Evaluating Treatment-Related Outcomes in the Era of Targeted Therapy for Rosai Dorman and Erdheim Chester Disease

Introduction:

Rosai Dorfman Disease (RDD) and Erdheim Chester Disease (ECD) comprise a rare group of non-Langerhans cell histiocytic diseases. Data pertaining to the basic molecular characteristics of non-Langerhans cell histiocytic disorders is well-established but literature regarding survival and therapeutic efficacy with targeted therapies in larger cohorts is sparse. New studies evaluating outcomes by response rates and survival have the potential to provide novel information as to clonal architecture and resistance patterns in histiocytic neoplasms.

Methods

A retrospective analysis of patients diagnosed with ECD or RDD at a single institution was conducted over a 20-year period (2002-2022). Inclusion criteria included patients aged ≥18 with a histopathologic diagnosis of RDD or ECD. A review of each patients’ treatment history was documented. Therapeutic categories were designated as surgery, local radiation, chemotherapy, immunotherapy or targeted therapy including BRAF or MEK inhibitors. Treatment responses were recorded as binary data, with a positive response indicating stable disease, partial or complete response and a negative response indicating progressive disease. This binary data was used to calculate overall response rate (ORR). Time interval from treatment initiation to any progression or date of last follow-up was noted in months and used to calculate progression free survival (PFS). Paired t-tests were used to determine if significant differences existed between each treatment type with respect to ORR and PFS. Absolute monocyte count was recorded on all patients who had progressed, both prior to and following re-institution of a new line in treatment.

Results

In this cohort, 20 patients were diagnosed with ECD and 35 with RDD; the median age was 48 years old. Of RDD patients, 80% (4 of 5) were treated with surgery and radiation prior to treatment with MEK inhibitor; 92% (23 of 25) had a response to surgical treatment, compared to 66% (6 of 9) treated with a MEK inhibitor, with a trend towards clinical significance (p-value = 0.069). 4.5% (1 of 22) of RDD patients received targeted therapy prior to surgery. RDD patients treated with a MEK inhibitor received a median of 3.2 prior lines of therapy before treatment with the MEK inhibitor. No RDD patients were treated with a BRAF inhibitor. Median PFS for RDD patients treated with surgery and radiation was 17 months versus 9 months when treated with MEK inhibitor (p=0.011). ECD patients, by contrast, were less heavily pretreated and received a median of only one line of therapy prior to targeted agents. 71% (10 of 14) of ECD patients were treated with targeted therapy prior to surgery. 21% of ECD patients (4 of 19) were treated with chemo/immunotherapy prior to targeted therapy. There was a trend towards higher overall response rates with targeted therapies, as 92% (11 of 12) of ECD patients responded to MEK and/or BRAF inhibitors compared to 66% (5 of 8) treated with chemo/immunotherapy (p=0.162). Median PFS for ECD patients treated with surgery was 84 months compared to 19 months when treated with any targeted therapy (p-value=0.002), which was a comparable pattern to the RDD cohort. Lastly, absolute monocytes for all patients (RDD and ECD combined) measured at the time of progression to the post-treatment nadir decreased by a mean of 0.1506 K/uL (p-value=0.010), like our previously reported data.

Conclusions

The historical heterogeneity in therapies and degree of pretreatment in RDD and ECD makes comparative response evaluation between treatment modalities challenging. Despite this, we found a significant trend in shorter PFS in patients who were more heavily pre-treated before the receipt of targeted therapy. A potential explanation for this phenomenon would be that early therapies eradicate or at least suppress the more dominant clones in these disease states, in turn, activating alternative pathways and making MAP Kinase signaling modulation less efficacious. Sequencing targeted therapies earlier in the treatment course of systemic RDD and ECD could alleviate this effect and is an important exploratory question in ongoing studies. Lastly, the clinically significant decrease in absolute monocytes following treatment resumption after progression is like prior investigations, suggesting that relative peripheral monocytosis may serve as a surrogate marker for disease status and treatment response in histiocytic disorders.