Lenalidomide in the treatment of Rosai Dorfman disease-a first in use report
Authors: Maria Rubinstein, Amer Assal, Marina Scherba, Jordan Elman, Robert White, Amit Verma, Marianna Strakhan, Farnoush Mohammadi, Murali Janakiram
Journal: American Journal of Hematology (2015)

To the Editor: A 43-year-old Hispanic male was evaluated waxing and waning bilateral submandibular masses, associated with fevers, night sweats, bilateral flank pain, and a 20-pound weight loss. The complete blood count revealed mild leukocytosis (13.6 × 109/l), and normocytic anemia with a left shift in the granulocyte series (11.7 × 109/l). ESR and CRP were 90 and 210, respectively. Electrophoresis was notable for a polyclonal hypergammaglobulinemia with free lambda chains. Excisional biopsy of the supraclavicular nodes showed sinus histiocytosis with emperipolesis which was S-100 positive and CD1a negative consistent with Rosai Dorfman disease (RDD) (Fig. 1). Histology in RDD. On the left is an H&F showing histiocytes, plasma cells, lymphocytes, and emperipolesis. On the right, the S100 stain highlights histiocytes containing lymphocytes and also shows intrasinusoidal location of histiocytes. There have been various reports of different agents used for the treatment of RDD; including corticosteroids, rituximab, chemotherapy, and radiotherapy 1. Typical initial treatment consists of high dose steroids at 1 mg/kg and our patient achieved a quick remission with a reduction in the size of cervical lymph nodes, a reduction of inflammatory markers, weight gain, and an improvement in his lytic lesions. Unfortunately, steroid tapering was associated with a relapse of RDD. During every relapse, the patient presented with increasing lymph nodes, fevers, weight loss, and an increase in inflammatory markers namely erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Due to the concern for long-term toxicity with steroids, the patient was started on Rituximab and underwent six cycles of chemotherapy with Cyclophosphamide, Vincristine, and Prednisone (CVP). The patient achieved remission but relapsed again after 2 months. The relatively short remission and relapse achieved by administering CVP suggested that RDD could have responded to the immunosuppressive component of the CVP regimen. The patient was treated with Cladribine which is known to markedly immunosuppress the lymphocytes but 3 months after such treatment, the patient relapsed once again. Since the patient responded to immunosuppression, he was switched to Azathioprine, which resulted in a partial response. But since he developed azathioprine induced visual loss, he was switched to thalidomide, an immunomodulating (Imid) agent. With thalidomide, he developed a Grade 3 skin rash and was switched to Lenalidomide and is currently in complete remission with Lenalidomide. Recent studies indicate that among the histiocytosis, RDD is not associated with BRAF mutations or other clonal abnormalities that are seen in other histiocytic disorders 2. This suggests that RDD could be an aberrant immune mediated disease rather than a clonal disorder. On the basis of the above response, we hypothesize two mechanisms of control (1) immunosuppression and (2) immunomodulation. In keeping with this hypothesis, the patient responded to immunosuppression with steroids (consistent with the literature), cyclophosphamide and azathioprine but did not achieve a remission. Why should immunomodulation work? Two mechanisms of action of Imids in RDD can be postulated. (1) RDD is associated with high levels of TNF-α and IL-6 3 and Lenalidomide is known to decrease TNF-α expression and decrease IL-6 levels 4. (2) RDD cells have strong expression of macrophage colony-stimulating factor (M-CSF) 5, which is the suspected mechanism for emperipolesis and human monocytes treated with M-CSF produced high levels of IL-10. IL-10 expression positively regulates the proliferation and differentiation of monocytes in conjunction with M-CSF. We hypothesize that M-CSF activated macrophages in RDD, induce IL-10 release and alter T-cell-mediated immune response which is abrogated by Lenalidomide 4. Our patient with RDD did not achieve remission with the previously studied treatments and only achieved remission with the use of Lenalidomide. The lack of clonal mutations and the response to immune suppression/immune modulation suggest that this could be an immune-mediated disease rather than a clonal disorder. Lenalidomide may be an appropriate therapy in refractory disease and the first reported case of Lenalidomide inducing remission in RDD. Maria Rubinstein,1 Amer Assal,1,2 Marina Scherba,3 Jordan Elman,2 Robert White,4 Amit Verma,1,2 Marianna Strakhan,2,5 Farnoush Mohammadi,2,5 Murali Janakiram1,2* 1Montefiore Medical Center, New York; 2Albert Einstein College of Medicine, New York; 3Memorial Sloan Kettering Cancer Center, New York; 4Weill Cornell Medical Center, New York; 5Jacobi Medical Center, New York