A breakthrough in epigenetic therapy targeting relapsed/refractory acute myeloid leukemia through biomarker modulation
Dr. Larson stared at the latest lab results, frustration mounting. For the third time this month, Maria's leukemia had stopped responding to conventional treatments. The 68-year-old grandmother's only remaining options were increasingly toxic with diminishing returns. But on his screen, a new set of data showed promise—a novel compound called mivebresib appeared to be hitting leukemia cells in a completely different way, not by poisoning them, but by reprogramming their genetic machinery. This approach represented a radical shift in acute myeloid leukemia (AML) treatment, one that might offer hope to patients like Maria who had exhausted standard options.
Acute myeloid leukemia is a devastating blood cancer characterized by the rapid growth of immature white blood cells that crowd out healthy blood cells in the bone marrow. What makes AML particularly challenging is its heterogeneity—no two patients' cancers are exactly alike at the molecular level.
For decades, treatment has relied primarily on intensive chemotherapy, but this approach comes with severe side effects and often fails to produce lasting remissions, especially in older patients.
Mivebresib (ABBV-075) represents a new class of investigational drugs called BET inhibitors. Unlike traditional chemotherapy, mivebresib doesn't directly damage DNA. Instead, it works by blocking the BET proteins that cancer cells depend on to read specific genetic instructions.
A landmark phase 1 clinical trial (NCT02391480) was designed to evaluate both the safety and biological activity of mivebresib, both alone and in combination with venetoclax, in patients with relapsed/refractory AML 3 . This first-in-human study represented a critical step in translating promising laboratory findings into potential patient benefits.
| Treatment Group | Number of Patients | Dosing Regimen |
|---|---|---|
| Mivebresib Monotherapy | 19 | 1.5, 2.0, or 2.5 mg daily |
| Mivebresib + Venetoclax | 25 | Various combination doses |
| Switched to Combination | 5 | After progression on monotherapy |
Total Patients Enrolled
Patients Receiving Combination Therapy
The most compelling aspect of this trial wasn't just whether patients responded clinically, but how researchers could measure the drug's direct impact on cancer cells at the molecular level—a concept known as pharmacodynamics.
| Pathway Component | Normal Function in Cancer | Effect of Mivebresib |
|---|---|---|
| BET Proteins (especially BRD4) | "Read" genetic instructions that promote cancer growth | Blocked from accessing their target genes |
| c-Myc | Master regulator of cell growth and proliferation | Downregulated, slowing cancer progression |
| BCL-2 (targeted by venetoclax) | Prevents cancer cells from self-destructing | Inhibited, allowing programmed cell death |
While the biomarker data provided compelling scientific evidence, the clinical outcomes for patients were equally important. The trial established that both mivebresib alone and in combination with venetoclax were generally manageable, with predictable side effects 3 .
| Response Category | MIV-Mono (n=19) | MIV-Ven (n=25) |
|---|---|---|
| Complete Remission (CR) | 0 | 2 |
| Complete Remission with Incomplete Blood Recovery (CRi) | 1 | 0 |
| Partial Remission (PR) | 0 | 2 |
| Morphologic Leukemia-Free State | 0 | 2 |
| Resistant Disease | 15 | 12 |
| Research Tool | Function | Key Finding |
|---|---|---|
| RNA Whole-Transcriptome Sequencing | Measures activity of all genes in a cell | Confirmed dose-dependent changes in gene expression after mivebresib treatment |
| Patient-Derived Xenograft (PDX) Models | Implants human AML cells into specialized mice | Created "co-clinical" models that mirrored patient responses to therapy |
| Flow Cytometry | Identifies and counts specific cell types | Measured reduction in human leukemia cells in mouse bone marrow and spleen |
| BH3 Profiling | Measures how close cells are to apoptosis | Helped identify which patients were most likely to respond to venetoclax-based therapy |
The investigation of mivebresib and other BET inhibitors represents a paradigm shift in cancer therapy—from toxic chemicals that damage all rapidly dividing cells to targeted agents that specifically disrupt the molecular machinery driving cancer growth.
BD2-selective BET inhibitors like ABBV-744 that may offer improved safety profiles 1
Combination strategies with other targeted agents 9
Identifying patients most likely to benefit from BET inhibition
Sequencing strategies to prevent or overcome treatment resistance
The journey from laboratory discovery to clinical application is long and challenging, but studies like these illuminate the path forward—one where we don't just poison cancer cells, but rather, reprogram their very nature.
Treatment guided by molecular profiling for maximum effectiveness