Acute myeloid leukemia has always represented one of the most complex challenges of modern hematology. When conventional treatments fail, when chemotherapy is no longer enough, what is left? An answer comes from AACR 2025, where researchers from the Sarah Cannon Research Institute presented findings that could change the rules of the game.
Four patients with relapsed or refractory acute myeloid leukemia have achieved complete remission thanks to FEEL-202, a cell therapy that uses modified natural killer cells. We're not talking about marginal improvements: we're talking about patients who had exhausted their treatment options and which now, after more than eight months, maintain lasting responses.
Reprogrammed Natural Killer Cells That Learn to Choose
SENTI-202 therapy is an evolutionary leap compared to traditional cell therapies. Senti Biosciences researchers they developed natural killer (NK) cells equipped with a technology called “logic gating,” a kind of intelligent control system that teaches cells when to attack and when to stop.
The mechanism is as elegant as it is sophisticated. The modified NK cells recognize two proteins present on the surface of leukemia cells: CD33 and FLT3. But here comes the ingenious part: they also include a “safety brake” that recognizes the EMCN protein present on healthy stem cells in the bone marrow. The result? The killer cells attack only the right targets, sparing healthy tissue.
Stephen Strickland, director of leukemia research at the Sarah Cannon Research Institute, explained that “this type of logic-gating behavior can only be implemented in cell therapies and is a potentially unique way to treat myeloid leukemia while overcoming tumor heterogeneity and preserving healthy cells.”
The Italian revolution of venetoclax that is saving lives
While futuristic therapies are being tested in the United States, in Italy myeloid leukemia is being fought with already available but equally revolutionary approaches. AIFA has approved the reimbursement of venetoclax, a drug that in combination with azacitidine is transforming the prognosis of the most fragile patients.
The numbers speak for themselves: in elderly patients not eligible for intensive chemotherapy, the venetoclax-azacitidine combination showed a median survival of 14,7 months versus 9,6 months for standard treatment. The VIALE-A studio confirmed that 37,5% of patients were alive at two years, compared to 16,9% of the control group.
The mechanism of action of venetoclax is equally precise: it inhibits the BCL-2 protein, responsible for the survival of leukemia cells, inducing them to programmed death. The synergy with hypomethylating agents such as azacitidine creates a devastating effect for the diseased cells, but tolerable for the organism.
San Raffaele's Engineered Lymphocytes That Recognize the Enemy
Researchers at the IRCCS San Raffaele Hospital have developed a complementary but equally innovative approach. Under the guidance of Professor Chiara Bonini, have developed a therapy based on T lymphocytes engineered with TCR receptors that recognize the tumor protein WT1.
The brilliance of this approach lies in its precision: the TCR receptors used were isolated from the blood of healthy subjects precisely because of their natural ability to recognize WT1, a protein essential for the survival of acute myeloid leukemia cells. Intellia Therapeutics has already received approval to begin its first clinical trial in the United States and the United Kingdom.
The technological innovation here is gene editing with CRISPR/Cas9: researchers replace the natural receptors of T lymphocytes with those specific for WT1, creating an army of immune cells highly specialized in tumor recognition.
Asciminib and the New Era for Chronic Myeloid Leukemia
For chronic myeloid leukemia, innovation has a name: asciminib. Approved in Spain in 2024, this drug represents the first STAMP (Specifically Target the ABL Myristoyl Pocket) inhibitor available for patients who have failed at least two lines of therapy with tyrosine kinase inhibitors.
Asciminib's mechanism of action is radically different from previous drugs: instead of blocking the catalytic site of the BCR-ABL1 protein, it binds to the myristoyl site, an approach that bypasses many of the resistances patients have developed to previous treatments.
In the ASCEMBL study, asciminib showed a major molecular response in 25,5% of patients versus 13,2% of bosutinib, with significantly better tolerability.
The Italian combination that is rewriting the protocols
Researchers of the GIMEMA Foundation they have developed an all-Italian protocol that combines venetoclax with FLAI (fludarabine, cytarabine, idarubicin) chemotherapy for young patients with high-risk acute myeloid leukemia.
The results are impressive: more than 50% of patients remain alive after two years from the start of treatment, compared to 20-25% in the literature with standard chemotherapy. The optimal dosage of venetoclax was identified as 400 mg, a fact that led to the enrollment of 60 additional patients to confirm these promising results.
David Marconi, first author of the study, underlined that “even if the study is not randomized, these results lead us to think that the new therapy is more effective” than conventional approaches.
Artificial Intelligence Accelerates Research
An often overlooked but crucial aspect in the evolution of myeloid leukemia therapies is the integration of artificial intelligence into clinical research. As we have told, experimental immunotherapies are benefiting from advanced computational approaches to identify patients most suitable for treatments.
Predictive analysis of genomic data enables personalized cell therapies, while machine learning algorithms accelerate the identification of new therapeutic targets. This integrated approach is reducing the development time of innovative therapies from decades to a few years.
The future is already here, but resources and organization are needed
Myeloid leukemia is undergoing an unprecedented transformation. From the programmable NK cells of SENTI-202 to the engineered T lymphocytes of San Raffaele, from innovative Italian combinations to new-generation inhibitors such as asciminib, the therapeutic landscape is enriching itself with options that until a few years ago seemed like science fiction.
But the real challenge is no longer technological: it is organizational and economic. These therapies require specialized centers, highly trained personnel and considerable investments. The cost of asciminib in the United States is $260.000 per year, that of SENTI-202 will probably be even higher.
Italy, with its excellent haematological tradition and the network of GIMEMA centres, has all the credentials to be a protagonist of this revolution. The challenge is to maintain universal accessibility to care without compromising innovation.
Perhaps, in the end, myeloid leukemia is teaching us that the future of medicine is not just about advanced technologies, but also about the ability to organize health systems that can make these innovations available to all who need them. And on this, frankly, there is still a lot of work to be done.
