Guillermo Garcia-Manero, MD, Department of Leukemia, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas, spoke with Oncology Learning Network about the clinical significance and potential implications of using a 5- versus 10-day decitabine dose schedule in patients with newly diagnosed acute myeloid leukemia (AML).

The results of the study in which Dr Garcia-Manero was a co-investigator were presented at the 2018 ASH Annual Meeting.

Transcript

Hello, I'm Guillermo Garcia-Manero. I am a Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The topic of discussion for this podcast today is, "The optimal dosing schedule of decitabine for patients with newly-diagnosed AML." The first question is, "What is the current standard dosing for decitabine in patients with AML?" And the answer is, that is 5 days, and this is based on data that was derived from a number of clinical trials for patients with high-risk myelodysplastic syndrome.

The 5 days schedule has become, over the years, the standard. And this is actually the dose and the schedule that was used also in the randomized trials of decitabine in AML.

So then the question is, what existing data led us to evaluate the use of decitabine in a 10- versus 5-days schedule in this patient population?

This is a very important question that has been asked now over the last 2 years since several important publications from the Washington University group in The New England Journal of Medicine that indicated that there was a very high response rate with a 10-day decitabine dosing schedule in patients with high-risk features, such as p53 mutations.

This is very important to us at MD Anderson, because in the early 2000s, when we performed the early phase 1 and phase 2 studies of decitabine in MDS and AML, we performed our phase I dose and scheduled the type of analysis, where we gave, actually, decitabine for prolonged periods, around 20 days, with significant response rates. From that original data, there was a possibility that longer exposure could be associated with improved response rates in patients with AML.

Now, we ask and looked in detail at this question of the p53 mutational status in regards to the 10-day decitabine schedule, and unfortunately, we were unable to see a specific effect of 10 days versus 5 days.

We looked not only at decitabine, but also at azacitidine.

To definitively answer this question, we recently published in Lancet Hematology a randomized trial, led by Dr Ravandi (and the first author was Dr Short from the leukemia department here at MD Anderson), where they studied in this phase 2 randomized trial the 5-day schedule of decitabine versus 10-day. Unfortunately, we don't see any advantage to 5 days versus 10 days, in terms of response or overall survival. Again, I believe that there is really no strong indication that longer schedules of decitabine are associated with any significant improvement in this patient population.

In terms of the description of the methods and results, as I mentioned, this was just recently published in Lancet Hematology, and this was also an oral presentation at the ASH meeting in San Diego just a couple of weeks ago. The study led by Dr Ravandi here at MD Anderson opened in 2013 and accrued until 2018, and enrolled 71 patients.

As mentioned earlier, there was basically no difference in terms of response with the 5-day versus 10-day, and all survival, including actually presence of cytogenetic alterations or p53 mutational status.

So what are the real world applications of these findings? The bottom line is that there is not a lot of indication to use a 10-day decitabine schedule in patients with AML, in our opinion. Although, on the other hand, one could argue that there is no true negative effect of doing that, and that perhaps some patients with more aggressive disease, in terms proliferative features, etc., may benefit a little bit more from these prolonged schedules, compared to the 5 days.

What are we doing right now, in terms of future research? The reality is that I think the whole field, both in AML and in MDS, is moving into doublets of decitabine or azacitidine with targeted interventions, such as IDH1/IDH2 inhibitors, FLT3 inhibitors, and of course, the most important combinations with apoptosis modulators, like ABT-199 or venetoclax, and/or immune therapy approaches, such as immune checkpoint inhibitors.

So in summary, this has been a very important question. We don't see a true targeting effect of decitabine for 10 days for AML patients with or without p53 mutations. But decitabine remains an important backbone for therapy, both in AML and in MDS.

Thank you for listening to this podcast.