Tapan Kadia, MD, Highlights Venetoclax Plus Chemotherapy for AML, MDS

Tapan M. Kadia, MD, Department of Leukemia, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas, highlights a phase 2 trial on venetoclax plus intensive chemotherapy in patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).

Transcript

Hi, my name is Tapan Kadia. I'm currently a professor in the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas. Delighted to be here and talking to you.

What's interesting is that for years we have been using intensive chemotherapy for younger and fit patients with AML. Over the years, we have intensified this therapy going beyond just giving 7+3. We've given a higher dose cytarabine for induction.

We have added a second nuclide analog, specifically cladribine to that program based on some data from the Polish study suggesting that it would improve responses and also improve overall survival (OS).

Our backbone regimen for many years has been a regimen called CLIA, which is C-L-I-A, which includes cladribine plus idarubicin and high-dose cytarabine as induction. Response rates have been in the 70 to 75 percent range with high levels of MRD eradication.

As we are studying this, and we are looking for newer ways of improving outcomes in patients with AML, we also noticed that recently we had approval of venetoclax, which is an oral BCL-2 inhibitor for patients with newly diagnosed AML who are older and unfit for intensive chemotherapy.

Based on the VLAA study, the HMA (hypomethylating agent) plus venetoclax showed a significantly improved response rate, but also a significant improvement in OS—about 14.7 months compared to the control arm.

We hypothesize that if venetoclax can significantly improve rates in lower-intensity therapy with HMA, potentially we could see a significant improvement also with intensive chemotherapy in younger and fit patients.

What we decided to do is design a study to add venetoclax to intensive chemotherapy in newly diagnosed younger and fit patients with AML. That was the genesis of the study—to study that and look at the safety, and once we had a good dose and schedule to look at the efficacy, and compare it to historical controls.

This study, as I mentioned, is a combination of venetoclax added to CLIA, which is cladribine, idarubicin and cytarabine. The venetoclax normally per label for lower intensity therapies given for 28 days in many of our own studies with low-intensity therapy we only give it for 21 days.

Because of the intensity of the regimen, we hypothesize that probably a lower dose of chemotherapy—just 7 days of venetoclax starting on day 2 up to day 8—would be sufficient and synergized with intensive chemotherapy. We felt that giving more than 7 days could potentially lead to prolonged myeloid suppression.

The regimen was cladribine 5 mg/m² daily for 5 days, combined with idarubicin 10 mg/m² daily for 3 days, cytarabine 1,500 mg/m² for 5 days. Then venetoclax orally given on days 2 through 8 for 7 days without a ramp-up.

Patients we treated were younger patients with a median age of 48 years of age from 18 to 64 years, because we did not think that older patients or unfit patients would be eligible for intensive chemotherapy of this kind.

What we found was tremendous, as I mentioned before, expected response rates with this intensive chemotherapy without venetoclax in the range of 70 to 80 percent.

With CLIA and venetoclax, the response rate was 95 percent. That’s a 95 percent rate of CR and CRI, which is high—it’s the highest we've ever seen. What's more, we had 85 percent of the patients having CR and only 10 percent having CRI. The responses were good deep responses with full count recovery.

On top of that, we look at something called minimal residual disease, which is MRD by flow cytometry in all the patients. 94 percent of patients who achieved remission achieved MRD negativity, which is a very high rate and suggests a very deep response.

So, what did we do? How do we make the leap?

We went from a response rate in this 70 to 80 percent range with CRs in the range of 60 to 70 percent, and now have a response rate of 95 percent, but also a deep remission rate with MRD rates going from 70 percent all the way up to 95 percent MRD negativity rate—so deep responses.

On top of that, one would say, "Well, OK, you're intensifying chemotherapy. You're going to have high toxicity and early mortality."

In fact, we did not see that. The early death rate at 4 and 8 weeks was 0 percent. The time to count recovery of the first cycle was just around 26 to 28 days for both neutrophils and platelet, suggesting a very good recovery of hematopoiesis.

So far, the CR duration has not been reached. In our patient population, the 1-year OS is over 80 percent very, very promising results. Still early and we wanted longer follow-up, but very promising nonetheless. During clinical practice, we need to learn how to better incorporate venetoclax to intensive chemotherapy.

As I mentioned, venetoclax added to low-intensity therapy has now become the standard of care and has widely applied across the country and around the world for older and unfit patients. If we start paying attention now to our fit patients who are younger with newly diagnosed AML, certainly the addition of venetoclax can be done in a safe manner. We showed that.

It can lead to high response rates and deep remissions, which can eventually lead to higher cure rates. As we learn more about it, get better at taking care of these patients, we can incorporate this to intensive chemotherapy and go from there.

We're doing a lot of different combinations with intensive chemotherapy. CLIA is one. We are trying to learn what patients best respond to intensive chemotherapy and who would benefit from lower intensity therapy.

For example, in a subset of patients who have P53-mutated AML, which is the toughest, we were hoping that we would see nice responses with this. The response rates are lower, probably the range of 50 to 60 percent in that subgroup, and survivals are not much better than what we would expect historically. We're looking at that subgroup and how to treat that differently.

We're using the venetoclax added to a slightly lower intensity approach, which is CPX-351, which is a liposomal formulation. We're studying that.

We're understanding what subtypes of patients do not achieve MRD negativity and how we can address those earlier. The biggest thing is that is the first approach where we combined venetoclax with a high dose cytarabine-based induction regimen for newly diagnosed younger and fit patients with AML. It shows that it can be done safely. At least to very high response rates and hopefully, this can translate into higher cure rates for newly diagnosed patients.

We still have work to do in many subsets. We are still seeing resistant disease, but the future is bright. We're excited to be treating these patients in the study.