The long-term clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has been little explored. A prospective multicenter registry-based cohort study conducted from December 2020 to July 2022 by the Spanish Transplant and Cell Therapy group, was used to analyze the relationship of antibody response over time after full vaccination (at 3–6 weeks, 3, 6 and 12 months) (2 doses) and of booster doses with breakthrough SARS-CoV-2 infection in 1551 patients with hematological disorders. At a median follow-up of 388 days after complete immunization, 266 out of 1551 (17%) developed breakthrough SARS-CoV-2 infection at median of 86 days (range 7–391) after full vaccination. The cumulative incidence was 18% [95% confidence interval (C.I.), 16–20%]. Multivariate analysis identified higher incidence in chronic lymphocytic leukemia patients (29%) and with the use of corticosteroids (24.5%), whereas female sex (15.5%) and more than 1 year after last therapy (14%) were associated with a lower incidence (p < 0.05 for all comparisons). Median antibody titers at different time points were significantly lower in breakthrough cases than in non-cases. A serological titer cut-off of 250 BAU/mL was predictive of breakthrough infection and its severity. SARS-CoV-2 infection-related mortality was encouragingly low (1.9%) in our series. Our study describes the incidence of and risk factors for COVID-19 breakthrough infections during the initial vaccination and booster doses in the 2021 to mid-2022 period. The level of antibody titers at any time after 2-dose vaccination is strongly linked with protection against both breakthrough infection and severe disease, even with the Omicron SARS-CoV-2 variant.

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The effectiveness of venetoclax (VEN) in relapsed or refractory acute myeloid leukemia (RR-AML) has not been well established. This retrospective, multicenter, observational database studied the effectiveness of VEN in a cohort of 51 RR-AML patients and evaluated for predictors of response and overall survival (OS). The median age was 68 years, most were at high risk, 61% received ≥2 therapies for AML, 49% had received hypomethylating agents, and ECOG was ≥2 in 52%. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi), was 12.4%. Additionally, 10.4% experienced partial response (PR). The CR/CRi was higher in combination with azacitidine (AZA; 17.9%) than with decitabine (DEC; 6.7%) and low-dose cytarabine (LDAC; 0%). Mutated NPM1 was associated with increased CR/CRi. Median OS was 104 days (95% CI: 56–151). For the combination with AZA, DEC, and LDAC, median OS was 120 days, 104 days, and 69 days, respectively; p = 0.875. Treatment response and ECOG 0 influenced OS in a multivariate model. A total of 28% of patients required interruption of VEN because of toxicity. Our real-life series describes a marginal probability of CR/CRi and poor OS after VEN-based salvage. Patients included had very poor-risk features and were heavily pretreated. The small percentage of responders did not reach the median OS.

Introduction High-dose methotrexate (HDMTX) is administered for the treatment of some cancers. HDMTX is usually safe but may crystallize in renal tubules causing acute kidney injury (AKI). Consequently, MTX elimination is delayed, resulting in a severe and life-threatening condition. No studies have been published about the impact of MTX toxicity in Spain. This study aims to estimate the incidence and management of MTX delayed elimination and toxicity. Methods A two-round Delphi study was performed to reach consensus between 10 medical experts on haemato-oncology and paediatric oncology with experience in the management of HDMTX treated patients from leading Spanish hospitals. An online questionnaire was developed based on national and international guidelines and previous evidence regarding HDMTX-related toxicity. Consensus was established at 80% agreement. Median and interquartile ranges were calculated, and incidence data were extrapolated to the Spanish general population. Results Out of 1.475 patients estimated to receive HDMTX treatment annually in Spain, 27.5% present MTX delayed elimination and 11.6% develop HDMTX-induced AKI (35.4% with severe systemic toxicities (>grade 3) and 18.8% develop chronic renal disease). Mortality is estimated in 4.2%. Immuno-enzymatic assay is used in most of the hospitals (90%) for MTX serum level monitoring. All experts use increased supportive care and high leucovorin as first-line treatment. Available treatments in experts’ hospitals in case toxicity persists are haemodialysis (90% of hospitals), glucarpidase (60%) and hemofiltration (50%). Most prevalent non-renal systemic toxicities are haematologic and mucositis (21–40% of patients). Patients with HDMTX-induced AKI require from intensive care (5% of patients), more than 3 sessions and 4 days of dialysis, and about 8.5 days of hospitalization (non-ICU patients) and 12 days in case of patients requiring ICU. Conclusions These results are the first evidence regarding HDMTX-induced AKI in Spain. Incidence and mortality results are in line with previous studies. Clinical management is based on preventive measures and the treatment depend on the availability in the hospital. The need for effective, safe and rapid treatment for the reduction of MTX toxic levels and the improvement of monitoring methods were noted by experts as urgent needs. Further observational studies to validate these results would be needed.

Prior studies of antibody response after full SARS-CoV-2 vaccination in hematological patients have confirmed lower antibody levels compared to the general population. Serological response in hematological patients varies widely according to the disease type and its status, and the treatment given and its timing with respect to vaccination. Through probabilistic machine learning graphical models, we estimated the conditional probabilities of having detectable anti-SARS-CoV-2 antibodies at 3-6 weeks after SARS-CoV-2 vaccination in a large cohort of patients with several hematological diseases (n= 1166). Most patients received mRNA-based vaccines (97%), mainly Moderna® mRNA-1273 (74%) followed by Pfizer-BioNTech® BNT162b2 (23%). The overall antibody detection rate at 3 to 6 weeks after full vaccination for the entire cohort was 79%. Variables such as type of disease, timing of anti-CD20 monoclonal antibody therapy, age, corticosteroids therapy, vaccine type, disease status, or prior infection with SARS-CoV-2 are among the most relevant conditions influencing SARS-CoV-2-IgG-reactive antibody detection. A lower probability of having detectable antibodies was observed in patients with B-cell non-Hodgkin's lymphoma treated with anti-CD20 monoclonal antibodies within 6 months before vaccination (29.32%), whereas the highest probability was observed in younger patients with chronic myeloproliferative neoplasms (99.53%). The Moderna® mRNA-1273 compound provided higher probabilities of antibody detection in all scenarios. This study depicts conditional probabilities of having detectable antibodies in the whole cohort and in specific scenarios such as B cell NHL, CLL, MM, and cMPN that may impact humoral responses. These results could be useful to focus on additional preventive and/or monitoring interventions in these highly immunosuppressed hematological patients.

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 .

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The hypomethylating agents, decitabine (DEC) and azacitidine (AZA), allowed more elderly acute myeloid leukemia (AML) patients to be treated. However, there are little direct comparative data on AZA and DEC. This multicenter retrospective study compared the outcomes of AZA and DEC in terms of response and overall survival (OS). Potential predictors associated with response and OS were also evaluated. A total of 626 AML patients were included (487 treated with AZA and 139 with DEC). Response rates were similar in both groups: CR was 18% with AZA vs. 23% with DEC (p = 0.20), CR/CRi was 20.5% vs. 25% (p = 0.27) and ORR was 32% vs. 39.5% (p = 0.12), respectively. Patients with leukocytes < 10 × 109/L, bone marrow blasts < 50% and ECOG ≥ 2 had higher ORR with DEC than with AZA. OS was similar in both groups: 10.4 months (95% CI: 9.2–11.7) vs. 8.8 months (95% CI: 6.7–11.0, p = 0.455), for AZA and DEC, respectively. Age (≥80 years), leukocytes (≥ 10 × 109/L), platelet count (<20 × 109/L) and eGFR (≥45 mL/min/1.73 m2) were associated with higher OS with AZA compared to DEC. In conclusion, we found no differences in response and OS rates in AML patients treated with AZA or DEC.