Understanding TP53 Mutations in AML and MDS: Expert Insights from ASH 2024

Mutations in the TP53 gene are a defining feature of high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). These mutations are found in 10–15% of AML/MDS cases and approximately 30% of therapy-related myeloid neoplasms. Patients with TP53-mutated disease are more likely to have poor prognosis, with shorter survival rates. Recognizing the complexity of this condition, experts gathered to discuss updates in TP53 mutations and the latest treatment strategies at the 66th annual American Society of Hematology (ASH) conference.

In this article, we'll highlight all you need to know about updates on TP53 disease and share the interview with one of the participant specialists at the educational session, Dr. Daniel Link. To continue reading more articles like this, visit: 

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1. Are TP53 Mutations All Alike?

We had the privilege of interviewing Dr. Daniel Link after his presentation, during which he explored how the specific type and number of TP53 mutations can influence patient outcomes and treatment efficacy. He also addressed the role of this gene on different cell life functions and how external factors such as UV damage, cellular stress, low oxygen levels, and lack of nutrients can affect the proper functions of TP53. Other findings include: 

• Not all mutations are the same; certain TP53 mutations may possess properties that worsen the prognosis
• Understanding the way TP53 mutations are formed is essential for risk stratification and personalizing treatment

Dr. Link also shared insights into the incidence of TP53 mutations; for instance, they are associated with older age and complex cytogenetics, but they are rare in pediatric AML, with only 4% of patients presenting them. 

Watch the interview below to hear Dr. Link explain the take-home message of this educational session in a comprehensive way. 

2. Non-Transplant Treatment Approaches for High-Risk TP53 Myeloid Disease

Dr. Marina Konopleva reviewed all emerging therapeutic strategies beyond transplantation for TP53-mutated AML/MDS. 

• Current Therapies 
  • Hypomethylating agents: they can offer a complete response in 15-20% of patients and a 40% overall response rate 
  • Immune-based therapies: like antibody-drug conjugates, vaccines, bispecific antibodies, and immune system harnessing therapies 

• New Therapies and Ongoing Trials
  • Chimeric antigen receptor (CAR) therapies
  • Eprenetapopt and Rezatapopt, p53 reactivators that help restore normal protein function
  • Arsenic trioxide (ATO)+ decitabine (phase 1 trial): Novel combination targeting myeloid-specific antigens
  • Magrolimab: currently in late phase of clinical development for AML
  • New treatment in early stages, SL-172154, for MDS patients; initial results show that 67% of patients are in complete remission
  • There are multiple ongoing trials of interest for AML and MDS; you can visit the clinical trial finder to look for trials, such as the STIMULUS study for MDS, the ENHANCE trial for AML, and so many more! 

At the conference, Dr. Konopleva said there is much hope in immune therapy for patients with TP53 mutations. These cutting-edge treatments offer hope for those who are ineligible for transplantation or need additional options.

Staying informed about ongoing advancements empowers you to discuss potential clinical trial opportunities with your care team. If you’re interested in exploring more treatment option updates, we have a comprehensive article that provides further details from a session on treatments for TP53 disease. You can read it here.

3. Transplant Options and Outcomes for TP53 Myeloid Disease

Dr. Hugo Fernandez addressed the challenges of using allogeneic hematopoietic stem cell transplantation for patients with TP53-mutated disease and what can be improved. He discussed how adjusting pre-transplant therapies can increase success rates and shared strategies to reduce the risk of relapse after transplantation.

While transplantation remains one of the few potentially curative options, understanding the risks and benefits can help patients make informed decisions about their care journey. There are several factors taken into account when thinking of a hematopoietic cell transplantation as an option: 

• Patient-related factors: age, health status, comorbidities, goals of care 
• Disease-related factors: MRD status, overall response rates, overall survival  
• Transplant-related factors: What conditioning treatment is best? Which maintenance therapy will induce the longest remission after transplant? What are the most common side effects?

Dr. Fernandez addressed the challenge that many guidelines limit treatment based on age, and many AML and MDS patients are over 65. So, he insisted to doctors in the audience that it is important to look beyond age limitations and focus more on individual health status, considering which therapy is safer, increases quality of life, and improves outcomes. 

During his presentation, he introduced results from the COMMAND trial, which reported 370 patients with TP53-mutated disease. Of these, 39% responded after the first stem cell transplant and 35% after subsequent therapy, with an overall survival of 24 months.

The comprehensive approach for TP53 disease was an induction therapy that considers the patient's goals, intensive chemotherapy, hypomethylating agents combined with venetoclax or a clinical trial, then an allogeneic HCT for responding patients and always tailoring a conditioning regimen. After HCT, the maintenance therapy that induces the longest remission, a hypomethylating agent combined with venetoclax, or considering a clinical trial. 

Conclusions

A key point discussed during these educational sessions was that in patients with complex karyotypes, it is not sufficient to look for TP53 only once; it's also important to identify how TP53 evolves over time at different stages of the disease. 

Facing a diagnosis of AML or MDS with TP53 mutations can feel overwhelming, but the updates shared at the 66th ASH conference bring hope and exciting possibilities for patients. Experts are working tirelessly to better understand these mutations and develop innovative therapies to improve outcomes.

From groundbreaking treatments like CAR-T cell therapy or drugs that reactivate p53 function to new strategies for making transplants safer and more effective, great advances are coming for patients with TP53-mutated disease. Most importantly, most of these are available through clinical trials, so if you or your loved one have been diagnosed with a TP53-mutated disease, make sure you explore all your options. 

The Key Takeaway? You’re Not Alone

Staying informed about new therapies and clinical trials can open doors to cutting-edge care. Talk to your specialist about these options and how they might fit into your treatment plan.

Source: 

• Handling Bad News: How to Best Manage TP53 Myeloid Disease