Ivosidenib Approved for IDH1-Mutant Myelodysplastic Syndromes With Amir Fathi, MD

Recently, the FDA approved ivosidenib for adult patients with relapsed or refractory myelodysplastic syndromes (MDS) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation. In this interview, Amir Fathi, MD, Director of the Leukemia Program at Massachusetts General Hospital, one of the leaders of the AG120-C-001 trial (NCT02074839), on which approval was based, sat down to further discuss the trial and approval, as well as what this could mean for the future treatment landscape of MDS.  

Amir Fathi, MD: Hello, my name is Amir Fathi. I’m an Academic Oncologist with a focus on bone marrow malignancies. I treat patients with myelodysplastic syndromes, acute leukemias, and other myeloid neoplasms. That’s where my academic interests lie. In addition, I develop clinical trials meant to improve the treatment of these patients.

Oncology Data Advisor: Before we begin, I wanted to ask you, what exactly are IDH1 mutations and how do they affect myelodysplastic syndromes?

Dr. Fathi: IDH stands for isocitrate dehydrogenase. This is an enzyme­ which many of us probably learned about in high school, college, medical school, or grad school—it’s a key enzyme in the Krebs cycle. Like many enzymes in the Krebs cycle, it ultimately leads to production of adenosine triphosphate (ATP) and energy for the cell and mitochondria—IDH1 for the cell, IDH2 for the mitochondria.

When there is a mutation in the gene that codes for these proteins, the proteins that result are altered. As a result of that alteration, the enzyme no longer catalyzes the typical reaction leading to the production of energy, but rather catalyzes the reaction to form this onco-metabolite called 2-hydroxyglutarate, or 2HG. 2HG builds up in the body and leads to the suppression of key enzymes that are important for the normal maturation and differentiation of white blood cells in the marrow.

As a result of that, there is a block in the normal maturation and differentiation, and cells get stuck at a very early immature malignant state. That’s how IDH mutations are thought to promote the malignant phenotype of MDS and acute myeloid leukemia (AML).

Oncology Data Advisor: Going into the approval, could you give us a brief overview of the trial that led to it?

Dr. Fathi: There was a larger series of patients—in the larger study of ivosidenib in myeloid malignancies—but this particular subgroup of 19 patients was focused on MDS. These were patients who were relapsed or refractory. Many of them had received prior treatments with hypomethylating agents but had progressed or relapsed following treatment and were looking for additional options for therapy.

They received ivosidenib, the IDH1 inhibitor, at a dose of 500 mg daily and in a continuous fashion. Patients were assessed for marrow response, tolerability, safety, and ultimately longer-term outcomes such as survival.

Oncology Data Advisor: How would you say this approval affects the current and future treatment landscape of MDS, particularly for IDH1-mutant diagnoses?

Dr. Fathi: Well, the study showed that a substantial subset of these patients derived benefit. Patients who were transfusion-dependent prior to starting treatment—meaning they were, because of their disease, dependent on red cell and platelet transfusions—a large proportion of them became independent after starting treatment. That’s remarkable.

About 40% of patients had marrow responses, meaning their marrow improved. Many of those were complete remissions, meaning their marrows no longer revealed dysplasia or increased blasts, but for all intents and purposes appeared normal. The responses were relatively durable. The time to response was around two months.

Patients who responded tended to respond for quite a long period of time, and the tolerability was also quite acceptable. The main tolerability concern with ivosidenib is QT interval prolongation on the electrocardiogram (EKG), and that particular QT prolongation can lead to arrhythmias, although it is relatively uncommon.

The other concern that needs to be looked at closely and monitored is the entity called differentiation syndrome. When the malignant cells begin to differentiate as a result of the mechanism of action of this drug, sometimes that leads to an inflammatory cytokine-mediated inflammatory cascade that can cause clinical repercussions for the patients.

With differentiation syndrome, patients can develop fevers, respiratory symptoms and decompensation, rash, pleural effusions, and kidney injury. When that happens, it can potentially be deadly, but this particular syndrome, if recognized early, is quite treatable with steroids. About 10% to 15% develop differentiation syndrome in studies of IDH inhibitors. But on most of these occasions, these episodes were managed effectively with steroids.

Altogether as a result of the relatively good tolerability and safety profile of the drug, the promising activity of the agent, and increasing the options that we now have for MDS patients who have progressed beyond the initial lines of treatment, I would say this has significantly impacted the landscape of treatment for MDS—keeping in mind that this drug is for the minority of patients with IDH1 mutations.

Oncology Data Advisor: Were there any limitations with this trial that will be addressed in future studies potentially?

Dr. Fathi: I think every clinical trial has limitations. MDS with an IDH1 mutation is a relatively uncommon entity, so the number of patients studied here in this sub-study was small. As opposed to a larger study, a smaller study has less power and therefore you can make the argument that the applicability of this data to the larger population may be incomplete.

But there is only so much you can do about that. If a mutation or a subtype of a disease is uncommon, it is uncommon, and you have to rely on the data that you have available in front of you in order to move forward in the field and improve outcomes for those patients.

I think over time, as people begin to use this drug in the community and in the real-world setting, they’ll gain even more experience, and I think there’ll be additional publications to further expand our knowledge about ivosidenib in the real-world setting and how it helps patients with MDS and other bone marrow cancers.

Oncology Data Advisor: The final question that I have for you is, are there any ongoing or future trials regarding MDS that you would like to highlight?

Dr. Fathi: Well, there are always going to be clinical trials that assess patients with myeloid malignancies, including MDS. There are targeted therapies that are currently under study or have been recently studied. Investigators, for low-risk MDS, are looking at luspatercept in earlier lines of treatment. They’re also assessing telomerase inhibition in low-grade MDS.

In higher-grade MDS, folks are looking at combinations of hypomethylating agent therapy and venetoclax. Certainly, the data that we talked about today with IDH-mutated MDS is important. I think the field is slowly moving forward. We certainly need additional promising agents to investigate.

Oncology Data Advisor: Thank you so much for this overview. We’re definitely looking forward to the future of this treatment landscape. Thank you so much, Dr. Fathi, and I hope you have a great rest of your day.

Dr. Fathi: Thank you. Take care now.

About Dr. Fathi

Amir Fathi, MD, is the Director of the Leukemia Program at Massachusetts General Hospital and an Associate Professor of Medicine at Harvard School of Medicine. His research interests and passion revolve around the development and clinical translation of novel therapies for myelodysplastic syndromes, acute leukemias, and other myeloid neoplasms. Dr. Fathi is an active participant and leader of clinical trials at the Dana-Farber/Harvard Cancer Center, where he is currently leading multiple clinical trials for patients with advanced leukemia and hematologic malignancies.

For More Information

Oncology Data Advisor (2023). Ivosidenib approved for IDH1-mutant relapsed or refractory myelodysplastic syndromes. Available at: https://oncdata.com/news/ivosidenib-approved-for-idh1-mutant-relapsed-or-refractory-myelodysplastic-syndromes

Transcript edited for clarity. Any views expressed above are the speaker’s own and do not necessarily reflect those of Oncology Data Advisor. 

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