Navigating the AML treatment landscape for patients who can and cannot receive a transplant 

Prognosis and treatment plans can vary for acute myeloid leukemia (AML) based on patients’ genetic risk group. Transplant and intensive chemotherapy are also less effective in older patients with AML. This may be due to primary refractory disease, comorbidities, and advancing age. 

At the 66th American Society of Hematology (ASH) conference, experts talked about new advances in AML treatment. Their presentations focused on mutation and measurable residual disease (MRD). They discussed how these factors inform treatment decisions for patients with AML, whether they are eligible for transplant or not. We share key insights on integrating mutation and MRD data in AML treatments.

What is the role of genetic mutational profiling in AML?

Genetic mutations may appear alone or in combination with other mutations and chromosomal abnormalities in AML. Genetic mutations like FLT3, NPM1, CEBPA, and IDH1/2 are important. They help clinicians decide on your risk group and treatment plan.

Targeted therapies improve outcomes. They are useful if you can’t have hematopoietic stem cell transplantation (HSCT). This might be due to age, comorbidities, or other factors. 

• Targeted therapies can help in the treatment of specific genetic mutations. FLT3 inhibitors like gilteritinib and midostaurin target FLT3 mutations. IDH inhibitors like ivosidenib and enasidenib target IDH mutations.
• Quizartinib is the only FLT3 inhibitor approved for maintenance therapy after allogeneic HSCT in patients who can receive a transplant.

Mutational profiling also helps to find out if you are a high-risk patient. This means you might need more intensive treatment regimens like HSCT. It also helps clinicians tailor chemotherapy to your specific genetic mutation.

Understanding MRD monitoring and why it is important

MRD assessment is a useful tool. It checks how well patients respond after induction therapy and aids in making treatment decisions. The most common methods to monitor MRD in AML are: Multiparameter flow cytometry (MFC), and Molecular MRD testing [polymerase chain reaction (PCR) and next-generation sequencing (NGS)]. 

The European LeukemiaNet (ELN) risk groups are considered when assessing prognosis using MRD monitoring in patients receiving intensive treatment. 

• For example, MRD assessment during intensive treatment helps with risk stratification in certain genetic subgroups. In patients with FLT3-ITD mutation, it is helpful after two cycles of treatment and in most other subgroups at the end of treatment or during follow-up.
• The ELN risk and genetic subgroups are recommended to decide the appropriate MRD monitoring method before and after allogeneic HSCT.

In the context of patients with AML who can receive a transplant:

• Patients with FLT3-mutated AML with no NPM1 mutation, who are MRD-NGS positive before and after allo-HSCT, will benefit from maintenance therapy after allo-HSCT.
• Low-intensity chemotherapy combined with venetoclax can lead to MRD negativity. It can also improve survival rates for patients with FLT3- and NPM1-mutated AML.
• For patients with FLT3-mutated AML with NPM1 mutation, allo-HSCT is advised without any further treatment if they have persistent MRD positive status following two cycles of chemotherapy. 
• Patients with MRD relapse should receive remission-inducing treatment before allo-HSCT.

How can novel agents and combination treatment help?

• The prognosis for older patients with AML who can’t receive a transplant has greatly improved. This is due to new targeted therapies and the standard treatment combining azacitidine and venetoclax (AZA-VEN). 
• In patients with AML who can receive a transplant, combination therapies like AZA-VEN and azacitidine plus ivosidenib (AZA-IVO) are now standard treatments. These therapies lead to improved patient outcomes.
• Combination regimens like HMA-VEN with inhibitors targeting genetic mutations like FLT3 , IDH1, IDH2 have proven effective. Early results from clinical trials suggest that these may improve outcomes for patients with high-risk mutations.
• Targeted therapies can boost remission and survival rates when combined with standard chemotherapy. This is especially true for patients with AML with high-risk mutations like FLT3-ITD and TP53 who can’t receive a transplant. For example,

• • AZA-IVO is a preferred option for IDH-mutated AML than HMA-VEN.

  • If available, clinical trials are recommended to HMA-VEN in TP53-mutated AML.

  • VEN plus gilteritinib (GILT) and AZA-VEN-GILT remain the recommended salvage treatment choice for relapsed/refractory FLT3-ITD-mutated AML.

  • Using cladribine (CLAD) with low-dose cytarabine (LDAC) and VEN helps improve outcomes for patients with K/NRAS-mutated or monocytic AML who have intermediate mPRS risk.

  • In NPM1-mutated and KM2TA-rearranged AML, combinations like LDAC-VEN and AZA-VEN have proven effective.

Future directions 

Using genetic and MRD data to sequence therapies is crucial for better treatment results. Future research should aim to improve mutation-informed therapies. It also should explore the best ways to include MRD tools in clinical guidelines and practice.

Conclusion

These insights show how AML treatments are evolving. They support the shift towards more personalized treatment strategies. These strategies consider mutation- and MRD-informed treatment plans for all patients, regardless of whether they can have a transplant or not. These approaches can open up more treatment options for patients who can’t have transplants. They can also help clinicians make informed decisions and improve patient outcomes. Further efforts to improve clinical outcomes will help integrate these tools into routine care.

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Sources:

Mutation- and MRD-informed treatment decisions for the transplant-eligible AML patient 

Mutation- and MRD-informed treatments for transplant-ineligible patients