Role of Molecular Testing in Acute Myeloid Leukemia

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

• PE: Temperature 99.1^oF, pallor of the conjunctiva, multiple ecchymosis on upper and lower extremities
• PMH: DM controlled on metformin, hypertension, BMI >35, recent history of pneumonia treated with oral antibiotics
• ECOG: 2

Diagnostic Work- Up

• Initial pertinent positive lab values:
  • WBC: 2.3 x 10³/µL, RBC: 3.1212 x 10⁶/µL, Hb: 9.3 g/dL, Ht: 23.1%, Plt: 83 x 10³/µL, LDH: 275 U/L, blasts: 36%, absolute neutrophil count: 320 cells/µL, PT: 16.1s,
  • Few auer rods noted on bone marrow aspiration
• Diagnosed with AML with 43% blasts on pathology evaluation, flow-cytometry confirms AML
• Molecular panel and cytogenic testing pending and RUSH requested
• Chest CT revealed patchy consolidation in the left lower lung lobe with ill-defined nodules
• EKG and Echocardiogram unremarkable
• Started on prophylactic voriconazole, cefpodoxime, and valacyclovir

Treatment

• Patient was started at this time on azacitidine and venetoclax; Azacitidine 75mg/m²Days 1-7 and Venetoclax Days 1-28. Venetoclax dose was 100mg with voriconazole.
• Was admitted for tumor lysis monitoring and hydration. Tolerated cycle 1 well. continue until disease progression or unacceptable toxicity
• Day 28 post-treatment bone marrow aspirate revealed low percent residual blasts (3% blasts by flow) with hypocellular BM (5-10% cellularity) and ANC 0.3, platelets 23K
• Venetoclax was interrupted at this time. Labs checked 2-3 times per week outpatient. Within 12 days after venetoclax interruption ANC>0.5 and platelets>50K.
• Cycle 2 started outpatient with standard dose azacitidine and venetoclax reduced to 14-21 days

Follow-up

• Patient subsequently developed pneumonia, treated with oral antibiotics
• Patient will continue routine bone marrow biopsies after cycle 4, and every 6 months thereafter or if disease progression is suspected