Unmet Needs and Future Direction in AML

Naval G. Daver, MD:We’ve made significant process going from 15% to 16% 5-year survival rates with azacitidine, decitabine in the past 2 decades to now 45% to 50% long-term survival rates with the addition of venetoclax with azacitidine, decitabine. Similar progress has been seen with low-dose cytarabine, venetoclax that is being extensively used in Australia and Europe. But, at the end of the day, we’re still talking about 40% to 45% long-term survival rates. So, the majority of patients are still going to either relapse or be refractory and not achieve a response over the 3-year to 5-year follow-up period.

Our big areas of research interest now at MD Anderson Cancer Center, in collaboration with a lot of academic centers across the country, has been to identify…those patients who are either not going to respond to the hypomethylating agent venetoclax or relapse early. I think we have a good idea about this, and a lot of this data is being presented this year and next year at some of the large national meetings. In general, we see patients who haveTP53mutations are either resistant, or even if they achieve a response to the hypomethylating agent venetoclax, the response is short, and they relapse. So, we don’t feel that this is the solution for those patients.

For the patients withTP53-mutated disease] we’re still looking for new approaches, and one of those that has shown very promising activity is a drug called APR-246. This is aTP53-directed therapy, and the combination of azacitidine and APR-246 has shown response rates greater than 90%, which has led to a phase 3 registrational study of this drug in MDS [myelodysplastic syndrome]. But if it’s positive, it will also be probably beneficial and used in AML [acute myeloid leukemia]. The other approach that we’re looking at forTP53-mutated cases is using immunotherapies, which have been very successful in many solid tumors in lymphoma and are being developed in AML. We do see that there are certain immunotherapies, such as the CD47 antibody, which is a macrophage checkpoint-directed therapy. In some early phase 1B data, that has shown high response rates in newly diagnosed AML andTP53when the azacitidine was combined with the CD47.

Now we’re looking at if it is possible to add drugs like the APR-246 or CD47 to the backbone of azacitidine, venetoclax to push not only the response rates but more important the durability as well as survival. I think a lot of these studies will be done and presented next year. The other group where there is still unmet need isFLT3-mutated. We do see that these patients respond initially to the azacitidine, venetoclax, but the response duration is short, and the median survival is 10 months to 12 months for newly diagnosed patients withFLT3-mutated disease with azacitidine, venetoclax.

We are now combining venetoclax withFLT3inhibitors, such as venetoclax with gilteritinib, venetoclax with quizartinib. We are even moving frontline treatment to do a triplet combination of azacitidine, venetoclax with gilteritinib or azacitidine, venetoclax with quizartinib. We are seeing…that the combination of venetoclax, gilteritinib is very active. This will be presented at the American Society of Hematology meeting this year. The response rate in relapsedFLT3AML is about 85%, where a single-agent gilteritinib will give you about 45% to 50% response rate. So, it looks like the doublet is very active, doubles response rate, and in general is very well tolerated.

Of course, as we do these strategies, we have to be aware of the myelosuppression, and we have to build in interruptions, use of growth factors, and that’s the reason all of these should be done in trials. Because I think if we just try to add “1 + 1 + 1,” the myelosuppression would be prohibitive and probably lead to high early mortality. I think a lot of these trials will guide the way, as to how we deliver these doublets and triplets in the best way, so that we can increase efficacy while maintaining the safety profile.

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