Lenalidomide/dexamethasone (len/dex) is now recommended as a preferred treatment option for patients with Rosai-Dorfman Disease regardless of mutation status, potentially expanding access to an effective, well-tolerated therapy.

In early June 2026, the National Comprehensive Cancer Network (NCCN) updated its treatment guidelines for Rosai-Dorfman Disease (RDD), elevating lenalidomide/dexamethasone (len/dex) to a preferred treatment recommendation for patients, irrespective of mutation status. The update is an important step forward for people living with RDD, a rare inflammatory disease that often involves a long diagnostic journey and significant unmet treatment needs. It also marks an important milestone for Every Cure, which partnered with Dr. Luke Chen and colleagues, applying its AI-driven drug repurposing platform and scientific expertise to help expand the appropriate use of len/dex for patients with RDD.

Prior to this update, len/dex was listed in the NCCN guidelines as an “other recommended” treatment. While this designation acknowledged the treatment’s promise, it likely contributed to len/dex being overlooked by prescribers and payers. Its elevation to a preferred treatment option could help increase clinician awareness, support broader adoption in practice, and expand insurance coverage. 

This guideline update reflects years of dedicated work by clinician-researchers who have observed the benefits of len/dex in patients firsthand, most prominently Dr. Luke Chen and his colleagues at Dalhousie University. Earlier this year, Dr. Chen, Every Cure researchers, and collaborators published findings in the American Journal of Hematology demonstrating that len/dex can be an effective and well-tolerated treatment for patients with difficult-to-treat RDD.

What is Rosai-Dorfman Disease? 

RDD is a rare inflammatory condition in which overactive immune cells called histiocytes accumulate in the lymph nodes and tissues throughout the body. This can lead to abnormal masses in the skin, lymph nodes, bones, and internal organs, and the disease can become life-threatening when vital organs are involved. Because symptoms vary widely and can resemble those of other conditions, patients often spend months or years seeking an accurate diagnosis.

Once diagnosed, treatment decisions can be challenging. RDD is highly variable, and the right treatment approach depends on disease location, severity, symptoms, and genetic mutation status. MEK inhibitors are a preferred primary treatment option for patients with RDD, particularly those with MAPK pathway mutations. However, many patients with RDD do not carry these targetable mutations, and for some patients MEK inhibitors can involve cost or tolerability considerations—underscoring the value of having additional effective treatment options.

What is len/dex and who benefits? 

Len/dex combines two existing medicines: lenalidomide, an FDA-approved immunomodulatory drug that helps regulate the immune system and reduce inflammation, and dexamethasone, a corticosteroid often used alongside lenalidomide to enhance its effects. Together, they form an oral combination therapy that can be taken at home, a practical advantage for patients managing a complex condition.

The combination is particularly valuable for the approximately two-thirds of RDD patients who do not carry targetable MAPK pathway mutations and therefore are not ideal candidates for MEK inhibitors. It may also offer an additional option for patients who have MAPK mutations but for whom MEK inhibitors are not the right fit due to tolerability or access considerations. 

The evidence base includes a prospective clinical trial, a case series, and multiple case reports. In the recent American Journal of Hematology study led by Dr. Chen and co-authored by Every Cure, 11 patients with difficult-to-treat RDD were evaluated, many of whom had already tried multiple prior treatments. Ten of the 11 patients experienced clinical or radiographic improvement.

Beyond efficacy, len/dex carries important practical advantages. Both lenalidomide and dexamethasone are now available as generics, making them potentially more accessible and affordable than newer targeted therapies. 

“Because rare diseases like RDD are very diverse in the way they affect patients and respond to therapy, it’s crucial to have many treatment options,” said Dr. Luke Chen. “Lenalidomide and dexamethasone is a good option for patients who don’t respond to, or don’t tolerate MEK inhibitors, and seems to work particularly well in patients with skin and subcutaneous disease. In many parts of the world, patients do not have access to MEK inhibitors, whereas lenalidomide and dexamethasone are widely available and accessible medications.”

Every Cure’s Role

Every Cure is a nonprofit organization on a mission to save and improve lives by repurposing drugs. By combining machine learning, biomedical knowledge graphs, and deep medical expertise, Every Cure works to close the gap between treatments that exist and treatments that reach patients, particularly in rare and underserved conditions where traditional drug development is often not feasible.

As part of a collaboration with Dr. Luke Chen and colleagues, Every Cure applied its AI platform to RDD. The platform systematically evaluated nearly 3,000 FDA-approved drugs to identify repurposed treatments with the greatest potential to benefit patients with RDD. Lenalidomide and dexamethasone emerged among the highest-ranked therapies, lending computational validation to the encouraging clinical outcomes observed by Dr. Chen and his colleagues.

Every Cure partnered with Dr. Chen and his team to evaluate the existing evidence, engage experts, and help communicate the findings to the medical community. This collaboration culminated in a co-authored publication in the American Journal of Hematology, which helped formalize the evidence supporting len/dex and contributed to its elevation within the NCCN treatment guidelines.

“The challenge in drug repurposing is not just identifying promising therapies, it’s ensuring they reach the patients who need them,” said Dr. Matt Goddeeris, Chief Scientific Officer of Every Cure. “The RDD example shows what’s possible when computational discovery, clinical expertise, and evidence generation work together. We’re excited to have contributed to this guideline update, which will help patients with RDD, and eager to repeat this success with promising therapies for other diseases in the future.”

The bigger picture

The NCCN guideline update for len/dex in RDD illustrates a much larger opportunity. Millions of people with rare, undertreated, or difficult-to-treat diseases may benefit from existing medicines that have yet to be identified, validated, or adopted for their condition. For many of these patients, drug repurposing offers one of the fastest and most cost-effective paths to new treatment options.

By combining AI with scientific and clinical expertise, Every Cure works to uncover these opportunities and accelerate their translation into patient care. The RDD story—from clinical observation to peer-reviewed evidence and preferred guideline status—demonstrates what is possible when rigorous science, clinical expertise, technology, and persistence come together.

Additional Resources

• Full publication in American Journal of Hematology: https://onlinelibrary.wiley.com/doi/10.1002/ajh.70309 
• Every Cure’s RDD page: https://everycure.org/rdd/ 
• Every Cure’s pipeline: https://everycure.org/portfolio/