Ryan Haumschild, PharmD, MS, MBA: Dr. McCloskey, what about the QUAZAR AML-001 trial? How does it affect the supportive use of maintenance therapy? [Could you] talk about the trial design and some of the results and the clinical implications that you've seen?

James McCloskey, MD: The bottom line is that this trial is important because it was a paradigm shift in the way we treat the disease, so established maintenance therapy is standard. To be honest, it was the first study that gave us excitement about maintenance therapy because before azacitidine, we had a lot of studies that failed to demonstrate a benefit for patients with this disease. QUAZAR was a clinical trial that was aimed to demonstrate or explore the benefit of continued oral hypomethylating therapy in patients with AML [acute myeloid leukemia]. It looked at the treatment of patients with a drug we now call azacytidine, which is often referred to as oral azacitidine—which may be a bit of a misnomer because it has very different pharmacokinetic and pharmacodynamic properties that made it appealing to explore in the maintenance therapy. We know that it provided a greater duration of drug exposure, a greater degree of change in the DNA methylation.

The trial was a randomized phase 3 study accruing patients over the age of 55 with newly diagnosed AML. Patients had all achieved a remission and were randomized to either azacitidine or a placebo. Investigators were blinded to this. All parties remained blinded even after disease progression. Patients remained on treatment until the time of disease progression; the primary endpoint was overall survival. This was the first study to demonstrate an improvement in overall survival. Overall survival in the placebo group was 14 months compared to 24.7 months in the azacitidine-treated group. That's a difference of 10 months. If we look at 1 year, that was a 73% survival compared to 56% survival; at 2 years, [it was] 51% compared to 37%, so these were certainly not trivial numbers. When you see those Kaplan-Meier curves, it wasn't a trivial separation. It took decades to move those curves apart. We were all excited by that, and that's provided momentum for us moving forward.

Along with that, there was a lot of valuable data. These were elderly patients with a median age of 68. It was particularly enriched for patients with NPM1 mutant disease because in the United States, if you're NPM mutant with normal cytogenetics, we don't traditionally transplant those folks. There was a significant number of MPL mutants in that study. Survival there was quite remarkably improved, 47 months compared to 15.9 months, [which is] a really striking difference in that patient population and [establishes this] across the board as standard care for these patients. Again, there were no mutational exclusions, so FLT3 mutants were treated on this trial as well. On the back end of that acceptable toxicity profile, grade 3 and 4 toxicities were limited. There is some myelosuppression that is crucial to be aware of. To Danielle's point, educating patients about the interventions and looking out for a fever is really important. Otherwise, the safety profile was also appealing in this patient population.

Ryan Haumschild, PharmD, MS, MBA: Those numbers of overall survival stand out because you're talking about clinically and statistical significance that changes the paradigm with our patients. That's exciting. How do we see more of that, and how do we introduce and make sure people are going on maintenance therapy more consistently and being managed?

This transcript has been edited for clarity.