Approaches to Managing Toxicity of Venetoclax

Harry Erba, MD, PhD: We are going to come back to CPX-351 (cytarabine and daunorubicin), and we have really dealt with these subsets of patients with FLT3 and IDH mutations already in our prior discussion in terms of their outcomes with azacitidine and venetoclax. Now, I think we really need to focus on what needs to be our roles as physicians who use this regimen when training the doctors who treat leukemia out there who do not. That is toxicity management. Courtney, you have published on this topic with Andrew Wei, MBBS, PhD, and, obviously, have a lot of experience. Do you want to lead us off? What are the things that they have to take into account?

Courtney DiNardo, MD: I think there are probably 3 main things when you are using Venetoclax regimens. 1 is the risk of tumor lysis syndrome (TLS), which is quite minimal with acute myeloid leukemia (AML). You do not see a lot of TLS. If you are going to see it, it is going to be in the first day or 2. You do want to follow those criteria, which is getting the white count down under 20,000 or so with Hydrea (hydroxycarbamide) before you start, making sure they are on allopurinol or something, monitoring the electrolytes—making sure they are not developing renal failure or a high potassium so that you can actually intervene in real time and doing that 2 to 3 day ramp—and making sure that Venetoclax interacts with a whole lot of other medications. If you are using an azole or ciprofloxacin or anything that is a CYP3A4 inhibitor, you need to be actually doing those dose reductions or else you are getting really high venetoclax levels. You will see a lot of cytopenias and toxicities.

Mark Levis, MD, PhD: Are you really dose reducing for ciprofloxacin?

Courtney DiNardo, MD: I have never used ciprofloxacin, actually.

Mark Levis, MD, PhD: Or are you using levofloxacin and you dose reduce?

Courtney DiNardo, MD: No, you do not need to with levofloxacin because it's not a CYP3A4 but—

Mark Levis, MD, PhD: It is moderate—

Courtney DiNardo, MD: Levaquin is not ciprofloxacin.

Mark Levis, MD, PhD: All right.

Courtney DiNardo, MD: I think ciprofloxacin is just as moderate as fluconazole and we just reduced for fluconazole so we should for ciprofloxacin, if you're using it. Then, the last and most important thing is just making sure that you are doing an end of cycle 1 bone marrow test because responses happen often and they happen quickly. You just do not want to be doing the same azacitidine for 4 cycles or 6 cycles like we used to do for AML. We cannot be just assuming the cytopenias are related to disease because they are probably not. You probably have your patient in a leukemia-free state. You must hold therapy for a week or 2, wait for counts to recover, and then start the next cycle.

Harry Erba, MD, PhD: Yes, I agree; in fact, if the peripheral blood blasts have cleared, I will do a bone marrow as early as day 21. If it shows a morphologic leukemia-free state, I am going to hold Venetoclax, then allow count recovery, and then even use granulocyte colony-stimulating factor, especially if they are still in the hospital. Then, when the absolute neutrophil count recovers, I will start cycle 2—not at day 28, when it recovers, and this is outside the label. I will give only 21 days in the second cycle; my rationale is that I gave them 21 days when they had disease and were at work. Why am I going to give them more later? In the VIALE-A study (NCT02993523), over half the patients actually went through 21-day cycles.

Vinod Pullarkat, MD: I assumed I mentioned that in the VIALE-A study, the drug was continued through the whole 28 days. I understand the rationale for doing 21 days, but you do see count recovery even when you continue the treatment. It is in the later cycles that the cytopenia become bigger problems so almost all patients will need those adjustments after they get into remission. We routinely use both factors and shorten the duration, but I would just mention that in the VIALE-A study, the drug was continued until complete remission (CR) without interruption.

Courtney DiNardo, MD: I think there is a helpful presentation that Keith Pratz, MD gave recently, looking at those patients who were shortened to 21 days and those who continued on for 28-days, trying to break down the cytopenia management. Different institutions did things differently and there is no right or wrong answer, but what it did show is that in those patients in remission who had ongoing cytopenias dropping to 21 days, their survival was not impacted at all. If anything, that line rode a little bit higher, so it is a very appropriate thing to do if you need to for a patient with cytopenias.

Harry Erba, MD, PhD: See, for me, it is the labeled population. These are people I never treated before, right? They were not using that or they got hypomethylating agent alone, and now, I am treating them. They do not want to be in the hospital any longer than they have to be, or at risk of neutropenic infections, so that is why I have adopted that, but this conversation and each of us doing something slightly different drives everyone crazy because the community gets different recommendations.

Vinod Pullarkat, MD: The problem is now I am seeing 70-day regimens and 14-day regimens and everybody has their own version of this for induction. That really bothers me.

Mark Levis, MD, PhD: That comes from the structure of the VIALE-A study. We all put patients on it and we did not adhere necessarily to the 28 days that the trial allowed us. Well, you could wait for the neutral account to recover, or the patient's not ready to start, so we all know there was some play in that.

Courtney DiNardo, MD: I think, for me, the question really—

Vinod Pullarkat, MD: After CR, I do not know.

Courtney DiNardo, MD: Oh, I am sorry.

Vinod Pullarkat, MD: No, I am saying after CR, there was a lot of play.

Mark Levis, MD, PhD: Well, I agree.

Courtney DiNardo, MD: I think it just brings the ultimate question to the forefront: what is the best use of Venetoclax? This trial was not designed to answer that question. Do you need continuous monotherapy of Venetoclax or is Venetoclax really synergizing well with the therapy you are giving? The most impact of the Venetoclax is in the first week or 2 and that discussion is important.

Mark Levis, MD, PhD: With 7 and 3, we are not obliged to start 7 and 3 at a fixed time after day 1 of the first time. We are not obliged to start consolidation. The HMA-VEN trial got everybody fixed: "You have to start day 29 or you're off-label. This is terrible." Well, we never did that in our field before.

Dan Pollyea, MD, MS: Right.

Harry Erba, MD, PhD: This is a very important conversation. You know what this says to me? People who are looking at this—if you do not have a lot of experience using this combination, Courtney is going to give her cell phone number to you any second now, or Mark will. No, just reach out to someone who has a lot of experience using it. You all have your contacts, like leukemia doctors, on speed dial, and I think it is a great partnership when taking care of older patients who can now stay close to their home and get effective therapy. Getting guidance from doctors who use this all the time is really the message I think that we need to give.

Transcript Edited for Clarity