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INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs have demonstrated efficacy in monotherapy and in combination with targeted therapies. However, there is little direct comparative data on AZA and DEC in first-line treatment, and we do not know which group of patients might benefit from each drug. Results of the full analysis set (FAS) were presented previously (Labrador J, et al. ASH 2020). Here, we report long-term clinical efficacy from prespecified patient subgroup analyses. METHODS We conducted a retrospective study to compare real-life clinical outcomes between AZA and DEC in patients with AML ineligible for intensive chemotherapy included in the PETHEMA registry, and analyzed clinical variables associated with response and overall survival (OS) between AZA and DEC. RESULTS A total of 626 patients were included for the FAS between 2006 and 2019. 487 (78%) received AZA and 139 (22%) received DEC. Baseline characteristics were comparable in both groups, except for the percentage of bone marrow blasts (44% vs. 34% in the DEC group compared to AZA, p=0.010). In the FAS, there was no difference in the CR, CR/CRi or ORR (CR/RCi + PR) rate: 18%, 20.5% and 32% with AZA vs. 23%, 25% and 39.5% with DEC (p=0.20, p=0.27 and p=0.12). In the subgroup analysis, DEC was associated with higher CR/CRi rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.088 - 0.801), bone marrow blast count < 50% (95% CI: 0.293 - 0.965), secondary AML (95% CI: 0.223 - 0.918) and adverse cytogenetics (95% CI: 0.171 - 0.857) (Figure 1A). DEC was associated with higher ORR rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.116 - 0.782), leukocytes < 10 x10 9/L (95% CI: 0.321 - 0.920) and bone marrow blasts < 50% (95% CI: 0.321 - 0.920) (Figure 1B) 120 days-mortality was 25.4% after AZA and 27.1% after DEC, p=0.70. Patients who did not achieve at least a PR had significantly higher 120-day mortality with both HMAs (OR 8.85 and 8.22 for AZA and DEC, respectively). In the subgroup analysis, patients with leukocytes ≥ 10 x10 9/L (95% CI: 1.069 - 4.157) and those with estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m 2 (95% CI: 1.249 - 4.664) had higher 120-day mortality with DEC than with AZA (Figure 1C) With a median follow-up of 12 months, median OS was 10.4 months (95% CI: 9.2 - 11.7) for AZA vs. 8.8 months (95% CI: 6.7 - 11.0) for DEC (p = 0.455). The subgroup analysis revealed that patients ≥ 80 years (95%: CI 1.005 - 2.341), with leukocytes ≥ 10 x10 9/L (95% CI 1.039 - 2.062), platelet count CONCLUSIONS Our study provides real-life data on the outcomes of AML patients treated with AZA compared to DEC in a large retrospective cohort with long-term follow-up. In addition, we identify for the first time some baseline characteristics that could benefit from AZA or DEC in terms of responses, 120-day mortality and OS. These findings could help us to choose the most appropriate HMA in monotherapy or for the development of new combinations. Figure 1 Figure 1. Disclosures de la Fuente: Novartis: Research Funding; Abbie: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Tolero Pharmaceutical: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Agios: Consultancy; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are a common choice for initial treatment in elderly patients with acute myeloid leukemia (AML). However, about 60% of patients are resistant and most will relapse after a complete response (including CR/CRi). Although relapse or refractoriness to HMAs is very common, very little is known about the therapeutic management of these relapsed or refractory AML (RR-AML) patients after HMAs. METHODS We conducted a retrospective study to describe and compare salvage treatment patterns and real-life clinical outcomes of those AML patients treated upfront with AZA or DEC included in the PETHEMA-AML Registry. RESULTS Between 2006 and 2019, we included 626 AML patients treated in first-line with HMAs, 487 (78%) received AZA and 139 (22%) received DEC. Overall response rate (CR/CRi+PR) was 33.7%, 32% in the AZA vs 39.5% in the DEC group (p=0.120). Patients treated with DEC had a higher median relapse free survival than those treated with AZA (25.6 vs. 17.5 months, p=0.027). No differences were observed in the overall survival between AZA and DEC. We observed 59.7% resistance after HMAs, 60% after AZA and 58.8% after DEC; and 6.5% had other type of response (< PR), 7.9% with AZA and 1.6% with DEC. In addition, 76/121 patients who achieved CR/CRi (62.8%) relapsed, 66/90 in the AZA group (73.3%) vs 10/31 in the DEC group (32.3%) (p=0.000). After relapse or resistance, 74.5% of patients received supportive care only (BSC), which included patients receiving transfusions and other supportive measures, including oral agents to control the white blood cell counts; 71.5% of patients in the AZA group and 84.3% of patients in DEC group (p= 0.004). No differences were observed in baseline characteristics at diagnosis of patients treated with BSC only, except for a higher proportion of patients with adverse cytogenetic risk in the AZA group (46.6% vs. 33.7%, p=0.039). Only 135 patients received a salvage therapy, 116 in the AZA group and 19 in the DEC group. Thirty-five out of 135 RR-AML treated patients (26%) continued receiving HMAs: 31 (26%) in the AZA group and 4 (22%) in the DEC group. In the AZA group, 19 (16%) patients continued with AZA and 12 (10%) switched to DEC, while in the DEC group 2 patients (11%) continued with DEC and 2 (11%) switched to AZA. Fifty-one patients (37.8%) received FLUGA (fludarabine and Ara-C), FLAG-IDA-Lite (fludarabine, Ara-C and idarubicin), Low-dose Ara-C or other non-intensive regimens, 43 patients (37%) in the AZA group and 8 (42%) in the DEC group. Other salvage therapies were administered in 34% of patients (33% in the AZA group and 37% in the DEC group). Salvage therapy was not available in 1% of patients. Response assessment was available in 113/135 of RR-AML treated patients, 98 in the AZA group and 15 in the DEC group. In the AZA group, 13.2% of the patients achieved a CR (n=13), 5.1% achieved CRi (n=5), 6.1% achieved a PR (n=6), 65.3% resistance (n=64) and 8.1% died (n=8). However, no patients in the decitabine group responded to salvage therapy, 86.7% resistance (n=13) and 13.3% died (n=2). If we exclude those patients who died before response was evaluated, the ORR (CR/CRi+PR) after salvage therapy was statistically significant between AZA (n=24/90, 26.7%) and DEC group (n=0/13, 0%), p=0.035. CONCLUSIONS This study shows and compares, for the first time to our knowledge, the patterns of salvage therapy in patients with RR-AML treated upfront with HMAs. Despite the similar response rate with both HMAs, the relapse free survival was lower after AZA. The absence of responses in patients with RR-AML initially treated with DEC could justify the similar OS between AZA and DEC observed. However, we should be very cautious due to the low number of RR-AML patients treated. Disclosures de la Fuente: BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Novartis: Research Funding. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

Abstract 4665 Introduction: Little is known about immune reconstitution (IR) of HIV+ adult patients treated with HAART and high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). Aims: To compare the IR in HIV+ and HIV- patients treated with ASCT, and to correlate it with clinical outcome. Material and Methods: From January 2007 to January 2011 all HIV+ patients with lymphoma or multiple myeloma treated with ASCT where prospectively included. HIV- patients with lymphoma or multiple myeloma treated with ASCT were included as control. IR lymphocytes (Ly) subsets in peripheral blood were quantified by flow cytometry (FACScan, Becton-Dickinson Immunocytometry Systems, San Jose, CA). Naïve ly, memory ly, memory-activated ly, effector ly, NK cytotoxic ly, B naïve ly and B memory ly were quantified at the time of transplantation as well as at 3, 6, 12 and 18 months after ASCT. Additionally, immunoglobulin value, neutrophil and platelet engraftment (>0.5×109/L and >20×109/L respectively) and infectious complications were recorded in both groups. The study was approved by the local Ethics Committee. Results: We included 14 patients, 6 HIV+ and 8 HIV-. All this patients were in complete remission at the time of the ASCT. All patients received BEAM conditioning regimen, except for Melphalan 200 in the case of MM. The median infused CD34 was 4,08×10e6 in HIV+ patients and 5.2 x10e6 in control patients. All HIV+ patients had undetectable viral load at the time of the ASCT. Values of ly populations are shown in Table 1. Median neutrophils days of engraftment: 11.5 days (11–13.75) in HIV- and 14 in HIV+ (12.75–17), platelets: 15 (13–28) and 30 (17–78) (p:≤0.05) respectively. Both groups reached IR at third month, while HIV+ group showed lower values especially for the T CD4 ly subgroup (not statistically significant). HIV+ patients had statistically significant lower values of CD4 memory ly and activated CD4 ly at 6th month, and lower values of NK ly at 3th month. On the other hand, we found lower values of B naïve Ly in HIV- patients at 6th month. There was no difference in the median value of immunoglobulin at 3, 6 and 12 months between both groups. Infections were more frequents in HIV+ patients: positive Aspergillus antigenemia (3/6 vs. 1/8), positive CMV antigenemia (3/6 vs. 1/6), fungal infection (2/6 vs. 0/8) and bacterial infections (5/ 6 vs. 2/8), nevertheless severe episodes didn't shown differences, as well as disease free survival and mortality. Conclusions: In this series, IR was reached at the third month in both HIV + and HIV- patients, with non-significant lower values for HIV+ patients. Despite infections were more frequent in HIV+ patients, this was not associated with a higher mortality. Median values of lymphocytes population studied. Yellow box remarked corresponds To the statistically significant results (p:≤0,05) Disclosures: No relevant conflicts of interest to declare.

Abstract 4859 BACKGROUND: Most patients with classical Hodgkin's Lymphoma (CHL) are cured with primary treatment. However, a proportion of them fail to first line treatment needing to be rescued with subsequent lines of chemotherapy and/or autologous or allogeneic stem cell transplantation (auto-SCT and allo-SCT, respectively). The identification of clinical and biological characteristics of these patients at diagnosis is still a challenge and most prognostic systems fail to identify a proportion of patients with worse prognosis. In this context, different groups are currently analyzing several biological markers as determinants of clinical outcome. It has been reported that Bcl-2 immunohistochemical expression in Hodgkinxs Reed Sternberg cells (HRSC) might confer a worse prognosis. OBJETIVE: To analyze clinical outcomes following 1st line chemotherapy according to Bcl-2 expression at diagnosis of CHL. PATIENTS AND METHODS: CHL patients, older than 16 years old, receiving at least 1 line of treatment, were retrospectively studied for Bcl-2 expression in diagnostic samples. For this purpose, tissue sections were immunostained and semiquantitatively assessed for this marker. Cumulative incidence (CI) of treatment failure, treatment failure free survival (TfFS) and overall survival (OS) were defined as primary outcomes. Treatment failure was considered when a different treatment regimen was set up due to relapse after CR or failing to achieve CR following 1st line. RESULTS: 103 patients (55 Bcl-2 positive patients and 48 Bcl-2 negative patients) were analyzed. Main patient and clinical features are shown in Table 1. Both cohorts were well balanced for the main prognostic factors. At a median follow up of 36m (2-221), 34m (2-140) for Bcl-2 negative patients and 38m (4.5-221) for Bcl-2 positive patients, CI of 3 years treatment failure was 19% and 50% for the negative and positive cohorts, respectively (p=0.02). 3 years TfFS after diagnosis was 75% for Bcl-2 negative patients vs 47% for Bcl-2 positive patients (p=0.1). Within the cohort of Bcl-2 negative patients, 9/48 (19%) underwent auto-SCT as part of rescue treatment while 18/55 (33%) of Bcl-2 positive patients received an SCT (13 auto-SCT and 5 allo-SCT) and 3 of them, a second SCT (allo) for the treatment of post-auto-SCT relapse. 3 years OS was 84.5% for negative and 86% for positive patients (p=NS). CONCLUSIONS: According to these preliminary results, Bcl-2 expression in HRSC at diagnosis may constitute an independent biological prognostic marker in CHL patients, seemingly associated with worse outcome and need of second line chemotherapy. More studies and a longer follow up is needed in order to confirm that aggressive treatment strategies such as SCT may overcome the negative impact in survival of Bcl-2 expression in this population. Disclosures: No relevant conflicts of interest to declare.

Introduction : The success of allogeneic stem cell transplantation (SCT) is conditioned by the dynamics and the result of the bidirectional interaction of immune reactions exerted by donor and recipient (alloreactivity/tolerance). Quantitative chimerism monitoring after SCT, mainly if performed on leukocyte lineages such as T lymphocytes (TL, CD3+), allows assessment of the immune interaction between donor and recipient. Objective : To evaluate the usefulness of chimerism quantification in activated lymphocytes (AL, CD25+) for the early detection of complications (graft failure/rejection, GVHD, relapse, etc.) which, eventually, would improve the efficacy of current therapeutic strategies. Material and methods: Chimerism quantification was done by microsatellite PCR (short tandem repeat, STR-PCR) on peripheral blood (PB) samples obtained every other week from 20 transplanted patients, as well as on leukocyte lineages, TL and AL, purified by immunomagnetic means (autoMACS, Miltenyi Biotec, purity>95%). Results : Three different patterns of chimerism dynamics were observed: 10 patients showed complete chimerism (CC) in all samples analyzed post-SCT. 6 patients showed mixed chimerism (MC) with lower percentage of recipient cells in AL than in TL. All this 6 patients spontaneously evolved to CC. 4 patients showed MC with higher percentage of recipient cells in AL than in TL. All these 4 patients showed decreasing MC (increasing percentage of recipient cells) in PB, TL and AL. Moreover, 3 of them showed complications involving the graft: graft failure (not recovered after two succesive transplants) and graft rejections (1 incipient), which recovered and achieved CC after donor leukocyte infusions. Concerning disease relapse, 1 case was observed in each of groups A and B, and three cases were observed in group C. Conclusions: Our results suggest that higher percentages of recipient cells in AL than in TL are associated with stronger host-versus-graft immune reactions and, therefore, with decreasing mixed chimerism and subsequently with various complications after SCT. On the contrary, lower percentages of recipient cells in AL than in TL predict the achievement of CC. Quantitative follow up of chimerism in AL (CD25+) increases the usefulness of the analysis of PB and TL (CD3+) samples, allowing to predict the dynamics of chimerism after SCT and favouring the early establishment of the appropriate therapeutic option in each transplanted patient.

Introduction: Methylation of CpG dinucleotides is a fundamental mechanism of epigenetic regulation in eukaryotic genomes that controls the expression of certain genes. FOX-P3 is a member of the forkhead/winged-helix family of transcriptional regulators which expression is constitutive in regulatory T lymphocytes CD4/CD25 (Treg). Recent evidence suggests that human effector T cells express FOX-P3, albeit transiently and with significantly lower levels. Therefore, FOX-P3 mehtylation within the promoter region and gene expression could play a role in allogeneic stem cell transplantation (alloSCT). Objective: To analyze the association between the mehtylation status and the levels of expression of FOX-P3 with the dynamics of chimerism and the development of complications after alloSCT. Patients and methods: The degree of methylation was quantified in a 600 pb CpG island within the regulatory sequence of FOX-P3 by quantitative methylation-specific real time-PCR from 32 peripheral blood (PB) samples obtained within the first month post-alloSCT. Moreover, the expression level of FOX-P3 mRNA was analyzed by real-time quantitative PCR in 18 patients from which RNA samples were available. Results were analyzed using Fisher’s exact test due to the reduced sample size. Results: A statistically significant association (Table 1) was observed between a higher degree of methylation in the FOX-P3 promoter and a lower incidence of acute graft versus host disease (GVHD) grades II-IV (35.3% vs a 88.9% in low methylation patients; p=0.014). Moreover, patients with higher degree of methylation showed significantly higher incidence of disease relapse (41.2% vs a 0% in low methylation patients; p=0.05). The observation of a high degree of methylation would reflect a lower amount of FOX-P3 expressing cells, both Treg and effector cells. Since Treg comprises a minority population, such observation would result from relative low levels of effector T cells, which would explain the lower graft-versus-host and graft-versus-leukemia effect observed in high mehtylation group. Surprisingly, when FOX-P3 mRNA levels were analyzed, an association with statistical significance between a higher methylation status and a higher expression of FOX-P3 (90% vs 55.8%; p=0.047) was observed. It has been shown that FOX-P3 is mainly produced by Treg while effector T cells produce very low amounts of FOX-P3 mRNA. In this sense, a higher amount of Treg cells produces high FOX-P3 mRNA levels and reduces the number of effector T cells, resulting in a higher methylation status in PB samples, in which most cells would have methylated FOX-P3. Low FOX-P3 expression would, in turn, indicate a lower amount of Treg to suppress the immune activation, resulting in higher amount of effector T cells and therefore would be associated with a lower methylation. Additionally, a significant association between higher FOX-P3 expression and lower incidence of death (7.7% vs 80%; p=0.007) was observed. Moreover, the main cause of death (3/4) in the group with lower expression of FOX-P3 was acute GVHD. The lower amount of effector T cells in PB samples with high FOX-P3 expression would protect from the development of GVHD. Conclusions: Both FOX-P3 mRNA expression and promoter methylation are of prognostic value for the development of complications post-SCT. These determinations would favor an early establishment of the immunotherapeutic options for an improved management of transplanted patients. Table 1. Association between FOX-P3 promoter methylation and mRNA expression with chimerism and complications post-SCT. MC, mixed chimerism; PB, peripheral blood; Fail/Reject., graft failure/rejection. p, Fisher`s Test. Methylation MC (PB) Fail/Reject. aGVHD (II-IV) cGVHD Relapse Exitus High 6/19 (31.6%) 4/19 (21.01%) 6/17 (35.3%) 10/13 (76.9%) 7/17 (41.2%) 5/19 (26.3%) Low 2/9 (22.2%) 0/9 (0%) 8/9 (88.9%) 3/8 (37.5%) 0/9 (0%) 4/9 (44.4%) p NS NS 0.014 NS 0.05 NS Expression MC (PB) Fail/Reject. aGVHD (II-IV) cGVHD Relapse Exitus High 4/13 (30.8%) 2/13 (15.4%) 6/12 (50%) 10/11 (90.9%) 3/12 (25%) 1/13 (7.7%) Low 0/5 (0%) 0/5 (0%) 4/5 (80%) 3/4 (75%) 1/5 (20%) 4/5 (80%) p NS NS NS NS NS 0,007