. In patients with longitudinal PB samples from baseline until progression to active MM (n=7), there was a significant decrease in helper effector memory CXCR3+CCR4+ and cytotoxic CD127+TIGIT+PD1+ T cells, together with a significant increase in adaptive NK cells and Tγδ CD69+ T cells. Conclusions: This is the first study performing CTC and immune monitoring every 6 months in PB samples from patients with SMM. Our results show a significant correlation between CTC counts and stable vs progressive disease, and suggest that CTC kinetics could be complementary to the 20/20/20 criteria for real-time identification of individual SMM patients at risk of developing active MM. Beyond CTC numbers, this study is uncovering key immune cell types associated with disease progression. Disclosures Terpos: Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Medison: Honoraria. Raab:Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Heidelberg Pharma: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ocio:Sanofi: Consultancy, Honoraria; Secura-Bio: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; MDS: Honoraria; GSK: Consultancy; Takeda: Honoraria; Asofarma: Honoraria. Martinez-Lopez:Novartis: Consultancy; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Janssen: Consultancy, Honoraria. de la Rubia:Amgen: Consultancy, Other: Expert Testimony; Celgene: Consultancy, Other: Expert Testimony; Janssen: Consultancy, Other: Expert Testimony; Ablynx/Sanofi: Consultancy, Other: Expert Testimony. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Ludwig:Celgene: Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Takeda: Research Funding; Seattle Genetics: Other: Advisory Boards. Goldschmidt:Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Incyte: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Molecular Partners: Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Merck Sharp and Dohme (MSD): Research Funding. Roccaro:European Hematology Association: Research Funding; AstraZeneca: Research Funding; Transcan2-ERANET: Research Funding; Italian Association for Cancer Research (AIRC): Research Funding; Janssen: Other; Celgene: Other; Amgen: Other. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Paiva:SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Abstract: Introduction: Decitabine and azacitidine have been increasingly used to treat patients with acute myeloid leukemia (AML) who are elderly or not suitable for intensive chemotherapy. Despite their widespread use, there is no consensus on their efficacy, with considerable variability between studies. Furthermore, they have not been directly compared in a randomized clinical trial. Our aim was to analyze and compare the efficacy of azacitidine and decitabine for the treatment of AML in elderly patients and/or patients not suitable for intensive chemotherapy. Methods: We included randomized controlled trials and retrospective studies enrolling adults diagnosed with newly diagnosed AML and treated with azacitidine or decitabine, not eligible for intensive chemotherapy. Only data from azacitidine or decitabine monotherapy arms were included. We included studies that reported at least one of the following outcomes: mortality, overall survival (OS), complete remission (CR), complete remission with incomplete hematologic recovery (CRi), partial response (PR). Results: The search strategy revealed 681 citations, before the duplicates were removed. Finally, 20 articles were included after analysis of abstracts and full text. In total, 23 patient cohorts were analysed (12 for azacitidine and 11 for decitabine). Table 1 shows the results of response, OS and 1-year mortality during azacitidine (75mg/m2 for 7d and 5d) and decitabine (20 mg/m2 for 5d and 10d) treatment. Comparing only the standard regimens, the overall response rate (ORR=CR+RCi+RP) for azacitidine (75 mg/m2, 7d) was 30% (95% CI 23%-37%) and for decitabine (20mg/m2, 5d) was 46% (95% CI 42%-50%), p & lt;0.001. The studies included in the azacitidine arm showed high heterogeneity (I2 =87.7%). In the case of one-year mortality, both regimens showed high heterogeneity among studies ( & gt;75%), and the result was significantly different between azacitidine (51% mortality, 95%CI: 46% -57%) and decitabine (72% mortality, 95%CI: 67% -76%), p & lt;0.001, but we only have data from 2 studies in the decitabine arm, with a substantial heterogeneity. Regarding OS, it was 10.90 months 95% CI: 8.92-12.89 months in case of azacitidine, and 8.57 months 95% CI: 7.02-10.13 months, p=0.221. Comparing the 5-day versus 10-day decitabine regimen, an ORR of 46% (95% CI 42-50) and 40% (95% CI 25-56), respectively, was observed (p=0.420). There was no significant difference in response rates, mortality and OS. For treatment with azacitidine for 5 days vs 7 days, an ORR of 36% (95% CI 13-60) and 30% (95% CI 23-37), respectively, was observed (p=0.613). Mortality was higher when administered for 5 days (72%, 95% CI: 61-82%) versus 7 days (51%, 95% CI: 46-57%), p=0.001. OS was lower when given for 5 days (6.28 months, 95% CI: 4.23-8.32 months) versus 7 days (10.9 months, 95% CI 8.92 -12.89 months), p=0.002. Conclusions: There is a lot of heterogeneity between the different studies. Despite this, it is observed that, although the ORR rate is higher in the case of decitabine than azacitidine, there are no significant differences in mortality at 1 year and in OS, which for both azacitidine and decitabine is close to 9 months. Furthermore, this study shows that there are no significant differences in the administration of decitabine for 5 or 10 days, but there are differences in the administration of azacitidine, with the recommended regime being 7 days. Disclosures No relevant conflicts of interest to declare.