Omer Hassan Jamy, MD, Assistant Professor, University of Alabama at Birmingham, highlights a retrospective study on hypomethylating agents (HMAs) plus venetoclax versus intensive chemotherapy for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript

Hello, everyone. My name is Omer Jamy, and I'm an assistant professor at the University of Alabama at Birmingham with a clinical focus on acute leukemias and bone marrow transplant.

What led us to do this retrospective study was the fact that there's not a whole lot of data in this space right now. Venetoclax was approved in combination with HMAs for treatment of patients with AML unfit to receive intensive chemotherapy in the first-line setting. However, we have been using venetoclax in the R/R setting as well.

How the outcomes of venetoclax and HMAs in the R/R setting compare to intensive chemotherapy, that's largely unknown. People are using this combination freely across the country, but it was worth looking at a comparison to see how outcomes would be compared to other agents that we've traditionally used.

We identified patients that had received combination of a HMA, be it azacitidine or decitabine, in combination with venetoclax for R/R AML.

Once we had identified that cohort, what we did was, we created a matched cohort. Matching was based on age of the patient, the risk of AML based on ELN 2017 criteria, the time to relapse—meaning early relapse, within 6 months, or late relapse, which is beyond 6 months—and the lines of therapy received for R/R AML.

Using this algorithm, we then created a matched cohort of patients that had received intensive chemotherapy. That could be any intensive chemotherapy but was mainly consisting of high-dose cytarabine-based regimen, like FLAG or CLAG or HiDAC.

What we did was then compare outcomes between the 2 arms. Because it was a matched study, the baseline characteristics between the 2 arms were well balanced. There was just a higher percentage of bone marrow blasts in patients that received intensive chemotherapy. Other than that, it was a well-balanced population.

The median age in both study arms was not statistically different—it was 58 in the intensive chemotherapy arm and 62 or 63 in the HMA/venetoclax arm. The initial outcomes that we looked at were rates of complete remission (CR), rates of refractory disease, (and) early mortality.

We found that, although the rates of composite CR, which we defined as the CR, or CR with incomplete count recovery, were similar between both arms, but those patients that received intensive chemotherapy had a higher rate of CR, whereas those patients that received HMA/venetoclax had a higher rate of CR with incomplete count recovery. Patients receiving intensive chemotherapy had a cleaner CR compared to those receiving HMA/venetoclax. Overall CR rates were similar. Rates of early mortality between the 2 arms were similar as well, as well as rates of refractory disease. There were no significant findings, as far as these variables were concerned.

A higher number of patients did proceed to transplant with intensive chemotherapy. That number was almost double in the intensive chemotherapy arm compared to the HMA/venetoclax arm. That was surprising because both populations were very close in terms of the median age. Whereas, like I said in the beginning, HMA/venetoclax was initially approved for elderly, unfit patients in the front-line setting—so those patients were older, over here, because once you've relapsed, no matter what your age is, you could receive it. That's why there were younger patients as well in the HMA/venetoclax arm that were just not able to proceed to transplant.

Then we looked at survival differences between the 2 arms. Overall, we did not find a statistically significant difference in overall survival (OS) between the 2 treatment groups. However, numerically, it favored the intensive chemotherapy arm, but that could have been due to chance.

Then we started looking at subset analyses and found that patients that had received just 1 round of induction chemotherapy, which at most centers in the United States consists of 3 days of anthracycline and 7 days of cytarabine, patients that were refractory to 1 round of intensive induction chemotherapy, 90 percent of the patients had received 7+3.

When we looked at those patients specifically, if they went on to receive a second round of intensive chemotherapy versus switching to HMA/venetoclax, there was a survival difference which was significant and which favored the intensive chemotherapy arm.

The median OS for those that had received intensive chemotherapy was around 20 months, whereas for those that had received HMA/venetoclax, was around 5 to 6 months. This was statistically significant.

Those patients that received intensive chemotherapy, they received a high-dose cytarabine-containing regimen, like I'd mentioned at the beginning, like FLAG, CLAG, HiDAC, or MEC. That was the significant finding from our study, whereas all other subset analyses did not yield a significant difference, but numerical differences favoring the intensive chemotherapy.

In conclusion, outcomes, if we were to look at the whole population, were similar between both arms. We recommend that a subset of patients that were refractory to just 1 round of chemotherapy, and if you think they're able to tolerate another round of intensive chemotherapy, they may benefit from a high-dose cytarabine-containing regimen compared to switching to HMA/venetoclax.

This is all within the context and limitations of this being a retrospective study. What happened in real time in terms of performance status, other variables is hard to comment on. Therefore, we have to keep that in mind. It still shows that HMA/venetoclax is a reasonable option for some patients, but wherever you think that a patient is fit, you may want to consider intensive chemotherapy in that situation.

Prior to 2017, we were very limited in our treatment options for AML. Since then, we've had a lot of drugs approved, which have demonstrated a survival benefit, but again, that benefit is not great. A lot of work still needs to be done, but venetoclax in particular has made its way into various settings when you are treating patients with AML.

I think a lot of people in the real-world setting are using it in the R/R setting. The FDA approval is for front-line, but many physicians, including myself, use it freely in the R/R setting, either in the context of a clinical trial or just off trial as routine or standard care as well.

When you use venetoclax in combination with a HMA, although it is sold as less-intensive chemotherapy, it has its own side effects. What that does is that a lot of people may feel comfortable switching to a combination which is less intense as compared to doing full-intensive chemotherapy.

One thing I think we may want to avoid is a premature switch to a combination which may be easier to give, which may not be best for certain patients. I made that switch a lot of times as well. A lot of variables go into it. I'm not saying that everybody should get 2 rounds of intensive chemotherapy. I think we should make a very careful decision if a person is refractory to 1 round of therapy to switch treatments or put them on a clinical trial before trying a second round of chemotherapy, which in particular would be a high-dose cytarabine-based regimen, which would be the standard in the US at least. Those are some of the implications of this study, just to highlight that it may not always be the right decision to switch to a venetoclax combination if the person is refractory to your standard induction chemotherapy alone.

Again, this is retrospective and small numbers. I'm not, by any means, advocating that everyone should follow these results. With time, we are hoping to have more patients in the retrospective setting to see if we can reproduce these results. Of course, going forward, the best way to prove these results would be to conduct a clinical study. We are discussing that. It is difficult to set that up at a single institution.

What we're trying to do is get multiple institutions on board to see if we've engaged their interest and proceed forward with a clinical trial comparing these 2 regimens head-to-head. I think that would be the gold standard for evidence-based medicine, a randomized clinical study.

While we work toward that goal, we want to make sure that—this was a small study—we're going to go back and look at more patients, find more patients, maybe instead of a one-to-one match, maybe find more patients in the intensive chemotherapy arm to increase the numbers and see if we're still able to reproduce these results.

Again, I would like to emphasize that this was a small retrospective study. By no means am I saying that this should be standard of care, but there's enough here to give someone pause before making big treatment decisions about patients with AML.