This year, due to COVID-19, the 25th European Haematology Association (EHA) annual congress ran virtual sessions over 10 days starting from 11th June. The reason why we attend these conferences is to inform you about any interesting new developments in patient care, research and emerging treatments in the different leukaemia types. Different sessions ran each day according to a particular theme, beginning with acute leukaemia. The focus of the blog this week will be on the emerging new treatment landscape in the acute myeloid leukaemia (AML) field and potential new developments in the CAR-T area.
Emerging combination treatments in the “hard-to-treat” AML population
Difficult-to-treat AML patients
In the EHA sessions, newly diagnosed older AML patients and patients with a TP53 mutation were referred to as “hard-to-treat” population.
AML is most common in older people. Typically, older newly diagnosed patients are less likely to withstand the standard intensive chemotherapy. Therefore, in most cases these patients will be offered a lower intensity treatment such as azacitidine.
Adding novel agents to azacitidine
With the development of many novel agents, in particular the BCL-2 inhibitor venetoclax, the aim of current and future clinical trials is to investigate effective combinations of these two treatments. For example, Dr Courtney DiNardo from United States presented results from the Phase III trial: VIALE-A, where the combination of venetoclax with azacitidine showed a significant improvement in the overall survival and remission in older AML patients than azacitidine alone.
Another promising combination presented at EHA was azacitidine with a CD47 antibody magrolimab. This was shown to be effective in this older/unfit AML population. Interestingly, it is even more effective in patients with a particular type of mutation that has historically been harder to treat, the TP53 mutation. The magrolimab works by targeting a molecule called CD47 on the surface of cancer cells. Cancer cells use CD47 as a “don’t eat me” signal by which the cancer cell is able to protect itself and avoid being destroyed by the immune system. Magrolimab targets and blocks this “don’t eat me” signal between the cancer cell and the immune cells, allowing activation of a process called macrophage phagocytosis. This means the cancer cells, in theory, will get ingested and destroyed. The current clinical trial for this combination can be found here: https://www.clinicaltrials.gov/ct2/show/NCT03248479?term=magrolimab&draw=2&rank=3
Another combination to mention is the azacitdine with APR-246. Encouraging clinical trial results were presented, again in this difficult-to-treat, TP53-mutated AML sub-type. The TP53 gene is mutated in some AML patients and usually linked with resistance to treatments and poor outcomes. This explains why these patients have historically been difficult to treat. The normal role of p53 protein is to stop cells becoming cancerous; however, this function is not carried out by the p53 protein made by these AML patients. The APR-246 is a small molecule that reactivates the p53 made by these patients and enables the reactivated p53 to carry out its cancer suppressing functions and eliminate the cancer cells.
Overall, these EHA sessions on hard-to-treat older and TP53-mutated AML patients highlighted that combination therapy is the way forward; many double and even triple combination approaches are likely to be investigated. Azacitidine is likely to be the backbone for many of these combinations. What we can conclude from the findings presented at EHA is that combinational approaches are demonstrating to be more effective than azacitidine alone.
There were quite a few presentations on CAR-T at EHA this year. There has been a lot of interest in the field of chimeric antigen receptor T-cells (CAR-T) therapy in the last few years. It has regularly been promoted as a new class of therapy with the potential to cure cancer. The success and approval for use in the UK of the two CAR-T therapies – tisagenlecleucel to treat acute lymphoblastic leukaemia (ALL) and axicabtagene ciloleucel for lymphoma – have likely inspired many other researchers to pursue this approach.
Developing the current technology
The EHA session presented results from studies confirming the success of the two approved CAR-T therapies. Remarkable remission rates were observed in both adults and children that had previously relapsed from or have refractory ALL. However, there were a few cases where patients had still relapsed from their disease. The research so far has identified the different mechanisms that may be causing this resistance. Current research is utilising this knowledge to improve this technology.
A limitation of CAR-T therapy is the associated toxicities, in particular the cytokine release syndrome (CNS). The EHA session made remarks on how different research groups are using mouse models to understand the science behind CNS. This will allow the researchers to come up with ways to treat or prevent CNS, effectively targeting this limitation of CAR-T.
The two main aspects researchers are looking at is how to monitor and improve CAR-T cell expansion and persistence in patients with ALL. This will help the CAR-T cells to perform its function and destroy the cancer cells effectively. Researchers are gaining a better understanding of CAR-T therapy. This knowledge will help scientists design better CAR-T therapies in the future, potentially managing CAR-T therapy relapse and toxicities.
New target – CD7 in ALL
The two currently approved CAR-T treatments target the CD19 molecule found on the surface of cancer cells in patients. A lot of research is focusing on finding different targets and hence different ways of destroying the cancer cells, as CD19 is not always present or can be hidden by cancer cells in response to treatment.
One study presented at EHA developed CAR-T therapy to target a molecule called CD7 in patients with relapsed and refractory ALL. The study confirmed that CD7 is found in ALL patients at diagnosis, relapse and during chemotherapy. The research on mouse models showed that by targeting this CD7, the survival of the mice was significantly improved. The cancer cells were effectively eliminated in the mouse model. This CAR-T therapy was then further trialled on ALL patients, where it showed great potential. The treatment was also well-tolerated by patients with relapsed and refractory ALL. As a result, it is currently undergoing phase I trials, the first stage of clinical trial where the safe and effective dosage is determined.
Many clinical trials within the field of CAR-T therapies are currently ongoing and it is a very interesting and emerging field. The advances in knowledge and understanding of CAR-T therapies will help scientists develop more effective treatments.
You can get more background information about CAR-T therapy in our free online booklet here: https://www.leukaemiacare.org.uk/wp-content/uploads/CAR-T-Therapy-Web-Version.pdf