Azacitidine-Based Combinations Represent New Treatment Possibilities in MDS

Mikkael A. Sekeres, MD, MS

The exploration of combination therapies with an azacitidine (Vidaza) backbone could alter the treatment landscape for patients with myelodysplastic syndromes (MDS), according Mikkael A. Sekeres, MD, MS.

Data are expected soon from the phase 3 ENHANCE trial (NCT04313881) evaluating azacitidine alone vs azacitidine and magrolimab, the phase 3 VERONA trial (NCT04401748) studying azacitidine alone vs azacitidine plus venetoclax (Venclexta), and the phase 3 STIMULUS-MDS2 trial (NCT04266301) investigating azacitidine alone vs azacitidine plus sabatolimab (MBG453).

“The future for higher-risk MDS is going to be combination therapies. We, as a group of health-care providers, need to become more comfortable in giving older adults these 2 therapies at the same time and managing those adverse effects so that older adults remain on those therapies,” Sekeres said in an interview with OncLive® following a State of the Science Summit™ on leukemia and lymphoma.

Sekeres discussed the changes to the classifications of MDS, the evolution of targeted therapies for patients with acute myeloid leukemia (AML), and approaches for patients with bone marrow failure syndromes. Sekeres is a professor of medicine and the chief of the Division of Hematology, Leukemia Section, at the University of Miami Health System and Sylvester Comprehensive Cancer Center in Florida.

OncLive^®: How has the classification of MDS changed recently?

Sekeres: We are in a quandary in the MDS world because the World Health Organization and [the International Consensus Classification (ICC)] have come up with different definitions of how to classify MDS.

Some of the major changes [include] now classifying some [cases of] MDS by molecular mutation. For example, [we now classify patients with] SF3B1 or TP53 mutations [separately], or patients with deletion 5q abnormalities. [Additionally], with the ICC classification system, we now have a category of MDS/AML for patients who have more than 10% [bone marrow] blasts. We are starting to see a shift in when we begin telling patients that they have AML, based on [bone marrow] blasts of 10%, as opposed to what it used to be at 20%.

Recognizing these mutations is important because our classification of the risk of patients who have MDS has also been changing. There was a publication of a personalized prediction model for patients with MDS in the Journal of Clinical Oncology [in 2021] that incorporates molecular mutations in an artificial intelligence and machine-learning algorithm. Furthermore, the molecular International Prognostic Scoring System has also been published, where we can enter mutation information into an online program to eventually develop a risk score for patients with MDS.

What do these changes mean for clinical practice?

One key takeaway is the importance of stratifying patients [based on risk] at the beginning [of treatment]. [It is also important to start to get comfortable with some of these new classification schemes that incorporate molecular mutations. These classifications will be critical in identifying the best therapy for our patients, and we are starting to use classifications to recommend patients for hematopoietic stem cell transplantation.

What key clinical trials are investigating the use of combination therapies in MDS?

One of the areas in the treatment of MDS that I am most excited about is combination therapies. We are waiting for trial results regarding combination therapies to [determine if] they are better than hypomethylating agent [HMA] monotherapy. We have 3 randomized trials that will be reporting out in 2024.

The [ENHANCE trial randomly assigned] patients to receive azacitidine vs azacitidine and the anti-CD47 monoclonal antibody, magrolimab. [VERONA] is randomizing patients to receive azacitidine vs azacitidine plus the BCL-2 inhibitor, venetoclax. [The STIMULUS-MDS2] trial is randomizing patients to receive azacitidine or azacitidine plus the checkpoint inhibitor, sabatolimab.

There are potentially exciting times ahead for patients with higher-risk MDS. We will see when these studies eventually report out their results in a little over a year.

What unmet needs still need to be addressed for patients with MDS?

Every patient who has MDS has a limited number of treatments that are available. There are a few lucky patients who have very low–risk MDS, where we do not need to treat it at all because they have relatively preserved blood counts and a good quality of life.

However, as soon as patients start to become profoundly anemic, we start down the treadmill of offering therapies, whether those are erythropoiesis stimulating agents [ESAs], luspatercept-aamt [Reblozyl] for those who have ring sideroblasts, lenalidomide [Revlimid] for those who have deletion 5q, or HMAs for those with lower-risk MDS with multiple cytopenias or those with higher-risk disease.

Those are all the agents we have, and then we start to go to therapies we do not use as often, such as immunotherapies. My toolbox does not have enough tools in it. The greatest unmet need in MDS is the need for more therapies, particularly in those patients with lower-risk disease who have already been exposed to an ESA.

Justin M. Watts, MD, with Sylvester Comprehensive Cancer Center discussed AML management during the meeting. How have targeted agents shifted the paradigm for older patients and treatment in the frontline setting?

The management of AML is often divided into how we use treatment approaches for patients who are younger, and that is rather arbitrarily defined as those patients who are over or under the age of 60 years. For those patients who are younger, we predominantly continue to use intensive cytotoxic therapy. However, we now have additional targeted agents that we add to what has been colloquially referred to as the 7+3 backbone of cytarabine and an anthracycline.

For example, patients who are FLT3 positive get treated with a drug that targets FLT3 up front—most commonly midostaurin (Rydapt).

We have increasingly gotten better options for those patients who are in the relapsed or refractory setting with AML. Additional agents that target FLT3-positive AML and other agents that are coming down the pike may do as well or better with fewer adverse effects [compared] with existing FLT3-targeted agents. In addition, we have drugs that target IDH1/2 for patients in the relapsed/refractory setting. These are starting to be moved into the up-front setting, particularly in older adults.

For older adults, the standard has become azacitidine plus venetoclax because the combination was shown in the [phase 3 Viale-a] trial [NCT02993523] to improve overall survival compared with azacitidine alone. More recently, [the phase 3 AGILE] trial [NCT03173248] that showed that the combination of azacitidine and the IDH1 inhibitor, ivosidenib [Tibsovo], allowed patients to live almost 3 times longer than those patients who received azacitidine alone.

Increasingly in patients who have AML, we are starting to incorporate targeted agents, not only in the relapsed/refractory setting, but now moving them to the up-front setting.

Namrata Sonia Chandhok, MD, also on the faculty at Sylvester, discussed treating bone marrow failure syndromes. How do physicians make treatment decisions for these patients?

Bone marrow failure syndromes are relatively rare. However, once a center declares an expertise in treating patients who have bone marrow failure conditions, these patients do tend to gravitate toward that center.

Dr Chandhok talked about immunosuppressive therapies for patients with aplastic anemia and the recent incorporation of eltrombopag [Promacta], which is a thrombopoietin mimetic, into the standard backbone therapy of antithymocyte globulin and cyclosporine.

Dr Chandhok also talked about new monoclonal antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and those patients who have atypical hemolytic uremic syndrome. A lot of the discussion was on defining which patients have bone marrow failure conditions and then dividing treatments into what specific type of bone marrow failure syndromes those patients have.

How have the emergence of novel therapies shifted the treatment paradigm across hematologic malignancies?

A recurring theme that we saw in our meeting on leukemia and lymphoma is that whether a patient has MDS, AML, bone marrow failure conditions, diffuse large B-cell lymphoma, or central nervous system lymphoma, we have a wealth of new drugs that are increasingly being developed and combined with previous therapies that have been established to improve outcomes in these patients. More and more, we are starting to recognize narrower subgroups of patients, such as those defined by molecular mutations who benefit from extensive combinations compared with what we have been given traditionally.

Is there any ongoing or planned research at Sylvester Comprehensive Cancer Center that you would like to highlight?

We have particular expertise in early phase drug development in patients who have hematologic malignancies. We are [constructing] a new building [dedicated to] addressing those patients who are in early phase clinical trials with a dedicated infusion unit. We have become experts particularly in first-in-human studies in leukemia and lymphoma, and in combination trials in patients with MDS.