BCL-2 Inhibitors With Hypomethylating Agents in AML

Naval G. Daver, MD:Azacitidine or decitabine in combination with venetoclax has been a major breakthrough in the treatment of older patients with acute myeloid leukemia [AML]. To understand the impact of this treatment, I think it’s important to understand the historical outcomes in these patients. This was one of the most difficult populations of patients to treat with leukemia. In patients above 65 years of age, we used to use drugs such as azacitidine, decitabine. These are called epigenetic therapies, or hypomethylating agents. There have been 3 phase III trials with these drugs showing the response rates with single-agent azacitidine, decitabine in older patients with AML above 65, who are not considered suitable for induction therapy, were about 20% to 30%. So that was our historical expectation—20% to 30% CR [complete response], CRi [complete remission with incomplete blood count recovery] response rates.

The combination of azacitidine-venetoclax was started as a phase IB study at 8 or 10 centers across the United States. Their rationale for this study was that we know that BCL2 is predominant and highly upregulated in almost all tumors, and the tumor that seems to upregulate it to the highest extent is acute myeloid leukemia. We knew that suppressing BCL2 would allow better cell death. BCL2 is basically an antiapoptotic protein. The tumors use it to protect themselves from apoptosis or cell death.

When you block the BCL2, you allow the tumors to undergo apoptosis. So, it’s almost double negative. You’re blocking the antiapoptosis signal, and hence you’re allowing apoptosis. In combination, …in many preclinical studies, it had been shown that azacitidine blocks MCL1, which is one of the escape pathways that becomes upregulated when you block BCL2. By blocking that escape pathway, you are then allowing a lot of synergy to happen, and so you’re seeing good responses.

Now this was preclinical, and we had to confirm it, and we did see with the initial patients treated on this clinical trial that the response rates that we were getting with the combination were about 75%. That’s not even double-triple of the 20% to 30% we got with azacitidine alone.

More impressively, the average median duration of time to get a response with azacitidine or decitabine alone, used to be about 3 to 4 months, and with the combination the median duration to response was 1 month to 1.2 months. So we knew in the first few patients, we were fortunate to treat them actually at The University of Texas MD Anderson Cancer Center, that this regimen was very different, more rapidly acting, more effective, and a higher response rate than we would get with azacitidine, decitabine alone.

The study continued to accrue, and a total of about 225 patients have been treated, and recent updates were presented last year at the American Society of Hematology and published in theBloodpaper. Courtney D. DiNardo, MD, MSCE, is the first author from our group, and the final analysis shows that the response rate, CR/CRi rate in patients with AML above 65, not fit for induction therapy, is about 70%, and the duration of response is about 12 months, which is also double of what we get with azacitidine, decitabine alone. Most importantly, with overall survival historically, we had less than 10% to 15% older patients with AML alive at 3 years or 5 years or longer. With this combination, we are seeing the 3-year survival is about 45% to 50%, so this is a much better chance for these patients to get long-term survival. The median survival with this combination is 17 and a half months, which is double of what was shown with azacitidine, decitabine alone.

So, because of this preclinical synergy that has now translated very nicely, we have seen 3 times higher response, double median survival, and a good chance of being alive at 3 years and hopefully at 5 years as well. We don’t have that follow-up yet, but we will soon. This has now become our regimen of choice and is US FDA approved. I think it should be the frontline treatment of choice in patients where we do not want to proceed with induction chemotherapy.

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