Abstract: CPX‐351 is approved for the treatment of therapy related acute myeloid leukemia (t‐AML) and AML with myelodysplastic related changes (MRC‐AML). The benefits of this treatment over standard chemotherapy has not been addressed in well matched cohorts of real‐life patients. Methods Retrospective analysis of AML patients treated with CPX‐351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry. Results Median age of 79 patients treated with CPX‐351 was 67 years old (interquartile range 62–71), 53 were MRC‐AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX‐351 was 52%, 60‐days mortality 18%, measurable residual disease 〈 0.1% in 54% (12 out of 22) of them. Stem cell transplant (SCT) was performed in 27 patients (34%), median OS was 10.3 months, and 3‐year relapse incidence was 50%. Using PSM, we obtained two comparable cohorts treated with CPX‐351 ( n  = 52) or IC ( n  = 99), without significant differences in CR/CRi (60% vs. 54%) and median OS (10.3 months vs. 9.1 months), although more patients were bridged to SCT in the CPX‐351 group (35% vs. 12%). The results were confirmed when only 3 + 7 patients were included in the historical cohort. In multivariable analyses, SCT was associated with better OS (HR 0.33 95% CI: 0.18–0.59), p   〈  0.001. Conclusion Larger post‐authorization studies may provide evidence of the clinical benefits of CPX‐351 for AML in the real‐life setting.

Abstract: 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 & lt; 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 & lt; 10 x10 9/L (95% CI: 0.321 - 0.920) and bone marrow blasts & lt; 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 & lt;20 x10 9/L (95% CI: 1.150 - 3.422) and those with eGFR ≥ 45 mL/min/1.73m 2 (95% CI: 1.040 - 2.059) did benefit for treatment with AZA compared to DEC (Figure 1D). 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.

Abstract: 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 ( & lt; 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: Background: Options to treat elderly patients with newly diagnosed AML include intensive, attenuated chemotherapy, hypomethylating agents (HMA) and supportive care (SC). HMA have proven their efficacy in DACO-016 (NCT00260832) and AML-001 (NCT01074047) clinical trials, with a median overall survival (OS) of 7.7 months (95%CI, 6.2 to 9.2) with decitabine (DEC) vs. 5.0 months (95%CI, 4.3 to 6.3) with therapy choice (TC), considered SC or low-dose Ara-C (LDAC). Median OS was 10.4 months with azacitidine (AZA) (95%CI, 8.0 to 12.7) vs. 6.5 months (95%CI, 5.0 to 8.6) with conventional care regimens (CCR), considered standard induction chemotherapy, LDAC or SC. However, there are few direct comparative data of AZA and DEC in the context of trials or real-life settings. Aims: Here, we compared clinical outcomes between AZA and DEC in AML patients not eligible for intensive chemotherapy in the epidemiologic PETHEMA registry. Methods: We included newly diagnosed AML patients treated with AZA (75 mg/m2/d IV or SC days 1-7) or DEC (20 mg/m2/d IV days 1-5) that were not eligible for intensive chemotherapy. Responses were recorded using IWG 2003 criteria. Rates of Complete Response (CR), complete response with incomplete recovery (CRi) and OS were co-primary endpoints. Results: Between 2006 and 2019, 638 patients were included. 497 (78%) received AZA and 141 (22%) received DEC as per physician judgement. Baseline characteristics were comparable in both groups (Table 1), except for bone marrow blasts count ≥ 30%, which was more frequent in DEC group (59.2% vs 77.1%, p & lt;0.001). The CR rate was 16.3% vs 20.6% (p = 0.23); composite CR (CR+CRi) was 18.5% vs 22% (p = 0.35), and the overall response rate (ORR, partial remission (PR) plus CR+CRi) was 29.2% vs 34.8% (p=0.20); for AZA vs DEC, respectively. A significantly higher ORR to AZA was associated with ECOG & lt;2 (33.9% vs. 12.4% in patients with ECOG ≥2, OR 0.22, 95% CI 0.10 - 0.49, p=0.000), de novo AML (35.3% vs. 21.9% in secondary AML; OR 0.38, 95% CI 0.20 - 0.71, p=0.002) and estimated glomerular filtrate rate ≥ 45 mL/min/1.73m2 (30.4% vs. 9.3% in patients with estimated glomerular filtrate rate ≥ 45 mL/min/1.73m2; OR 0.15, 95% CI 0.034 - 0.67, p=0.013); while bone marrow blast count & lt; 50% was the only factor influencing ORR to DEC (43.7% vs. 25% in ≥ 50% bone marrow blasts, p=0.029). With a median follow up of 12 months, median OS was 10.0 (95% CI 8.7 - 11.2) vs 8.0 (5.7- 10.2) months for AZA vs DEC, respectively (p = 0.46) (Figure 1). Median OS was 21 (17.8 - 24.1) vs 16 (12.6 - 19.3) vs 6 months (5.0 - 7.0) for patients who achieved CR/CRi vs PR vs no response (p & lt;0.001) (Figure 2). Additional subgroup analyses by baseline characteristics performed to compare AZA vs DEC revealed that patients ≥ 80 years did benefit for treatment with AZA, median OS of 8 vs. 4 m (p=0.042), as well as patients with WBC ≥ 10 x109/L (8 vs. 5 m, p=0.036), platelet count & lt;20 x109/L (8 vs. 4 m, p=0.021) and those with estimated glomerular filtrate rate ≥ 45 mL/min/1.73m2 (10 vs. 5m, p=0.033). Conclusions: This is a large retrospective comparison with long-term follow-up of clinical outcomes associated with AZA and DEC treatment for patients with AML patients not eligible for intensive chemotherapy. There were no significant differences in ORR, CR/CRi or OS between AZA and DEC. However, patients with WBC ≥ 10 x109/L, platelet count & lt;20 x109/L and estimated glomerular filtrate rate ≥ 45 mL/min/1.73m2 could benefit from AZA in terms of OS. Disclosures Tormo: Janssen: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria. Ramos:Amgen: Consultancy, Other: travel grant ; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel grant , Research Funding; Novartis: Consultancy, Other: travel grant; Takeda: Consultancy, Other: travel grant ; Daiichi-Sankyo: Other: travel grant ; Merck-Sahrp & Dohme: Other: travel grant; Rovi: Other: travel grant; Roche: Other: travel grant ; Jannsen: Other: travel grant; Abbvie: Consultancy, Other: travel grant .

Abstract: In 2020, the COVID-19 pandemic followed a two-wave pattern in most countries. Hospital admission for COVID-19 in one wave or another could have affected mortality, especially among the older persons. The objective of this study was to evaluate whether the admission of older patients during the different waves, before SARS-CoV-2 vaccination was available, was associated with a different mortality. We compared the mortality rates of patients hospitalized during 2020 before (first wave) and after (second wave) July 7, 2020, included in the SEMI-COVID-19 Registry, a large, multicenter, retrospective cohort of patients admitted to 126 Spanish hospitals for COVID-19. A multivariate logistic regression analysis was performed to control for changes in either the patient or disease profile. As of December 26, 2022, 22,494 patients had been included (17,784 from the first wave and 4710 from the second one). Overall mortality was 20.4% in the first wave and 17.2% in the second wave (risk difference (RD) − 3.2%; 95% confidence interval (95% CI) − 4.4 to − 2.0). Only patients aged 70 and older (10,973 patients: 8571 in the first wave and 2386 in the second wave) had a significant reduction in mortality (RD − 7.6%; 95% CI − 9.7 to − 5.5) (unadjusted relative risk reduction: 21.6%). After adjusting for age, comorbidities, variables related to the severity of the disease, and treatment received, admission during the second wave remained a protective factor. In Spain, patients aged 70 years and older admitted during the second wave of the COVID-19 pandemic had a significantly lower risk of mortality, except in severely dependent persons in need of corticosteroid treatment. This effect is independent of patient characteristics, disease severity, or treatment received. This suggests a protective effect of a better standard of care, greater clinical expertise, or a lesser degree of healthcare system overload.