Trial reportClinical cancer research : an official journal of the American Association for Cancer Research2021
Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions.
Trial report in Clinical cancer research : an official journal of the American Association for Cancer Research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07283094 (FHD-286 With Low-Dose Weekly Decitabine/Venetoclax in Patients With Acute Myeloid Leukemia), which is not on this map. Cited by 27 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
FHD-286 With Low-Dose Weekly Decitabine/Venetoclax in Patients With Acute Myeloid Leukemia
Who cites it
27 citing papers in PubMed, 33 citations in OpenAlex.
- Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs.Nature communications · 2025Trial
- FLT3-ITD signals for CEBPA and p53 proteolysis by the ubiquitin-proteosome pathway.Research square · 2026Article
- FLT3-ITD signals for CEBPA and p53 proteolysis by the ubiquitin-proteosome pathway.bioRxiv : the preprint server for biology · 2026Article
- Epstein-Barr Virus-host epigenetic interplay: mechanisms of regulation and therapeutic potential.Clinical epigenetics · 2026Review
- Evaluation of mTOR, NFκB and BCL-2 Inhibitor Activity In Vitro in Karpas 1106P, a Primary Mediastinal B-Cell Lymphoma Cell Line.Hematology reports · 2026Article
- RRM1 inhibition sensitizes lung adenocarcinoma to decitabine treatment.Cell death & disease · 2026Article
- Evaluation of mTOR, NFκB, and BCL-2 Inhibitor Activity In Vitro on Diffuse Large B-Cell Lymphoma Cells.Current issues in molecular biology · 2026Article
- Concomitant plasma cell myeloma and chronic myelomonocytic leukemia in elderly: diagnostic complexity, therapeutic challenges - case report and literature review.Annals of medicine and surgery (2012) · 2026Article
- DNA methyltransferase inhibitors in hematological malignancies and solid tumors.International journal of cancer · 2026Review
- Combining drugs that bypass p53 to treat TP53-mutated leukemias.Blood advances · 2025Article
- Epigenetic regulation of cancer stemness.Signal transduction and targeted therapy · 2025Review
- Systemic Therapy for Unresectable Hepatocellular Carcinoma: Current Landscape and Future Directions.International journal of molecular sciences · 2025Review
- Getting the right combination to break the epigenetic code.Nature reviews. Clinical oncology · 2025Review
- An Open-Label Phase II Trial of Pembrolizumab, an Immune Checkpoint Inhibitor Alone or in Combination With Oral Azacitidine as Second-Line Therapy for Advanced Head and Neck Squamous Cell Cancers.Health science reports · 2025Article
- Single low-dose decitabine as frontline therapy of acute myeloid leukaemia, with venetoclax salvage.Journal of cellular and molecular medicine · 2024Article
- Immune-dysregulation harnessing in myeloid neoplasms.Cancer medicine · 2024Review
- Molecular responses in decitabine- and decitabine/ venetoclax-treated patients with acute myeloid leukemia and myelodysplastic syndromes.Haematologica · 2024Article
- Unfolding the complexity of epigenetics in male reproductive aging: a review of therapeutic implications.Molecular biology reports · 2024Review
- Flow cytometry of DNMT1 as a biomarker of hypomethylating therapies.Cytometry. Part B, Clinical cytometry · 2024Article
- Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy.Cell reports · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
purposeAzacitidine and decitabine are hypomethylating agents (HMA), that is, both inhibit and deplete DNA methyltransferase 1 (DNMT1). HMAs are standard single-agent therapies for myelodysplastic syndromes and acute myelogenous leukemias. Several attempts to improve outcomes by combining HMAs with investigational agents, excepting with the BCL2-inhibitor venetoclax, have failed in randomized clinical trial (RCT) evaluations. We extract lessons from decades of clinical trials to thereby inform future work. EXPERIMENTAL
designSerial single-agent clinical trials were analyzed for mechanism and pathway properties of HMAs underpinning their success, and for rules for dose and schedule selection. RCTs were studied for principles, dos and don'ts for productive combination therapy.
resultsSingle-agent HMA trial results encourage dose and schedule selection to increase S-phase-dependent DNMT1 targeting, and discourage doses that cause indiscriminate antimetabolite effects/cytotoxicity, because these attrit myelopoiesis reserves needed for clinical response. Treatment-related myelosuppression should prompt dose/frequency reductions of less active investigational agents rather than more active HMA. Administering cytostatic agents concurrently with HMA can antagonize S-phase-dependent DNMT1 targeting. Supportive care that enables on-time administration of S-phase (exposure-time)-dependent HMA could be useful. Agents that manipulate pyrimidine metabolism to increase HMA pro-drug processing into DNMT1-depleting nucleotide, and/or inhibit other epigenetic enzymes implicated in oncogenic silencing of lineage differentiation, could be productive, but doses and schedules should adhere to therapeutic index/molecular-targeted principles already learned.
conclusionsMore than 40 years of clinical trial history indicates mechanism, pathway, and therapeutic index properties of HMAs that underpin their almost exclusive success and teaches lessons for selection and design of combinations aiming to build on this treatment foundation.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.