Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 12

BCL2 Inhibition in AML: VIALE-A Study

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Harry P. Erba, MD, PhD: I want to move things around. Before I come back to a targeted therapy against the IDH mutations, I want to talk about inhibition of BCL2 in AML [acute myeloid leukemia]. We will all agree that the VIALE-A study has been practice-changing, at least in the United States. As a top-line review of this study, before we get into some specific questions, I will start by saying that the VIALE-A study was a study of treatment-naïve patients with AML who were either 75 years of age or older or had a comorbidity that precluded intensive chemotherapy. In this study, azacitidine with venetoclax was compared with azacitidine with placebo. The primary end point of the study was reached: There was an improvement in median survival from 10 months with placebo-azacitidine, which is similar to what was seen in the QUAZAR AML-001 study, to almost 15 months with azacitidine-venetoclax. For me, 1 of the more impressive things about those Kaplan-Meier curves is that, with follow-up ongoing, the curves have not come together at least by 24 months, which happened in the QUAZAR AML-001 study, where azacitidine was compared with conventional care regimens. There was a 34% reduction in the risk of mortality, and the other benefits that were seen were higher response rates and higher rates of transfusion independence with azacitidine-venetoclax.

With that as a background, we are all using this regimen, but I want to turn to Eunice to talk through some practical issues, specifically around monitoring and risk of tumor lysis syndrome, antifungal prophylaxis, and how to manage cytopenia. These are the important issues that we need to convey to our colleagues who may not see as many patients with AML as we do. Eunice?

Eunice S. Wang, MD: I would be happy to. When we decide to administer venetoclax-azacitidine for an older or unfit individual, we have to take into consideration the management of toxicities. The first question that comes up is whether the patient is eligible to be treated in the inpatient setting vs the outpatient setting. Unlike an HMA [hypomethylating agent] alone or azacitidine, the combination of venetoclax and azacitidine is myelosuppressive: 70% to 80% of individuals will develop neutropenia, and others will develop significant degrees of thrombocytopenia. That is going to require these individuals to be closely monitored not only during the first week of administration of both agents but also for 2 to 3 weeks following that.

There are some guidelines that have been published looking at the requirements that are needed to support an individual in the outpatient setting. Those include the ability to monitor the patient or see the patient on a daily basis or at least 3 times a week to check laboratories and manage tumor lysis syndrome, which occurs with initial dose escalation, with IV [intravenous] fluids and tumor lysis monitoring labs as well as medications. They also include the need for very frequent red blood cell and platelet transfusions: at least 2 to 3 times a week. In fact, those requirements are difficult to achieve in many community settings; even in academic settings we are not necessarily set up to do that. The NCCN [National Comprehensive Cancer Network] Guidelines in this newly revised supportive care regimen suggest at least hospitalizing these individuals potentially for the first week of treatment as you dose escalate the venetoclax, given all those requirements for tumor lysis monitoring, etc.

In terms of subsequent management, we always, at our facility at Roswell Park Comprehensive Cancer Center, administer antifungal medications and CYP3A inhibitors—posaconazole is our preferred agent. We then initiate that in the setting of expected neutropenia with these patients, we dose reduce according to the azole drug and the product insert. There have been several studies of venetoclax and several questions from all the speakers at the ASH [American Society of Hematology] Annual Meeting 2020 about the concomitant use of azole antifungals, and I have not heard of anybody who has seen a significant difference in the efficacy of the agents based on the use or nonuse of azole antifungals. That is based on your institutional practice, and there is some geographical variation in that as well.

In terms of adverse-event monitoring in the second and third weeks, if you are able to maintain that type of regimen, we would recommend that you do so either in the inpatient setting or the outpatient setting. Major causes of mortality were pneumonia, sepsis, and neutropenic fever. In the VIALE-A trial, those were low in the single-digit range; however, I have been told in the community that, given the lack of access to those resources, it could be as high as 10% to 40%. It is important to recognize that this is not azacitidine alone. These are patients who are going to be severely myelosuppressed. I have had some patients in the community being started on this regimen showing up in the ER [emergency department] with a white blood cell count of 0 and a platelet count of 3 per mm3. We would strongly advise close management. At our facility, we offer to admit the patients for the first cycle to get them through their first day 21 and day 28, start the second cycle, and transition them back to the community.

I ask that individuals consult closely with an academic center for guidance. We have had physicians call us every few days to say, “The platelet count is now 10 per mm3. What should we do?” or “It’s going back up again.” If patients achieve sufficient cytoreduction on day 21 or day 28 bone marrow biopsy, that is like the day 14 bone marrow biopsy with 7+3 chemotherapy: We can use that bone marrow biopsy to hold venetoclax for ANCs [absolute neutrophil counts] less than 500 per mm3. We administer growth factors, we transition them to outpatient, then start the next cycle with truncation of subsequent venetoclax and azacitidine dosing based on cytoreduction that we are getting from the cytopenia. I hope that addressed all 4 of the questions that you asked, Harry. I gave a bit of time left for somebody else to speak for this section.

Harry P. Erba, MD, PhD: Eunice, that was wonderful. I appreciate the detail that you went into because here is the bottom line: HMA-venetoclax is able to improve the survival of older and infirm patients with AML, but it was done in the context of a clinical trial with specific rules on how to handle drug-drug interactions, tumor lysis syndrome, and myelosuppression. If we do not follow the supportive care in the clinical trial, what we have learned since is that we are not going to be able to reproduce those regimens. In fact, there are some real-world data out there that suggest that many patients are not receiving as many cycles of HMA-venetoclax as in the clinical trial, suggesting to me that clinicians may be backing off this regimen prematurely because of apparent or presumed toxicities of the regimen and not knowing how to manage it.

Eunice S. Wang, MD: I agree with that completely. I could not agree more.

Harry P. Erba, MD, PhD: I appreciate you taking the time to do that.

Transcript Edited for Clarity