Menin Inhibitors: Promising New Drug Treatment for Aggressive Leukemia

Michael Rosensweig with dog

Michael Rosensweig with Snow, photographed in the summer of 2020, before his latest disease recurrence

  • MSK Leukemia Service Chief Eytan Stein is leading the first-ever clinical trial of revumenib, a drug for some cases of acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL).
  • The pill, a targeted therapy in a new class called menin inhibitors, has shown benefit in treating both adults and children with certain subtypes of acute leukemia.
  • Revumenib recently was granted Breakthrough Therapy Designation from the U.S. Food and Drug Administration.

When Michael Rosensweig learned in May 2021 that his acute myeloid leukemia (AML) had returned for a fourth time, it was difficult news to receive. He had been in remission for more than eight years.

This time, though, he had an option for a new and less grueling treatment. Rather than face another round of intensive chemotherapy requiring weeks of hospitalization, Michael found out that he qualified for a groundbreaking clinical trial (research study) of an experimental targeted therapy called revumenib (then known as SNDX-5613). The drug, which is in a new class called menin inhibitors, was developed based on research conducted at Memorial Sloan Kettering Cancer Center (MSK).

Positive Leukemia Trial Results Using Menin Inhibitors

On March 15, 2023, MSK hematologic oncologist Eytan Stein, MD, published results from the first clinical trial of revumenib in Nature. More than half of patients with certain molecular changes in their cancer responded to the drug. These changes are either an MLL rearrangement (also called a KMT2A rearrangement) or a mutation (change) in the gene NPM1. Based on the data from this trial, on December 6, 2022, revumenib was granted Breakthrough Therapy Designation from the U.S. Food and Drug Administration, a recognition that acknowledges the potential for this new drug.

Combined, MLL rearrangements and NPM1 mutations occur in about 40% of people with AML. In addition, MLL rearrangements also occur in acute lymphocytic leukemia, including about 80% of infant cases.

“People with these types of alterations tend to have very aggressive disease,” says Dr. Stein, Chief of the Leukemia Service and Director of MSK’s Program for Drug Development in Leukemia. “What we’ve seen in this study is very promising, especially for this patient population.”

In the Nature paper, Dr. Stein and his colleagues reported that 53% of patients responded to revumenib, and 30% had a complete response or a complete response with partial hematologic recovery, which means that no cancer was detectable in their blood. Of the patients who achieved a remission, more than 78% were negative for measurable residual disease, meaning that by the most sensitive methods, leukemia could not be detected.

Menin Inhibitors Are a New Targeted Therapy for Leukemia in Children and Adults

The phase 1 trial enrolled 68 patients at nine hospitals around the country. All of them had seen their leukemia come back after other treatments, like Michael, or had never responded well to traditional chemotherapy drugs in the first place.  

Most of the patients in the trial had leukemia that was caused by either a mutation in a gene called NPM1 or an MLL rearrangement, a kind of chromosome abnormality in which one piece of a chromosome breaks off and attaches to another chromosome. Both of these changes require a protein called menin to drive cancer growth. By blocking the interaction of menin with mutated NPM1 or the MLL rearrangement, revumenib turns leukemia cells back into normal blood cells.

What we've seen in this study is very promising, especially for this patient population.
Eytan M. Stein hematologic oncologist

The early research on menin inhibitors was done by Scott Armstrong, MD, PhD, when he worked at MSK in the mid-2010s. Also participating in that research was leukemia oncologist Ross Levine, MD, MSK’s Deputy Physician-in-Chief for Translational Research.

Revumenib Leads to a Better Quality of Life During Treatment for Leukemia

Revumenib is a pill that’s taken at home. “Being able to do treatment from home and just be normal for a while was nice, as opposed to being stuck in a hospital bed for months,” Michael says. “The drug did what it was supposed to do and was much easier on my body.”

Michael says he experienced no side effects, which was a relief compared with his earlier chemotherapy treatments. Overall, the side effects observed in the trial were not serious, and no patients had to drop out because of them.

“Menin inhibitors appear to be very well tolerated and are easy to take,” Dr. Stein says. “This is everything you want in a targeted therapy.”

Revumenib is also relevant for pediatric leukemias, which frequently carry the genetic changes targeted by the drug. Responses have been seen in some children with relapsed leukemias treated on this trial, according to pediatric oncologist Neerav “Neal” Shukla, MD, of MSK Kids.

Revumenib Offers More Options for Treating Aggressive Leukemias

Leukemia in patients who responded to the drug was controlled, on average, for nine months before the patients developed resistance to the drug. Twelve of the patients who responded, including Michael, went on to receive a stem cell or bone marrow transplant (BMT). Because transplants require that patients have very low levels of cancer in their blood, it’s likely that many of these transplants would not have been possible without revumenib.

“The ultimate goal of these new treatments is to cure our patients,” Dr. Stein says. “For many, a transplant may be the best option. But for others, we hope to eventually develop combination therapies that will help to avoid, or get around, drug resistance.”

Michael received the BMT — his fourth one — in October 2021. It was performed by hematologic oncologist Sergio Giralt, MD, who is the Deputy Division Head of MSK’s Division of Hematologic Malignancies. Michael received stem cells from an unrelated donor who was found in a public registry. The 34-year-old software engineer was first diagnosed with AML when he was a junior at the Massachusetts Institute of Technology. He is now back at work and doing well.

Understanding How Resistance to Revumenib Develops

In addition to reporting on the success of revumenib, a second paper published in Nature on March 15 described the genetic changes in the leukemia that led to drug resistance. This research used patient samples as well as cells grown in the lab. The co-senior authors of that study were Dr. Armstrong, Dr. Levine, and MSK hematologic oncologist Sheng Cai, MD, PhD.

“The level of response that we saw in patients enrolled on the trial was terrific, but not 100%. Whenever we test the efficacy of a novel cancer therapy by itself, we anticipate resistance mechanisms in this setting,” Dr. Cai says. “What these studies teach us — in particular, when these leukemias are forced to mutate to evade this drug — is that we are, in fact, getting to the Achilles’ heel of this aggressive disease.”

He adds: “That is a powerful lesson, and this research offers new opportunities to develop strategies to overcome this resistance, which is the next frontier in targeted therapies.”

The revumenib trial was funded by Syndax Pharmaceuticals.

Dr. Stein’s disclosures are as follows: Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Novartis: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Syndax Pharmaceuticals: Consultancy.

Dr. Cai discloses the following relationships and financial interests: Dava Oncology (Provision of Services); Imago Biosciences (Ownership/Equity Interests; Provision of Services [uncompensated]).