Clinical characteristics and treatment outcomes in patients with histiocytic neoplasms harboring class 3 MAP2K1 mutations, including treatment with the ERK inhibitor ulixertinib.
Authors: Diamond Eli L. , Yabe Mariko , Petrova-Drus Kseniya , Rosenblum Marc , Rotemberg Veronica , Lacouture Mario E. , Rampal Raajit , Francis Jasmine , Knoerzer Deb , Kreider Brent , Abdel-Wahab Omar Ibrahim , Durham Benjamin Heath 
Published: June 2022

e19081 Background: Histiocytic neoplasms (HN) are clonal myeloid disorders with diverse clinical phenotypes. HN nearly invariably harbor mutations of the mitogen activated protein kinase (MAPK) pathway, including the BRAFV600E mutation in HN subtypes that are responsive to BRAF inhibition. More recently characterized, the second most frequently mutated gene driving HN is MAP2K1, with broad responsiveness to MEK inhibition reported. The most common MAP2K1 variant observed in our cohort (n=300 patients) is the exon 3 p.E102_I103 in-frame deletion, among the Class 3 MAP2K1 mutants predicted to be resistant to allosteric MEK inhibition. We present clinical and treatment characteristics of HN patients with Class 3 MAP2K1 mutations. Methods: Patients with HN and exon 3 p.E102_I103del or similar mutations identified by tumor sequencing were included. Sites of disease were captured. First- and later-line treatments were categorized as observation, chemotherapy (vinblastine, cytarabine, cladribine, methotrexate), immune modulation (anakinra or interferon), MEK inhibition (trametinib or cobimetinib), or ERK inhibition (ulixertinib). Clinical and radiologic responses were captured as partial response (PR), complete response (CR), or progressive disease (PD). PD includes relapse following PR or CR. Results: 16 patients were identified. 8 (50%) were female, and median age at HN diagnosis was 31 (range 22-58). 10 patients had Langerhans cell histiocytosis (LCH), 4 had Erdheim-Chester disease (ECD), 2 had mixed histiocytosis. Sites of HN were bone (16; 100%), lymph node (8; 50%), brain (8; 50%), skin/subcutaneous (4; 25%), retroperitoneum (3; 19%), cardiovascular (3; 19%), abdomen (2; 13%), reproductive (1; 6%) and other sites (5; 31%). Mutations identified were MAP2K1 p.E102_103del (13; 81%), p.L101_103delinsF (1; 6%), p.P105_I107delinsL (1; 6%), and p.I103_A106del (1; 6%). 2 (13%) patients had spontaneous regression of disease and were observed; 3 (19%) patients had CR to first-line chemotherapy. 3 (19%) patients have had CR/PR to first-line MEK inhibition. 8 (50%) patients had PD following chemotherapy and/or immune modulation; of those, 1 was lost to follow-up, 4 had CR/PR to MEK inhibition; however, 3 had PD despite MEK inhibition. These three patients and one treatment-naïve patient were treated with an oral ERK1/2 inhibitor, ulixertinib, on prospective protocols. 3 of 4 had a clinical or radiologic PR (1) or CR (2). Conclusions: Histiocytic neoplasms with Class 3 MAP2K1 mutations represent a diverse spectrum of disease characterized by frequent bone, nodal and neurologic involvement, by frequent resistance to chemotherapy. This entity is resistant to MEK inhibition in some patients, a phenomenon previously undocumented, and responsive to ERK inhibition, which may be a promising therapeutic approach to HN.