I am glad that there are several late-phase studies with lower-intensity approaches in high-risk MDS. This patient population tends to be older, and there is quite a bit of heterogeneity in terms of both comorbidities and patient preferences regarding treatment. We are looking for ways to advance combination therapies that can be tolerated by patients who would not tolerate more intensive approaches. Additionally, progression after azacitidine or decitabine remains a great unmet need; these patients do poorly, and new treatment strategies are needed.

Given the current landscape, I think that the focus on newer first-line MDS treatments in clinical trials is justified, but I do wonder if there is a way to achieve advancements beyond the first line or to optimize therapeutic sequencing and combinations once the initial response is lost. Once we have a couple of positive phase 3 studies in MDS, we will then be able to address sequencing and/or patient selection for specific combinations, but we are not in that position yet.

There is a strong desire to change the paradigm in high-risk MDS, and investigators have been setting a very high bar in clinical trials of lower-intensity treatments. It is important to set realistic expectations and to recognize that advances in high-risk MDS may emerge more incrementally over the longer-term. For example, a phase 3 study assessing APR-246 plus azacitidine in patients with TP53-mutated disease was powered to see a difference in complete remission (CR) rates compared with azacitidine alone. In a press release, we learned that the trial did not meet its primary end point. The combination arm did have a rate of complete responses of 33.3% compared with 22.4% in the azacitidine monotherapy arm, but the difference between the 2 arms did not meet the predefined threshold for statistical significance. In my view, even an incremental gain, such as what was observed in this study, could be meaningful in the long run.

In a similar vein, it may be worth revisiting how we measure success to better capture these incremental improvements. The CR criteria in MDS, especially in high-risk MDS, may not be optimal. I believe that there is a need to identify better surrogate end points, whether that might be the mutation burden or a minimal residual disease (MRD)–based metric.

In pursuing advancements in higher-risk MDS, I tend to think in terms of the totality of the approach, with upfront treatment that improves our response rate and allows for more bridging to allogeneic stem cell transplantation or more durability of responses in patients who are not going to transplant. Even after transplant, we can think of other strategies, such as maintenance therapy using hypomethylating agents. 

Three of the more promising agents that are being studied in lower-intensity combination regimens for high-risk MDS are venetoclax, magrolimab, and sabatolimab. These are all being studied in ongoing phase 3 trials. With venetoclax, I think that we are still trying to determine whether there is a survival advantage for all patients with high-risk MDS or for only those in certain subsets. Magrolimab and sabatolimab are 2 of the immune therapies, and then there are also studies looking at combinations that are incorporating targeted therapy for patients with IDH mutations. The goal should really be to start moving toward doublet and triplet therapies and to improve our response rates while examining different end points. And then, if we have more active therapies, we can start looking at MRD.

MRD assessments using flow cytometry are more challenging in MDS than in AML because the disease risk is often not adequately defined by the myeloblast percentage. We do not have a historical benchmark for MRD in MDS because hypomethylating agents act as differentiating agents, so we do not see much change in the variant allele frequencies of mutations. If newer therapies achieve higher response rates and higher percentages of MRD, then the use of MRD as a surrogate is definitely a goal that we could pursue in clinical trials.

As noted by my colleagues, in the MDS space, we have not yet seen a phase 3 trial showing improved outcomes with combination therapy vs azacitidine alone. In AML, we have 2 phase 3 trials that have confirmed survival benefit with lower-intensity combinations: the VIALE-A and the AGILE studies. However, I think that a challenge in both high-risk MDS and AML is that the more agents we add to lower-intensity treatments, the more those regimens start becoming intermediate-intensity treatments.

The VIALE-A study with azacitidine plus venetoclax has changed the standard of care for our older patients with AML who are ineligible for chemotherapy and who are receiving a lower-intensity combination. Historically, with azacitidine alone, the incidence of remission was 30% or less, and survival was less than 1 year. In VIALE-A, we saw composite CRs in 66.4% of patients taking azacitidine plus venetoclax vs 28.3% of those taking azacitidine plus placebo, as well as a median overall survival of 14.7 months in the azacitidine-plus-venetoclax group vs 9.6 months in the azacitidine-plus-placebo group. We are moving the needle, and, increasingly, the question arises of whether deeper responses and longer survivals will be achieved by adding something else. To do that, the venetoclax regimen would likely have to be attenuated a bit, being mindful of myelosuppression.

The other phase 3 trial of lower-intensity treatment in AML is the AGILE study by Montesinos et al, who evaluated ivosidenib plus azacitidine in patients with IDH1-mutated AML who were ineligible for intensive chemotherapy. The estimated rate of a patient remaining event free at 12 months was 37% in the ivosidenib-plus-azacitidine group and 12% in the placebo-plus-azacitidine group. The median overall survival was 24 months with ivosidenib plus azacitidine and 7.9 months with placebo plus azacitidine. This really highlights the importance of knowing whether the patient has a mutation that can be targeted.

Immune therapies such as magrolimab and sabatolimab also appear promising in AML. Magrolimab is a CD47 antibody that appears to have some TP53 agnostic responses. Sabatolimab is a TIM-3 inhibitor that may help patients overcome T-cell exhaustion. Both are being explored in combination with azacitidine. While we do not yet have US Food and Drug Administration approvals, phase 3 studies are ongoing, and results are eagerly anticipated.