BCL-2 Inhibitors in AML: Treatment Considerations

Naval G. Daver, MD:The venetoclax and hypomethylating agent, as well as venetoclax in combination with low-dose cytarabine regimens, have been major breakthroughs in the frontline treatment. This offers an option with very high response rates and potential long-term survival that did not exist until a few years ago for older patients with AML [acute myeloid leukemia], as well as the patients with AML who could not get induction chemotherapy. That has been a very positive field of development, and it’s being used very extensively across the United States.

In general, venetoclax is a well-tolerated medication. It’s an oral pill. It does not cause hair loss and has limited gastrointestinal adverse effects. We do not see severe nausea, vomiting, mucositis, diarrhea, or skin rashes. However, 1 of the on-target adverse effects that is seen with venetoclax is prolonged myelosuppression, especially for neutrophil recovery but also for platelet recovery. When we initially started doing the trials with the venetoclax in combination with hypomethylating agents, the way the trials were designed was very similar to what we do with the number of receptor targeted therapies likeFLT3inhibitors,IDHinhibitors, we would do with venetoclax continuously.

We started realizing that the response rates were very high, 75% to 80%, but a number of those patients achieved what we call a CRi [complete remission with incomplete hematologic blood count recovery] or MLFS [morphological leukemia-free state], meaning their bone marrow was cleared out, but their counts were not recovering. Cautiously we started after the first 30 or 40 patients to allow for interruptions of venetoclax at the end of the cycle. With that we did see that a number of patients will maintain their response, but this actually allowed them to recover from the myelosuppression of venetoclax and have recovery of neutrophils and platelets. Today the way we do it, we have very streamlined guidelines. These have been published, and more publications will be coming out in some high impact journals on how I treat or how I use venetoclax-based treatments.

In general, what we do is on day 1, we will start the treatment with, let’s say, azacitidine and venetoclax. They will get the standard dose, 7 days of azacitidine, venetoclax daily, and we will continue it daily from day 1 to the end of the cycle. Somewhere between day 21 and day 28, which is the end of the cycle, we do a bone marrow aspiration. We then use that to decide the next step. If the bone marrow shows that there’s no leukemia, there are no blasts, and flow cytometry shows very limited or no acute leukemia, but the counts are still low, we know that these low counts are more likely from venetoclax myelosuppression—not because of leukemia affecting the bone marrow.

Then, we will stop the venetoclax once we have confirmed that the leukemia is cleared out, and there is a morphological remission. What we see is it usually takes 12 days to 14 days or 12 days to 15 days, and the neutrophils and platelets will recover. We usually like the neutrophils to be at least above 0.5. Above 1 would be ideal along with platelets above 40 or 50, and then we will embark on the next cycle, azacitidine, again for 7 days. We drop the venetoclax to 14 days or 21 days to avoid the recurrent myelosuppression. By using this kind of approach with bone marrow-based interruption after confirming a morphological remission, we see much higher proportion of patients who achieve a complete remission with the count recovery as compared to what we used to see in the past.

The other important thing is how we adjust the dose of the venetoclax for the antifungals, the azoles. What we have noticed in some drug interaction studies was that most of the antifungals increased the venetoclax levels. With posaconazole, we usually reduce the venetoclax dose to 70 or 100. The label dose is 70. Some studies have been doing it 70 and some have been doing it 100 because posaconazole increases venetoclax blood levels by 4-fold to 8-fold. Also with voriconazole, we usually drop the venetoclax to 100, and then with Cresemba or isavuconazole, we would drop the venetoclax to 200.

But I think it’s very important to note that doing the end-of-cycle bone marrow and then using that to determine the next steps is important. Let’s say the end-of-the cycle bone marrow that we did between day 21 and day 28 showed active disease: the patient was not in morphological remission. Then, of course, we would not interrupt the venetoclax, we would keep going. We would do another 2 weeks of the venetoclax and repeat a bone marrow. Many patients will go into delayed remission, and then again you can interrupt, wait for count recovery, and follow the sequence. But, if the patient still has active disease, which is probably now 10% of all patients you treated, then we would just go on to the next cycle. I think a lot of people get confused because they feel that we are doing these interruptions as a standard, but we actually do it based on the bone marrow.

The adjustment of the venetoclax duration often can be confusing as people feel that the interruptions are done irrespective of the bone marrow situation. But I think the key here is to use the end-of-cycle bone marrow to guide the decision because what we do not want to do is stop the venetoclax in somebody who has active disease. If we do find on the bone marrow that we do on day 28, that there is actual residual leukemia and morphological remission has not been achieved, then you do not want to stop the venetoclax.

We will keep it going. We’ll repeat a bone marrow in 2 weeks, and then at that time if the patient has remission, then we interrupt and allow for count recovery. But at that time if the patient still has active disease, which is now a small percentage of patients, then we will go on directly to the cycle number 2. The point is basically one must do an end-of-cycle on bone marrow and use that bone marrow to see the status of remission, the cellularity and the counts, and then make a decision.

In some cases, what we see is even after doing the end-of-cycle bone marrow—seeing that the patient is in remission, the counts are low and interrupting the venetoclax—the counts may not recover even after 14 days, 18 days. In those patients we will use growth factors. Again, this is uncommon but there are some patients where we have to do that. What we do see is using 2 to 3 days of growth factor—Neupogen is the growth factor we use for white cells—will often bring the white count up very quickly, and then we are able to proceed with the next cycle.

In rare cases, even after giving a long interruption and using growth factors, very few patients, I would say 2% to 3% of patients, may still require more time. In those patients, once we have done a bone marrow to confirm remission, I have waited up to 3 weeks to 4 weeks. But, again, that has to be done very cautiously after making sure that the patient is in remission and that the low counts are not in any way due to the leukemia.

In general, we are not using HMA [hypomethylating agent] monotherapy in patients with acute myeloid leukemia. We are able to administer the venetoclax to 98% to 99% of our patients. In general, by using the end-of-cycle bone marrow interrupted schedule, growth factors as needed, prophylactic antibiotics, antifungals, we find that this regimen is tolerable even in patients who are 80 years of age to 85 years of age. We actually have a patient even 90 years of age, a few of them, who were on this.

The only time I would maybe consider using azacitidine alone is if for some reason I was very worried about the compliance of the patient. If I was concerned that this patient would not come during cycle 1 for labs twice a week and for transfusions as needed, which are more commonly needed with venetoclax added to the azacitidine, then that may be the very rare exception where I would consider azacitidine alone. But I would say, again, in our experience at The University of Texas MD Anderson Cancer Center, we have treated probably around 200 and some patients frontline with azacitidine, venetoclax, and I don’t think any of those patients we treated with just azacitidine alone.

Now, when we talk about MDS [myelodysplastic syndrome] and CMML [chronic myelomonocytic leukemia], it’s a different story. We are still using azacitidine or other combinations, azacitidine with immunotherapies or other drugs because we don’t have the clear established data or as robust data as in AML. But, in AML, I don’t feel that there’s a role for azacitidine single-agent therapy.

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