By any other name …

In this issue of Blood, Döhner et al¹ provide a post hoc analysis of data from the QUAZAR trial of oral azacytidine (“oral aza”) therapy for patients with acute myeloid leukemia (AML),² focusing on the survival impact of NPM1 and FLT3 mutations in the context of a flow cytometry–based assay for measurable residual disease (MRD). The analysis indicates that treatment with oral aza conferred a survival benefit regardless of FLT3 or NPM1 mutational status, including the favorable (NPM1 mutated/MRD negative) and unfavorable (FLT3 mutated/MRD positive) combinations. FLT3 and NPM1 mutations are frequent molecular dance partners that are found in a significant fraction of AML cases, so the demonstration of the efficacy of oral aza in these very common subtypes of the disease make a reasonable case for the real-world applicability of this therapy.

Do we finally have a maintenance therapy for patients with AML? After remission has been achieved and intensive chemotherapy is completed, AML patients and their physicians settle in for a nervous 2- or 3-year vigil, knowing full well that relapse (and death) are very possible, and wishing there was some way to minimize the risk of that relapse. An effective maintenance therapy that can decrease relapse risk has been somewhat of a holy grail for the field. To date, the only maintenance treatment associated with a survival benefit is FLT3 inhibition in the posttransplantation setting.^3,4 Many different maintenance approaches (eg, chemotherapy, immunotherapy, small molecules) have been tried over the decades, but nothing has really emerged. Rashidi et al produced an elegant and exhaustive meta-analysis on this subject in 2016 and rather despondently concluded that there was no substantial evidence for the use of maintenance therapy in AML.⁵ They made the salient observation that “the benefit of maintenance seems more apparent after suboptimal induction and consolidation.” That comment seems highly applicable to the QUAZAR trial, in which enrolled patients who had achieved remission after intensive induction and a limited amount of consolidation were deemed unfit for further intensive consolidation.

Oral aza as used in the QUAZAR study isn’t really maintenance, it is simply ongoing less toxic treatment. In fact, in its approval summary for oral aza, the US Food and Drug Administration (FDA) took pains to point out that this drug did not meet the Agency’s definition of a maintenance therapy and labeled it as continuation therapy.^6,7 

What’s in a name? Does anyone treating AML even care what type of therapy we call this drug? And how do we best use it to help our patients? Going forward, at least in the United States and likely soon much of the rest of the world, the types of patients who enrolled in QUAZAR are more likely to be treated with the less intensive venetoclax-based regimens rather than 7+3 and intensive consolidation.⁸ There probably won’t be very many patients who fit into the strict indication in the FDA label.

Label restrictions and definitions notwithstanding, azacytidine has evolved into becoming an essential backbone of treatment for a large and growing fraction of AML patients, and we now have an oral version of the drug, albeit one with very different pharmacokinetics. A resourceful research community can and should go in all sorts of directions with this important new tool. Currently, patients aren’t particularly enamored with the concept of treatment with parenteral azacytidine and venetoclax extending indefinitely (eg, for years). Finding some way of using oral aza with venetoclax would seem to be the first order of business. Circling back to FLT3, we know that FLT3 mutations are associated with shorter responses to the lower-intensity venetoclax regimens,⁹ but the combination of FLT3 inhibitors with venetoclax can be rather toxic.¹⁰ The combination of oral aza and an FLT3 inhibitor could be introduced after venetoclax-based induction, and we can call this therapy either maintenance or continuation (or call it a rose …). The list goes on: oral aza plus IDH inhibitor, oral aza plus menin inhibitors, etc. In the current world of AML drug development, the real work often begins after a drug is approved.

Conflict-of-interest disclosure: M.L. reports consultancy for Abbvie, Amgen, Astellas, Bristol-Myers Squibb, Daiichi Sankyo, Jazz, Menarini, and Takeda.