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You Make the Call: What second-line therapies would you recommend for Rosai-Dorfman disease following a modest partial response to prednisone?

January 9, 2024

January 2024

Kenneth L. McClain Professor, Baylor College School of Medicine Director, Histiocytosis Program Director, Pediatric Lymphoma-Histiocytosis Fellowship Program Texas Children’s HospitalKenneth L. McClain
Professor, Baylor College School of Medicine
Director, Histiocytosis Program
Director, Pediatric Lymphoma-Histiocytosis Fellowship Program
Texas Children’s Hospital
Houston, Texas


I have a 23-year-old male patient who presented with lymphadenopathy, underwent an excisional lymph node biopsy, and was diagnosed with classic (nodal) Rosai-Dorfman disease (RDD). He has bulky lymphadenopathy, and high-dose prednisone (1-1.5 mg/kg for six weeks) has only resulted in a modest partial response. He continues to have bulky cervical lymphadenopathy and a lymphedema in his left leg due to enlarged inguinal lymph nodes. Given the rarity of his disease, what second-line therapies are available?


The most common presentation of RDD is marked cervical, axillary, or inguinal lymphadenopathy, but involvement of the nasal cavity (in 11% of cases), bones (5-10%), skin (10%), brain and spinal cord (5%), kidney (4%), lungs (2%), heart (0.2%), and, even less frequently, the eyes, testes, and breasts has also been reported. Organs other than lymph nodes are involved in 43% of cases.

Histologically, the entity is comprised of CD163+, CD68+/-, S-100+, CD1a- large histiocytes with characteristic normal lymphocytes trafficking in the cytoplasm (emperipolesis). The microscopic findings in extranodal RDD lesions often include more prevalent fibrosis and fewer histiocytes with emperipolesis.1 The clinical findings and histology are often not straightforward, and consultation with an expert in histiocytic diseases may be helpful.

Although initial presentation at any of these sites might be asymptomatic, progressive enlargement of lymph nodes or masses in the various organ sites could lead to expected symptoms such as dyspnea, pain, cough, proptosis, hematuria, flank pain, and visual deficits. Other systemic symptoms may include fevers, night sweats, weight loss, and fatigue, which are likely secondary to elevated levels of TNFα, IL-6, and other inflammatory cytokines. There is no convincing link to any viral infection. Since 2016, mutations in KRAS, NRAS, ARAF, MAP2K1, and PIK3CA have been reported.

RDD is most prevalent in children and young adults but may be seen in patients above 70 years of age. Evaluations after a careful history and physical include a complete blood count, sedimentation rate or C-reactive protein test, liver functions, immunoglobulins, and comprehensive metabolic panel. Some investigators include a cytokine panel, specifically looking for elevations of IL-6 and TNFα. Imaging with a PET scan is most helpful, but additional ultrasounds, chest x-rays, CT, or MRI evaluation of head and neck, chest, or abdomen sites may be indicated. In some pediatric cases of isolated lymphadenopathy, there might be a slow, spontaneous resolution over many months.

Treatment with corticosteroids has been used, resulting in transient decrease in lymph node size, but rebound frequently occurs when therapy is stopped. Surgical resection of a limited number of involved lymph nodes may be practical in some patients, but it is not a common intervention in our clinic. RDD lesions have responded to a variety of chemotherapy agents, including oral methotrexate and mercaptopurine; 6-thioguanine; cytarabine, prednisone, and vincristine; or lymphoma regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or thalidomide, lenalidomide, rituximab, imatinib, and clofarabine.1

Findings from a series of 16 patients with RDD treated with cobimetinib were published in 2022.2 The majority of these patients had involvement of more than one site, often involving bones, kidneys, and the central nervous system. Patients with RDD with one of the previously listed mutations experienced better responses (88%) than those whose RDD lacked the mutations (38%). Likewise, the patients with mutated RDD had a markedly better progression-free survival (100% vs. 29%). Recent and ongoing clinical trials exploring the efficacy of cobimetinib to treat patients with histiocytic disorders include NCT02649972 and NCT04079179.


  1. Abla, O, Jacobsen E, Picarsic J, et al. Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood. 2018;131(26):2877-2890.
  2. Abeykoon JP, Rech KL, Young JR, et al. Outcomes after treatment with cobimetinib in patients with Rosai-Dorfman disease based on KRAS and MEK alteration status. JAMA Oncol. 2022;8(12):1816-1820.


I have a 66-year-old female patient who was diagnosed with severe acquired aplastic anemia. Her bone marrow biopsy was hypocellular as expected and did not show concerning myeloid mutations. Her karyotype and fluorescence in situ hybridization panel for myelodysplastic syndromes were normal. She had a small paroxysmal nocturnal hemoglobinuria clone. She received horse anti-thymocyte globulin (ATG), cyclosporine, and a limited course of eltrombopag because of issues with insurance coverage. She had what seemed like a partial response initially. Unfortunately, at six months post-treatment, she did not have full count recovery or transfusion independence. Her platelets remain consistently in the low 20,000/mL range, but she has not needed a transfusion. Her absolute neutrophil count ranges between 800 and 1,200 µL. Her hemoglobin (Hb)/retic remain low, and she needs packed red blood cells every few weeks to keep her Hb greater than 7.0 g/dL. She has no past medical history and is an incredibly fit 66 year old.

Initially, I was considering an allogeneic hematopoietic cell transplant (alloHCT) as second-line therapy (rather than rabbit ATG [rATG]); however, we have limited good donor options. Her brother is in his early 60s and is a haploidentical match. The best matched unrelated donors  we have are 9/10 (7/8) matches, but all are young donors who are willing and able to donate bone marrow. I have not had a good experience with patients who fail second-line rATG and then go to transplant for third-line treatment. She appears to be doing incredibly well, but I wish the donor options were better. Would you proceed with a 7/8 matched unrelated donor alloHCT in this setting or plan for second-line rATG?

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Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.




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