Long-term outcome of 117 patients with Erdheim-Chester disease and mixed histiocytosis receiving targeted therapies (BRAF and MEK inhibitors): A monocentric experience.

Abstract

7560 Background: Erdheim–Chester disease (ECD), an inflammatory myeloid neoplasm from the L group, is an histiocytosis associated with multisystem infiltration. Around 1500 cases have been reported worldwide since 1930. In 15% of cases, ECD is associated with another histiocytosis corresponding to mixed histiocytosis. Before 2004, 60% of patients died within 3 years after diagnosis. The targetable BRAFV600Emutation is present in as much as 70% of all ECD cases. Targeted therapies (BRAF inhibitors in April 2012, followed by MEK inhibitors after 2015) have revolutionized the therapeutic options and prognosis of refractory ECD and mixed histiocytosis. Methods: This retrospective study was conducted between April 2012 and December 2019 on 117 ECD patients who received targeted therapies in the French National Referral Center for Histiocytosis at Pitié-Salpêtrière Hospital in Paris, France. 28 patients (pts) (24%) had a mixed histiocytosis. Results: 43 (36.7%) pts were female and 95/116 exploitable pts (81.9%) had a BRAF V600E mutation. 12 (10.3%) pts had a co-ocurring hemopathy (myeloproliferative neoplasm or myelodysplastic syndrom). Age at diagnosis was 57.2 yr (+/- 13.8). The main sites of involvement were: vascular (“coated aorta”) in 85 pts (73%), heart in 83 pts (71%), xanthelasma in 30 pts (26%), central nervous system in 56 pts (48%) and peri-renal (“hairy kidney”) in 84 pts (72%). 34 pts (29%) had previously received corticosteroids, and 63 pts (54%) interferon alpha regimen (mainly PEG interferon). 86 (74%) pts received the BRAF inhibitor vemurafenib, and 42 (36%) pts the MEK inhibitor cobimetinib (some patients receiving both). 25 pts died during follow-up. The median survival of patients with targeted therapies in december 2019 was undefined, whereas the patients with no targeted therapies had a median survival of 133 months (HR 0.64 (0.42-0.99); p = 0.04). Among the 117 pts, only 2 had a progression of VAF of mutations within genes frequently mutated in myeloid neoplasms. The most serious adverse events were cutaneous (squamous cell carcinoma, basocellular carcinoma, DRESS) and acute pancreatitis with BRAF inhibitors, whereas chorioretinitis and left ventricular dysfunction were seen with MEK inhibitors. None of the patients receiving targeted therapies progressed. Conclusions: Targeted therapies (BRAF and/or MEK inhibitors) were found dramatically efficacious in 117 patients with severe and refractory ECD and mixed histiocytosis, improving survival of patients.