Talati Highlights “Game-Changing” Potential of Venetoclax/HMA Combos for Elderly AML

Early data suggest that the low-intensity combination of venetoclax (Venclexta) and hypomethylating agents (HMAs) may be a “game-changer” for patients with relapsed/refractory acute myeloid leukemia (AML), according to Chetasi Talati, MD, especially for older patients who may not be candidates for intensive chemotherapy.

“The bigger question that we all need to think about is: What about these patients who are borderline in terms of performance status or who we think can go either way in terms of intensive chemotherapy versus a non-intensive chemotherapy regimen?” said Talati. “What our data show us is that a lower-intensity regimen with venetoclax/HMA used up front may provide a survival benefit and higher response rates. It's a game-changer for our older patients; chemotherapy is not the only answer here.”

In November of 2018, the FDA granted an accelerated approval for venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for patients with newly diagnosed AML who are over the age of 75 or are ineligible for intensive induction chemotherapy due to comorbidities.

In a multicenter, retrospective, chart review presented during the2020 European Hematology Association Congress, study investigators examined real-world evidence of adult patients with newly diagnosed disease who were treated with venetoclax and HMA combinations in the real-world setting. Early results showed that after a median follow up of 10.5 months and 5.8 months for the venetoclax and control cohorts, respectively, the survival rates in the venetoclax cohort was 100% at 3 months and 79% at 6 months; for the control cohort, these rates were 75% at 3 months and 48% at 6 months.

In an interview with OncLive, Talati, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center, further discussed early results from a multicenter chart review examining treatment patterns and outcomes of patients with newly diagnosed AML who received venetoclax/HMA combinations in the real-world setting and the next phase of the ongoing research initiative.

OncLive: Could you discuss the rationale for the utilization of venetoclax in this patient population?

Talati: Venetoclax is a BCL-2 inhibitor that has been studied in combination with HMAs, such as azacitidine and decitabine, specifically in a patient population that is not eligible to receive intensive induction chemotherapy. In the initial phase 1 study, that population was defined as patients who were 75 years of age and older and those who were 65 years and older and were considered ineligible to receive intensive chemotherapy.

Venetoclax has been approved for use in other malignancies, such as chronic lymphocytic leukemia. [The agent] has [also] been studied in multiple myeloma and other hematologic malignancies, as well. In AML, we know there is a high expression of BCL-2, so there is a rationale as to why venetoclax would [be able] to provide some antileukemic effect.

In preclinical [research] and an early-phase study, [investigators looked at] a patient population that was more relapsed/refractory; [in that population], the agent did not produce such a robust response; the response rate was approximately 20%. Therefore, venetoclax was then studied in a combination in patients with newly diagnosed disease. The phase 3 study was based on phase 1 data. The combination has been a game-changer.

What inspired the retrospective, real-world analysis of venetoclax that you led?

This is a multicenter project; it’s not a prospective clinical trial. This is basically a retrospective study where we are examining how venetoclax is being used in a real-world setting. If you ask 10 different physicians who are treating their patients with an HMA/venetoclax combination, you're going to hear different opinions [on how they use this approach in practice].

Different geographic areas and institutions that have their own standards, and different antimicrobial agents are being used as prophylactic medications. Dose reductions and the schedule of the medications also varies. Additionally, in older patients specifically, there is a group of patients whom we still consider to be borderline to receive intensive chemotherapy. For this population, we don't really know whether HMA/venetoclax or intensive chemotherapy is more beneficial. That type of prospective study may never be [conducted].

As such, the whole idea behind this initiative is to use data from multiple institutions to retrospectively [assess] where patients have been treated with different [methods], dosing schema, and schedules, and compare them with intensive chemotherapy regimens. Again, intensive chemotherapy regimens can also vary a bit based on different institutions; [variances may exist with regard to] 7+3, different dosing of cytarabine or daunorubicin, and high-dose cytarabine-based regimens, which may include fludarabine versus cladribine. The overall purpose [of this work] is to examine the pattern of use with HMA/venetoclax and compare them retrospectively with different cohorts.

What we presented is just the start of this research. We are hoping to collect more data and submit [what we learn for presentation at] the 2020 ASH Annual Meeting; hopefully, by that time we’ll have a larger cohort and subgroups to examine.

Could you provide an overview of the different cohorts examined?

[We used a] small patient population. We looked at a total of 32 patients; half received HMA/venetoclax and the other half received intensive chemotherapy. Patients [included in the analysis] have newly diagnosed AML. We are trying to control both of the cohorts and match them for age and extramedullary leukemia (EML) risk.

The majority of the patients are older, 60 years and older; 37% to 40% [of patients] are 75 years and older. When you look at the risk stratification, it's fairly equally matched, as the majority of patients are of adverse risk because they are older. This patient population tends to have higher-risk AML compared with those who are younger; approximately 70% of these patients have an adverse-risk profile.

The decision of intensive chemotherapy versus HMA/venetoclax is all treating physician–related. It's not a randomized study, so depending on where the patient came from, the decision on which chemotherapy or regimen they would receive had already been made. The intensive chemotherapy used was mainly CPX-351 (Vyxeos); this is the liposomal formulation of cytarabine and daunorubicin that is approved for AML with myelodysplasia-related changes, which is a higher risk of AML. Also, a group of patients were treated with 7+3 combinations and a minor subgroup received treatment with cladribine or high-dose cytarabine-based regimens.

What findings were presented during 2020 EHA Congress?

The data are premature; the study is ongoing. The first thing we wanted to examine was the remission rates or overall response rates (ORRs) in this older patient population. Ultimately, we also want to look at overall survival (OS) and relapse-free survival. At this time, we focused more on the ORRs reported in both of these cohorts. We also examined survival at 3 months and 6 months because we had that median follow-up for both cohorts where it seemed statistically possible to calculate those numbers; as such, we presented those numbers, as well.

Several patterns were observed. Some patients would receive prophylactic antimicrobials, including strong CYP3A4 inhibitors like voriconazole (Vfend) or fluconazole (Diflucan), which would lead to dose reductions with venetoclax. Other patients did not receive [those agents]. It's a combination of those patients, but that's how to see how venetoclax is being used in the community, and in the real-world [setting].

When we looked at the OS for these patients, the 3- and 6-month cutoffs where we do have follow up, the survival was a little bit longer for patients who received HMAs/venetoclax compared with intensive chemotherapy regimens. The survival at 3 months was 100% for HMA/venetoclax and 75% for intensive chemotherapy; at 6 months, the survival was at 79% versus 48%, respectively. When you look at that survival data—which is usually the gold standard when you talk about how effective a treatment is—it is pretty striking that [an agent] that's supposed to be lower intensity [and can be used in the] outpatient [setting] is [showing benefit that] is better, if not the same, as [what is being seen with] the intensive chemotherapy regimens.

[This] is extremely important, especially for our older patients, where we are trying to keep them out of the hospital as much as possible. The goals may be different for these patients in terms of maintaining their quality of life versus cure. In AML, the cure comes from transplant, and many of these older patients may not even be eligible for that [approach]. The goals are a little bit different for these patients compared with a younger patient population.

We are also trying to get more detail on dose interruptions; that's extremely important, especially with venetoclax, because of cytopenias. Many very different methods are being used to dose reduce venetoclax. The standard dose and approved dose of venetoclax is 400 mg with a 3-day ramp up. Then, if you are on antimicrobials, the dose is reduced accordingly by 50% or 75%. However, there are different opinions in terms of how we should dose reduce venetoclax when patients are in remission, and whether we should change the dosing of venetoclax [from] 400 mg to 200 mg, or whether the schedule [should be truncated]. We want to evaluate these patterns.

What are the next steps for this research initiative?

This is just the beginning. We are hoping to have a significantly larger cohort, [so we will be] able to address the survival question [with regard to] the newly diagnosed patients who received treatment with HMA/venetoclax versus intensive chemotherapy. Secondly, we are also trying to compare HMA/venetoclax with azacitidine. We now have data from the phase 3 VIALE-A study, which showed that azacitidine/venetoclax met the primary end point of OS.

Another big question is in the relapsed/refractory setting. What do we do for patients who relapse? We don't really have that many standard-of-care options for these patients unless they have a mutation that we can target with treatment, such as IDH1/2 or FLT3. For many of these patients in the relapsed/refractory setting, we tend to use is HMA/venetoclax if they have not received that treatment before. That’s another exciting topic that we are trying to explore further.

Reference

Talati C, Asghari H, Abedin S, et al. Treatment patterns and outcomes of newly diagnosed acute myeloid leukemia patients receiving venetoclax combinations vs other therapies: results from the AML real world evidence (ARC) initiative. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract PB1831.