Investigating the correlation between small molecular inhibitor utilization, peripheral blood monocytes, and treatment outcomes in Rosai Dorfman disease

Abstract

Rosai Dorfman disease (RDD) is a non-Langerhans cell histiocytic neoplasm characterized by sinus histiocytosis with variable emperipolesis. There is a limited understanding of the factors that contribute to disease progression. Traditional management of RDD consists of local therapies (resection, radiation) for localized disease and myelosuppression for systemic disease; targeted medications have also recently been introduced into clinical practice as an additional therapeutic modality. The goals of this study are to compare the impact of targeted therapies to conventional management of RDD and identify trends in laboratory data that may provide insight into disease progression. A retrospective analysis was conducted at a single institution over a 20-year period in 35 adult patients with histopathologic evidence of RDD without confounding secondary malignancies. Clinical data points included laboratory evaluation, molecular diagnostics, imaging, and therapies rendered. Binary data was utilized for statistical analysis and comparison of outcomes by treatment type and utilization of targeted agents. Evaluation of treatment response varied based on anatomic disease sites and baseline imaging modality. To standardize the radiographic analysis, we included PERCIST (if PET was utilized) or RECIST assessments (in the cases of CT or MR imaging). Conventional therapies rendered included local treatment (surgery, radiation, intralesional injections), systemic corticosteroids, immunotherapy, and chemotherapy while targeted agents included only small molecule inhibitors. In this analysis, primary disease was identified in cutaneous, osseous, and CNS structures (17, 11, and 6/35 patients respectively). Management consisted of surgery (12/35 patients), steroid and myelosuppressive therapies (9/35 each), immunotherapy (5/35), and targeted molecular agents (5/35). In evaluating outcomes, the proportion of partial responses was substantially higher in recipients of molecular as compared to conventional therapy (4/5 patients compared to 6/29) while complete responses were more common in the conventional therapy cohort (12/29 compared to 1/5). Lastly, an evaluation of peripheral blood absolute monocytes in all patients who had progressed on therapy identified a significant decrease in pre-progression values as compared to values following therapy re-institution (averages of 0.70 and 0.27 K/µL, respectively; p = 0.0002, 95% CI 0.652–0.2360). Larger-scale studies are needed to further evaluate the relevance of the monocyte trends that were identified in terms of their relationship to disease status. This study is the largest analysis of Rosai Dorfman disease, that we are aware of, from a single institution. In this cohort, the utilization of small molecule inhibitors corresponded to a greater increase in partial responses than conventional therapies, although the opposite effect has been observed in complete responses. This finding can be attributed to the recent introduction of targeted agents and shorter follow-up. We anticipate higher complete response rates with the use of small molecule in ongoing analyses over a longer follow-up period. The recognition of relative monocyte elevation prior to disease progression is an intriguing and to our knowledge, novel finding in the field of Rosai Dorfman disease. Future studies aimed at elucidating the implications of this trend are in progress.