Incorporating Mutational Panel Testing Remains Crucial in MDS

David Sallman, MD

Next-generation sequencing (NGS) and broad-base mutational panels can improve understanding of a patient’s disease and inform treatment decisions, therefore mutational testing should be incorporated early into the treatment of those with myelodysplastic syndrome [MDS], according to David Sallman, MD.

“The incorporation of mutational testing allows us to identify those groups [with poor outcomes],” Sallman said. “Patients with p53 mutation are a molecular subset with the poorest outcomes, and this group should be subdivided from all the other [subgroups]. There is a lot of data to support that.”

In an interview with OncLive^®, Sallman, assistant member of the Department of Malignant Hematology at Moffitt Cancer Center, discussed incorporating mutational testing of patients with myelodysplastic syndrome into clinical practice, and strategies that can be utilized to treat this population.

OncLive^®: What should physicians keep in mind when incorporating mutational panel testing for MPNs/MDS into clinical practice?

Sallman: The goal of my presentation was [to explore] how we can incorporate mutation or molecular testing into standard practice for patients with myelodysplastic syndrome. Historically, we had clinical models which would define lower vs higher risk, but now we can personalize the prognosis prediction of these patients much more. There are some key [patient subgroups] such as those with p53 mutations, which [is a] poor molecular subset that we focus on.

From a treatment perspective, for [patients with] myelodysplastic syndrome, we do have some cutting-edge frontline trials for patients with p53 mutations, including [a phase 2 study with] eprenetapopt [APR-246; NCT03588078] and [a phase 3 trial with] magrolimab [NCT04778397]. These trials are ongoing, with different combinations. IDH1 and IDH2 mutations can also be targeted. More broadly, particularly in patients who fail standard frontline therapy, [we are] thinking about molecular subsets that we can target.

How has mutational panel testing been incorporated into clinical practice so far? Have there been any barriers to implementation?

For many key opinion leaders, and most community practices, it is standard to require a comprehensive, next-generation sequencing panel. These [panels] often include a minimum of 20 genes, with the average being 40 or 50 genes, and up to 600 genes. The panel is usually broad-based and done either at an academic center or commercially.

There have been some barriers, with the major one being cost. Although these [tests] have been adopted in The National Comprehensive Cancer Network® guidelines and many other practice algorithms, they can still be a challenge and a barrier for patients. Importantly, [the testing is not something that can be done at] a single time point. We need it at diagnosis but will also often [do mutational testing] sequentially in patients who progress on standard therapy. This [testing will] shape all our management, both in terms of prognosis and treatment selection.

What are some challenges that remain in this space?

[Some] active drugs may [perform] exceptionally well [for some subsets and not others]. For example, venetoclax [Venclyxto] has great activity in elderly, non-fit patients with acute myeloid leukemia [AML], and myelodysplastic syndrome. Unfortunately, in the p53-mutant subset, the response rates do not appear that different in [terms of] complete remission rate. We need to think about p53-mutant and p53 wild type trials [separately]. Sometimes when [all subsets are] put together, it will muddy data, both on a positive and a negative basis, for agents that are ultimately effective or not effective.

Is there any ongoing research in this space that you'd like to highlight?

The International Working Group Molecular Committee has been working for years on defining an optimal molecular model. Eventually, we will have a list of mutations, and maybe the percentage of each mutation, to put it into a computational database. This will provide a more refined prognosis for patients, which is one big step. This will further help us [understand] who is low-risk and who is high-risk. Ideally, that will lead to better and more well-run trials to improve the outcomes for our patients, including those who should ultimately go to allogeneic stem cell transplant, which is really the only curative option for patients today.

What is the current state of treatment for patients with p53 mutations?

For those p53-mutant disease, 1 agent of interest is eprenetapopt, which is a p53 reactivator that showed synergistic response rates and outcomes in phase 1/2 data [that were] overall, more favorable than historical [data]. This led to a randomized phase 3 trial, [which evaluated] azacitidine [Onureg] plus eprenetapopt vs azacitidine alone. Unfortunately, results from approximately a year ago showed that although the complete remission rate was higher, it did not reach true statistical significance. We look forward to the formal presentation of these data. Are there potential subsets that we need to better focus on? Clearly there is activity. How we move that drug towards approval is an important [open] question. There will be key presentations focused on this both in MDS, as well as in AML and post allogeneic stem cell transplant.

Another interesting agent is magrolimab, which is a first-in-class IgG4 monoclonal antibody that inhibits CD47 and SIRPα. This block sends a signal to allow macrophages to eat the cancer cells. In MDS, as well as in p53-mutant AML, the combination has been synergistic. This has led to the development of 3 ongoing registrational trials, [enrolling patients with] high-risk MDS, p53-mutant AML, and all comer AML in the unfit setting.

Finally, IDH1 and IDH2 inhibitors are approved in AML, but they are not approved in MDS. We could argue that response rates may even be higher [in AML] as a mutation may occur earlier. However, in small numbers of patients with [MDS], response rates have been at least as good, if not better. There is an ongoing registrational trial looking at single agent ivosidenib [Tibsovo] for patients with relapsed or refractory MDS, and [we] really encourage patients to get on the study because it is a rare subgroup, but it is a nice potential option.

What is your take home message regarding your presentation?

We need to do [next-generation] sequencing at the start [of treatment], and frequently thereafter, because if we do not look, we do not know. Mutations can change over time. Separately, [we need to] make the mutations go away. The concept of minimal residual disease [MRD], which is an emerging concept for myelodysplastic syndrome, is going to be key. There are several, high-sensitivity techniques, such as error-corrected sequencing and duplex sequencing, available. Ultimately, when we have the best therapies, they are going to lead to the best MRD eradication by serial sequencing. Do the testing and think about serially evaluating both to define the quality of response as well as to identify other options.