DAC Group Research Articles

Decitabine-based treatment strategy improved the outcome of HSCT in JMML: a retrospective cohort study.

Pre-HSCT disease control, suboptimal long-term prognosis, and a high recurrence incidence (RI) continue to pose significant challenges for hematopoietic stem cell transplantation (HSCT) in juvenile myelomonocytic leukemia (JMML) patients. This retrospective cohort study assessed the effectiveness of a decitabine (DAC)-based protocol in JMML patients undergoing HSCT. The pre-HSCT treatment includes initial and bridging treatment. The efficacy of DAC monotherapy versus DAC combined with cytotoxic chemotherapy(C-DAC) as initial treatment was compared, followed by DAC plus FLAG (fludarabine, cytarabine, and GCSF) as bridging treatment. The HSCT regimens were based on DAC, fludarabine, and busulfan. Post-HSCT, low-dose DAC was used as maintenance therapy. The study endpoints focused on pretransplantation simplified clinical response and post-HSCT survival. There were 109 patients, including 45 receiving DAC monotherapy and 64 undergoing C-DAC treatment. 106 patients completed bridging treatment. All patients were administered planned HSCT regimens and post-HSCT treatment. The initial treatment resulted in 88.1% of patients achieving clinical remission without a significant difference between the DAC and C-DAC groups (p=0.769). Clinical remission rates significantly improved following bridging treatment (p=0.019). The 5-year overall survival, leukemia-free survival, and RI were 92.2%, 88.4%, and 8.0%, respectively. A poor clinical response to pre-HSCT treatment emerged as a risk factor for OS (hazard ratio: 9.8, 95% CI: 2.3-41.1, p=0.002). Implementing a DAC-based administration strategy throughout the pre-HSCT period, during HSCT regimens, and in post-HSCT maintenance significantly reduced relapse and improved survival in JMML patients. Both DAC monotherapy and the DAC plus FLAG protocol proved effective as pre-HSCT treatments.

Decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance treatment significantly improves survival outcomes in relapsed/refractory B-ALL patients

ObjectiveWe aimed to evaluate the efficacy of decitabine consolidation after treatment with CD19/CD22 chimeric antigen receptor T-cell (CAR-T) for patients with relapsed/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL). MethodsWe retrospectively analysed 48 patients with r/r B-ALL who received CD19/CD22 CAR-T therapy between September 2017 and May 2021. Sixteen patients received decitabine consolidation (20 mg/m2/day for 5 days at 3-month intervals) after CAR-T therapy (DAC group), while 32 patients did not receive decitabine consolidation (CON group). Overall survival (OS), leukaemia-free survival (LFS), and cumulative incidence of relapse (CIR) were evaluated in both groups. Time-to-event analysis was performed using the Kaplan-Meier method. ResultsThe median follow-up periods in the DAC and CON groups were 41.2 months and 28.6 months, respectively. The 4-year OS and 4-year LFS rates in both groups were 93.3 % and 64.3 % (P=0.029) and 87.5 % and 55.9 % (P=0.059), respectively. The 1-year CIR was 6.25 % and 28.6 %, respectively. Univariate and multivariate Cox regression analyses showed that decitabine consolidation after CAR-T therapy was significantly associated with superior OS (hazard ratio [HR]: 0.121, 95 % confidence interval [CI]: 0.015–0.947, P=0.044), and bridging to haematopoietic stem cell transplantation after CAR-T therapy was significantly associated with superior LFS (HR: 0.279, 95 %CI: 0.093–0.840, P=0.023). ConclusionsOur study recommends decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance strategy to improve the survival outcomes of patients with r/r B-ALL.

Low-dose decitabine-intensified modified conditioning regimen alleviates aGVHD in AML/MDS patients treated with allogeneic hematopoietic stem cell transplantation.

The widespread adoption of Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) has significantly improved the survival rates of patients with hematological malignancies. However, Graft-Versus-Host Disease (GVHD) remains a formidable complication, threatening patient prognosis. Recent research has indicated that decitabine (DAC), known for its hypomethylating properties may also exhibit immune-regulatory capabilities and a potential for reducing GVHD incidence and enhancing survival. We retrospectively reviewed data from AML/MDS patients who underwent Allo-HSCT at our center from January 2010 to January 2023. From a total of 251 patients with complete data, we employed propensity score matching (PSM) to create 100 matched pairs (200 patients) for comprehensive trial analysis. Patients receiving low-dose DAC-containing regimen were matched with those who did not receive DAC. Patients in the DAC group exhibited a significantly lower incidence of grade II-IV acute GVHD (aGVHD) compared to non-DAC group (21% vs. 38%, P=0.013). Univariable and multivariable logistic regression analysis demonstrated DAC intervention as a protective factor against grade II-IV aGVHD (P=0.017, OR=0.47, 95% CI 0.23-0.81; P=0.018, OR=0.46, 95% CI 0.24-0.87). Multivariate competing risk regression further supported administration of decitabine as a protective factor against grade II-IV aGVHD (P=0.038, SHR=0.53, 95%CI 0.29-0.97). There was no significant difference between both groups concerning chronic GVHD, infection, disease relapse, overall survival, disease-free survival and GVHD free, relapse free survival. In MRD negative or intermediate risk subgroup, the grade II-IV aGVHD ameliorating effect of DAC was confirmed as well. Low-dose DAC-intensified modified conditioning regimen could improve prognosis in AML/MDS Patients treated with allogeneic hematopoietic stem cell transplantation.

Inhibitory effect and related mechanism of decitabine combined with gemcitabine on proliferation of NK/T cell lymphoma cells.

Background: EBV-associated lymphoma is a neoplasm with a poor prognosis, highly aggressive, and progressive rapidly. There is no standard clinical treatment protocol. Decitabine and gemcitabine are known to have anticancer properties against cells of various cancer, respectively. However, the effect of the combination medication on NK/T cell lymphoma cells and potential mechanisms have not been thoroughly investigated. Methods: Human NK/T cell lymphoma cells NK92MI were treated with decitabine and gemcitabine alone or in combination. Experiments, including the Cell Counting Kit-8 and flow cytometry, were performed to investigate how the combination of decitabine and gemcitabine affects the biological behavior of NK92MI cells in vitro. mRNA sequencing, RT-PCR, and western blotting were used to detect changes in the related signal pathway, mRNA, and protein expressions. Results: Decitabine and gemcitabine significantly inhibited the viability and proliferation of NK92MI cells in a dose-dependent manner. The combination index was less than 1 after treating with two drugs, which was a significant synergistic effect. The decitabine concentration with the best synergistic effect was 4.046µM, and the gemcitabine concentration was 0.005µM. Flow cytometry showed that combining two drugs could significantly promote apoptosis and arrest the cell cycle at the S phase. In the combined DAC and GEM group, caspase3 protein levels were higher than in either group alone or the control group. The transcriptome sequence, KEGG, and PPI analysis showed that the differential genes after combined treatment were mainly enriched in signal pathways related to cell proliferation, adhesion, and migration compared with using alone and control groups. Based on the sequencing results, we further investigated the role of DAC and GEM in ferroptosis-related signaling molecules using RT-PCR and Western blot techniques. RT-PCR and western blotting showed that the expression levels of HMOX1 and EBV cleavage gene BRLF1 were higher in the group with combined DAC and GEM than in the group alone and the control group, while the protein and mRNA expression levels of SLC7A11 were lower than the others. In addition, the GPX4 protein expression level in the combination group was lower than in the drug-alone and control groups. In addition, the combination treatment increased the ROS level of NK92MI cells. Conclusion: Our current findings suggested that decitabine had an inhibitory effect on the proliferation of NK92MI cells when co-treated with gemcitabine. This combination may increase the expression of ferroptosis-related signaling molecules, thus inhibiting the proliferation of NK92MI cells. It also promoted apoptosis in NK/T cell lymphoma. For patients with NK/T cell lymphoma, this novel combination may provide clinical benefits.

A comparison of single and double arterial cannulation for cardiopulmonary bypass for acute type A aortic surgery: A single center, retrospective observational study.

Background: Acute type A aortic dissection (ATAAD) is a cardiovascular emergency and has high mortality and morbidity. We retrospectively compared the effects on outcomes of single arterial cannulation via axillary artery (AAC) with double arterial cannulation via axillary and femoral artery (DAC) in patients who underwent cardiopulmonary bypass (CPB) for ATAAD.Methods: Between January 2017 and May 2021, four hundred 29 patients who underwent aortic arch repair with circulatory arrest for ATAAD were divided into AAC group (n = 283) and DAC group (n = 146). The propensity score-matched (PSM) analysis were performed to compare the characteristics and outcomes of the groups.Results: After PSM (n = 137 in each), the DAC group had a longer duration of CPB (229 vs 244, p = 0.011), aortic cross-clamp time (121 vs 149, p < 0.001), durations of Intensive Care Unit (ICU) stay (7 vs 8, p = 0.014) and hospital stay (19 vs 25, p < 0.001) compared with AAC group. The incidences of dialysis (21% vs. 31%, p = 0.073), postoperative stroke (9% vs 15%, p = 0.143), ECMO support (2% vs 7%, p = 0.077), in-hospital mortality (7% vs 14%, p = 0.071) and follow-up mortality (10% vs 19%, p = 0.059) showed no significant difference between two groups. Multivariate logistic regression analysis showed postoperative ECMO (OR: 16.69, 95% CI: 1.78-156.29; p = 0.014) or stroke (OR: 11.34, 95% CI: 2.64-48.72; p < 0.001) were associated with in-hospital mortality. Univariate Cox regression results showed stroke history (OR: 4.61, 95% CI: 1.90-11.16; p = 0.001), aortic valvuloplasty (OR: 0.21, 95% CI: 0.07-0.59; p = 0.003), postoperative ALT day1 (OR: 1.00, 95% CI: 1.00-1.00; p = 0.008), ECMO (OR: 16.30, 95% CI: 4.78-55.61; p < 0.001), tracheotomy (OR: 3.78, 95% CI: 1.08-13.20; p = 0.037), postoperative stroke (OR: 4.61, 95% CI: 1.90-11.16; p < 0.001) and re-exploration for bleeding (OR: 3.52, 95% CI: 1.01-12.27; p = 0.048) were associated to follow-up mortality.Conclusions: For surgical treatment of ATAAD with CPB when compared to double axillary and femoral artery, single axillary cannulation was associated with shorter durations of CPB and ACC as well as ICU and hospital stays but no with significant difference in mortality.

Efficacy and Safety of Hypomethylating Agents in Chronic Myelomonocytic Leukemia: A Single-Arm Meta-analysis.

Background Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm with features of the myelodysplastic syndromes (MDSs) and myeloproliferative neoplasm presenting with peripheral blood monocytosis and an inherent risk for transformation to acute myeloid leukemia, while the abnormal DNA methylation plays a critical role in the pathogenesis of MDS, which is a disease of disordered differentiation. Recently, with the rapid development of molecular biology, hypomethylating agents (HMAs) for the treatment of MDS has gradually become a research focus. The objective of this study was to evaluate the benefits and risks of HMAs for patients with CMML. Materials and Methods PubMed, Embase, the Cochrane Library, and three Chinese databases were searched for studies published before November 2020 that used HMAs in CMML. Results The pooled objective response rate (ORR), complete response (CR), and partial response (PR) were 50.0, 21.0, and 2.0%, respectively. The proportion of patients with minor response (MR) was significantly higher for decitabine (DAC) than for azacitidine (AZA). There was no significant difference in hematologic improvement, ORR, CR, and PR rates between the DAC and AZA groups. Hematological toxicity included neutropenia grade 3/4 (14.0%), anemia grade 3/4 (17.0%), and thrombocytopenia grade 3/4 (22.0%). Conclusion This study showed that HMAs were effective and safe in the treatment of CMML, but large multicenter study would be needed to confirm the efficacy of HMAs for the treatment of CMML with different risk level and genetic abnormality, to support individualization treatment theoretically.

Comparison of Single Axillary vs. Dual Arterial Cannulation for Acute Type a Aortic Dissection: A Propensity Score Matching Analysis

BackgroundThe optimal arterial cannulation site for acute aortic dissection repair is unclear, especially for complex arch surgery. Axillary artery cannulation is widely accepted but adding femoral artery cannulation to it was considered to potentially improve perfusion and early outcomes. To clarify this point, a comparison of perioperative outcomes for these two different cannulation strategies was conducted regarding the pathological features of dissection.MethodsFrom January 2010 to December 2019, 927 consecutive patients underwent a total arch replacement combined with frozen elephant trunk for acute type A aortic dissection. The data, including detailed pathological features, were retrospectively collected and analyzed. Propensity score matching and multivariate logistic regression analysis were used for adjusting confounders that are potentially related to the outcome.ResultsA total of 523 patients (56.3%) accepted a dual arterial cannulation (DAC group), and 406 patients (43.7%) received a single axillary artery cannulation (SAC group). In total, 388 pairs of patients were well-matched. Whether before or after adjusting the preoperative characteristics by matching, there were no significant differences in operative mortality (6.7 vs. 5.4%, P = 0.420 before matching; 5.4 vs. 5.4%, P = 1 after matching), stroke (6.7 vs. 5.4%, P = 0.420 before matching; 6.4 vs. 5.2%, P = 0.435 after matching), spinal cord injury (5 vs. 5.7%, P = 0.640 before matching; 5.4 vs. 5.7%, P = 1. After matching), and acute renal failure requiring dialysis (13.8 vs. 9.6%, P =0.050 before matching; 12.6 vs. 9.5%, P = 0.174) between the two groups. Dual arterial cannulation was not an independent protective factor of operative mortality (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.55–1.86), stroke (OR 1.17, 95% CI 0.65–2.11), spinal cord injury (OR 1.17, 95% CI 0.65–2.11), and acute renal failure requiring continuous renal replacement therapy (CRRT) (OR 1.24, 95% CI 0.78–1.97) after adjusting for confounding factors by multivariable logistic regression analysis. In the subgroup analysis, no advantage of dual arterial cannulation was found for a particular population.ConclusionsSingle axillary artery cannulation was competent in the complex arch repair for acute aortic dissection, presenting with a satisfactory result as dual arterial cannulation. Adding femoral artery cannulation was necessary when a sufficient flow volume could not be achieved by axillary artery cannulation or when a lower limb malperfusion existed.

Efficacy and safety of venetoclax combined with azacitidine versus CAG regimen combined with decitabine in elderly patients with relapsed acute myeloid leukemia

Objective: To compare the efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) versus CAG regimen combined with decitabine (DAC) in elderly patients with relapsed acute myeloid leukemia (AML). Methods: From January 2018 to August 2020, the clinical data of forty-five elderly patients with relapse AML at the First Affiliated Hospital of Soochow University were retrospectively analyzed, including 31 males and 14 females. The median age was 66 (60-80) years old. Eighteen patients were administrated with VEN and AZA, while the other 27 were in CAG with DAC. The complete remission (CR) rate, partial remission (PR) rate, total remission rate (ORR), adverse events and overall survival (OS) were compared between the two groups. Results: At the end of the treatment, the ORR in VEN with AZA group was 77.8% (14/18); including 11 CR and 3 PR. In CAG with DAC group, the ORR was 37.0% (10/27); including 8 CR and 2 PR (P=0.007). Subgroup analysis suggested that VEN with AZA had a higher ORR in patients stratified as intermediate and poor-risk (P=0.013) or with DNA methylation mutations (P=0.007). Main adverse events in both groups were bone marrow suppression, infections, nausea and vomiting, anorexia and fatigue. Grade Ⅲ-Ⅳ cytopenia developed in lower incidence of VEN with AZA group, such as leukopenia (66.7% vs. 100%, P=0.002), anemia (50.0% vs. 92.6%, P=0.002), thrombocytopenia (72.2% vs. 96.3%, P=0.031) and neutropenia (61.1% vs. 92.6%, P=0.014). In addition, less grade Ⅲ-Ⅳ infections occurred in VEN with AZA group (66.7% vs. 33.3%, P=0.028), as well as grade Ⅲ-Ⅳ gastrointestinal events (40.7% vs. 11.1%, P=0.032), grade Ⅲ-Ⅳ fatigue (55.6% vs.11.1%, P=0.003) compared with CAG with DAC group. The 1-year OS in VEN with AZA group versus CAG with DAC group was 42.9% and 31.6% respectively (P=0.150). Conclusion: VEN combined with AZA proves favorable efficacy and tolerablity in elderly patients with relapsed AML.

Decitabine in Combination with Fludarabine and Cyclophosphamide As Lymphodepletion Regimen Followed By CD19/CD22 Bispecific Targeted CAR-T Therapy Significantly Improves Survival in Relapsed/Refractory B-ALL Patients: A Pilot Study

Background: CD19/CD22 bispecific targeted chimeric antigen receptor T cell (CAR-T) therapy has achieved impressive progress in patients with relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL), with high rates of complete remission (CR). However, T cell exhaustion caused by de novo DNA methylation restricts the capacity of CAR-T. Decitabine (DAC), a DNA methyltransferase inhibitor, has been demonstrated to reverse exhaustion-associated DNA-methylation programs, promote the rejuvenation of CAR-T cells and enhance anti-leukemic effect of CAR-T cells in vitro. To date, there are limited reports about the use of DAC as a part of lymphodepletion therapy before CAR-T cell therapy. Here, we report efficacy and safety of DAC in combination with fludarabine and cyclophosphamide (FC) regimen followed by CD19/CD22 CAR-T cell therapy for patients with R/R B-ALL.Method:We conducted a phase 1/2 clinical trial to investigate the efficacy and safety of CD19/CD22 CAR-T in the treatment of R/R B-ALL (NCT03614858). Fourteen patients were treated with DAC (total dose 100mg/m 2 in 3 days) followed by FC regimen (fludarabine 30mg/m 2 × 3d and cyclophosphamide 300mg/m 2 × 3d) (DAC group), while twelve patients received FC regimen prior to CAR-T cell infusion (CON group). A total of 1 or 2 × 10 7 CAR-T cells/kg were infused at dose escalation.Results: Baseline characteristics of patients in both groups had no significant differences except previous hematopoietic stem cell transplantation (HSCT). There were more patients with relapse after HSCT in DAC group (42.9% versus 0%, P=0.017). All patients did not achieve remission before lymphodepletion. The day 28 CR rates were 100% in DAC group and 91.7% in CON group. Furthermore, minimal residual disease (MRD) negative CR rates were 71.4% and 58.3%, respectively (P = 0.683). There was no significant difference in the proportion of nontransplant patients after CAR-T treatment between two groups. Among the nontransplant patients after CAR-T infusion in DAC group, 16.7% (1/6) of patients relapsed at 4 months. However, among 4 nontransplant patients in CON group, 1 patient achieved NR after CAR-T therapy and 3 patients relapsed at 1.5, 5, and 10 months. There were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 88.9% (DAC) versus 33.3% (CON), P = 0.01 and 3-year LFS, 92.3% (DAC) versus 21.8% (CON), P = 0.002. Multivariable analysis showed that addition of DAC to the lymphodepletion regimen was associated with better OS (hazard ratio [HR] 0.107, [95% CI, 0.013-0.875], P = 0.037) and LFS (HR 0.081, [95% CI, 0.01-0.65], P = 0.018). Cytokine release syndrome was observed in all patients.Conclusion: In summary, DAC in combination with FC regimen followed by CD19CD22 CAR-T cells was feasible and well tolerated. Our study demonstrated DAC combined with FC was an independent prognostic factor correlated with better survival in relapsed/refractory B-ALL patients. DisclosuresNo relevant conflicts of interest to declare.

Targeting miR-126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells.

BackgroundMyelodysplastic syndrome (MDS) arises from a rare population of aberrant hematopoietic stem and progenitor cells (HSPCs). These cells are relatively quiescent and therefore treatment resistant. Understanding mechanisms underlying their maintenance is critical for effective MDS treatment.MethodsWe evaluated microRNA‐126 (miR‐126) levels in MDS patients’ sample and in a NUP98‐HOXD13 (NHD13) murine MDS model along with their normal controls and defined its role in MDS HSPCs’ maintenance by inhibiting miR‐126 expression in vitro and in vivo. Identification of miR‐126 effectors was conducted using biotinylated miR‐126 pulldown coupled with transcriptome analysis. We also tested the therapeutic activity of our anti‐miR‐126 oligodeoxynucleotide (miRisten) in human MDS xenografts and murine MDS models.ResultsmiR‐126 levels were higher in bone marrow mononuclear cells from MDS patients and NHD13 mice relative to their respective normal controls (P < 0.001). Genetic deletion of miR‐126 in NHD13 mice decreased quiescence and self‐renewal capacity of MDS HSPCs, and alleviated MDS symptoms of NHD13 mice. Ex vivo exposure to miRisten increased cell cycling, reduced colony‐forming capacity, and enhanced apoptosis in human MDS HSPCs, but spared normal human HSPCs. In vivo miRisten administration partially reversed pancytopenia in NHD13 mice and blocked the leukemic transformation (combination group vs DAC group, P < 0.0001). Mechanistically, we identified the non‐coding RNA PTTG3P as a novel miR‐126 target. Lower PTTG3P levels were associated with a shorter overall survival in MDS patients.ConclusionsMiR‐126 plays crucial roles in MDS HSPC maintenance. Therapeutic targeting of miR‐126 is a potentially novel approach in MDS.

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients’ outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37–0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.

Decitabine With or Without Micro-Transplantation for the Treatment of Intermediate or High-Risk Myelodysplastic Syndrome: A Chinese Single-Center Retrospective Study of 22 Patients.

The treatment outcomes of intermediate or high-risk myelodysplastic syndrome (MDS) remain unsatisfactory. This study was designed to evaluate the safety and efficacy of human leukocyte antigen (HLA)-mismatched hematopoietic stem cell micro-transplantation (MST) in patients with MDS. A total of 22 patients with MDS, ranging between the ages of 39 and 74, were enrolled in this study. Eleven patients were given decitabine (DAC), a DNA methyltransferase inhibitor, combined with HLA-mismatched MST (MST-DAC group), and the remaining patients were given decitabine only (DAC group). The median overall survival (OS) of the MST-DAC group was higher than that of the DAC group (24 vs. 14.3 months; HR 0.32; 95% CI: 0.11–0.96; p = 0.04), although it is a study with small samples. The overall response rate (ORR), marrow complete remission (mCR), plus hematological improvement (HI) rates of the MST-DAC group were higher than that of the DAC group (81.8 vs. 54.5%, p = 0.36; 63.6 vs. 27.3%, p = 0.09, respectively); however, there were no statistical differences between the two groups, which may be attributed to the limited number of cases evaluated in this study. No graft-vs.-host disease was observed in the MST-DAC group. Patients in the MST-DAC group demonstrated a slightly lower incidence of hematological and non-hematological adverse events (AEs). DAC combined with HLA-mismatched MST may provide a novel, effective, and safe treatment for use in intermediate or high-risk MDS pathologies.

Evaluation of Reduced-Dose Decitabine and Azacitidine for Treating Myelodysplastic Syndromes: A Retrospective Study

BackgroundHypomethylating agents (HMA) are considered the first-line therapy for high-risk myelodysplastic syndromes (MDS). However, as the efficacy and safety of rational dosing regimens are lacking, we evaluated the effectiveness and safety of reduced-dose azacitidine (AZA) vs. decitabine (DAC) in adult MDS patients.Material/MethodsThis retrospective study was conducted at the Institute of Hematology & Blood Diseases Hospital, for hospitalized MDS patients diagnosed (WHO 2008 classification criteria) from May 2006 to February 2020. These AZA- and DCA-naive patients treated with AZA 100 mg/(m2·day) for 5 days to 7 days or DAC 20 mg/(m2·day) for 3 days to 4 days, or 20 mg/(m2·day) 1 day/week for 3 weeks/month were assessed for treatment responses and adverse events.ResultsOf the 158 enrolled MDS patients, 120 and 38 patients were administered reduced-dose DAC and AZA, respectively. All the patients received a median of 2 treatment cycles. The overall response rates (ORR) were 50.0% and 73.3% in the AZA and DAC groups, respectively (P=0.007). The percentage of platelet transfusion dependence in the AZA group was lower than the DAC group (P=0.026). The multivariate analysis demonstrated that the DAC treatment was a significant factor for improved responses (OR 2.928; 95% CI 1.267–6.896; P=0.012), and the absolute neutrophil count (ANC) was a predictor of the ORR (OR 0.725; 95% CI 0.558–0.898; P=0.008). Neutropenia (P=0.016) and infection (P=0.032) incidences were higher in the DAC group.ConclusionsThe reduced-dose DAC group demonstrated a better response than the AZA group in MDS patients with different prognostic risks. The patients’ pre-treatment ANC was a significant factor associated with the ORR.

719. Clinical Outcomes of Single versus Double Anaerobic Coverage for Intra-abdominal Infections

BackgroundDouble anaerobic coverage (DAC) is often used for intra-abdominal infections (IAIs) post-operatively. The primary objective of the study was evaluating length of hospital stay (LOS), in-hospital post-operative complications, and re-admission within 30 days of discharge due to post-operative complications in patients who received piperacillin/tazobactam plus metronidazole versus piperacillin/tazobactam for IAIs post-operatively. The secondary objective was comparing in-hospital mortality and hospital-acquired Clostridioides difficile infections (CDI) between the two groups.MethodsThis was a retrospective, cohort study including adults with surgically managed IAIs at an urban community hospital between January 1, 2016 and June 30, 2019. The following data were collected: age, sex, body mass index, comorbidities, Charlson Comorbidity Index (CCI), 5-day post-operative body temperature, American Society of Anesthesiologists (ASA) pre-operative assessment score, surgical wound classification, and IAI diagnosis. Multivariate analysis and aggregate resampling of the sampling distribution were conducted. An alpha of < 0.05 was considered statistically significant.ResultsOut of 163 patients, 96 patients received piperacillin/tazobactam plus metronidazole and 67 patients received piperacillin/tazobactam. The patients who received DAC were sicker with higher CCI (p=0.021) and 5-day post-operative body temperature (p=0.013). They were also at a higher risk for surgical site infections (p=0.002). Double anaerobic coverage was more often used for acute cholecystitis (p=0.0001) and gastrointestinal perforations (< 0.0001). After adjusting for these variables, DAC was associated with longer LOS (median 9 days vs. 4 days, p< 0.0001) and in-hospital post-operative complications (23% vs. 9%, p< 0.0001). There were more re-admissions within 30 days of discharge due to post-operative complications in the single anaerobic coverage group (4% vs. 1%, p=< 0.0001). In-hospital mortality (4% vs. 0%) and hospital-acquired CDI (1% vs. 0%) were only observed in DAC group.ConclusionDouble anaerobic coverage was associated with no clinical benefit in surgically managed IAIs and in some cases may produce worse outcomes.Disclosures All Authors: No reported disclosures

Low-Dose Decitabine Assists Human Umbilical Cord-Derived Mesenchymal Stem Cells in Protecting β Cells via the Modulation of the Macrophage Phenotype in Type 2 Diabetic Mice.

Background Progressive β-cell dysfunction, a major characteristic of type 2 diabetes (T2D), is closely related to the infiltration of inflammatory macrophages within islets. Mesenchymal stem cells (MSCs) have been identified to alleviate β-cell dysfunction by modulating macrophage phenotype in T2D, but the restoration of β-cells by a single MSC infusion is relatively transient. Decitabine (DAC) has been reported to polarize macrophages towards the anti-inflammatory phenotype at low doses. We therefore investigated whether low-dose decitabine could enhance the antidiabetic effect of MSCs and further promote the restoration of β-cell function. Methods We induced a T2D mice model by high-fat diets and streptozotocin (STZ) injection. Mice were divided into five groups: the normal group, the T2D group, the DAC group, the MSC group, and the MSC plus DAC group (MD group). We examined the blood glucose and serum insulin levels of mice 1, 2, and 4 weeks after MSC and/or DAC treatment. Dynamic changes in islets and the phenotype of intraislet macrophages were detected via immunofluorescence. In vitro, we explored the effect of MSCs and DAC on macrophage polarization. Results The blood glucose and serum insulin levels revealed that DAC prolonged the antidiabetic effect of MSCs to 4 weeks in T2D mice. Immunofluorescence staining demonstrated more sustainable morphological and structural amelioration in islets of the MD group than in the MSC group. Interestingly, further analysis showed more alternatively activated macrophages (M2, anti-inflammatory) and fewer classically activated macrophages (M1, proinflammatory) in islets of the MD group 4 weeks after treatment. An in vitro study demonstrated that DAC together with MSCs further polarized macrophages from the M1 to M2 phenotype via the PI3K/AKT pathway. Conclusion These data unveiled that DAC prolonged the antidiabetic effect of MSCs and promoted sustainable β-cell restoration, possibly by modulating the macrophage phenotype. Our results offer a preferable therapeutic strategy for T2D.

Improved survival of AML patients by addition of cladribine to standard induction chemotherapy.

One hundred and eight consecutive acute myeloid leukemia (AML) patients aged 60 or less treated with two different induction regimens were retrospectively analyzed. Induction regimen for the first 50 consecutive patients was DA3+7, and the following 58 patients received cladribine 5mg/m2 on days 1 through 5 in addition to DA3+7 (DAC). There were no significant differences in the median age and the proportion of patients with unfavorable characteristics between the two groups. Remission after induction chemotherapy was achieved in 30/50 (60%) patients in DA3+7 and in 46/58 (79%) in DAC group (p = 0.028). The median survival in the DA3+7 group was 18months, while in the DAC group it was not reached (p = 0.034). We confirmed results from other research groups by demonstrating improved remission induction rate and overall survival of AML patients aged 60years or less treated with DAC induction compared with standard DA3+7 induction chemotherapy.

Use of sofosbuvir based regimen in patients with end-stage renal disease and chronic hepatitis C; an open label, non-randomized, single arm, single center study from Pakistan.

we aimed to determine the virological response and safety of Sofosbuvir-based direct-acting antiviral agents (DAAs) in chronic hepatitis C (CHC) patients on long-term hemodialysis (HD). With the advent of interferon-free DAAs, the treatment of CHC has been revolutionized. Pakistan is among the countries where novel sofosbuvir (SOF)-free antiviral agents are not available. This non-randomized, single-arm, open-label study enrolled all HD patients with chronic HCV infection after informed consent. They were treated with SOF in combination with Ribavirin (RBV) with either interferon (IFN group) or daclatasvir (DAC group), with the virological response assessed according to standard guidelines. Data were analyzed using SPSS version 20.00. Out of 133 patients, the majority (72.9%) were males with the mean age of 31.92 ± 9.88 years. Most patients (50.3%) had HCV genotype (GN) 1, followed by GN 3 in 42.9%, 4 in 1.48% and 2 in 0.7%, while mix GN was documented in 6 (4.4%) patients. Among these, 60 (45.1 %) patients received standard SOF, IFN, and RBV (IFN group) and 73 (54.9 %) received SOF, DAC and RBV (DAC group). End of treatment and sustained virological response at 12 weeks post-treatment were achieved in 133 (100%) and 129 (97 %) patients, respectively. The adverse effects were anemia in 58 (43.6 %) patients and elevated alanine transaminases in 11 (8.1%) patients. SOF in combination with either IFN or DAC is an equally efficacious and effective treatment regimen for patients on maintenance HD, especially in resource-poor countries.

Efficacy and Safety Evaluation of Elderly Patients with AML Based on Clinical Common Chemotherapy Regimens Under Real-World Events

Objective: To investigate the efficacy and safety of common clinical chemotherapy regimens in the treatment of elderly patients with AML, and to explore the effects of age stratification, gene mutation and leucocyte stratification on the survival of elderly patients with AML. Method: Part I: Collect all the literature published to January 2019 on the efficacy and adverse reactions of "3+7" regimen in the treatment of elderly AML patients compared with "3+7" regimen, or decitabine(DAC) combined with pre-excitation regimen. Evidence-based evidence is obtained by evaluating the efficacy and adverse reactions of "3+7" regimen compared with DAC regimen, pre-excitation regimen and DAC combined with pre-excitation regimen, respectively. The difference of efficacy and adverse reactions between the above schemes was confirmed. Part II: Retrospective analysis of clinical data of 90 elderly patients with AML (non-M3) hospitalized in the Department of Hematology, Sichuan Provincial People's Hospital from January 31, 2015 to January 31, 2019. These patients were divided into "3 + 7" group, the DAC group, and the DAC combined with the pre-excitation group according to the chemotherapy regimen. Complete response rate, partial response rate, and overall survival of each group were compared to evaluate the efficacy response. And explore the effects of genetic mutation, risk stratification, age stratification, ECOG score, white blood cell stratification on the survival of elderly AML. Results: Part I: A total of 12 articles were included, including 1715 elderly patients with AML. Through subgroup analysis, the results showed that the "3+7" regimen was superior to the DAC regimen in terms of CR; the infection of the "3+7" chemotherapy regimen was higher than that of the pre-excitation regimen. The mortality rate of "3+7" group was higher than that of pre-excitation group. Part II: The study included 90 patients, "3+7" group included 42 patients, DAC group included 12 patients, DAC combined pre-excitation group included 36 patients. In the three groups, the CR rate of the "3+7" chemotherapy group was 61.9%; the CR rate of the DAC group was 58.3%, while DAC combined with HAG or CAG treatment was 52.8%(P&gt;0.05). In low risk group, the CR rate of the "3+7" chemotherapy regimen was 75%, the DAC group was 60%, while DAC+HAG/CAG was 75% (P=0.401). But the DAC+HAG/CAG group showed a survival advantage compared with the "3+7" group. There was no significant difference in survival between patients with FLT3-ITD mutations compared with those who without mutations. The OS of patients between 60 to 65 years were significantly better. The white blood cells were divided into &lt;30×10^9/L group, 30-50×10^9/L group, 50-100×10^9/L group, and there was no difference in CR and OS in the group. About the time of neutropenia, the "3+7" chemotherapy regimen lasted for 15 (2-23) days, the DAC group was 11 (8-22) days, and the DAC+HAG/CAG was 16 (8-36) days, the difference between groups was between the DAC group and the DAC combined pre-excitation group (P=0.031). About platelet recovery time, "3+7" chemotherapy regimen lasted 12.5 (2-23) days, while DAC group lasted 11 (8-20) days and DAC+HAG/CAG group lasted 8 (5-16) days. Statistical differences could be observed in platelet recovery time between DAC group and DAC combined pre-excitation group (P=0.017). Lung infection rate was 83.3% in the "3+7" group, 77.8% in the DAC combined pre-excitation group, and the DAC group infection rate was 73.8%. 83.3%. Conclusion: Compared with other age groups, patients aged 60-65 have survival advantages. DAC-based drugs are more beneficial to patients than 3+7 chemotherapy. OS of patients without poor prognosis genome was significantly better than those with three or more poor prognosis genomes, while FLT3-ITD mutation had little effect on OS of elderly AML patients. The prognosis of patients with hyper-leucocyte is worse than that of patients without hyper-leucocyte, but WBC count has little effect on the long-term survival of patients with non- hyper-leucocyte. DAC group had obvious inhibitory effect on megakaryocytes. Disclosures Zheng: Pfizer: Research Funding.

Successful Treatment of Chimeric Antigen Receptor T Cell Therapy in Refractory or Relapsed Acute Leukemia Patients with TP53 alterations

Backgrounds: Refractory or relapsed(R/R) acute leukemia (AL) patients with TP53 alterations have a dismal outcome with current therapy. Recently, chimeric antigen receptor T cells (CAR-T) therapy has emerged as a novel immunotherapy modality in treating patients with R/R acute B lymphocytic leukemia (B-ALL) patients, with consistently high response rates and durable remissions and even cures across multiple studies. However, successful treatment of CAR-T therapy in R/R AL with TP53 alterations has been a challenge. Here, we conducted a phase II trial testing efficacy and toxicities of CAR-T therapy in R/R AL patients with TP53 alterations. Methods: The second generation CAR-T cells were successfully made from 9 patients' autologous lymphocytes and 2 donors' allogeneic lymphocytes and qualified tests were done before infusion to patients. CAR constructs used were humanized CAR targeting CD19, CD22 or tandem CD19 and CD22 according to the expression levels of each target on blasts. In this ongoing trial, 11 R/R AL patients with TP53 alterations (10 with TP53 mutations and 1 with TP53 deletions) including 2 relapsed after allo- allogeneic hematopoietic stem cell transplantation were included to evaluate the efficacy and safety of CAR-T therapy. Among the enrolled 11 R/R patients, 9 patients were diagnosed with B-ALL, 1 was diagnosed with acute myeloid leukemia (AML) and 1 was diagnosed with mixed phenotype acute leukemia (MPAL) (B-ALL and AML). After leukapheresis, all patients received fludarabine-based lymphodepletion chemotherapy with FLAG regimen (Fludarabine 30mg/m2 × 5d, Cytarabine 2g/m2 × 5d and Granulocyte-colony stimulating factor 300ug ×6d) in two cases, FC regimen (Fludarabine 30mg/m2 × 3d and Cyclophosphamide 300mg/m2 × 3d) in five cases, and FC+DAC regimen (Decitabine 50mg × 3d, Fludarabine 30mg/m2 × 3d and Cyclophosphamide 300mg/m2 × 3d) in four cases. Two days after chemotherapy, autologous/allogeneic CAR-T cells were infused within 2 to 4 days in a dose-escalation. Results: With a median (range) dose of 1×107/kg (0.1-1.5×107/kg) CAR-T cells, we observed a high response rate with 10/11 (90.9%) evaluated R/R patients achieved complete remission (CR) and 9/11 (81.8%) patients achieved molecular CR (mCR). Moreover, Most cases (8/11, 72.7%) only experienced mild to moderate cytokine release syndrome (CRS) and no neurological toxicity were observed. With a median follow-up of 10 months, 3 cases died of progressive disease including 1 case failed to response to CAR-T therapy, 1 case achieved CR and relapsed after CAR-T therapy and 1 case achieved mCR after CAR-T therapy and relapsed after the following allo-HSCT, and the left 8 cases still kept in mCR and alive. The one-year overall survival (OS) and leukemia-free survival (LFS) rates were 68.4% and 78% respectively. The 2-year cumulative incidence of relapse was 22.2%, and the non-relapse mortality rate was 0%. Further subgroup analysis showed that all 6 cases who received decitabine therapy (DAC group) achieved and maintained in mCR, while only 2 cases achieved and kept in mCR and 3 cases died from progressive disease in the cases without receiving decitabine therapy (Non-DAC group). The median OS and LFS for Non-DAC group was 10 and 16.375 months respectively, while the median OS and LFS for DAC group were unreached. Relative IL-6 and CRP levels increased dramatically in DAC group than that in Non-DAC group. However, there were no significant difference on treatment related toxicities between cases in DAC group and Non-DAC group. Conclusions: Our trial indicates that CAR-T therapy is a safe and powerful salvage approach to R/R AL patients with TP53 alterations and application of decitabine may fuel CAR-T therapy and reduce the relapse rate without increasing therapy related mortality incidences in this high risk population. Disclosures No relevant conflicts of interest to declare.

Decitabine As Part of a Modified Bu-Cy Conditioning Regimen Significantly Improved the Outcome of High-Risk AML Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background :Relapse remains a major cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially in patients with high-risk acute myeloid leukemia (AML). Therefore, how to eradicate the minimal residual disease and prevent of relapse are of great importance to improve the outcome of allo-HSCT for these high risk AML patients. M ethods :We retrospectively investigated decitabine (DAC) as part of a modified Bu-Cy regimen for high-risk AML patientsundergoing allo-HSCT. Fifty-nine patients received DAC (20 mg/m2/d,i.v.) for 5 days, followed by modified Bu-Cy (DAC group). A control (CON) of 177 patients (pair-matched 1:3) received modified Bu-Cy only. Results:Median follow-up was 402 (85-1504) days. There was no difference in graft versus-host disease occurrence. Treatment-related mortality (day 100) was 0% (DAC) and 6.2% (CON). The DAC group had better 2-year overall survival (OS, 77% versus 64%, P=0.018) and leukemia-free survival (LFS, 73% versus 56%, P=0.007). The differences were more substantial among patients with active disease: OS, 83% (DAC) versus 47% (CON), P=0.01 and LFS, 77% (DAC) versus 34% (CON), P=0.002. Median time to relapse was 187 days (DAC) versus 86 days (CON) and two-year relapse rates were 10% (DAC) and 49% (CON) for patients with active disease. Patients with cytogenetic monosomy 7 or 7q- abnormality responded better. Conclusions: Our data indicate that novel conditioning regimen containing DAC may be an effective and well-tolerated strategy and confer a subgroup-specific survival advantage in high-risk AML patients undergoing allo-HSCT. Disclosures No relevant conflicts of interest to declare.