Rapidly Progressing Acute Myeloid Leukemia - Episode 4

Determining Response Rates to Oral Therapy in AML

Naval G. Daver, MD:Recently we have analyzed, presented, and published molecular subgroup analyses of response rates and survival with the hypomethylating agents, azacitidine, decitabine in combination with venetoclax. What we see is that there are certain patients in whom the responses and survival are very dramatic and very positive. These includeNPM1,IDH1,IDH2, and in some analyses,RUNX1. Patients who have 1 of these underlying mutations seem to have response rates of 85% to 90% or higher to the hypomethylating agent venetoclax, and these responses are very durable. WithNPM1,IDH1, andIDH2we see that at 3 years, more than 85% of the patients have maintained their response. These patients have a very high chance of…being cured, we think, with this doublet combination, which is a low intensity therapy, outpatient, and much better tolerated than traditional anthracycline, cytarabine induction.

There are also molecular groups that unfortunately do not have as robust or as durable a response. These includeTP53, as well asFLT3mutation patients. Interestingly, with these patients, we see that the response rates are not too bad. They’re about 50% to 60%, so a little lower than the 70% to 80% we would see in the general population. We did an analysis at The University of Texas MD Anderson Cancer Center, and an analysis has also been done on the large dataset that was multinational study. We see that the median survival forTP53with the hypomethylating agent venetoclax is about 7 months to 8 months. This is a little better than we would get with azacytidine, decitabine alone where it was about 6 months but definitely left much to be desired.

WithFLT3, this is quite interesting. Historically, based on preclinical data, we expectedFLT3to be resistant to venetoclax, and in a single-agent study we did find that patients withFLT3-mutated disease were resistant to venetoclax. In the combination, we started thinking that since the response rate is about 60% to 65%, maybe we are overcoming it. But, again, what we see is that the survival, especially ofFLT3-ITD-mutated disease treated with azacitidine, venetoclax is about 10 months to 12 months, which again is better than azacitidine alone, 6 months to 7 months. But it is not ideal and potentially adding eitherFLT3inhibitors or using a doublet of azacitidine,FLT3inhibitor may be better. So, these are the areas where there’s a lot of research ongoing how to improve azacitidine, venetoclax therapy further.

In general, in oncology, and the same applies in leukemia, there is also preference for the outpatient regimen, lower toxicity, and oral therapy. Venetoclax is an oral drug. Now it’s given in combination with azacitidine and decitabine, which are given either IV [intravenously] or subcutaneously. But the nice thing is that these can be done as an outpatient procedure. They do not require hospitalization and definitely not prolonged hospitalization. So, at this time, that is one of the positive features that a lot of physicians and patients like about this regimen as compared to standard induction.

There is data emerging also with an oral formulation of azacitidine, as well as an oral formulation of decitabine. So many of us feel, in the near future, in the next 2 years to 3 years, it is possible that we could be having a complete oral regimen—oral azacitidine or oral decitabine with venetoclax. We could see a new patient with acute leukemia, give them 2 pills with close monitoring of blood work, and all of the treatment could be oral and outpatient. If somebody would have said this 20 years ago, it would have been unheard of. So, this is quite dramatic progress that is happening in the field.

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 99.1oF, 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