Musa Yilmaz, MD, Assistant Professor, Department of Leukemia, MD Anderson Cancer Center, University of Texas, discusses a highly active triplet combination—quizartinib, decitabine, and venetoclax—for patients with FLT3-ITD mutated acute myeloid leukemia (AML). These data were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Transcript

Hello. I'm Dr. Musa Yilmaz. I'm one of the faculty members at MD Anderson Cancer Center in the leukemia department.

As we all know, development of FLT3 inhibitors have changed how we treat FLT3-mutated AML. This has been going on for the last 20 years. There are multiple FLT3 inhibitors right now under use. Particularly, midostaurin, which is a first-generation FLT3 inhibitor, has been approved in younger patients, FLT3 mutated AML, in combination with chemotherapy, based on the phase 3 randomized data, which showed improvement in overall survival (OS). This is in younger patients.

When it comes to older patients, unfortunately, the outcomes are not good. The standard-of-care chemotherapy, which is HMA plus venetoclax for patients with FLT3-ITD mutated AML, according to an analysis published last year in ASH, it's only 11 months in this subgroup of patients. That's really poor. 

Even the studies that use hypomethylating agents with FLT3 inhibitors such as sorafenib, in elderly patients, the outcomes in the front-line setting, overall survival is only about 8 to 9 months.

These are the reasons that motivated us to develop better therapies.

In our study, what we tried to do here is we used the backbone, which is the hypomethylating agent plus venetoclax, and we added a third drug, a FLT3 inhibitor. In our study, we used a second-generation FLT3 inhibitor, which is quizartinib, which has been studied in multiple as a single agent or in combination with other chemotherapies. 

Now, in this protocol, we use it as a third drug. We call this a triplet regimen for FLT3-mutated AML. Our study is a phase 1 and 2. We allowed patients relapse refractory (R/R), not on the front line, R/R FLT3-ITD-mutated AML. Also newly diagnosed, but the initial part, the most patients that I'm going to be talking about, they are mostly R/R patients.

The regime included decitabine. We used decitabine 10 days as an induction. They received 5 days off going forward in the subsequent cycles. Venetoclax we used for 2 weeks during induction. Everybody gets their bone marrow by day 14. We looked at the bone marrow. If it shows morphological remission, venetoclax stops there, but the FLT3 inhibitor continues. This is roughly how we used this triplet regimen.

In the study that we most recently updated in last year EHA meeting, we treated 17 patients, R/R arm. These are multiple treated patients. The median number of therapies were 3, so half received a prior transplant. About 80 percent of the patients already received FLT3 inhibitors, so we are talking about a heavily treated patient population.

Even in those, out of 17, 12 patients achieved remission. This was obviously a quite response rate in this category, and not only response. Also, the regimen was tolerable. 30-day mortality was 0 percent. None of the patients died within the first month of therapy.

Half of the responders, 6 out of 12 responders, were able to proceed with allogeneic bone marrow transplant. We'd hope that they can cure the disease.

In terms of toxicity, we have seen the most important toxicity is myelosuppression with this combination regimen, and infections such as pneumonia. Atropine fevers were common. Obviously, these are handled accordingly.

When we are talking about quizartinib, it's always good to mention QTC prolongation. In our treatment schema, none of the patients had a grade 3 or higher QTC prolongation, which is one of the known potential side effect of the drug. Probably, this is because we used lower doses than the single agents. This is our thought.

We are, as I told you, a small number of patients, but we are enrolling more and more. This study particularly becoming more attractive for patients who failed particularly gilteritinib, which is the standard-of-care FLT3 inhibitor in AML patients.

Speaking of front line, we only treated, reported at least, 4 patients right now because there are other priorities. In these 4 patients, all of patients responded and all achieved deep responses. They are all alive and in remission at the last time of follow-up.

I believe that there is a particular use in clinical practice in patients in R/R. Obviously, we prefer to treat these patients on clinical trials. Number 1 reason is that this regime, we finished the phase 1. We are still on phase 2 in extension. There are still something to figure out in terms of the dosing schedule because the number 1 toxicity of this triple drug combination is myelosuppression.

I don't think it is fair to say that it is ready for prime time use in standard-of-care practice. If you think of it, although we use quizartinib, someone can design azacitidine, venetoclax with an FDA-approved agent such as gilteritinib or midostaurin, but I don't think it's quite ready for that.

I would encourage for those patients to be enrolled on the clinical trials because right now we are studying this on quizartinib in this study. Also we're studying aza-ven gilteritinib combinations. These are at level of phase 2. Once the data matures more. Once we have more patients, it definitely seems to be deserving to be studied in a randomized fashion. 

We are indeed interested in expanding this study. Right now, we are expanding the phase 2. We are on the phase 2 expansion arm. We are adding more patients to our phase 2 study. We are the only center studying quizartinib and HMA in combination in the United States, perhaps in the world for that matter, and we are expanding it. 

The next step would be, once we establish the schedule and dosing, perhaps that would be really interesting to see this triplet regimen being tested in a multi-center, multinational level in front-line elderly patients who are not fit for intensive chemotherapy to be tested in a newly diagnosed setting and see if adding a FLT3 inhibitor to HMA-ven backbone indeed improves OS.