On December 30, 2025, Tatiana Schlossberg, the daughter of Caroline Kennedy and granddaughter of John F. Kennedy, passed away from Acute Myeloid Leukemia (AML). Before her death, Schlossberg had spoken candidly about the inversion 3 chromosome mutation that she carried, a mutation that can often lead to rapid disease progression and a poor prognosis.
Before Schlossberg’s diagnosis, there had been little in the mainstream media about this rare but genetic anomaly that leads to aggressive AML. Now, people are learning more about the inversion 3 mutation, including its clinical presentation, prognosis, and the efforts being made to best help those who carry the mutation.
“The inversion 3 mutation drives a very aggressive leukemia biology that is considered high risk,” explains Dr. Mona Jhaveri, founder, executive director, and chairman of the board at Music Beats Cancer. “This type of rare AML has a low remission rate, a high relapse rate, and a low chance of survival.”
The presence of the inversion 3 mutation can greatly influence treatment decisions between the patient and doctor.
What is the inversion 3 mutation?
The inversion 3 mutation is a deeply complex and rare subtype that affects only 1 to 1.6% of newly diagnosed AML cases. It can occur in people who have never been diagnosed with a blood cancer in the past or in people who have had prior diagnoses of myelodysplastic syndrome (MDS) or chronic myeloid leukemia (CML) that has progressed to AML. The mutation typically arises in adulthood, having accumulated in bone marrow cells over time, and the median age of people with identified inversion 3 mutations is 65, making a patient such as Tatiana Schlossberg an outlier at the age of 35.
In patients who carry the mutation, it can be the central driving force in their being diagnosed with AML. The mutation is essentially a mix-up in the DNA that happens on the 3rd chromosome, causing certain DNA on the chromosome that controls when critical genes are turned “off” and “on” to become flipped. As a result, a gene called MECOM (also known as EV11) is “turned on” too strongly, prompting blood cells to begin to behave abnormally.
This mutation, which accelerates cell division, speeds the development of leukemia in the body, contributing to a rapid decline in the patient.
Features of the inversion 3 mutation
“The diagnosis for the inversion 3 mutation is complex,” explains Dr. Jhaveri. Clinically, the presentation is unusually aggressive, with high or rapidly rising white blood cell counts, low platelets and anemia, an enlarged spleen, and a history of some other subset of blood cancer. Despite advancements in cancer research and understanding of the mutation, the prognosis for patients remains poor, with a very high risk of relapse even if remission is achieved.
“The standard survival is measured in months rather than years,” says Dr. Jhaveri.
Double inversion 3 is also possible in an incredibly rare number of cases, leading to an even faster decline and short survival prognosis.
Treatment options for patients
There is no universally accepted “best” course of action to take against the inversion 3 mutation, given how rare cases continue to be and how challenging this subset of AML is to treat. “Molecular testing matters and can direct the best treatment options,” Dr. Jhaveri explains. “With the inversion 3 mutation, patients can pursue clinical trials offering them access to a range of new therapies such as venetoclax combinations, immunotherapies, antibody-based drugs, and early-stage cell therapies.”
Standard AML therapies, such as intensive combination chemotherapy and hypomethylating agents (HMAs) like azacitidine or decitabine, are routinely used. Still, they produce similar remission rates and overall poor long-term results.
The best chance of durable disease control seems to be allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission, with patients who receive this treatment after first complete remission typically living longer than those who receive chemotherapy alone.
“In terms of treatment, there is currently no single targeted therapy that can neutralize the inversion 3 mutation,” Dr. Jhaveri says. “However, combination therapies are increasing the remission rates. If remission is achieved, an allogeneic stem cell transplant can offer the best chance of longer survival. That said, many patients with this rare leukemia relapse even after a transplant.”
Many clinicians recognize that current treatment options are far from ideal. Some treatments, such as Venetoclax, a BCL-2 inhibitor used in combination with HMAs or low-dose cytarabine, have shown promise among older patients or as a bridge to eventual transplant, but have not shown consistent benefits in patients with the inversion 3 mutation.
Emerging research and looking into the future.
“While progress today is faster than ever before, more support is needed to advance worthy treatments to the finish line,” says Dr. Jhaveri.
Research on the mutation continues, and high-profile cases like Tatiana Schlossberg’s help spur further research and education. There remains intense interest in conducting in-depth research on the inversion 3 mutation, especially given its poor outcomes. However, novel treatment approaches, such as targeting the EVI1/MECOM-driven transcriptional program and associated super-enhancers with bromodomain and extra-terminal motif (BET) inhibitors, remain largely experimental.
As researchers learn more about how this mutation works at the molecular level, they will continue to open doors to new, more effective treatments to improve outcomes in the near future.