A simple blood test might soon tell doctors which patients will respond to a revolutionary cancer treatment — and which won't.
The fight against acute myeloid leukemia (AML), an aggressive blood cancer, has long been a race against time. For decades, treatment options for older or medically frail patients were limited, with often discouraging outcomes.
Then came venetoclax, a revolutionary targeted therapy that changed the standard of care. When combined with hypomethylating agents like decitabine, this regimen offered new hope, with impressive response rates approximately 70%. Yet curiously, not all patients benefited equally. Researchers noticed a pattern: those whose leukemia cells exhibited monocytic differentiation—a more mature, immune-like cell type—often responded poorly. This article explores the crucial scientific detective work unraveling this medical mystery and the quest to overcome this resistance.
Average response rate to venetoclax+decitabine
Patients with monocytic AML who don't respond well
Patients in the key resistance study 1
Venetoclax is not traditional chemotherapy. It belongs to a sophisticated class of drugs known as BH3-mimetics that function as precision-guided weapons against cancer 6 . Its target is BCL-2, a specific protein that acts like a "survival switch" on cancer cells, preventing them from undergoing programmed cell death (apoptosis) 3 6 .
Decitabine is a hypomethylating agent. It works through an epigenetic mechanism, meaning it alters how genes are read without changing the DNA sequence itself. By removing "methyl tags" that silence important genes, decitabine helps restore normal cellular functions, including the control of cell growth and death.
AML is not a single disease. The French-American-British (FAB) classification system categorizes it based on how the cancer cells look and what they resemble. FAB M4 and M5 subtypes, also known as acute myelomonocytic and monocytic leukemia, represent leukemias where the cells have differentiated toward monocyte-like cells 1 .
When combined with venetoclax, decitabine primes the cancer cells, making them more vulnerable to the apoptosis-inducing effects of venetoclax. This monocytic maturation state is critically important for understanding response to venetoclax-based therapies.
To definitively understand why some patients failed venetoclax+decitabine therapy, researchers conducted a detailed retrospective study, examining the medical records and diagnostic data of 155 newly diagnosed AML patients treated with this regimen 1 .
The researchers employed a two-pronged approach to identify monocytic leukemia:
An experienced hematopathologist reviewed bone marrow smears and classified cases as M5 (monocytic) or non-M5 according to the established FAB criteria 1 .
Because FAB classification can be subjective, the team also used flow cytometry, a technique that detects specific proteins on cell surfaces. They developed a scoring model based on the expression of monocytic markers (CD4, CD14, CD64, CD11b) and the loss of an immature marker (CD117). Patients with a high score were classified as having "monocyte-like AML" 1 .
The findings were striking and consistently pointed in one direction. The table below summarizes the stark contrast in treatment outcomes.
| Outcome Measure | Monocyte-like AML | Non-Monocyte-like AML | P-value |
|---|---|---|---|
| Composite Complete Remission (CR/CRi) | 26.7% | 80.0% | < 0.001 |
| Median Progression-Free Survival | 2.1 months | 8.8 months | < 0.001 |
| Median Overall Survival | 9.2 months | 19 months | 0.013 |
Multivariate analyses confirmed that the monocytic immunophenotype was an independent predictor of lower response rates and a higher risk of disease progression, even after accounting for other known risk factors 1 . This provided strong clinical evidence for what earlier lab experiments had suggested: monocytic subclones are inherently less sensitive to venetoclax-induced cell death 1 .
The ability to uncover this resistance mechanism relied on a suite of specialized research tools and biological concepts.
| Tool or Concept | Function in Research |
|---|---|
| Flow Cytometry | A technology used to analyze the physical and chemical characteristics of cells, such as the presence of specific surface proteins (CD markers). It was crucial for defining the "monocyte-like" immunophenotype 1 . |
| Next-Generation Sequencing (NGS) | A high-throughput method for determining the DNA sequence of a cell's genome. It allows researchers to identify mutations in genes like TP53, IDH1/2, and NPM1, which also influence treatment response 1 . |
| BH3 Profiling | A functional assay that measures how "primed" a cell is for apoptosis. This tool helped establish the molecular basis for why some cells are sensitive to BCL-2 inhibition while others are not 6 . |
| French-American-British (FAB) Classification | The traditional morphological system for classifying AML into subtypes (M0-M7) based on how the cells look under a microscope 1 . |
| ELN 2022 Risk Stratification | An international consensus system that classifies AML patients into risk groups (favorable, intermediate, adverse) based on genetic abnormalities, guiding prognosis and treatment decisions 1 . |
Science is rarely straightforward. While the study above highlights a clear challenge, another recent analysis presented a contrasting view. A 2025 retrospective study of 41 patients found that FAB M5 patients actually had excellent outcomes with venetoclax+HMA, with a median overall survival that was not reached and was significantly longer than that of non-M5 patients 4 . This study noted that M5 patients were more likely to have FLT3-ITD and NPM1 mutations, which are associated with better responses to venetoclax, potentially explaining the differing results 4 .
This contradiction underscores the complexity of AML. It's not just one factor, but the interplay of cellular maturity, genetic mutations, and treatment protocol that determines the outcome. This evolving understanding has spurred research into innovative strategies to overcome resistance.
Using a 10-day regimen of decitabine with venetoclax, instead of the standard 5-day schedule, has shown improved response rates in high-risk AML, including monocytic subtypes and those with RUNX1 and TP53 mutations 7 .
A regimen of high-dose, multi-frequency decitabine over 3 days combined with venetoclax (DEC3-VEN) has demonstrated high efficacy (86.7% response rate) and manageable toxicity, offering another potent alternative 5 .
Combining venetoclax with other targeted agents, such as FLT3 or IDH inhibitors for patients with those specific mutations, can help overcome resistance pathways that are co-opted by monocytic cells .
Clinicians note that some AML patients don't respond well to venetoclax+decitabine despite overall promising results.
Researchers identify monocytic differentiation (FAB M4/5) as a potential marker of resistance 1 .
Laboratory research reveals why monocytic cells are less sensitive to BCL-2 inhibition 6 .
Some studies show good outcomes for M5 patients with specific mutations, highlighting AML complexity 4 .
The discovery that monocytic differentiation can drive resistance to venetoclax+decitabine is more than a footnote in a medical journal; it is a beacon guiding the future of AML therapy.
It highlights a critical shift from a one-size-fits-all approach to a nuanced, personalized medicine strategy. By using tools like flow cytometry and genetic sequencing, clinicians can now better identify which patients are less likely to respond to standard venetoclax therapy.
The scientific journey—from observing a clinical pattern, to uncovering the biological mechanism, and finally to developing innovative solutions like extended dosing—exemplifies the iterative nature of medical progress. As research continues to untangle the complex web of resistance, the goal remains clear: to ensure that every patient, regardless of their leukemia's subtype, has an effective and life-extending treatment option.