Rapidly Progressing Acute Myeloid Leukemia - Episode 2
Naval G. Daver, MD:Mutational testing is a very important part of the initial diagnostic workup for new patients with acute myeloid leukemia [AML] today. The way I like to think about the mutational testing is it depends on what the backbone of therapy is going to be. If we’re going to use high-dose induction therapies, such as cytarabine anthracycline-based, then chromosome and mutational testing is extremely critical. If the patient has anFLT3, orFLT3mutation, then we would add a drug called midostaurin, which is aFLT3inhibitor to the 3 + 7 regimen. This is shown in phase 3 studies to improve survival and response rate, and it’s quite well tolerated. On the other hand, if the patient has a core binding factor chromosome change, in version 16 8;21 chromosome alterations, then we would add gemtuzumab ozogamicin, an antibody drug conjugate, to the backbone of 3 + 7, which also can improve the overall survival of 20% or so in that core-binding factor population.
If the patient has anIDH1orIDH2, there are trials looking at adding IDH inhibitors with some early promising data. If a patient has what we call secondary AML, or MDS [myelodysplastic syndromes]-associated cytogenetic changes, then there’s a drug called Vyxeos, or CPX-351, that is approved in this indication and has shown improved survival.
There are 4 different treatments that you could give to a young patient with induction therapy, either adding a drug or using an adjutant drug, all of which have shown superiority to the standard 7 + 3. So mutational chromosome testing is quite critical because you want to give the patient the best chance by selecting the appropriate regimen.
In older AML, the mutational testing is also important, but not as critical to selecting the therapy. It still plays an important prognostic role. Patients who haveNPM1,IDH1andIDH2mutations, core binding factor, in general tend to do much better. Those who have adverse mutations such asTP53,ASXL1, andFLT3, tend to do worse.
However, therapeutically, we don’t have the degree of segregation of treatments like in younger patients with AML. For most older patients with AML, if we decide that they’re not good candidates for high-dose induction, like this patient, because of comorbidities or organ dysfunction or age, then usually starting off with the hypomethylating agent with venetoclax, either azacitidine or decitabine, or low-dose cytarabine with venetoclax is quite reasonable. There will be data shown at the American Society of Hematology Meeting in 2019, and published in the near future, showing that the response rates across different mutational groups with hypomethylating agent and venetoclax are actually quite well maintained, between 50% and 75%. Survival-wise, the people who have the high-risk mutations,TP53,FLT3, they do have a poorer survival, but it is still better than azacitidine or decitabine alone.
So I think in the community it’s reasonable to send the molecular testing, rush it if you can, but if you have decided that this patient should not get cytarabine anthracycline induction therapy, I don’t think it will be wrong to start the azacitidine with venetoclax or decitabine with venetoclax, and then use the mutational testing to either fine-tune or consider other therapies in the relapsed setting.
Transcript edited for clarity.
Case: A Male With Rapidly Progressing Acute Myeloid Leukemia
A 64-year-old male presented with a 2-week history of subjective fever, fatigue, shortness of breath, dizziness, and cough
H & P
Diagnostic Work- Up