Acute Myeloid Leukemia: Evolving Through Targeted Therapies - Episode 8
Harry Paul Erba, MD, PhD: Let me move on to the next part of the conversation about this regimen. I agree that this is a new standard of care. HMA [hypomethylating agent] monotherapy should not even be considered for our patients anymore. To put the benefit of this in perspective, we have to remember that in the United States almost two-thirds of patients, at least half over the age of 65 years old, don’t even get treated for AML [acute myeloid leukemia], and that’s because of the low response rates important with HMAs. That’s because we didn’t really see a survival benefit with the HMAs. But this is different. We have a median survival of 15 months with AZA-VEN [azacitidine-venetoclax] compared with 10 months with AZA [azacitidine] alone.
Not only that, the curves aren’t coming together. What I find most interesting is that the curves aren’t coming together. A few of those patients, 10%, did go on to get a transplant in the phase 1 study, but that’s very few. I think 1 or 2 in the VIALE-A study actually got a transplant.
You have to put this into context because the median survival of untreated patients with AML, based on SEER [Surveillance, Epidemiology, and End Results] registry data are 2 months. It’s not 15 months versus 9 or 10 months; it’s 15 months versus 2 months. We have to get away from the therapeutic nihilism in older AML patients. In fact, the greatest survival benefit is actually seen in those over the age of 75 years old. That’s my commentary. We won’t see those response rates—we won’t see that improvement in survival—unless we manage the toxicities of this regimen the way they were managed on the clinical trial and really educate people how to do that.
I’m going to turn to Amir to start us on a conversation of some of the toxicities associated with this regimen. What are the pitfalls? What are the caveats? How do you get patients through this? Let’s start with tumor lysis.
Amir Fathi, MD: Well, that’s an easy 1. There isn’t much tumor lysis with HMA and venetoclax in AML. There are reports, so it’s important to watch and be careful, especially with the first few doses. But it’s much less common than what you would see with chronic lymphocytic leukemia, a scenario that is a much more challenging situation. Thank you, Harry, for allowing me to follow up with the very pleasant and uplifting data associated with HMA-VEN [venetoclax]. I’m happy to do so because I really think there are some challenges with the combination.
I worry that this combination is being pervasively used and increasingly used in the community. One of the challenges with the combination of HMA and venetoclax is the lack of consistency regarding the approach to its use. Do you give it for 4 weeks? Do you give it for 3 weeks? Do you give it for 2 weeks? I’m referring to venetoclax. Do you pause after the first cycle of treatment? Do you do a marrow after the first cycle of treatment? If you have low blasts, do you wait or do you continue?
What do you do with additional drugs that may come onboard? For example, the azoles are the most common challenging drugs. These are scenarios that require a lot of education. I do worry, based on what I have seen in my practice, that this degree of education and pervasiveness of knowledge is not yet there. When you say that there are amazing data we see in the phase 2 or the phase 3 data, I’m extremely happy about that. Like everybody else on this panel, I’m very reassured by the data that were presented 2 days ago.
But I worry that the real world is also very different when it comes to HMA–VEN [venetoclax], just as it is with HMA. I can’t tell you how many patients we’ve admitted to our ICUs [intensive care units] who have been treated in the community with HMA–VEN [venetoclax] cycle after cycle after cycle and end up with severe marrow suppression, infections, and bleeding complications.
Ultimately what we need is a consistent treatment. I can tell you what I do. I suspect it’s probably similar to what other folks do here; maybe not. There might be nuances and that’s part of the challenge. What I do is I start with the 4 weeks of treatment with venetoclax, plus azacitidine or decitabine. And after the first 3½, 4 weeks, I do a marrow biopsy to see what I have. If the marrow is empty, I allow count recovery and then resume. If it is full of blasts, I go with the second cycle.
Harry Paul Erba, MD, PhD: Amir, let me hold you up for 1 second because you left out a very important clause. If the marrow is empty of blast, you allow count recovery by holding the venetoclax, right?
Amir Fathi, MD: Of course. That’s what I meant to say, holding the venetoclax and basically waiting until starting the next cycle until there is count recovery. If this process of marrow suppression happens over and over again, there is a need for decreasing the intensity. Generally I reduce to 3 weeks or 2 weeks. There is a variability when it comes to that.
Finally, with concurrent medications such as the azoles—isavuconazole, voriconazole, posaconazole—you have to reduce the dose. That is something else that I see in the community that doesn’t always follow, even with fluconazole. It does require adjustment of dose; otherwise, you’re going to get in trouble with marrow suppression.
I don’t think this is the equivalent of HMA when it comes to tolerability. It’s not. It’s much better tolerated than induction chemotherapy, but it is less tolerated than HMA. Because of the enhancement and the efficacy and the improvement in the overall survival, I agree with my colleagues that it should be the new standard. But I don’t agree that there are no patients in whom HMA alone is not appropriate. There are scenarios where I’m really worried about marrow suppression and patients who have AML, and I may still use decitabine or azacitidine.
Transcript Edited for Clarity