Gene Expression and DNA Methylation Profiling Suggest Potential Biomarkers for Azacitidine Resistance in Myelodysplastic Syndrome.

Myelodysplastic syndrome/neoplasm (MDS) comprises a group of heterogeneous hematopoietic disorders that present with genetic mutations and/or cytogenetic changes and, in the advanced stage, exhibit wide-ranging gene hypermethylation. Patients with higher-risk MDS are typically treated with repeated cycles of hypomethylating agents, such as azacitidine. However, some patients fail to respond to this therapy, and fewer than 50% show hematologic improvement. In this context, we focused on the potential use of epigenetic data in clinical management to aid in diagnostic and therapeutic decision-making. First, we used the F-36P MDS cell line to establish an azacitidine-resistant F-36P cell line. We performed expression profiling of azacitidine-resistant and parental F-36P cells and used biological and bioinformatics approaches to analyze candidate azacitidine-resistance-related genes and pathways. Eighty candidate genes were identified and found to encode proteins previously linked to cancer, chronic myeloid leukemia, and transcriptional misregulation in cancer. Interestingly, 24 of the candidate genes had promoter methylation patterns that were inversely correlated with azacitidine resistance, suggesting that DNA methylation status may contribute to azacitidine resistance. In particular, the DNA methylation status and/or mRNA expression levels of the four genes (AMER1, HSPA2, NCX1, and TNFRSF10C) may contribute to the clinical effects of azacitidine in MDS. Our study provides information on azacitidine resistance diagnostic genes in MDS patients, which can be of great help in monitoring the effectiveness of treatment in progressing azacitidine treatment for newly diagnosed MDS patients.

A pharmacodynamic assay to monitor treatment with the hypomethylating cytosine analogs, decitabine and azacitidine.

Hypomethylating therapies using decitabine or azacitidine are actively investigated to treat acute myeloid leukemia, myelodysplastic syndromes, as maintenance therapy after allogenic stem cell transplant and hemoglobinopathies. The therapeutic mechanism is to de-repress genes that have been turned off through oncogenesis or development via methylation. The therapy can be non-cytotoxic at low dosage, sparing healthy stem cells and operating on committed precursors. Because the methods of determining maximum tolerated dose are not well suited to this paradigm, and because the mechanism of action, which is depletion of DNA methylase 1 (DNMT1), is complex and dependent on passing through a cell cycle, a pharmacodynamic assay that measures DNMT1 can inform clinical trials aimed at establishing and improving therapy. Herein, we provide an assay that measures DNMT1 relative levels in circulating T cells of peripheral blood.

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical ß-catenin pathway.

BACKGROUND: 5-Fluorouracil (5FU) is a primary chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC). However, the development of drug resistance has significantly limited its clinical application. Therefore, there is an urgent need to determine the mechanisms underlying drug resistance and identify effective targets. In recent years, the Wingless and Int-1 (WNT) signaling pathway has been increasingly studied in cancer drug resistance; however, the role of WNT3, a ligand of the canonical WNT signaling pathway, in OSCC 5FU-resistance is not clear. This study delved into this potential connection. METHODS: 5FU-resistant cell lines were established by gradually elevating the drug concentration in the culture medium. Differential gene expressions between parental and resistant cells underwent RNA sequencing analysis, which was then substantiated via Real-time quantitative PCR (RT-qPCR) and western blot tests. The influence of the WNT signaling on OSCC chemoresistance was ascertained through WNT3 knockdown or overexpression. The WNT inhibitor methyl 3-benzoate (MSAB) was probed for its capacity to boost 5FU efficacy. RESULTS: In this study, the WNT/ß-catenin signaling pathway was notably activated in 5FU-resistant OSCC cell lines, which was confirmed through transcriptome sequencing analysis, RT-qPCR, and western blot verification. Additionally, the key ligand responsible for pathway activation, WNT3, was identified. By knocking down WNT3 in resistant cells or overexpressing WNT3 in parental cells, we found that WNT3 promoted 5FU-resistance in OSCC. In addition, the WNT inhibitor MSAB reversed 5FU-resistance in OSCC cells. CONCLUSIONS: These data underscored the activation of the WNT/ß-catenin signaling pathway in resistant cells and identified the promoting effect of WNT3 upregulation on 5FU-resistance in oral squamous carcinoma. This may provide a new therapeutic strategy for reversing 5FU-resistance in OSCC cells.

Evaluation of the Combined Effect of Caffeine and 5-Fluorouracil on Colorectal Cancer Cell Lines.

BACKGROUND: Cancer is the second leading cause of death in the world. Colorectal cancer is the third leading cause of cancer death. Today, there are several options for treating colorectal cancer such as chemotherapy, surgery, radiotherapy, immunotherapy, and gene therapy. 5-Fluorouracil is known as a suitable candidate for the treatment of various cancers, especially colorectal cancer. However, the use of this drug is limited, so it is usually used in combination with other drugs and agents. Based on the evidence obtained, this study attempted to evaluate the combined effects of 5-fluorouracil and caffeine on colorectal cancer cells. METHODS: In this study, initially HCT116 and HEK293 cell lines were cultured as cancer and normal cells, respectively. These cell lines were then evaluated for cytotoxicity, induction of apoptosis, and rate of cell migration. All data were analyzed by statistical methods. RESULTS: The results indicated that a combination of caffeine and 5-FU augmented their cytotoxicity in HCT116 cells but reduced cytotoxicity in HEK293 cells. No reduction was observed in the migration of HCT116 cells that were treated with caffeine or a combination of caffeine and 5-FU. Also, it seems that caffeine reverses the apoptotic effect of 5-FU in HCT116 cells.

Oral Delivery of Photopolymerizable Nanogels Loaded with Gemcitabine for Pancreatic Cancer Therapy: Formulation Design, and in vitro and in vivo Evaluations.

Background: Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients. Methods: We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug. Results: Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91±7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07±19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM's AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙µg/mL) compared to oral free-GEM (19.04 hr∙µg/mL) after oral administration (p<0.01), highlighting NGs' efficacy in impeding rapid drug metabolism and enhancing retention. Conclusion: In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.

Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD).

Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.

Autophagy degrades immunogenic endogenous retroelements induced by 5-azacytidine in acute myeloid leukemia.

The hypomethylating agent 5-azacytidine (AZA) is the first-line treatment for AML patients unfit for intensive chemotherapy. The effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, evidence supporting higher ERE MAPs presentation after AZA treatment is lacking. Therefore, using proteogenomics, we examined the impact of AZA on the repertoire of MAPs and their source transcripts. AZA-treated AML upregulated both CTA and ERE transcripts, but only CTA MAPs were presented at greater levels. Upregulated ERE transcripts triggered innate immune responses against double-stranded RNAs but were degraded by autophagy, and not processed into MAPs. Autophagy resulted from the formation of protein aggregates caused by AZA-dependent inhibition of DNMT2. Autophagy inhibition had an additive effect with AZA on AML cell proliferation and survival, increased ERE levels, increased pro-inflammatory responses, and generated immunogenic tumor-specific ERE-derived MAPs. Finally, autophagy was associated with a lower abundance of CD8+ T-cell markers in AML patients expressing high levels of EREs. This work demonstrates that AZA-induced EREs are degraded by autophagy and shows that inhibiting autophagy can improve the immune recognition of AML blasts in treated patients.

Adding the epigenomic signature to the prognostic jigsaw of myelodysplastic neoplasm?

Defining mechanisms of resistance to hypomethylating agents (HMAs) and biomarkers predictive of treatment response remains challenging in myelodysplastic neoplasm (MDS). Currently available prognostic tools that predict overall survival and transformation to acute myeloid leukaemia have not been powered to predict responses to HMAs. Noguera-Castells et al. comprehensively characterized the epigenomic profile in patients with MDS treated with azacitidine and described a methylation signature-based prognostic tool in predicting responses to azacitidine. Commentary on: Noguera-Castells et al. DNA methylation profiling of myelodysplastic syndromes and clinical response to azacitidine: a multicentre retrospective study. Br J Haematol 2024;204:1838-1843.

DNA methylation profiling of myelodysplastic syndromes and clinical response to azacitidine: A multicentre retrospective study.

Real-world data have revealed that a substantial portion of patients with myelodysplastic syndromes (MDS) does not respond to epigenetic therapy with hypomethylating agents (HMAs). The cellular and molecular reasons for this resistance to the demethylating agent and biomarkers that would be able to predict the treatment refractoriness are largely unknown. In this study, we shed light on this enigma by characterizing the epigenomic profiles of patients with MDS treated with azacitidine. Our approach provides a comprehensive view of the evolving DNA methylation architecture of the disease and holds great potential for advancing our understanding of MDS treatment responses to HMAs.

TRIM29 facilitates gemcitabine resistance via MEK/ERK pathway and is modulated by circRPS29/miR-770-5p axis in PDAC.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Chemotherapy based on gemcitabine (GEM) remains the first-line drug for patients with advanced PDAC. However, GEM resistance impairs its therapeutic effectiveness. Therefore, identifying effective therapeutic targets are urgently needed to overcome GEM resistance. METHODS: The clinical significance of Tripartite Motif Containing 29 (TRIM29) was identified by exploring GEO datasets and TCGA database and its potential biological functions were predicted by GSEA analysis. The regulatory axis was established by bioinformatics analysis and validated by mechanical experiments. Then, in vitro and in vivo assays were performed to validate the roles of TRIM29 in PDAC GEM resistance. RESULTS: High TRIM29 expression was associated with poor prognosis of PDAC and functional experiments demonstrated that TRIM29 promoted GEM resistance in PDAC GEM-resistant (GR) cells. Furthermore, we revealed that circRPS29 promoted TRIM29 expression via competitive interaction with miR-770-5p and then activated MEK/ERK signaling pathway. Additionally, both in vitro and in vivo functional experiments demonstrated that circRPS29/miR-770-5p/TRIM29 axis promoted PDAC GEM resistance via activating MEK/ERK signaling pathway. CONCLUSION: Our results identify the significance of the signaling axis, circRPS29/miR-770-5p/TRIM29-MEK/ERK, in PDAC GEM resistance, which will provide novel therapeutic targets for PDAC treatment.

Skeletal Muscle-Derived Irisin Enhances Gemcitabine Sensitivity and Suppresses Migration Ability in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: High skeletal muscle mass might be a prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC); however, the underlying reason is unclear. We hypothesized that myokines, which are cytokines secreted by the skeletal muscle, function as suppressors of PDAC. We specifically examined irisin, a myokine, which plays a critical role in the modulation of metabolism, to clarify the anticancer mechanisms. METHODS: First, the effect of the conditioned medium (CM) from skeletal muscle cells and from irisin-knockdown skeletal muscle cells on PDAC cell lines was evaluated. We then investigated the effects and anticancer mechanism of irisin in PDAC cells, and evaluated the anticancer effect of recombinant irisin in a PDAC xenograft mouse model. Finally, patients undergoing pancreatic resection for PDAC were divided into two groups based on their serum irisin level, and the long-term outcomes were evaluated. RESULTS: The CM enhanced gemcitabine sensitivity by inducing apoptosis and decreasing cell migration by inhibiting epithelial-mesenchymal transition (EMT) in PDAC cell lines. The CM derived from irisin-knockdown skeletal muscle cells did not affect the PDAC cell lines. The addition of recombinant irisin to PDAC cell lines facilitated sensitivity to gemcitabine by inhibiting the mitogen-activated protein kinase (MAPK) pathway, and decreased migration by inhibiting EMT via the transforming growth factor-ß/SMAD pathway. Xenografts injected with gemcitabine and recombinant irisin grew slower than the xenografts injected with gemcitabine alone. The overall survival was prolonged in the high-irisin group compared with that in the low-irisin group. CONCLUSIONS: Skeletal muscle-derived irisin may affect PDAC by enhancing its sensitivity to gemcitabine and suppressing EMT.

Deciphering the role of Enterococcus faecium cytidine deaminase in gemcitabine resistance of gallbladder cancer.

Gemcitabine-based chemotherapy is a cornerstone of standard care for gallbladder cancer (GBC) treatment. Still, drug resistance remains a significant challenge, influenced by factors such as tumor-associated microbiota impacting drug concentrations within tumors. Enterococcus faecium, a member of tumor-associated microbiota, was notably enriched in the GBC patient cluster. In this study, we investigated the biochemical characteristics, catalytic activity, and kinetics of the cytidine deaminase of E. faecium (EfCDA). EfCDA showed the ability to convert gemcitabine to its metabolite 2',2'-difluorodeoxyuridine. Both EfCDA and E. faecium can induce gemcitabine resistance in GBC cells. Moreover, we determined the crystal structure of EfCDA, in its apo form and in complex with 2', 2'-difluorodeoxyuridine at high resolution. Mutation of key residues abolished the catalytic activity of EfCDA and reduced the gemcitabine resistance in GBC cells. Our findings provide structural insights into the molecular basis for recognizing gemcitabine metabolite by a bacteria CDA protein and may provide potential strategies to combat cancer drug resistance and improve the efficacy of gemcitabine-based chemotherapy in GBC treatment.

Decitabine combined with cold atmospheric plasma induces pyroptosis via the ROS/Caspase-3/GSDME signaling pathway in Ovcar5 cells.

BACKGROUND: High methylation of the DFNA5 gene results in the absence of GSDME, a key protein that mediates pyroptosis, while decitabine demethylates the DFNA5 gene, resulting in high expression of the GSDME protein. Cold atmospheric plasma (CAP) is a novel anti-cancer method that induces tumor cell death. METHODS: The pyroptosis induced by decitabine in combination with CAP in Ovcar5 cells was evaluated. In particular, mitochondrial membrane potential was estimated by JC-1 staining, dehydrogenase (LDH) release was assessed by ELISA, Annexin V/PI staining was detected by flow cytometry, the cell cycle changes were evaluated using PI staining followed by detection by flow cytometry, and Caspase-9 cleavage, Caspase-3 cleavage and GSDME expression were evaluated by western blot. RESULTS: Decitabine resulted in high expression of the GSDME in Ovcar5 in a concentration-dependent manner and increased tumor cell sensitivity to CAP. CAP induced mitochondrial damage and activated the Caspase-9/Caspase-3 pathway. Therefore, decitabine combined with CAP induced Ovcar5 cell pyroptosis through Caspase-3 mediated GSDME cleavage. Reactive oxygen species (ROS) generated by CAP treatment played an important role in the CAP/decitabine combination-induced production of ROS, activation of Caspase-9/Caspase-3, GSDME cleavage and pyroptosis that ROS scavenger NAC inhibited all these processes. CONCLUSIONS: CAP combined with decitabine induced Caspase-3 activation, which cleaved decitabine-upregulated GSDME and ediated pyroptosis.

Azacitidine Post-transplant Maintenance Improves Disease Progression in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome.

BACKGROUND: Maintenance after allogeneic hematopoietic cell transplantation (alloHCT) with hypomethylating agents has yielded conflicting results. MATERIALS AND METHODS: We conducted a single center retrospective matched-control analysis with the study group (5-azacitidine [AZA] group) including adults with FLT3-negative acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received post-transplant AZA maintenance off clinical trial (n = 93). A matched control group was comprised of contemporaneous AML/MDS patients who did not receive any maintenance (n = 357). Primary endpoint was disease progression. RESULTS: The AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years, P = .01) and lower hematopoietic comorbidity index (median: 2 vs. 3, P = .04) in the AZA group. The 3-year cumulative incidence of progression in the AZA and control groups was 29% vs. 33% (P = .09). The protective effect of AZA on progression was limited to patients with high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009). This led to improved progression-free survival both in high-risk AML and MDS patients with maintenance (HR = 0.2, 95% CI = 0.1-0.6, P = .004 and HR = 0.4, 95% CI = 0.2-0.9, P = .04). CONCLUSION: AZA maintenance was associated with a lower progression rate in patients with high-risk FLT3-negative AML or MDS, and AZA maintenance should be considered for post-alloHCT maintenance in this subset.

ISG15 Promotes Progression and Gemcitabine Resistance of Pancreatic Cancer Cells Through ATG7.

Chemoresistance is an obstacle of improving pancreatic cancer (PC) prognosis. However, the biological function of ISG15 in PC and whether it correlates with the resistance to chemotherapy are still unknown. Here, we aimed to reveal the clinical significance of ISG15 in PC and its regulatory mechanism in cancer progression and resistance to therapy. The level of ISG15, a protein involved in post-translational modifications, is elevated in PC tissues. Clinically, higher ISG15 expression correlates with higher PC grades, stronger resistance to treatment and poorer prognosis. Moreover, ISG15 promotes the proliferation, migration, invasion, colony formation of PC cells and resistance to Gemcitabine, a classic chemotherapeutics for PC, both in vitro and in vivo. ISG15 promotes progression and resistance to therapy in PC cells by binding to ATG7, reducing its degradation, and thereby leading to enhanced autophagy in PC cells. ISG15 may be used as both a potential diagnosis marker and sensitizer for chemotherapeutics such as Gemcitabine during PC intervention.

Novel insights into the role of translesion synthesis polymerase in DNA incorporation and bypass of 5-fluorouracil in colorectal cancer.

5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent in colorectal cancer, and resistance to 5-FU easily emerges. One of the mechanisms of drug action and resistance of 5-FU is through DNA incorporation. Our quantitative reverse-transcription PCR data showed that one of the translesion synthesis (TLS) DNA polymerases, DNA polymerase η (polη), was upregulated within 72 h upon 5-FU administration at 1 and 10 µM, indicating that polη is one of the first responding polymerases, and the only TLS polymerase, upon the 5-FU treatment to incorporate 5-FU into DNA. Our kinetic studies revealed that 5-fluoro-2'-deoxyuridine triphosphate (5FdUTP) was incorporated across dA 41 and 28 times more efficiently than across dG and across inosine, respectively, by polη indicating that the mutagenicity of 5-FU incorporation is higher in the presence of inosine and that DNA lesions could lead to more mutagenic incorporation of 5-FU. Our polη crystal structures complexed with DNA and 5FdUTP revealed that dA:5FdUTP base pair is like dA:dTTP in the active site of polη, while 5FdUTP adopted 4-enol tautomer in the base pairs with dG and HX increasing the insertion efficiency compared to dG:dTTP for the incorrect insertions. These studies confirm that polη engages in the DNA incorporation and bypass of 5-FU.

Tumor-derived interleukin 35 mediates the dissemination of gemcitabine resistance in pancreatic adenocarcinoma.

Rapid development of drug resistance after chemotherapy is a major cause of treatment failure in individuals with pancreatic ductal adenocarcinoma (PDAC). In this study, we illustrate that tumor-derived interleukin 35 (IL-35) mediates the accelerated resistance of PDAC to gemcitabine (GEM). We observe that GEM resistance can spread from GEM-resistant PDAC cells to GEM-sensitive cells, and that IL-35 is responsible for the propagation of chemoresistance, which is supported by sequencing and experimental data. Additionally, we discover that GEM-resistant cells have significantly higher levels of IL-35 expression. Mechanistically, aberrantly expressed IL-35 triggers transcriptional activation of SOD2 expression via GP130-STAT1 signaling, scavenging reactive oxygen species (ROS) and leading to GEM resistance. Furthermore, GEM treatment stimulates IL-35 expression through activation of the NF-κB pathway, resulting in acquired chemoresistance. In the mouse model, a neutralizing antibody against IL-35 enhances the tumor suppressive effect of GEM. Collectively, our data suggests that IL-35 is critical in mediating GEM resistance in pancreatic cancer, and therefore could be a valuable therapeutic target in overcoming PDAC chemoresistance.

Real-world Effectiveness of Azacitidine in Treatment-Naive Patients With Higher-risk Myelodysplastic Syndromes.

INTRODUCTION: Azacitidine (AZA) is an approved frontline therapy for higher-risk myelodysplastic syndromes (HR-MDS); however, poor survival denotes unmet needs to increase depth/duration of response (DOR). METHODS: This retrospective study with patient chart review evaluated AZA effectiveness in 382 treatment-naive patients with HR-MDS from a US electronic health record (EHR)-derived database. Responses were assessed using International Working Group (IWG) 2006 criteria; real-world equivalents were derived from EHRs. Primary endpoint was IWG 2006-based complete remission rate (CRR). Secondary endpoints were EHR-based CRR, IWG 2006- and EHR-based objective response rates (ORRs), duration of CR, DOR, progression-free survival, time-to-next-treatment, and overall survival (OS). RESULTS: Using IWG 2006 criteria, the CRR was 7.9% (n = 30); median duration of CR was 12.0 months (95% CI, 7.7-15.6). In poor cytogenetic risk (n = 101) and TP53 mutation (n = 46) subgroups, CRRs were 7.9% (n = 8) and 8.7% (n = 4), respectively. ORR was 62.8% (n = 240), including a hematologic improvement rate (HIR) of 46.9% (n = 179). Using EHR-based data, CRR was 3.7% (n = 14); median duration of CR was 13.5 months (95% CI, 4.5-21.5). ORR was 67.8% (n = 259), including an HIR of 29.3% (n = 112). Median follow-up was 12.9 months; median OS was 17.9 months (95% CI, 15.5-21.7). CONCLUSIONS: Consistent with other studies, CRRs and median OS with AZA in treatment-naive patients with HR-MDS were low in this large, real-world cohort. Novel agents/combinations are urgently needed to improve these outcomes in HR-MDS.

Clinical Outcomes in Patients With Refractory Anemia With Excess Blasts (RAEB) Who Receive Hypomethylating Agents (HMAs).

BACKGROUND: We sought to understand the clinical effectiveness associated with use of hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) for patients with refractory anemia with excess blasts (RAEB; an established proxy for higher-risk myelodysplastic syndromes/neoplasms) in contemporary and representative real-world settings. PATIENTS AND METHODS: We used the Surveillance, Epidemiology and End Results (SEER)-Medicare database, a linkage of cancer registry and Medicare claims data, to identify patients aged ≥ 66 years diagnosed with RAEB, between 2009 and 2017 in the United States, and who received AZA or DEC as first-line therapy. Outcomes measured were overall survival (OS), event-free survival (EFS), and incidence of progression-related acute myeloid leukemia (AML). RESULTS: Of 973 eligible patients, 738 (75.8%) received AZA and 235 (24.2%) received DEC; 6.4% received hematopoietic cell transplantation during follow-up. In the overall population, median OS was 13.9 months (95% confidence interval [CI]: 12.9-15.0), median EFS was 5.2 months (95% CI: 4.9-5.7), and 38.0% of patients progressed to AML. Incidences of AML progression and death were 25.6% and 29.9%, respectively, at Year 1, and 34.3% and 44.8%, respectively, at Year 2. There were no significant differences in clinical benefits between AZA and DEC. CONCLUSION: Median OS with both HMAs remained significantly shorter than in the AZA-001 clinical trial, highlighting how patient outcomes vary between clinical and real-world settings. Further research is required to understand why these disparities exist.