New drug combinations pave the way for personalised leukaemia therapies

Researchers from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), have published a landmark review on BH3 mimetics—a new class of drugs that are reshaping the treatment landscape for acute myeloid leukaemia (AML), one of the most aggressive and treatment-resistant blood cancers.

 

AML has long challenged clinicians because leukaemia cells evade cell death by overexpressing proteins from the BCL-2 family. In healthy cells, they have a built-in self-destruct programme called apoptosis, which is controlled by a family of proteins called BCL-2 proteins. AML survives through suppressing apoptosis, enabling malignant cells to resist standard chemotherapy. BH3 mimetics are small-molecule inhibitors that directly target these pro-survival proteins, restoring the balance of the apoptotic pathway and allowing cancer cells to die.

 

The most successful of these drugs to date is venetoclax, a highly selective BCL-2 inhibitor. Clinical trials have shown that when combined with standard-of-care therapies such as hypomethylating agents (HMAs) or low-dose cytarabine (LDAC), venetoclax achieves significantly better remission and survival outcomes. These combinations are already approved by the US Food and Drug Administration (FDA) for newly diagnosed AML patients aged 75 and older, or those deemed unfit for intensive chemotherapy.

                                                                                                                     

Assistant Professor Alan Prem Kumar from the Department of Pharmacology, and NUS Centre for Cancer Research at NUS Medicine, who co-led the study with Assistant Professor Courtney DiNardo, The University of Texas MD Anderson Cancer Center, USA, said, “Venetoclax has transformed the treatment landscape for AML. For the first time, patients who were previously considered too frail for intensive chemotherapy have access to a treatment that significantly improves their chances of remission and survival.”

 

The team’s findings, published in Nature Reviews Clinical Oncology, provide a comprehensive overview of the clinical impact of BH3 mimetics and chart future directions for optimising their use. To reach their conclusions, the research team conducted an extensive review of over 1,000 peer-reviewed articles, evaluating 236 high-quality publications. The analysis examined mechanisms of drug resistance, the therapeutic impact of BH3 mimetics, advances in profiling techniques, and the development of next-generation treatment strategies.

 

The review highlights several important findings about BH3 mimetics and their role in treating acute myeloid leukaemia. These drugs demonstrate potent anti-cancer activity, effectively inhibiting pro-survival BCL-2 proteins and proving capable of eradicating even non-dividing leukaemia cells with complex mutations.

 

Clinically, venetoclax has already transformed therapy, particularly for older or unfit patients who were once considered too frail for intensive chemotherapy. Its success has also spurred the development of multiple new drug combinations designed to improve outcomes further. However, venetoclax is not a cure-all. Many patients relapse as cancer cells switch their survival dependence to other proteins such as MCL-1 or BCL-xL, or develop mutations in genes such as TP53, KRAS, and FLT3.

 

“Cancer cells are highly adaptable, and resistance to therapy remains the biggest hurdle in AML treatment,” explained Donavan Jia Jie Tan, first-year medical student at NUS Medicine and a co-author of the study. “By targeting multiple pathways simultaneously—through new drugs, combination regimens, or advanced drug delivery systems—we can close off escape routes and improve the durability of treatment responses.”

 

“Tools such as BH3 and mitochondrial profiling are now paving the way for treatment strategies tailored to each patient’s cancer biology, allowing clinicians to predict responses and refine care on an individual basis” said Dr Lam Hiu Yan, research fellow with Dr Kumar’s group and another co-author in the study. “This information can help clinicians predict whether venetoclax will be effective or whether alternative BH3 mimetics targeting MCL-1 or BCL-xL should be used”.

 

“The future of AML treatment lies in personalisation,” said Asst Prof Kumar. “Instead of a one-size-fits-all approach, we can now tailor therapy to each patient’s biology, improving effectiveness and reducing unnecessary toxicity.”

 

Professor Chng Wee Joo, Yong Loo Lin Professor in Medical Oncology, NUS Medicine, and Senior Consultant at the Division of Haematology, Department of Haematology-Oncology, National University Cancer Institute, Singapore, who is not involved in the study, added, “We are now able to offer AML patients, especially older adults and those with other medical conditions, a therapy that is both tolerable and effective. The improvements in remission and survival we are seeing would have been unthinkable just a decade ago. The next step is to refine these treatments further, making them more precise and accessible for patients worldwide. With ongoing research, we hope to turn what was once a rapidly fatal disease into a more manageable, chronic condition.” Prof Chng is also Vice President (Biomedical Sciences Research), Office of the Deputy President (Research and Technology), NUS, and Senior Principle Investigator, Cancer Science Institute of Singapore, NUS.

 

Ongoing clinical trials are exploring venetoclax in combination with novel agents such as FLT3 inhibitors and CD47-targeting drugs, with the potential to extend benefits to more patient groups. Other BH3 mimetics targeting MCL-1 and BCL-xL are also under investigation, supported by technological advances in drug design.

---

---