Azacitidine In Acute Myeloid Leukemia Research Articles

Efficacy of Venetoclax and Azacitidine in Acute Myeloid Leukemia Compared to Azacitidine Monotherapy: Real-World Experience.

The combination of venetoclax (VEN) and azacitidine (AZA) (VEN+AZA) leads to higher complete remission rates and longer overall survival (OS) in patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive combination chemotherapy. In practice, the doses of VEN and AZA are reduced at the attending physician's discretion to avoid adverse events; however, the impact of dose and duration reductions has not been fully clarified. We analyzed whether the efficacy was maintained with reduced VEN+AZA compared to AZA monotherapy in the real world. A total of 33 patients were included; 17 (10 newly diagnosed, 7 primary refractory or relapsed) received VEN+AZA, and 16 (7 newly diagnosed, 9 primary refractory or relapsed) received AZA. We analyzed complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, OS, and the incidence of adverse events. CR/CRi were achieved in 7/17 (41.2%) and 11/17 (64.7%) patients in the VEN+AZA group and 0/15 (0%) and 2/15 (6.7%) patients in the AZA group, respectively. The CR/CRi rate was higher in the VEN+AZA group than in the AZA group (p=0.001). OS was longer in the VEN+AZA group than in the AZA group (p=0.03), with a median of 506 days [95% confidence interval (CI)=234-585 days] and 208 days (95% CI=52-343 days), respectively. The doses of the VEN+AZA combination were reduced at the attending physician's discretion, resulting in a higher CR/CRi rate and longer OS than AZA monotherapy and is considered useful for AML in the real world.

Preclinical Efficacy of the Menin-KMT2A Inhibitor JNJ-75276617 in Combination with Venetoclax and Azacitidine in AML

Background: JNJ-75276617 is a highly selective and orally bioavailable small molecule targeting the menin- histone-lysine N-methyltransferase 2A (KMT2A) protein-protein interaction. Pharmacologic disruption of this interaction was previously shown to induce differentiation and block progression of KMT2A-r or NPM1c acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (ALL) in preclinical models (Kwon, ASH 2022). Small-molecule inhibitors including JNJ-75276617 are being explored clinically as a treatment for KMT2A- and NPM1-altered leukemias, which represent an area of high unmet medical need. Hypomethylating agents (e.g. azacitidine, decitabine) in combination with venetoclax have significantly improved clinical outcomes for AML patients and have become a preferred frontline treatment for AML patients ≥75 years of age, or who have comorbidities that preclude use of intensive induction chemotherapy. Although promising responses are seen in the frontline setting, unfortunately many patients relapse highlighting the need for better therapies and more effective combinations. JNJ-75276617 was previously shown to inhibit HOX/Meis1 stemness genes and induce differentiation genes in KMT2A- or NPM1-altered leukemic cells. Here, we evaluated whether JNJ-75276617, which induces differentiation followed by cell death, could enhance the mechanisms of action triggered by venetoclax plus azacitidine, which primarily drives apoptosis by displacing anti-apoptotic proteins. Results: JNJ-75276617 exhibited synergistic effects with venetoclax alone or in combination with azacitidine in AML cells bearing KMT2A-r in vitro. Proliferation assays in KMT2A-r MOLM-13 AML cells showed that doublet combination of JNJ-75276617 plus venetoclax induced a synergistic antiproliferative effect in vitro that was significantly increased when compared to JNJ-75276617 or venetoclax monotherapy. The triplet combination of JNJ-75276617 plus azacitidine and venetoclax further induced a synergistic antiproliferative effect that was significantly increased when compared to JNJ-75276617 monotherapy or the doublet combination of venetoclax plus azacitidine. In the disseminated KMT2A-r MOLM-13 model in mice, monotherapy treatment with JNJ-75276617 at 10 mg/kg and azacitidine at 2 mg/kg induced a significant ILS of 35% each compared to the vehicle control group (p<0.0001 each), while 6% ILS was observed for mice treated with 100 mg/kg venetoclax (p=0.0076). The combination of azacitidine plus venetoclax, resulted in a significant ILS of 53% compared to the vehicle control (p<0.0001). Doublet combination treatment with either JNJ-75276617 plus azacitidine or plus venetoclax resulted in a significant ILS of 106% or 256%, respectively, as compared to the vehicle control (p<0.0001 each). The JNJ-75276617 triplet combination with azacitidine plus venetoclax induced a significant ILS of 277%, as compared to the vehicle control group (p<0.0001). These results further showed that either the doublet combinations of JNJ-75276617 plus venetoclax or azacitidine, or the triplet combination provided a superior increase in survival as compared with the clinical standard regimen of azacitidine plus venetoclax (p<0.0001 each). In a disseminated NPM1c model (OCI-AML3), JNJ-75276617 doublet or triplet combination with azacitidine and venetoclax also yielded superior survival versus the standard azacitidine plus venetoclax regimen, however triplet efficacy seemed most strongly driven by JNJ-75276617. Conclusions: These studies suggest that the doublet combinations of either JNJ-75276617 plus venetoclax or azacitidine, or the triplet combination could potentially provide a beneficial treatment option for KMT2A- or NPM1-altered AML, and support the recently initiated clinical trial investigating JNJ-75276617 in combination with AML-directed therapies, including venetoclax and azacitidine (NCT05453903). JNJ-75276617 is also being clinically investigated as a monotherapy for R/R acute leukemia (NCT04811560).

Azacitidine Combined with Novel Flavonoid Derivative GL-V9 Demonstrated Synergistic Anti-Leukemia Effect in Acute Myeloid Leukemia By Targeting DDIT4/mTOR Signaling

Background Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of malignant progenitor cells and impaired cell differentiation. GL-V9, a nature compound derived from wogonin, has shown superior anti-tumor potential by inhibiting cancer cell growth. Azacitidine (AZA), a DNA hypomethylation agent, has demonstrated therapeutic efficacy against AML. In this study, we investigated the anti-leukemia effect and potential mechanism of AZA combined with GL-V9 in AML cells, aiming to provide evidence for future clinical treatment. Methods We employed Cell Counting Kit-8 (CCK-8) to assess cell viability, Annexin-V/PI staining followed by flow cytometry analysis to measure apoptosis. CalcuSyn analysis was used to evaluate the synergistic effect. RNA-seq was performed in U937 cells and differentially expressed genes (DEGs) were identified and subjected to KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. RT-qPCR and Western Blot were used to examine gene expression. Results Our results demonstrated significant cell proliferation arrest in U937 and MV4-11 cells treated with the combination of AZA and GL-V9, compared to the single drug ( Fig. 1A&B). CalcuSyn analysis showed a strong synergistic effect for the combination ( Fig. 1A&B). Similar results were also found in primary AML cells derived from 2 AML patients [patient 1 exhibited t(6;11) (q27;q23) chromosomal translocation, while Patient 2 presented with secondary AML, transformed from CMML (Chronic Myelomonocytic Leukemia) and featured ASXL1 and SRSF2 mutations] ( Fig. 1C&D). Moreover, AZA plus GL-V9 induced a substantial increase in cell apoptosis in U937 and MV4-11 cells compared to the single drug ( Fig. 1E&F). Consistently, the AZA+GL-V9 combination led to a notable increase in the protein level of Bax, BAD, BIM, and a decrease in BCL2 ( Fig. 1G). These data indicated the combination of AZA with GL-V9 has synergistic anti-leukemia effects in AML. To understand the underlying mechanisms of this synergy, we performed RNA-seq analysis in U937 cells, identifying 1385 and 586 DEGs (|log 2FC|≥2.0, P<0.05) upon AZA or GL-V9 treatment, respectively ( Fig. 2A). The mTOR signaling pathway exhibits prominent enrichment in the KEGG analysis of the overlapping DEGs between AZA and GL-V9 ( Fig. 2B). DDIT4, a negative regulator of mTOR emerged as one of the top DEGs in response to both AZA and GL-V9 treatment. Importantly, the AZA+GL-V9 treatment exhibited a higher expression level of DDIT4 compared to either drug alone and suppressed the phosphorylation of mTOR ( Fig. 2C). Additionally, the DDIT4 expression level was significantly decreased in AML patients, which derived from a public database (TCGA-AML, GSE13159)] ( Fig. 2D) and Zhongda Hospital (Nanjing, China) compared to the healthy controls ( Fig. 2E). To be noticed, high DDIT4 expression was associated with extended overall survival (P=0.021) ( Fig. 2F) and relapse-free survival (P=0.015) ( Fig. 2G), indicating DDIT4 may act as a tumor suppressor in AML. These findings suggested that the combination may exert the anti-leukemia effect by targeting the DDIT4/mTOR signaling pathway, as summarized in Fig. 2H. Conclusions Our study provides novel evidence of the synergistic effect on cell growth arrest and apoptosis treated with a new nature compound derived from wogonin combined with AZA in AML. Furthermore, we identified the mechanism underlying the synergy through targeting of DDIT4/mTOR signaling. These results offer preliminary support for the potential application of this combination therapy in treating AML patients.

The Benefit of Venetoclax + Azacitidine in Acute Myeloid Leukemia

The Benefit of Venetoclax + Azacitidine in Acute Myeloid Leukemia

Acquired resistance to venetoclax plus azacitidine in acute myeloid leukemia: In vitro models and mechanisms

The combination of venetoclax (VEN) and azacitidine (AZA) has become the standard of care for acute myeloid leukemia (AML) patients who are ≥ 75 years or unfit for intensive chemotherapy. Though initially promising, resistance to the combination therapy is an issue and VEN + AZA-relapsed/refractory patients have dismal outcomes. To better understand the mechanisms of resistance, we developed VEN + AZA-resistant AML cell lines, MV4-11/VEN + AZA-R and ML-2/VEN + AZA-R, which show > 300-fold persistent resistance compared to the parental lines. We demonstrate that these cells have unique metabolic profiles, including significantly increased levels of cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP), changes in fatty acid and amino acid metabolism and increased utilization and reliance on glycolysis. Furthermore, fatty acid transporter CD36 is increased in the resistant cells compared to the parental cells. Inhibition of glycolysis with 2-Deoxy-D-glucose re-sensitized the resistant cells to VEN + AZA. In addition, the VEN + AZA-R cells have increased levels of the antiapoptotic protein Mcl-1 and decreased levels of the pro-apoptotic protein Bax. Overexpression of Mcl-1 or knockdown of Bax result in resistance to VEN + AZA. Our results provide insight into the molecular mechanisms contributing to VEN + AZA resistance and assist in the development of novel therapeutics to overcome this resistance in AML patients.

Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia.

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.

Synergistic Anti-Tumor Effect on Novel Combination of Selinexor with Azacitidine in AML By Targeting XPO1/eIF4E/C-MYC Signaling

Background: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with high mortality and poor outcome. Highly effective therapy options are always needed for AML. Selinexor (KPT-330) is an oral bioactive selective CRM1 (XPO1) inhibitor, and the clinical trial showed the combination of KPT-330 over standard induction therapy benefits much for AML patients. Azacitidine (AZA), a DNA hypomethylation agent, can induce cell apoptosis and exhibit potential therapeutic efficacy against AML. However, it has not yet determined the anti-tumor effect of KPT-330 with AZA in AML. Here we examined the anti-leukemia effect and potential mechanism of KPT-330 combined with AZA in AML cells to provide evidence for further clinical trials. Methods: A total of 64 AML patients’ BM samples and 64 normal control from healthy volunteers were obtained from Zhongda Hospital Southeast University, in which the 2 patients’ samples were further treated with indicated drugs in vitro. Cell Counting Kit-8 (CCK-8) was used for cell viability assay, Annexin-V/PI staining following flow cytometry analysis for apoptosis, and qPCR and Western Blot for gene expression in AML cell lines and patient samples. CalcuSyn analysis was performed for a synergistic effect. RNA-seq was performed in U937 cells treated with 0.7uM AZA for 48 hrs, and the significantly differentially expressed genes (DEGs) were identified and gene set enrichment analysis (GSEA) was performed. Results: Cell proliferation arrest and apoptosis were significantly observed in U937 and MV4-11 cells treated with the combination of KPT-330 with AZA compared to single drug control (data not shown). Then, we further explored the synergistic effect of the combination in patients’ samples. Results showed that cell growth arrest and apoptosis significantly increased in primary samples from two de novo AML patients compared to the single drug controls, and CalcuSyn analysis showed a synergistic effect of the combination on cell growth arrest (Fig. 1A &1B). To understand the mechanisms underlying the synergy, RNA-seq analysis was performed in U937 cells treated by 0.7uM AZA and 4655 DEGs were identified. XPO1, eIF4E, and MYC are in the top DEGs upon AZA treatment, and GSEA analysis indicated MYC_TARGETS and apoptosis pathway are enriched in DEGs (Fig. 1C &1D ). Moreover, the mRNA level of XPO1 and eIF4E was increased in our AML patient cohort compared with healthy controls (Fig. 1E), and the high expression of XPO1 or elF4E are associated with poor outcome (Fig. 1F). XPO1 is the key component of nuclear-exporting machinery; elF4E, the cargo of XPO1 is translation initiation factor and plays a critical role in translational machinery, which regulates the C-MYC translation. It is also reported that AZA regulates the transcription of C-MYC by affecting methylation. We observed a combination of KPT-330 with AZA significantly down-regulated the mRNA and protein level of oncogene eIF4E and C-MYC in two of the patients’ samples compared to single drug controls (Fig. 1G &1H ). Also, C-MYC knock-down was not only significantly increased the apoptosis in U937 cells compared to scramble shRNA (shCTL) control, but also significantly enhanced the combination-mediated apoptosis compared to that of single drug control in U937 cells (Fig. 1I). these data indicated that XPO1/eIF4E/C-MYC signaling plays critical roles in the combination-mediated anti-leukemia, and the mechanistic model is summarized in Fig.1J. Conclusions: Our data for the first time showed the synergistic effect of a novel combination of KPT-330 with AZA on cell growth arrest and apoptosis in AML patients and also identified the underlying mechanism by targeting XPO1/eIF4E/C-MYC signaling. Our results also highlighted the feasibility of the clinical trial for the combination in the therapy of AML patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-world effectiveness of CPX-351 vs venetoclax and azacitidine in acute myeloid leukemia

AbstractCPX-351 and venetoclax and azacitidine (ven/aza) are both indicated as initial therapy for acute myeloid leukemia (AML) in older adults. In the absence of prospective randomized comparisons of these regimens, we used retrospective observational data to evaluate various outcomes for patients with newly diagnosed AML receiving either CPX-351 (n = 217) or ven/aza (n = 439). This study used both a nationwide electronic health record (EHR)-derived de-identified database and the University of Pennsylvania EHR. Our study includes 217 patients who received CPX-351 and 439 who received ven/aza. Paitents receiving ven/aza were older, more likely to be treated in the community, and more likely to have a diagnosis of de novo acute myeloid leukemia. Other baseline covariates were not statistically significantly different between the groups. Median overall survival (OS) for all patients was 12 months and did not differ based on therapy (13 months for CPX-351 vs 11 months for ven/aza; hazard ratio, 0.88; 95% confidence interval, 0.71-1.08; P = .22). OS was similar across multiple sensitivity analyses. Regarding safety outcomes, early mortality was similar (10% vs 13% at 60 days). However, documented infections were higher with CPX-351 as were rates of febrile neutropenia. Hospital length of stay, including any admission before the next cycle of therapy, was more than twice as long for CPX-351. In this large multicenter real-world dataset, there was no statistically significant difference in OS. Prospective randomized studies with careful attention to side effects, quality of life, and impact on transplant outcomes are needed in these populations.

Cost-effectiveness analysis of azacitidine maintenance therapy in patients with acute myeloid leukemia

ABSTRACT Background The QUAZAR AML-001 trial (NCT01757535) showed survival benefits with the maintenance treatment of oral azacitidine(CC-486) for acute myeloid leukemia(AML) in first complete remission. We conducted a cost-effectiveness analysis to explore the costs and benefits of oral azacitidine in AML. Methods We constructed a Markov model to evaluate the economic value of oral azacitidine. The time horizon was 10-years. The health utility scores and until prices of medical costs were acquired from previous studies and GoodRX. The transition probabilities were derived from the survival curves of the QUAZAR AML-001 study. Outcomes were measured in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Results Compared with placebo, oral azacitidine improved 0.39 QALY, with an increasing cost of $458,928.66. The ICER of oral azacitidine is $1,176,740.15(P < 0.05). Deterministic sensitivity analysis showed that the price of oral azacitidine has a significant impact on ICERs (P < 0.05). Probability sensitivity analysis showed that the probability of cost-effectiveness for oral azacitidine is 0. Conclusion In the United States, oral azacitidine is unlikely to be cost-effective for AML patients at current prices. Clinical trial registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT01757535)

Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience

目的探究维奈克拉联合阿扎胞苷（Ven+AZA）在初治不适合强化疗（unfit）及难治（≥1次强化诱导化疗未缓解）/复发（R/R）急性髓系白血病（AML）患者中的近期疗效。方法回顾性分析北京大学血液病研究所2019年6月1日至2021年5月31日接受Ven+AZA治疗（Ven 100 mg第1天、200 mg 第2天、400 mg第3～28天；阿扎胞苷75 mg/m2第1～7天）的初治unfit及R/R AML患者60例。分析各组完全缓解/血细胞计数未完全恢复的完全缓解（CR/CRi）率、微小残留病（MRD）转阴率及总体反应率（ORR）。结果60例初治 unfit及R/R AML患者，中位年龄54（18～77）岁，男性33例（55.0％），中位随访时间4.8（1.4～26.3）个月。其中初治unfit患者24例（40.0％），R/R患者36例（60.0％）。初治unfit组及R/R组中位治疗疗程均为1（1～5）个。24例初治unfit患者（依据NCCN预后分层：低危8例、中危2例、高危14例）经第1疗程Ven+AZA治疗后，17例（70.8％）达CR/CRi，3例（12.5％）达部分缓解（PR），ORR为83.3％。其中9例患者接受第2疗程治疗，2例接受第3疗程治疗。17例CR/CRi患者中8例（47.1％）经2个疗程治疗后MRD转阴。36例R/R患者经第1疗程诱导治疗后，21例（58.3％）达CR/CRi（其中7例MRD转阴，占33.3％），3例（8.3％）PR，ORR为66.7％。R/R患者中12例治疗≥2个疗程，第2疗程治疗后无新增缓解患者，累计MRD转阴14例（66.7％）。R/R患者中低危组（CR至血液学复发≥18个月）12例，其余24例为高危组。低危R/R组1个疗程后10例（83.3％）达CR/CRi，CR/CRi率显著高于高危R/R组［45.8％（11/24），P＝0.031］。在60例患者中，13例伴IDH1/2突变及4例TP53阳性患者经1个疗程治疗后均达CR/CRi，18例NPM1突变阳性患者1个疗程CR/CRi率为77.8％，5例RUNX1-RUNX1T1伴c-kit D816患者（2例初诊，3例复发）均未获缓解。Ven+AZA作为诱导及再诱导治疗总体耐受性好。结论Ven+AZA在初治unfit及R/R AML患者中均获得较高的治疗反应率，部分缓解患者可快速获得MRD转阴。其在伴NPM1、IDH1/2、TP53等基因突变的AML患者中疗效显著。

Ex Vivo Drug Sensitivity Testing to Predict Response to Venetoclax + Azacitidine in Acute Myeloid Leukemia: Interim Results of the Prospective Multicenter Phase II Venex Trial

Ex Vivo Drug Sensitivity Testing to Predict Response to Venetoclax + Azacitidine in Acute Myeloid Leukemia: Interim Results of the Prospective Multicenter Phase II Venex Trial

Safety and Short-Term Efficacy of Venetoclax Combined with Azacitidine in Acute Myeloid Leukemia: A Single Institution Experience

IntroductionThe oral anti-apoptotic B-cell lymphoma 2 protein inhibitor (venetoclax) combined with hypomethylating agents (azacitidine) has shown promising activity in patients with acute myeloid leukemia (AML). However, there are no single center real-world research results with relatively large sample size in China. The purpose of this study is to explore the safety and short-term efficacy of venetoclax combined with azacitidine (Ven + AZA) in previously untreated patients who were ineligible for standard chemotherapy and patients with relapsed/refractory (R/R) AML in China.MethodsA retrospective study was conducted on 60 previously untreated patients who were ineligible for standard chemotherapy and patients with R/R AML who received Ven + AZA (venetoclax，100mg D1、200mg D2、400mg D3-28；azacitidine, 75mg/m2 D1-7) in the Peking University Institute of Hematology from March 15, 2019 to May 20, 2021. The incidence of adverse events (AE), complete remission (CR)/CR with incomplete hematological recovery (CRi) rate, objective remission rate (ORR) and minimal residual disease (MRD) status in patients with different risk stratification and different gene subtypes were analyzed.ResultsPatient CharacteristicsThe median age was 54 (18-77) years, 33 males (55.0%), and the median follow-up time was 4.8 (1.4-26.3) months. Among the 60 patients, 24 (40.0%) were previously untreated patients who were ineligible for standard chemotherapy and 36 (60.0%) were R/R patients. The median cycles of Ven + AZA in the two groups were both 1 (1-5). The median follow-up time of them were 2.9 (1.5-13.2) and 118 (1.4-26.3) months, respectively.In the previously untreated patients who were ineligible for standard chemotherapy, 2 were over 75 years old, 16 cases were diagnosed with active infection, 6 had organ dysfunction. According to the risk stratification of NCCN, it was divided into 8 cases of favorable-risk, 2 cases of intermediate-risk and 14 cases of poor-risk. According to the time from CR to hematological recurrence, the R/R group was divided into 12 cases in the favorable-risk group (CR to hematological recurrence ≥18 months) and 24 cases in the poor-risk group (CR to hematological recurrence <18 months, no remission after 1 cycle of therapy, no remission after ≥2 cycles of therapy).EfficacyIn the previously untreated patients who were ineligible for standard chemotherapy, after the first cycle of Ven + AZA treatment, 17/24 (70.8%) cases achieved CR/CRi, 3/24 (12.5%) cases achieved partial remission (PR), and the ORR was 83.3%. Among the CR/CRi patients, 8/17 (47.1%) achieved MRD negative after 2 cycles of therapy. Four patients achieved CR/CRi after the first cycle of Ven + AZA, ineligible factors (active infection) were eliminated, followed by chemotherapy, and MRD achieved negative after 1-2 cycles of consolidation therapy.The median duration of induction therapy in R/R group was 28 (14-28) days, and the total CR/CRi rate was 58.3%. 11/24 (45.8%) cases achieved CR/CRi after one cycle of Ven + AZA in the poor-risk R/R group, and 10/12 (83.3%) cases achieved CR/CRi in the favorable-risk R/R group, which was significantly superior than that in the poor-risk group (P = 0.031). The efficacy in patients with different risk stratification and gene subtypes are displayed in Table.SafetyThe incidence of hematological AEs was 100%, and the incidence of neutropenic fever was 40.0% (24/60). The incidence of grade 3-4 leukopenia was 86.7% (52/60), of which 60.0% (36/60) occurred before therapy, and the incidence of grade 3-4 leukopenia caused by therapy was 26.7% (16/60). The incidence of grade 3-4 anemia was 71.7% (43/60), of which 51.7% (31/60) occurred before therapy, and the incidence of grade 3-4 anemia caused by therapy was 20.0% (12/60). The incidence of grade 3-4 thrombocytopenia was 76.7% (46/60), of which 60.0% (36/60) occurred before therapy, and the incidence of grade 3-4 thrombocytopenia caused by therapy was 16.7%. The most common non hematological AE was infection, followed by gastrointestinal AE. Infection mainly included pneumonia (13.3%) and soft tissue infection (6.7%), both of which were grade 3-4.ConclusionVen + AZA has acceptable safety in previously untreated patients who were ineligible for standard chemotherapy and patients with R/R AML, can achieve a high response rate, and some patients can achieve MRD negative in China. It is effective in patients with NPM1, IDH1/IDH2 and TP53 positive. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison Between Decitabine and Azacitidine for Patients With Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndrome: A Systematic Review and Network Meta-Analysis.

Background: The hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) have been widely used in patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (HR-MDS). However, few direct clinical trials have been carried out to compare the efficacy and adverse events (AEs) between these two agents. The clinical choice between them is controversial. A systematic review and network meta-analysis (NMA) was performed to compare the efficacy, safety, and survival of DAC and AZA in AML and HR-MDS patients.Methods: We systematically searched MEDLINE, Embase, Web of Science, and Cochrane Library through March 15, 2021. Randomized controlled trials (RCTs) on AML or HR-MDS patients comparing the efficacy and safety between DAC and AZA or comparing one of HMAs to conventional care regimens (CCR) were selected.Results: Eight RCTs (n = 2,184) were identified in the NMA. Four trials compared AZA to CCR, and four compared DAC to CCR. Direct comparisons indicated that, compared to CCR, both AZA and DAC were associated with higher overall response (OR) rate (AZA vs. CCR: relative risk (RR) = 1.48, 95% CI 1.05–2.1; DAC vs. CCR: RR = 2.14, 95% CI 1.21–3.79) and longer overall survival (OS) (AZA vs. CCR: HR = 0.64, 95% CI 0.50–0.82; DAC vs. CCR: HR = 0.84, 95% CI 0.72–0.98), and AZA showed higher rate of complete remission with incomplete blood count recovery (CRi) (HR = 2.52, 95% CI 1.27–5). For the indirect method, DAC showed a higher complete remission (CR) rate than AZA in patients with both AML (RR = 2.28, 95% CI 1.12–4.65) and MDS (RR = 7.57, 95% CI 1.26–45.54). Additionally, DAC significantly increased the risk of 3/4 grade anemia (RR = 1.61, 95% CI: 1.03–2.51), febrile neutropenia (RR = 4.03, 95% CI: 1.41–11.52), and leukopenia (RR = 3.43, 95% CI 1.64–7.16) compared with AZA. No statistical significance was found for the other studied outcomes.Conclusion: Compared to CCR, both AZA and DAC can promote outcomes in patients with AML and HR-MDS. DAC showed higher efficacy especially CR rate than AZA (low-certainty evidence), while AZA experienced lower frequent grade 3/4 cytopenia than patients receiving DAC treatment.

Early Results from a Biomarker-Directed Phase 2 Trial of Sy-1425 in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Demonstrate DHRS3 Induction and Myeloid Differentiation Following Sy-1425 Treatment

Early Results from a Biomarker-Directed Phase 2 Trial of Sy-1425 in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Demonstrate DHRS3 Induction and Myeloid Differentiation Following Sy-1425 Treatment

Hemophagocytic lymphohistiocytosis as an unexpected complication of Venetoclax+Azacitidine in Acute Myeloid Leukemia

Background: Venetoclax is a drug that targets BCL-2 protein in cancer cells, first approved for chronic lymphocytic leukemia, this drug has showed efficacy also in acute myeloid leukemia in non-intense chemotherapy candidates in combination with hypomethylating agents as azacitidine and decitabine. This scheme has shown efficiency in acute myeloid leukemia reporting overall response rate (CR) in 61% in untreated elderly patients combined with azacitidine or decitabine. Febrile neutropenia was reported in 30%, thrombocytopenia in 47%, and serious infections in 33%. Hemophagocytic lymphohistiocytosis (HLH) is an uncommon hematologic disorder caused by a proinflammatory state manifested by cytopenias and elevation of acute phase reactants; it is a severe complication of some diseases and to our knowledge it has never been reported secondary to venetoclax plus azacitidine. Early treatment is fundamental for success in HLH. Case series: Three cases of HLH secondary to venetoclax plus azacitidine have appeared in our medical group in patients treated for acute myeloid leukemia. One elderly woman and elderly men with previously untreated acute myeloid leukemia presented HLH with laboratory and bone marrow findings, both responded to dexamethasone plus ruxolitinib. The third case was documented in a male diagnosed with blast phase chronic myeloid leukemia who also responded to dexamethasone plus ruxolitinib. No patient died from HLH. Conclusion: Here we report three cases of patients with HLH after the treatment with azacitidine plus venetoclax. We suspect that the great effect of venetoclax in synergy with azacitidine can liberate enough proinflammatory cytokines in the medullar niche to induce HLH. Early recognition is vital for soon treatment and successful management of this potential complication.

Maintenance Therapy Improves AML Outcomes Regardless of MRD Status or Consolidation Cycles.

New data from the phase III QUAZAR AML-001 trial confirm the benefits of maintenance therapy with oral azacitidine in acute myeloid leukemia regardless of patients' minimal residual disease status or the number of consolidation cycles prior to study enrollment.

A Randomized Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy

A Randomized Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy

Efficacy, Safety, and Pharmacokinetics (PK) of Azacitidine (AZA) in Children and Young Adults with Acute Myeloid Leukemia (AML) in the Phase 2 AZA-AML-004 Trial

Efficacy, Safety, and Pharmacokinetics (PK) of Azacitidine (AZA) in Children and Young Adults with Acute Myeloid Leukemia (AML) in the Phase 2 AZA-AML-004 Trial

Abstract B009: The histone deacetylase inhibitor pracinostat and its metabolite SB991 are active as single agents and in combination with 5-azacitidine in acute myeloid leukemia cells

Abstract Background: Pracinostat (SB939) is a class I, II and IV histone deacetylase inhibitor (HDACi), currently in phase 3 in combination with azacitidine for acute myeloid leukemia (NCT03151408). We have reported its strong preclinical activity in lymphomas as a single agent and in combination with several targeted anti-lymphoma agents (AACR 2018, AACR 2019). Here we report the anti-proliferative activities of pracinostat and its primary metabolite SB991 as single agents and in combination with the demethylating agent 5-azacitidine in acute myeloid leukemia (AML) cell lines. Methods. To assess anti-proliferative activity cells were exposed to increasing doses of pracinostat, SB991 (Helsinn) and vorinostat (LC Laboratories) alone or in combination (pracinostat and SB991) with increasing doses of 5-azacitidine (Selleckchem) for 72h, followed by the MTT assay. The Chou-Talalay index was used to determine synergism. Combination indexes (CI) defined the following: additive effect (CI 0.9-1.1), synergism (CI 0.3-0.9) and antagonism (CI &amp;gt; 1.1).For apoptosis and cell cycle analyses cells were treated with 250 nM pracinostat for 72 hours. Results. HL-60 and MV-4-11 cells responded well to pracinostat with IC50 values of 362 nM and 93 nM, respectively. IC50 values obtained for SB991, the main metabolite of pracinostat, were 233 nM and 85 nM for HL60 and MV-4-11, respectively. These IC50 values compared well with those obtained for vorinostat, which equaled 710 nM for HL-60 and 205 nM for MV-4-11. Combination of pracinostat with 5-azacitidine showed synergism in both AML cell lines (CI = 0.51 for HL-60 and CI = 0.69 for MV-4-11). Combination of SB991 with 5-azacitidine achieved synergism in MV-4-11 cells (CI = 0.54) but was not beneficial in HL-60 cells (CI = 1.23). Pracinostat moderately induced apoptosis in HL-60 cells while MV-4-11 cells underwent massive apoptosis. Cell cycle analysis revealed marked G2/M arrest plus moderate accumulation of cells in the sub-G1 phase for HL-60 cells, which was in agreement with the moderate induction of apoptosis measured by Annexin V staining. Also in agreement with the apoptosis analysis, MV-4-11 cells treated with pracinostat all accumulated in the sub-G1 phase. Conclusions. Pracinostat and its main metabolite SB991 exhibited robust anti-proliferative activity as single agents in HL-60 and MV-4-11, comparing favourably with the FDA approved HDACi vorinostat. Pracinostat mediated its anti-proliferative action by inducing apoptosis and G2/M cell cycle arrest. Combination of pracinostat with 5-azacitidine enhanced its activity in AML cells. These results provide pre-clinical rationale for the ongoing phase 3 trials of pracinostat in combination with azacitidine in AML. Citation Format: Afua Adjeiwaa Mensah, Filippo Spriano, Eugenio Gaudio, Annalisa Bonifacio, Emanuela Lovati, Claudio Pietra, Francesco Bertoni. The histone deacetylase inhibitor pracinostat and its metabolite SB991 are active as single agents and in combination with 5-azacitidine in acute myeloid leukemia cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B009. doi:10.1158/1535-7163.TARG-19-B009

Phase I Study of Pracinostat in Combination with Gemtuzumab Ozogamicin (PraGO) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Background: Relapsed/Refractory AML (RR-AML) represents an area in urgent need for new treatments, particularly among patients ineligible for intensive chemotherapy. Newer options exist for AML with mutations involving IDH1, IDH2, or FLT3, but in AML without these mutations, only gemtuzumab ozogamicin (GO) is currently approved. GO is a calicheamicin-conjugated antibody directed against the CD33 antigen, commonly found on AML. Mechanistically, GO binds to the CD33 antigen on AML forming a complex which is internalized, resulting in intracellular delivery of calicheamicin, DNA double-strand breaks and cell death.GO recently received re-approval for patients with RR-AML on the basis of the Mylofrance-1 trial, which demonstrated a CR rate estimated at 26%. This clinical trial was designed to assess the safety of adding pracinostat, a histone deacetylase inhibitor (HDACi) to GO. Inhibition of histone deacetylases has been shown to induce an open chromatin structure and potentially restore transcription of critically silenced genes. In AML, single agent pracinostat has demonstrated potential anti-leukemic activity (Abaza et al. Cancer 2017). We hypothesize that, HDACi may mediate histone unwinding, a more open chromatin structure, and potentiate DNA-targeted delivery of calicheamicin within AML blasts. Further, pre-clinical data suggests HDAC inhibition could also increase CD33 expression in myeloid leukemia cells, thereby allowing for increased GO binding to AML blasts (ten Cate et al. Leukemia 2007). Previously, vorinostat, another HDACi, has been used in combination with GO and azacitidine in AML. While that trial reported limited efficacy, this trial will incorporate a fractionated GO dosing schedule, as well as the use of a more potent HDACi, both of which may improve efficacy. Study Design and Methods: This is a prospective, investigator-initiated, phase 1 clinical study that is aimed at determining the safety of pracinostat + GO (PraGO) combination in patients with R/R AML (ClinicalTrial.gov identifier NCT03848754). Secondary end points are to evaluate response rates, 6-month progression free survival (PFS) and overall survival (OS). Eligible patients are either aged ≥ 60 years with RR- AML to at least one line of therapy, or patients 18-59 years with RR-AML to at least two lines of intensive induction chemotherapy, or one line of therapy if deemed unsuitable for further intensive chemotherapy. Diagnosis of acute promyelocytic leukemia (APL), hematopoietic stem cell transplantation (HCT) within 60 days of enrollment, evidence of veno-occlusive disease (VOD) at any time post-transplant, or active graft versus host disease (GVHD) requiring systemic immunosuppressive therapy are major exclusion criteria. Patients will be enrolled into two potential dosing cohorts. Cohort 1 will receive pracinostat at 45mg orally, three times weekly for three weeks. GO will be administered at 3 mg/m2 on Days 1, 4, and 7. The first dose of GO will be administered two hours after the first pracinostat dose. Responding patients will subsequently receive maintenance with GO alone at 2 mg/m2 on Day 1. Up to 5 cycles of GO will be administered to responders. Cohort 2 will receive pracinostat at 60 mg orally, three times weekly for three weeks. GO administration will remain the same for induction. Responding patients in this cohort will be eligible for maintenance with pracinostat at 45 mg orally, three times weekly for three weeks. GO will still only be given D1 in each maintenance cycle. A standard 3+3 design will be utilized to determine escalation to Cohort 2. DLTs will be assessed during the 1st cycle only. The study schema is diagrammatically illustrated in figure 1. With the hypothesis that HDAC inhibition may lead to increased CD33 expression, RNA seq will be performed on blasts isolated on BM aspirate, pre- and post pracinostat treatment. Other potential antibody targets will also be assessed, including CD22 and CD38. To date, one patient has been enrolled. This 72 years old male with MPN/MF transformed to AML, refractory to CLAG (cladribine, cytarabine, G-CSF) induction. On study, he achieved a partial remission after 1st induction cycle (bone marrow blast from 20% --&gt; 6.4%), with normalization of counts albeit with very short follow up, no SAE or DLTs were observed. Figure 1 Disclosures Runaas: Agios: Honoraria; Blueprint Medicine: Honoraria. Michaelis:Novartis: Consultancy; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; Macrogeneics: Research Funding; Pfizer: Equity Ownership, Research Funding; ASTEX: Research Funding; Bioline: Research Funding; BMS: Research Funding; Celgene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Millenium: Research Funding; Janssen: Research Funding. Atallah:Helsinn: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy. Abedin:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria; Actinium Pharmaceuticals: Research Funding; Pfizer Inc: Research Funding; Helsinn Healthcare: Research Funding.