Unfavorable Cytogenetic Risk Research Articles

BCAR3 and BCAR3-related competing endogenous RNA expression in hepatocellular carcinoma and their prognostic value.

Hepatocellular carcinoma (HCC) is a malignant tumor that has a high incidence and mortality worldwide. Despite extensive studies, the detailed molecular mechanism of HCC development remains unclear. Studies have shown that the occurrence and development of HCC are closely related to abnormal gene expression. BCAR3 has been shown to be overexpressed in a variety of malignant tumors. However, the role of BCAR3 in HCC remains unclear. To investigate the expression of BCAR3 and BCAR3-related competing endogenous RNAs (ceRNAs) in HCC and their clinical significance, in order to provide new ideas for the diagnosis and treatment of HCC. The data of HCC were obtained from the Cancer Genome Atlas database and The Genotype Tissue Expression, including transcriptome data and clinical information. Multiple common databases, including UALCAN, Timer 2.0, cBioPortal, LinkedOmics, starBase, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, were used to analyse the expression of BCAR3, prognostic value, genetic alteration, co-expressed genes, differentially expressed genes, BCAR3 gene-related ceRNAs and functional enrichment analysis in HCC patients. Kaplan-Meier analysis, univariate and multivariate Cox regression analysis were used to analyze survival prognosis and the Spearman test was used to measure correlations between BCAR3 and immune functions. And R language package was used to analyze the correlation between BCAR3 and immune invasion of HCC. Our study indicated that BCAR3 was differentially expressed in various tumor tissues. The over-expression of BCAR3 gene was an unfavorable prognostic indicator for HCC patients, and associated with unfavorable cytogenetic risk and gene mutations. Moreover, most immune cells were positively correlated with BCAR3 (P < 0.05). According to the results of functional enrichment analysis, BCAR3 was involved in the positive regulation of epidermal growth factor receptor signaling pathway and ERBB signaling pathway, and was related to DNA replication and GTPase regulator activity. Finally, our study found that based on RAB30-DT and miR-19b-3p pathways, targeting BCAR3 might promote the occurrence and development of HCC. Collectively, this study indicated that the BCAR3 gene was involved in the occurrence and development of HCC, and it might be a new biomarker and therapeutic target for HCC, but the specific mechanism remains to be further verified.

Real-World Utilization of Daratumumab in Front-Line Treatment of Newly Diagnosed Multiple Myeloma: A Retrospective Observational Study

Introduction: Daratumumab (DARA), a CD38 monoclonal antibody, has demonstrated remarkable efficacy among newly diagnosed (ND) and relapsed/refractory multiple myeloma (MM) patients. The introduction of a quadruplet therapy with an addition of DARA per the GRIFFIN trial has improved the treatment paradigm. However, the real-world data on treatment patterns and utilization of DARA in front-line treatment are limited. This study aimed to evaluate the real-world utilization of DARA in front-line treatment and examine factors that may impact the utilization of DARA-based regimen in NDMM. Methods: We conducted a retrospective observational study of all patients, age ≥ 18, with clinical MM who were newly diagnosed and treated within the Yale New Haven Health (YNHH) system between August 1, 2020 and August 31, 2022. We manually reviewed clinical presentation, age at diagnosis, gender, race, ethnicity, Revised International Staging System (R-ISS) stage, Eastern Cooperative Oncology Group (ECOG) performance status (PS), insurance type, practice setting, immunoglobulin (Ig) isotype, hemoglobin (Hb), creatinine (Cr), and calcium (Ca) at diagnosis, presence of bone lesion, bone marrow plasma cell (BMPC) %, cytogenetic abnormalities, transplant eligibility, and treatment response based on the International Myeloma Working Group (IMWG) criteria at 3 months after front-line therapy. Descriptive statistics were performed with Pearson's χ²-test using GraphPad PRISM version 9.0.0. Results: We identified 241 patients with NDMM during the study period within the YNHH system. Overall median age at diagnosis was 69 years (interquartile range: 61-78). 60.2% (n=145) were male, 68% (n=164) identified themselves as white and 90% (n=217) as non-Hispanic. 51.9% (n=125) had R-ISS stage II and 65.6% (n=158) had ECOG PS of 0-1. 63.1% (n=152) were treated at a community practice setting and 53.9% (n=130) had commercial insurance. 55.6% (n=134) had IgG isotype and 41.1% (n=99) had unfavorable risk cytogenetics which was defined as a 17p deletion, t(4;14), t(14;16), t(14;20), gain or amplification of 1q, 1p deletion, and chromosome 1 translocations. 28.2% (n=68) received front-line quadruplet therapy: DARA+lenalidomide (LEN)+bortezomib (BORTE)+dexamethasone (DEX) (n=54), DARA+cyclophosphamide+BORTE+DEX (n=10), or DARA+LEN+carfilzomib (CARFIL)+DEX (n=4). 58.5% (n=141) received triplet therapy, 8.3% (n=20) received doublet therapy, 0.83% (n=2) received monotherapy, and 4.1% (n=10) opted for hospice care. 41.5% (n=100) received DARA in front-line treatment: quadruplet as above (n=68), triplet of DARA+LEN+DEX, DARA+BORTE+DEX, or DARA+CARFIL+DEX (n=31), and doublet of DARA+DEX (n=1). Factors including gender (male vs. female, p=0.018), practice setting (academic vs community, p=0.014), R-ISS stage (I vs II vs III vs unknown, p=0.003), Ig isotype (IgG vs IgA vs light chain vs other, p=0.006), cytogenetic abnormalities (standard risk vs unfavorable risk, p=0.02), and transplant eligibility (transplant eligible vs transplant ineligible, p=0.001) were associated with the adoption of DARA in front-line treatment. While 51.7% (n=46) of the patients treated at an academic practice setting received DARA in front-line treatment, only 35.5% (n=54) of the patients treated at a community practice setting received such treatment. 69% (n=69) of those who received DARA-based regimen in front-line treatment achieved at least a very good partial response (VGPR) at 3 months compared to 54.6% (n=77) of those who received non-DARA-based regimen. There were no significant differences in age, race, ethnicity, ECOG PS, insurance type, laboratory data (Hb, Cr, and Ca) at diagnosis, presence of bone lesion, and BMPC % between the group treated with DARA-based regimen and the group treated with non-DARA-based regimen. Conclusion: This analysis of real-world data from patients with NDMM highlighted underutilization of DARA in front-line treatment, especially at a community practice setting. Gender, practice setting, R-ISS stage, Ig isotype, cytogenetic abnormalities, and transplant eligibility were significantly associated with the adoption of DARA in front-line treatment. Additionally, utilization of DARA in front-line treatment was associated with a better treatment response at 3 months, suggesting that interventions to promote the utilization of DARA will help improve outcomes of NDMM patients.

Preliminary Results from a Phase 2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Cfi-400945 As a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (TWT-202)

Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase, Polo-like kinase 4 (PLK4). PLK4 is a highly conserved master upstream regulator of centriole duplication and is critical for maintenance of genomic integrity. Aberrant expression of PLK4 results in centrosome amplification, often seen in aneuploid cancers, pointing to a potentially causative role for PLK4 in genome instability and cancer progression. An investigator-initiated study using a 28-day continuous CFI-400945 dosing schedule at the Princess Margaret Cancer Center (PMCC) demonstrated clinical activity in AML [Murphy et al., 2020] and responses were seen in high-risk pts with adverse cytogenetics, including those with TP53 mutations. CFI-400945 was tolerated with clinically manageable toxicities and the dose limiting toxicity (DLT) was colitis. The recommended phase 2 dose was 96mg. A newer crystal form of CFI-400945 was introduced after the PMCC study. Consequently, the optimal dosing of CFI-400945, including as a combination agent, are not yet clinically defined and are the rationale for this study. Study Design and Methods: This study is a multi-part phase 1/2 study of CFI-400945 as a single agent and in combination with hypomethylating agents (HMA) (NCT04730258). For Part 1, pts with relapsed and/or refractory AML, MDS, or CMML after >1 prior therapy will be included. Pts with MDS or CMML must have progressed or had a lack of response after at least 4 cycles of hypomethylating agents. For Part 2, pts should have relapsed and/or refractory AML or untreated MDS or CMML. Untreated pts who decline or are ineligible for intensive therapy may be included. The study uses a standard 3 + 3 design, and the dosing schedule is 21 days on and 7 days off (28-day cycle) - this is to potentially avoid the colitis seen in the study at PMCC. The maximum tolerated dose (MTD) will be defined as the dose level where the number of dose-limiting toxicities (DLTs) is <1 out of 6 at highest dose level at or below the maximally administered dose. Pharmacokinetics (PK) and pharmacodynamic (PD) markers will be assessed. Results: As of the 30Jun22 data cut off, 9 pts had been enrolled into the study. Four (44%) pts had AML, 2 (22%) had MDS, 3 (33%) had CMML. The median number of prior therapies was 2 (range 1-4), and 2 (22%) pts had received a stem cell transplant. Six (66%) were male and the median age was 69 (range 22-75). Three of 4 AML pts had unfavorable risk cytogenetics by ELN 2017 criteria, and 2 pts (1 each with MDS, CMML) with TP53 mutations. Five pts received 32mg and 4 pts 48mg. There have been no DLTs. There have been 8 (89%) SAEs with the following occurring in >2 pts (febrile neutropenia (6 pts), pneumonia (2 pts)). Common treatment emergent adverse events (TEAE) in > 2 pts were febrile neutropenia 6 pts (67%), hypokalemia 5pts (56%), anemia and hypomagnesemia 4 pts each (44%), hypophosphatemia, diarrhea, abdominal pain, nausea, vomiting, dyspnea, peripheral edema 3 pts each (33%). Thirty-three percent (20 events, 3 pts) of the grade 3 or greater TEAE's were considered related to CFI-400945. There have been no CR or PR per ELN response criteria observed to date, however, there were 2 (50%) SD per IWG criteria at the 48 mg dose level (1-MDS, 1-CMML). Pharmacokinetic (PK) evaluations indicated that the mean terminal-life ranged from 7 - 10 hours. Low accumulation was observed after 21 days of daily dosing (AR <2-fold). In general, exposure in this study is overlapped with that observed in the PMCC study. PD studies evaluating the effect of CFI-400945 on markers of mitosis, ploidy, and centriole function are ongoing. Conclusion: CFI-400945 has been generally well tolerated and TWT-202 continues to enroll in Part 1. There have been no responses per ELN to date but there was SD in 2 pts (48 mg dose). Lack of DLTs suggest dose level is still suboptimal at time of submission. PK characteristics support daily dosing of CFI-400945 and PD studies are ongoing. Dose escalation continues in this study and updated data will be presented.

Efficacy and Safety of Tandem Autologous Stem Cell Transplantation in Multiple Myeloma: A Retrospective Single-Center Analysis in China

Background: The role of tandem autologous stem cell transplantation (ASCT) in multiple myeloma remains debatable, and data on tandem ASCT in China are limited. This study aimed to review the efficacy and safety of tandem ASCT in Chinese patients with myeloma. Methods: We performed a retrospective analysis of 50 patients with newly diagnosed multiple myeloma (NDMM) who underwent tandem ASCT between November 2014 and January 2021 in our center. Results: From the first transplant, the median progression-free survival (PFS) and overall survival (OS) in patients with NDMM were 52.4 months (95% confidence interval [CI]: 22.9-81.9) and not reached, respectively. There were no significant differences in PFS and OS based on sex, platelet count, hemoglobin, subtype, β2-microglobulin, renal function, ISS stage, R-ISS, cytogenetic risk, induction regimens, remission status pre-first transplant. Patients with initially elevated lactate dehydrogenase (LDH) levels or without maintenance therapy (MT) had worse PFS and OS. The LDH level was a predictor in univariate analysis but not in multivariate analysis for PFS (P = 0.775, HR 1.24, 95% CI 0.28-5.4) and OS (P = 0.112, HR 4.86, 95% CI 0.69-34.3). Multivariate analysis revealed that MT absence was an independent adverse factor for PFS (P = 0.003, hazard ratio [HR] 0.092, 95% CI 0.019-0.442) but not for OS. No transplant-related mortality was observed. Mucositis, engraftment syndrome, and infection were common but manageable complications. One patient developed acute lymphoblastic leukemia. Conclusion: Upfront tandem ASCT could overcome the adverse prognosis of ISS stages and unfavorable cytogenetic risk and could be performed feasibly and safely in patients with myeloma. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Epigenetic Landscape Predicts Overall Survival and Remission Duration in Adult Acute Myeloid Leukemia

INTRODUCTION: Epigenetic dysregulation is a hallmark of Acute Myeloid Leukemia (AML). Although recurrent epigenetic-related mutations have been identified, the understanding of how they affect pathophysiology and leukemogenesis remains incomplete. We used proteomics to assess the epigenetic landscape in AML and identified new prognostic phenotypes and therapeutic targets. METHODS: Using Reverse Phase Protein Array (RPPA) 405 proteins (327 total; 78 post-translational modified) were measured in 818 samples from newly diagnosed adult AML patients and normalized to CD34+ cells. These included Histone H3 total and H3K4Me 1, 2, 3, K9Me2, K27Me3, K27Ac and K36Me3 Modification Marks (HMM) expression. Categorical clinical variables were compared with Fisher's Exact with simulated p-values (10000 replicates), and continuous ones with Wilcoxon or Kruskal-Wallis tests. Univariate (UV) and Multivariate (MV) models for Overall Survival (OS) and Remission Duration (RD) were built with Cox proportional hazards model (CoxPH). Differentially Expressed Proteins were determined using the Kruskal-Wallis test (p<0.05) and pairwise Dunn's tests with p-values adjusted with the False Discovery Rate method (p<0.05). RESULTS: Using unbiased hierarchical clustering, patients were clustered into 4 groups (Fig. 1, C1 to C4) based on the expression of 2 Repressive HMM (H3K27Me3 and H3K9Me2), and 5 Activating HMM (H3K27Ac, H3K36Me3, H3K4Me3, H3K4Me2, H3K4Me1). High repression and low activation HMM were prominent in C1, while C4 had the opposite pattern. Higher expression of all marks and Total H3 defined C2, and C3 had lower expression of all marks, and Total H3. Importantly, when normalized by Total H3, HMM expression of both C2 and C3 are close to average, representing a chromatin state between C1 and C4. Compared to the other groups, patients in C4 were older (66yo vs 62yo; p=0.006), and had more secondary AML (55% vs 43%; p=0.007) and unfavorable cytogenetic risk (55% vs 37%; p<0.001). Mutations weren't exclusively associated with any cluster: ASLX1 and NPM1 mutants were more frequent in C1 and C2 (27% vs 13%; p<0.001; 23% vs 15%; p=0.015), WT1 more in C1 and C3 (9% vs 3.7%, p=0.018), and EZH2, PTPN11, RAS and RUNX1 happened more in C3 and C4 (7.7% vs 1.7%, p<0.001; 13% vs 5.6%, p=0.002; 26% vs 14%, p<0.001; 22% vs 14%, p=0.015). The effect of HMM expression on OS (Fig. 2) showed that patients with high repression and low activation (C1) did significantly better (Median OS (MS) = 19mo, Median RD (MRD)>102mo), and those with the opposite pattern of low repression and high activation (C4) did significantly worse (MS=7mo, MRD=16mo). Patients with an intermediary chromatin state were close to the average OS (C2: MS=14mo, MRD=20mo; C3: MS=12mo, MRD=24mo). In the UV CoxPH model, C1, C3 and C4 predicted OS (HR=1, 1.3, 1.4, 2.3; p=ref., 0.007, 0.001), as did age, secondary AML, complex karyotype, and CEBPA, FLT3, KIT, JAK2, NPM1, PTPN11, SRSF2 and TP53 mutations. In the MV model C1, C3 and C4 were again predictive for OS (HR=1, 1.5, 2.4, 2.7; p=ref., 0.003, 0.006), together with age, secondary AML, and PTPN11, SRSF2 and TP53 mutations. For RD, in the UV model, all clusters predicted RD (HR=1, 1.9, 1.8, 2.7; p=ref., 0.002, 0.005, 0.001), as did age, secondary AML, complex karyotype, and FLT3, NPM1, RUNX1 and TP53 mutations. In the MV model of RD, all clusters were predictors (HR=1, 1.8, 1.8, 2.7; p=ref., 0.045, 0.038, 0.003), together with age, complex karyotype and RUNX1 mutation. Differentially Expressed Proteins, from the other 397 proteins, for C4 revealed high activation of VEGF, ErbB and FcεRI signaling pathways, unveiling potential new druggable targets. CONCLUSION: HMM expression found that opposing chromatin states, with a more closed (C1) or open (C4) chromatin, significantly affected prognosis. Moreover, the epigenetic landscape was useful to predict OS and RD: compact chromatin equals high OS and RD (C1), and a loose one means poor OS and RD (C4), whereas an intermediary state (C2/C3) leads to average OS and RD. The expression pattern of the worst OS group showed high activation of specific signaling pathways which could be targeted to improve OS and RD. It would be worthwhile to correlate the findings with ATAC-seq, ChIP-seq, RNA-seq and DNA methylation analysis, in order to determine the loci responsible for the observed phenotypes in each cluster, and also WGS to identify possible new drivers of chromatin aberrations in AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TP53 and Complex Karyotype Represent a Very High-Risk Group in Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation: An International Collaborative Analysis

BackgroundTP53 mutations (TP53MT) have been associated with poor outcomes in various hematologic malignancies, but no data exist on its role in patients with myelofibrosis undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Although HSCT remains the only curative treatment for myelofibrosis and its numbers continue to increase worldwide, its inherent treatment-related morbidity and mortality make adequate patients counseling crucial. Here, we took advantage of a large international multicenter cohort to evaluate the role of TP53MT in this setting. Patients and Methods Clinical data on myelofibrosis patients undergone first HSCT in 7 US and European centers, with detailed information on cytogenetics and NGS-based TP53MT at the time of transplant were collected. Results Among 349 included patients, 49 (13%) had detectable TP53MT, of whom 16 showing a multi-hit configuration. Median variant allele frequency (VAF) was 20.3% (range, 2.9-97.6%). No difference in age at HSCT was noted in TP53MT carriers as compared to wild type cases (median 56 vs 57 years, respectively). Cytogenetic risk (Tefferi et al. 2018) was favorable (n=248, 71%), unfavorable (n=79, 23%), and very high (n=22, 6%) with complex karyotype present in 36 patients (10%). Accordingly, when compared to wild type cases TP53MT carriers were enriched in the unfavorable cytogenetic risk category (20% vs 39%, P=0.01) and, importantly, in patients with complex karyotype (7% vs 29%; P<0.001). No significant difference was observed between both groups when accounting for ontogenesis of myelofibrosis (primary vs secondary), blood counts, constitutional symptoms, nontransplant (DIPSS) and transplant-specific risk stratification (MTSS), co-occurring mutations such as driver mutations (JAK2, CALR, MPL), high-risk mutations (ASXL1, SRSF2, IDH1/2, EZH2) and mutational burden. With a median follow-up from HSCT of 5.8 years for the TP53MT and 9.2 years for the non- TP53MT group, the 6-year OS achieved 35% vs 64%, respectively (P<0.001). As a result, median OS was 1.5 years (95% confidence interval [CI], 0.3-2.8 years) for the TP53MT vs 13.5 years (95% CI, 9.2-17.8) for the wild-type group. When stratified according to TP53 status and clonal burden (VAF), 6-year OS was 45% for monoallelic vs 24% for multi-hit TP53MT carriers (P=0.25), and 46% vs 27% for VAF <20% and VAF >20%, respectively (P=0.21). Current cytogenetic risk stratification showed no discrete survival differences (P=0.59), whereas complex karyotype still impacted on post-HSCT outcomes, with a median OS of 1.9 years (95% CI, 0-4.2) in such setting vs 13.5 years in cases with other karyotypes (P<0.001). Of note, interaction test for TP53MT and complex karyotype was not significant (P=0.25). TP53MTcarriers showed also significantly higher 6-year cumulative incidence of relapse (35% [95% CI, 21-49%] vs 17% [95% CI, 13-21%]; P=0.001) when compared to the non-TP53MT group. A total of 19 TP53MT patients (39%) experienced post-HSCT relapse with 10 (20%) presenting as leukemic transformation vs only 7 (2%) in the non-TP53 group. Importantly, nor the rate nor the time to leukemic transformation differed according to the TP53MT type. Furthermore, nonrelapse mortality was not significantly different between the TP53MTand wild-type group (P=0.22). In terms of cytogenetics, again the current risk stratification failed to separate patients with different relapse risks (P=0.73), whereas 6-year cumulative incidence of relapse achieved 31% in cases harboring complex karyotype as compared to 19% in patients with other cytogenetic configurations (P=0.03). When adjusting in 2 models either for MTSS or DIPSS, TP53MTand complex karyotype were independently associated with worse OS, showing HR of 1.76 (95% CI, 1.14-2.74) or 2.10 (95% CI, 1.34-3.31) and 1.64 (95% CI, 1.00-2.66) or 1.84 (95% CI, 1.10-3.08), respectively. While MTSS maintained its significant power (P<0.001), DIPSS was not significantly associated with OS (P=0.70). In terms of relapse, TP53MT, complex karyotype, circulating blasts and increasing MTSS scores independently associated with post-HSCT outcomes. ConclusionTP53 and complex karyotype represent a very high-risk group in myelofibrosis undergoing HSCT, informing prognostication for OS. Importantly, these features may also facilitate patient counseling regarding relapse after HSCT, together with current transplant-specific tools.

A clinical case of the effective combined use of BCL-2 and PI3K inhibitors in the treatment of a patient with an unfavorable chronic lymphocytic leukemia with transformation into diffuse large B-cell lymphoma (Richter’s syndrome)

Understanding the molecular biological basis of chronic lymphocytic leukemia (CLL) pathogenesis and stratification of patients into risk groups has now led to significant advances in treatment. New targeted drugs with different mechanisms of action (bruton’s tyrosine kinase inhibitors, bCL-2 inhibitors, pI3K inhibitors) have significantly improved the prognosis of high-risk CLL patients. In some CLL cases the nodular tumor component can change to a more aggressive subtype of lymphoma (often diffuse large b-cell) with preservation of the small-cell leukemic component with the CLL phenotype (Richter’s syndrome), usually characterized by rapid progression and poor prognosis. The issue of treatment efficacy in patients with Richter’s syndrome still remains unresolved. The results of new drugs clinical trials are often contradictory and cannot yet be recommended for routine use in clinical practice. The low incidence of Richter’s syndrome, the lack of a unified view of the pathogenesis and therapy approaches make the search for effective drugs an urgent task, so each clinical observation is of undoubted interest.A clinical case of CLL patient with unfavorable molecular cytogenetic risk and transformation into diffuse large b-cell lymphoma (Richter’s syndrome) is presented. The combined use of bCL-2 inhibitors (venetoclax) and pI3K (duvelisib) led to the achievement of partial remission followed by a gradual increase in the positive antitumor effect.

Клинико-экономические и этические аспекты оценки исходов терапии пациентов с множественной миеломой высокого цитогенетического риска

According to European authors, patients with multiple myeloma (MM) and high cytogenetic risk have shorter values of progression free survival (PFS) and overall survival (OS) as compared with standard hazard. More frequent hospitalizations mean potentially high expenses associated with management of patients with unfavorable cytogenetic risk. Cost and availability of treatment of oncological patients relate to one of pressing ethical issues. Another important aspect of this issue consists in an effective use of available approved modes of therapy in patients with various survival prognosis, which is especially critical for early lines of therapy. It has been proven that early administration of more effective modes based on individual characteristics both of a patient, and a disease will improve the total survival of patients. This will result in reduction of economic resources spent on selecting new modes of treatment in patients with a disease recurrence and correction of possible adverse effects and hospitalization.

Pan-cancer analysis of oncogenic TNFAIP2 identifying its prognostic value and immunological function in acute myeloid leukemia

BackgroundTumor necrosis factor alpha-induced protein 2 (TNFAIP2), a TNFα-inducible gene, appears to participate in inflammation, immune response, hematopoiesis, and carcinogenesis. However, the potential role of TNFAIP2 in the development of acute myeloid leukemia (AML) remains unknow yet. Therefore, we aimed to study the biological role of TNFAIP2 in leukemogenesis.MethodsTNFAIP2 mRNA level, prognostic value, co-expressed genes, differentially expressed genes, DNA methylation, and functional enrichment analysis in AML patients were explored via multiple public databases, including UALCAN, GTEx portal, Timer 2.0, LinkedOmics, SMART, MethSurv, Metascape, GSEA and String databases. Data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Beat AML database were used to determine the associations between TNFAIP2 expression and various clinical or genetic parameters of AML patients. Moreover, the biological functions of TNFAIP2 in AML were investigated through in vitro experiments.ResultsBy large-scale data mining, our study indicated that TNFAIP2 was differentially expressed across different normal and tumor tissues. TNFAIP2 expression was significantly increased in AML, particularly in French–American–British (FAB) classification M4/M5 patients, compared with corresponding control tissues. Overexpression of TNFAIP2 was an independent poor prognostic factor of overall survival (OS) and was associated with unfavorable cytogenetic risk and gene mutations in AML patients. DNA hypermethylation of TNFAIP2 at gene body linked to upregulation of TNFAIP2 and inferior OS in AML. Functional enrichment analysis indicated immunomodulation function and inflammation response of TNFAIP2 in leukemogenesis. Finally, the suppression of TNFAIP resulted in inhibition of proliferation by altering cell-cycle progression and increase of cell death by promoting early and late apoptosis in THP-1 and U937AML cells.ConclusionCollectively, the oncogenic TNFAIP2 can function as a novel biomarker and prognostic factor in AML patients. The immunoregulation function of TNFAIP2 warrants further validation in AML.

P1326: FACTORS ASSOCIATED WITH THE OUTCOME OF ALLO-HSCT FOR ADVERSE-CYTOGENETIC RISK ACUTE MYELOID LEUKEMIA

Background: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the unique intention-curative consolidation strategy in patients with Acute Myeloid Leukemia (AML) with unfavorable cytogenetic risk. It is a high-cost procedure with significant transplant-related mortality (TRM), therefore, the correct selection of candidates for allo-HSCT resembles as a crucial issue. Aims: To describe the outcome of this procedure and to identify those patients who could obtain a better benefit. The primary endpoint was Overall Survival (OS) and secondary endpoints were relapse-free survival (RFS), cumulative incidence of Graft-versus-host disease (GVHD), cumulative incidence of relapse and (TRM). Methods: We conducted an observational retrospective study in patients with adverse-risk cytogenetically defined AML (Upon the European LeukemiaNet 2017 criteria and the results of the Next Generation Sequencing) who underwent a first allo-HSCT in two tertiary referral centers between 2010 and 2020. Results: We analyzed 82 patients with a median age at the moment of transplant of 55 (R 22-73) years. The median time from diagnosis to transplant was 5 (IR 4-7) months. Forty-two (51,2%) were women. Twenty-six patients (31,7%) had an identical HLA sibling donor and 37 (45,1%) had an unrelated HLA identical donor. A myeloablative conditioning was performed in 60 (51%) patients and in 48 (59,8%) the source of HSC was bone marrow. The majority (81,7%) had a first complete remission (CR1) at the moment of transplant and 13,4% had a partial response or a refractory disease (PR/RD). The 41,5% patients had a low comorbidity index score (HCT-CI<3). With a median follow up of 36 months, the OS at 1 and 3 years was 67% (95% CI 64-66%) and 48% (95% CI 45-51%) respectively. The RFS at 1 and 3 years was 62% (95% CI 61-63%) and 45% (95% CI 43-47%), the cumulative incidence of relapse at 1 and 3 years was 18% (95% CI 11-28%) and 29% (95% CI 19-40%) and the TRM at 1 and 3 years was 21% (95% CI 13-30 %) and 28% (95% CI 19-39%) respectively. The cumulative incidence of acute GVHD grade III-IV at day +100 was 17% (95% CI 9-26%). The cumulative incidence of moderate-severe chronic GVHD at 1 and 3 years was 21% (95% CI 13-30 %) and 31% (95% CI 21-42%) respectively. There were no differences in OS regarding age (p=0,2), sex (p=0,9), HCT-CI score (p=0,7), type of donor (p=0,4), acute GVHD (p=0,5), HSCT source (p=0,06), conditioning (p=0,04) and subtype of ELN2017 (p=0,9). A worse OS was observed in patients with PR/RD (HR 1,5 95% CI 1,2-1,9) (p<0,01) compared to those in first complete remission. The OS at two years was 28% (95% CI 26-30) and 59% (95% CI 58-60) respectively (Figure 1). Sixty-six patients were analyzed for OS depending on the development of cGVHD. The OS at 2 years of the patients who did not develop cGVHD (n= 32) was 58% (95% CI 56-60) of those with a mild cGVHD (n=10) was 85% (95% CI 83-87) of those with a moderate cGVHD (n=15) was 79% (95% CI 77-81) and of those who develop a severe cGVHD (n=9) was 64% (95% CI 61-67). Therefore, a worse OS was observed in patients who did not develop cGVHD or had a severe grade compared to those who had a mild or moderate cGVHD HR 5 (95% CI 1,8-15) (p<0,01). Image:Summary/Conclusion: In our series, Allo-HSCT in adverse-cytogenetic risk AML are associated with better OS when it is performed in first complete remission and its benefit is unclear performed in partial response or in a refractory disease, where other strategies should be considered. The development of mild or moderate cGVHD was associated with a better overall survival.

P499: THE PHASE 1B OMNIVERSE TRIAL OF ORAL AZACITIDINE IN COMBINATION WITH VENETOCLAX FOR TREATMENT OF RELAPSED/REFRACTORY OR NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (TRIAL IN PROGRESS)

Background: For older patients (pts) with acute myeloid leukemia (AML) who are ineligible for standard intensive chemotherapy (IC) regimens, traditional lower-intensity AML treatment (Tx) options include low-dose cytarabine (LDAC) or hypomethylating agents (HMAs; azacitidine [AZA] and decitabine), which are generally well tolerated but associated with suboptimal outcomes vs IC [Vey 2020]. Therefore, there remains a need for less toxic and more efficacious lower-intensity AML Tx regimens, especially agents that can be administered in the outpatient setting, which may increase convenience and reduce resource utilization. Venetoclax (VEN) is an oral, selective, small-molecule BCL2 inhibitor that has demonstrated considerable activity when combined with LDAC or HMAs in older pts with AML. In a recent phase 3 trial, VEN + injectable AZA significantly improved response and survival vs AZA alone in IC-ineligible pts with newly diagnosed (ND) AML [DiNardo 2020]. In the USA, VEN is approved in combination with an HMA or LDAC for Tx of pts with ND AML ≥ 75 years (y) of age or who cannot use IC due to comorbidities. Oral-AZA (CC-486) is approved for pts with AML in first remission (CR1) after IC who are ineligible for transplant or other curative therapies. In the randomized, phase 3 QUAZAR AML-001 trial of Oral-AZA in pts with AML in CR1 after IC, Oral-AZA 300 mg QD for 14 days (d)/28d Tx cycle was generally well tolerated and associated with significantly improved overall survival vs placebo. Gastrointestinal symptoms were the most common adverse events reported with Oral-AZA [Wei 2020]. Oral-AZA has also shown clinical activity in pts with active AML [Savona 2015]. As incorporation of AZA into DNA is S-phase-restricted, extended Oral-AZA dosing regimens (> 7d/28d Tx cycle) increase drug incorporation into cycling tumor cells to prolong epigenetic activity throughout the Tx cycle [Laille 2015]. An all-oral VEN + Oral-AZA combination regimen allows for outpatient administration and thus improves pt adherence [Eek 2016]. Aims: Describe the study design and objectives of the OMNIVERSE trial of Oral-AZA + VEN in older pts with ND AML or pts with AML relapsed/refractory (R/R) to prior Tx. Methods: OMNIVERSE (NCT04887857) is a multicenter, open-label, 2-part phase 1b trial (Figure). The key objectives of the trial are to assess safety and determine the maximum tolerated dose of Oral-AZA + VEN in pts with R/R AML (WHO 2016 criteria) ineligible to receive further IC (part I), and then in pts with ND AML ≥ 75 y of age, or those ≥ 18–74 y of age ineligible for IC or HSCT due to comorbidities (part 2). Main eligibility criteria include an ECOG performance status of 0–2 (ECOG 3 is allowed for pts ≥ 18–74 y of age with comorbidities) and an unfavorable cytogenetic risk profile for pts with ND AML. The initial dose of Oral-AZA is 300 mg QD × 14d/28d cycle, with de-escalation to 200 mg × 14d/28d cycle allowed for dose-limiting toxicities. VEN 400 mg is taken orally QD in continuous 28d cycles (or for 21d/cycle for dose level –2). A modified toxicity probability interval-2 design is used to evaluate the planned dose levels. The sample size is dependent on the dose levels included in the study (≤ 18 pts/part). Results: N/A Image:Summary/Conclusion: Study enrollment began in 2021. The trial is ongoing at clinical sites in the United States and Australia.

Oral azacitidine plus venetoclax in patients with relapsed/refractory or newly diagnosed acute myeloid leukemia: The phase 1b OMNIVERSE trial.

TPS7068 Background: For patients (pts) with acute myeloid leukemia (AML) who cannot undergo intensive chemotherapy (IC), lower-intensity treatment (Tx) regimens, including low-dose cytarabine (LDAC) and hypomethylating agents (HMAs; azacitidine [AZA], decitabine), are generally well tolerated but are associated with lower response rates than IC [Vey 2020]. Similarly, the BCL2 inhibitor, venetoclax (VEN), has shown antileukemic activity, although only modest clinical benefit as monotherapy [Konopleva 2016]. VEN + AZA shows synergistic activity in preclinical models, enhancing leukemic cell apoptosis in vitro and anti-tumor activity in vivo [Jin 2020]. In IC-ineligible pts with ND AML, VEN + injectable AZA significantly increased complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates ( P &lt; 0.001) and prolonged overall survival (OS; P &lt; 0.001) vs AZA only [DiNardo 2020]. VEN, in combination with an HMA or LDAC, is approved in the US for Tx of pts with ND AML ≥ 75 years (y) of age or who cannot undergo IC due to comorbidities. Oral-AZA (CC-486) is approved for Tx of pts with newly diagnosed (ND) AML in first CR or CRi after IC who cannot receive curative therapy (eg, HSCT). In the phase 3 QUAZAR AML-001 trial, maintenance Tx with Oral-AZA 300 mg QD for 14 days (d)/28-d Tx cycle improved OS and relapse-free survival vs placebo in older pts in CR/CRi after IC [Wei 2020]. Incorporation of AZA into DNA is S-phase-restricted; thus, extending AZA exposure over a longer duration by using an oral formulation increases the opportunity for cycling tumor cells to incorporate the drug to sustain therapeutic activity [Laille 2015]. Additionally, an all-oral combination regimen allows for outpatient administration to optimize pt convenience and reduce resource utilization. Methods: OMNIVERSE (NCT04887857) is an open-label, multicenter, 2-part phase 1b trial. The main goals are to evaluate safety and establish the maximum tolerated dose of Oral-AZA + VEN in pts ≥ 18 y of age with relapsed/refractory AML who are ineligible for further IC ( part 1), and subsequently, in pts with ND AML ≥ 75 y of age, or pts 18–74 y of age with comorbidities that prevent use of IC or HSCT ( part 2). Key eligibility criteria include ECOG performance status of 0–2 (ECOG 3 is allowed for pts 18–74 y of age with comorbidities) and unfavorable-risk cytogenetics for pts with ND AML. The Oral-AZA starting dose is 300 mg QD × 14 d/28-d cycle, which can be de-escalated to 200 mg QD × 14 d depending on dose-limiting toxicities; oral VEN 400 mg QD is taken continuously (or 21 d/cycle for dose level −2). A modified toxicity probability interval-2 design is used to evaluate dose levels. Sample size depends on the dose levels utilized (≤ 18 pts/part). Enrollment began in 2021. The trial is ongoing at clinical sites in the United States and Australia. Clinical trial information: NCT04887857.

High Expression of DC-STAMP Gene Predicts Adverse Outcomes in AML.

Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy with poor prognosis. We explored the RNA sequence data and clinical information of AML patients from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database to search for the core molecule for prognosis. The DC-STAMP expression was significantly higher in AML patients, which was linked to old age, unfavorable cytogenetic risk, and death (all p < 0.05). Furthermore, it was revealed that high DC-STAMP expression was an independent unfavorable factor for overall survival (OS) by univariate analysis [hazard ratio (HR): 2.683; 95% confidence interval (CI): 1.723–4.178; p < 0.001] and multivariate analysis (HR: 1.733; 95% CI: 1.079–2.781; p = 0.023). The concordance index (C-index 0.734, 95% CI: 0.706–0.762), calibration curves, and decision curve analysis showed the certain predictive accuracy of a nomogram model based on multivariate analysis for OS. In addition, we found that the differentially expressed gene (DEG) enrichment pathways of high- and low-DC-STAMP expression group enrichment pathways were focused on channel activity and platelet alpha granule by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), while gene set enrichment analysis (GSEA) pathways were mainly involved in mTORC1 signaling and TNF-α signaling via the NF-kB pathway. Moreover, a protein–protein interaction (PPI) network demonstrated that DC-STAMP interacted with two hub genes (PPBP and PF4), which were highly regulated and associated with poor survival. Finally, high DC-STAMP expression showed a significantly positive correlation with four immune cell [NK CD56 (dim) cells, macrophages, cytotoxic cells, and CD8 (+) T cells] infiltration and high level of immune checkpoint genes (PDCD1, CD274, CTLA-4, and TIGIT). Therefore, our results suggest that high expression of DC-STAMP predicts adverse outcomes for AML patients.

The Application of Decitabine in Combination with G-CSF, Low-Dose Cytarabine and Aclarubicin in AML-MRC: A Single Center Case Control Study

▪Background: It is difficult for AML-MRC patients to achieve complete remission (CR) and these patients develop recurrence and die of either disease progression or associated complications. The CAG regimen (cytarabine, aclarubicin and G-CSF) has been widely used in treating patients with AML-MRC in Asia. Decitabine (DAC) was approved to the treatment of MDS and reported to achieve higher response rate (67%) in AML with unfavorable-risk cytogenetics. Several studies reported low dose DAC in combination with chemotherapy to treat AML.Purpose:To evaluate the clinical efficacy and safety of low-dose decitabine in combination with small-dose CAG regimen (D-CAG regimen) in the treatment of AML-MRC, compared to CAG regimen.Methods:A total of 80 patients with newly diagnosed AML-MRC from September 2015 to January 2020 in our center were included in the study. 43 cases were initially treated with G-CSF for priming, in combination with cytarabine of 10-mg/ m 2q12h for 14 days and aclarubicin of 20 mg/day for 4 days (CAG regimen) and other 37 cases were initially treated with decitabine of 20 mg/m 2 for 5 days and small-dose CAG regimen (cytarabine of 10-mg/ m 2q12h for 7 days, aclarubicin of 10 mg/day for 4 days, and G-CSF for priming (D-CAG regimen). After induction chemotherapy, the patients who achieved CR received consolidation chemotherapy or hematopoietic stem cell transplantation (HSCT).Results:Among a total of 80 patients, the median age was 55 years (18-69 years) and 32 of them were male. Baseline characteristics of patients between D-CAG group and CAG group showed no significant differences (table 1). For the overall AML-MRC patients, the MLFS rate of D-CAG group was higher than the MLFS rate of CAG group after two courses of D-CAG regimen (62.2% v. s. 48.8%, χ2 =8.727, P=0.013, bilateral). Seven patients in CAG group did not response and then received D-CAG regimen as induction therapy, and five of them achieved MLFS (5/7) and one achieved PR (1/7). Among the population with less than 9 months of AML-MRC and/or MDS history, the MLFS rate (74.1%, 20/27) of D-CAG group was statistically higher than the MLFS rate (42.9% 15/35) of CAG group (74.1% v. s. 42.9%, χ 2 =1.909, p=0.008). Compared to the CAG group, the high-risk patients classified according to SWOG criteria in D-CAG group achieved a better MLFS rate (80.0% v. s. 26.1%, χ 2 =11.392, P=0.003, bilateral). Except patients receiving HSCT, the probability of OS and LFS for patients between D-CAG group and CAG group did not show any significant difference, but among the population with less than 9 months of AML-MRC and/or MDS history, the DCAG group showed a better probability of OS than the CAG group (58.3%±18.6% v. s. 11.3%±10.3%, p=0.006).Conclusion: In conclusion, patients with AML-MRC have a poor prognosis, and might benefit from D-CAG regimen as the induction therapy. For patients with less than 9 months of AML-MRC/MDS history or with poor karyotypes, the MLFS rate for patients in D-CAG group was higher than patients in CAG group. DisclosuresNo relevant conflicts of interest to declare.

OMNIVERSE: A Phase 1b/2 Study of Oral Azacitidine Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed (ND) Acute Myeloid Leukemia (AML)

OMNIVERSE: A Phase 1b/2 Study of Oral Azacitidine Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed (ND) Acute Myeloid Leukemia (AML)

High expression of long noncoding RNA NORAD is associated with poor clinical outcomes in non-M3 acute myeloid leukemia patients

Objective/BackgroundDysregulation of long noncoding RNA NORAD has been identified in human solid tumors. However, the expression profile of NORAD and its clinical implications in acute myeloid leukemia (AML) is unclear. The current study aimed to explore the NORAD expression status and its clinical significance in non-M3 AML patients. MethodsNORAD expression was evaluated in 60 de novo non-M3 AML patients and 49 healthy individuals using quantitative reverse transcription–polymerase chain reaction method. The correlation between NORAD transcription levels and clinicopathologic characteristics was statistically studied. ResultsCompared with the healthy controls, NORAD was consistently higher in non-M3 AML patients (p = .01). Furthermore, initial NORAD upregulation occurred more frequently in patients with unfavorable cytogenetic risk (p = .02). The non-M3 AML patients were divided into NORAD high-expressing (NORADhigh) and NORAD low-expressing (NORADlow) groups based on the median NORAD expression level. Univariate analyses revealed that patients with high expression levels of NORAD had relatively poor overall survival (p = .03) and relapse-free survival (RFS) (p = .01). Additionally, multivariate analysis highlighted that NORAD upregulation was an independent risk factor for RFS. ConclusionOur observations indicate the fact that high expression of NORAD could be an unfavorable risk factor in non-M3 AML patients, and NORAD might be a novel therapeutic candidate for future treatments targeting AML.

Prognostic Impacts and Dynamic Changes of Cohesin Complex Gene Mutations in De Novo Acute Myeloid Leukemia

BackgroundPatients with acute myeloid leukemia (AML) have remarkable heterogeneity in the pathogenesis, clinical features, and treatment outcomes. Risk-stratification is one of the most critical factors in the treatment of these patients. Cohesin is a multimeric protein complex, composed of four core subunits, including SMC1A, SMC3, RAD21 and either STAG1 or STAG2 proteins. Studies regarding the clinical and prognostic relevance and dynamic changes of cohesin gene mutations in de novo AML patients are limited and the findings are controversial. In this study, we aimed to investigate the clinical, biological and prognostic implications of cohesin gene mutations in a large cohort of de novo AML patients.MethodWe analyzed cohesin gene mutations and their clinico-biological associations in 391 adult patients with newly diagnosed de novo non-M3 AML. To evaluate the dynamic changes of cohesin and co-occurring gene mutations, sequential analyses of gene mutations by targeted next generation sequencing using HiSeq platform (Illumina) were performed in 386 samples from 116 patients during follow-ups. Furthermore, to investigate the pathophysiological pathways associated with cohesin gene mutations, gene expression microarray analysis was performed in 173 patients, including 10 cohesin-mutated and 163 wild-type patients, who had enough mRNA for analysis.ResultsWe found 37 patients (9.5%) had cohesin gene mutations, most prevalent in RAD21 (3.8%) and STAG2 (3.1%). Except for one patient with concurrent mutations in STAG2 and RAD21, the mutations in these component genes were mutually exclusive, suggesting a convergence of biological effects of these mutations (Figure 1). Mutations in STAG2 and RAD21 were mainly truncations or frameshift mutations (10/12, 83.3% and 12/15, 80%, respectively) while those in SMC1A and SMC3 were mostly missense mutations (7/8, 87.5% and 2/2, 100%, respectively). Cohesin mutations were inversely associated with complex karyotype (P=0.023) and unfavorable-risk cytogenetics (P=0.003). Interestingly, six (16.7%) of the 38 patients with t(8;21) had cohesin gene mutations, all in RAD21, while none of the patients with inv(16) had any cohesin mutation. Compared with other cohesin genes mutations, STAG2 mutations more frequently co-occurred with RUNX1 mutations (27.3% vs. 0%, P=0.023) and tended to co-occurred with ASXL1 mutations (25.0% vs. 4.0%, P=0.084), but less frequently with NPM1 mutations (0% vs. 32.0%, P=0.036) (Figure 1) . In multivariate Cox proportional hazards regression analyses for overall survival (OS) and disease-free survival (DFS), the presence of cohesin gene mutations was an independent favorable factor (P=0.047 and 0.028, respectively). A scoring system incorporating cohesin mutations and other prognostic factors could well stratify the patients into different risk groups, which could be validated in another independent cohort. Serial analyses by next generation sequencing showed that two patients lost the original cohesin mutations during disease evolution, while none of the patients without the mutation acquired a novel one at relapse. We applied Bradley-Terry model to evaluate the temporal order of gene mutations in cohesin-mutated patients. The STAG2 mutations occurred as an early event, while RAD21 and SMC1A mutations occurred relatively late. Ingenuity Pathway Analysis revealed ERK1/2 as a hub gene in cohesin mutation-associated biological pathways. Furthermore, Gene Set Enrichment Analysis demonstrated that cohesin gene mutations were closely associated with several biological pathways involved in hematopoietic/myeloid/blood cell-related functions, including differentiation of blood cells (P=7.96×10-11), proliferation of blood cells (P=3.22×10-10), apoptosis (P=1.39×10-8), and cell death of blood cells (P=9.12×10-8).ConclusionCohesin gene mutations were independent prognostic factors in de novo AML. Further, cohesin gene mutations were strongly associated with the biological function related to proliferation and differentiation of blood cells. Sequential analyses showed cohesin gene mutations might be lost during disease evolution, but none of the patients without the mutation acquired a novel one during the clinical course indicating they may not be critical in disease progression. Further prospective studies with larger cohorts are warranted to confirm our findings. [Display omitted] DisclosuresTsai:Celgene International Sàrl: Research Funding. Hou:Celgene International Sàrl: Research Funding. Tang:Celgene International Sàrl: Research Funding. Kuo:Celgene International Sàrl: Research Funding. Lin:Celgene International Sàrl: Research Funding. Yao:Celgene International Sàrl: Research Funding. Li:Celgene International Sàrl: Research Funding. Huang:Celgene International Sàrl: Research Funding. Ko:Celgene International Sàrl: Research Funding. Lin:Celgene International Sàrl: Research Funding. Wu:Celgene International Sàrl: Research Funding. Chen:Celgene International Sàrl: Research Funding. Tsai:Celgene International Sàrl: Research Funding. Tien:Celgene International Sàrl: Research Funding.

Evaluating Acute Myeloid Leukemia Induction Regimens in Elderly Patients with Unfavorable Risk Cytogenetics That Are Candidates for Intensive Remission Therapy

Background/purpose: Standard acute myeloid leukemia (AML) induction regimens have reduced response in elderly patients. As an alternative, hypomethylating agents have better tolerability, but poorer response rates. Venetoclax, an oral anti-apoptotic protein BCL-2 inhibitor, was approved in combination for the treatment of newly-diagnosed AML adults 75 years or older and is supported by NCCN guidelines in combination with hypomethylating agents or low dose cytarabine for special patient populations. This study evaluated the outcomes of AML induction regimens in unfavorable risk patients 60 years old or older that were candidates for intensive remission induction therapy. Methodology: This was an IRB-approved retrospective chart review of AML patients with unfavorable risk cytogenetics aged 60 or older admitted to the Baptist Hospital of Miami Oncology Unit between February 1st, 2018 and August 1st, 2019, an 18-month period. Patients were included if they received one of the following AML induction regimens: daunorubicin + cytarabine (7+3), liposomal daunorubicin/cytarabine (CPX-351), venetoclax + decitabine (VEN +DEC), venetoclax + azacitidine (VEN+ AZA), or venetoclax + low dose cytarabine (VEN + LoDAC). For the purpose of the study, the 7+3 and CPX-351 regimens were classified as high intensity, while the VEN+ DEC, VEN+AZA, and VEN+LoDAC regimens were classified as low intensity. The primary outcome assessed was the rate of complete morphologic remission (CR) and complete morphologic remission with incomplete count recovery (CRi). Additional secondary outcomes included rate of induction failure, relapse free survival (RFS), time to complete remission, transplant status and eligibility, length of stay (LOS), and incidence of any-grade treatment-related toxicities. Results: A total of 20 patients were identified. Of the 20 patients, 9 (45%) received induction with 7+3, 3 (15%) received CPX-351, 5 (20%) received VEN+DEC, and 3 (15%) received VEN +AZA, thus 12 (60%) received high intensity regimens, while 8 (40%) received low intensity. The primary outcome of CR/CRi rate was 75% in the high intensity group vs. 63% in the low intensity group (P=0.0922). Furthermore, the rate of induction failure, median time to CR/CRi, median LOS, and transplant eligibility were similar between the high and low intensity groups. The median RFS was 272 days in the high intensity groups vs. 223 days in the low intensity groups (P=0.1496). The median duration of neutropenia was 30 days in the high intensity group vs. 34 days in the low intensity group while the median duration of thrombocytopenia was 31 days in the high intensity groups vs. 32 days in the low intensity group. Finally, the rate of grade 3 and 4 toxicities was 100% in the high intensity group vs. 88% in the low intensity group (P=0.0003), with higher incidences of grade 3 febrile neutropenia, grade 4 thrombocytopenia, and grade 1 and 2 liver enzyme elevations noted in the high intensity group. Conclusion: There were no statistically significant differences between the CR/CRi rates and median RFS of the high and low intensity groups, while there were significantly less grade 3 and 4 toxicities noted in the low intensity group. Venetoclax-based regimens are an acceptable alternative to intensive induction therapy in unfavorable risk patients over the age of 60 due to similar outcomes and less toxicity. Disclosures No relevant conflicts of interest to declare.

Pretreatment Next-Generation Sequencing Is Associated with Response to Induction Chemotherapy in Patients Newly Diagnosed with Acute Myeloid Leukemia

Introduction: Next-generation sequencing (NGS) has redefined the genetic landscape of acute myeloid leukemia (AML) and has prognostic and, potentially, therapeutic implications in AML.Advances in the biological understanding of AML pathogenesis have led to the approval of new targeted agents that increase the therapeutic options for the treatment of AML. Despite these approvals, induction chemotherapy is still widely used for the treatment of patients newly diagnosed with AML. Unfavorable risk cytogeneticand secondary AML have been associated with low responses to induction chemotherapy. In the current study, we investigated the predictive role of molecular abnormalities detected with NGS related to responses to induction chemotherapy in newly diagnosed AML patients. Methods:We used the Medical Archival Retrieval System to identify newly diagnosed AML patients who had NGS analysis performed at our institution.. Patients treated with induction chemotherapy at AML diagnosis were included in the analysis. Response to therapy was evaluated two weeks after therapy was initiated and at count recovery. The difference in distribution of each mutation between the patients who responded to chemotherapy after one or two courses of induction chemotherapy and non-responders was analyzed using Fisher's exact test and the Cochran-Armitage Trend test. Findings with an expected false discovery rate ≤ 10% were reported as positive. The study was approved by the University of Pittsburgh IRB committee. Results: One hundred twenty-seven newly diagnosed AML patients (median age 61 years, interquartile range 51-68 years) were treated with induction chemotherapy. Sixteen patients (13%) had favorable risk cytogenetics, 73 patients (58%) had intermediate risk cytogenetics, and 36 patients (29%) had unfavorable risk cytogenetics. The most common molecular event was an NPM1 (28%) mutation followed by DNMT3A (25%), FLT3-ITD (22%), NRAS (13%), ASXL1 (12%), TET2 (12%), and TP53 (11%) as shown in Figure 1. Eighty-five of 127 patients (67%) achieved CR after one course of chemotherapy with idarubicin and cytarabine (7+3) and 17 patients (13%) responded after a second course with mitoxantrone and etoposide. Twenty-five patients (20%) did not respond to one or two courses of induction chemotherapy. From the 102 patients that responded, measurable residual disease (MRD) data were available in 59 (58%) patients. 29% patients were MRD positive and 71% patients were MRD negative. Secondary AML and poor cytogenetics were associated with poor response. Among the 17 genes with at least 5% prevalence, only TP53 mutations were associated with worse response. TP53 mutations increased monotonically with worse outcomes; TP53 mutations were present in only 2% of those responding to one course of chemotherapy, in 18% responding to two courses, and in 38% with no response to either course (p &amp;lt; 0.0001). Ninety-three percent of patients (13 of 14 patients) with TP53 mutations had poor cytogenetics. After induction chemotherapy, 21% of patients with TP53 mutations achieved CR and 14% achieved morphologic leukemia-free state (MLFS); 2 patients achieved CR after one course and, after the second course, 1 patient achieved CR and 2 patients MLFS. From the 5 patients that responded, 4 had available MRD data; 2 patients were MRD positive and 2 patients were MRD negative. NPM1 mutations were associated with higher response rates to induction chemotherapy (p =0.002). Ninety-four percent of patients (32 of 34 patients) with NPM1 mutations had intermediate cytogenetics. After induction chemotherapy, 92% of patients with NPM1 mutations achieved CR and 3% achieved MLFS; 32 patients (89%) achieved CR after one course. Two patients received a second course; one patient achieved CR and one MLFS. From the 34 patients that responded, 20 patients had available MRD data; 9 patients were MRD positive and 11 patients were MRD negative. Conclusion: Among 17 gene mutations detected using NSG at AML diagnosis, only TP53 and NPMI mutations were associated with responses to induction chemotherapy. Patients with TP53 mutations at AML diagnosis were associated with lower response rates to induction chemotherapy, whereas NPM1 mutations were associated with improved response. Disclosures Raptis: INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Hou:Genentech: Consultancy, Other: PI; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Other: PI. Dorritie:Kite-Gilead: Research Funding; Juno Therapeutics: Research Funding. Sehgal:TP Therapeutics: Research Funding; Prothena: Research Funding; Gilead Sciences: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Research Funding.

Cytogenetics and mutations could predict outcome in relapsed and refractory acute myeloid leukemia patients receiving BCL-2 inhibitor venetoclax

Venetoclax, a selective B cell leukemia/lymphoma-2 (BCL2) inhibitor, has recently shown activity in relapsed or refractory (R/R) acute myeloid leukemia (AML). Effective biomarkers for identifying patients most likely to respond to venetoclax-based treatment are of clinical utility. In this study, we aimed to evaluate the efficacy and safety profiles of venetoclax-based therapy in a total 40 R/R AML patients and identify the potentially predictive factors for response. Overall response rate was 50%, including 9 (22.5%) complete response (CR) or CR with incomplete hematologic recovery of either neutrophil or platelet counts (CRi). Median time to best response was 1.4months and the median overall survival (OS) was 6.6months. Presence of intermediate-risk cytogenetics predicted better OS compared to unfavorable-risk cytogenetics. Patients harboring NPM1, RUNX1, or SRSF2 mutations seemed to have higher CR/CRi rates and median OS was significantly longer in RUNX1-mutated patients. On the contrary, patients with FLT3-ITD, TP53, or DNMT3A mutations did not reach any objective response and had worse OS. No laboratory or clinical tumor lysis syndrome was observed and the most common adverse events were prolonged cytopenias which resulted in 67.5% of febrile neutropenia. Patients with concurrent use of azole antifungals had similar incidence of cytopenias compared with those without azole antifungals. In summary, we demonstrate that venetoclax is an effective and well-tolerated salvage option for R/R AML patients. Survival benefits were particularly remarkable in patients with intermediate-risk cytogenetics or RUNX1 mutations. In contrast, TP53, NRAS, and DNMT3A mutations as well as FLT3-ITD conferred negative impact on survival.