Clinical and PET Responses to Long-Term High-Dose Interferon-α Treatment Among Patients with Erdheim-Chester Disease
Authors: Cao Xinxin , Niu Na , Sun Jian , Cai Hao , Wang Feng-dan , Wang Yi-ning , Zhong Ding-rong , Duan Ming-hui , Zhou Dao-bin , Li Jian 
Published: October 2019

Abstract
Objectives: Erdheim-Chester disease (ECD) is a rare multi-systemic form of histiocytosis. Treatment with BRAF inhibitors has markedly improved outcomes for patients with ECD; however, the estimated annual cost of BRAF inhibitors is approximately $50,000 in China. Interferon-α (IFN-α)has been used with variable efficacy as a treatment for ECD. The estimated annual cost of IFN-α is approximately $1600 in China. The aim of the current study was to describe the long-term treatment outcomes and efficacy of FDG-PET for evaluating therapeutic responses among a cohort of ECD patients who were treated with IFN-α.
Methods: We retrospectively evaluated newly diagnosed ECD patients who received 600 MIU or 900 MIU of IFN-α, three times/week subcutaneous for at least 1 month at Peking Union Medical College Hospitalbetween January 2010 and May 2018. All patients were followed up every 3-6 months. We defined the most active lesion measured by standardized uptake value (SUV) on FDG-PET before treatment as target lesions. We used the ratios between most active target lesion SUV and liver SUV (SUVmax/SUVliver) for follow-up, to eliminate heterogeneity.
Results: A total of 32 patients (16 male and 16 female) met the inclusion criteria. Four of them were diagnosed with mixed ECD and Langerhans cell histiocytosis. The median age at diagnosis was 48 years (range, 6-66 years). The median number of involved organs was four (range 1-8). The main sites of involvement were the bones (93.8%), retroperitoneum (40.6%), lungs (37.5%), vasculature (37.5%), central nervous system (CNS, 34.4%), pericardium (28.1%), pleura (21.9%), skin (18.8%), pituitarium (15.6%), heart (12.5%), retro-orbital involvement (12.5%), nerve root (9.4%), muscles (6.3%), thymus (6.3%), thyroid (3.1%) and breasts (3.1%). Two patients did not have an adequate amount of tissue available for genomic testing. BRAFV600Emutations were detected among 21/30 patients (70.0%). The most active target lesions at baseline detected by FDG-PET were bone (58.3%), followed by CNS (15.0%), pleura (5.0%), nerve root (5.0%) and muscle (5.0%). In all, 26 patients (81.3%) received IFN-α as the first-line treatment. Four patients (12.5%) received IFN-α after cytarabine based chemotherapy as maintenance therapy. Two patients (6.2%) received IFN-α as second-line therapy. The median duration of IFN-α therapy was 18.5 months (range, 1-51 months). One patient stopped IFN-α treatment because of intolerable adverse effects after 8 months. The overall clinical response rates were 80.0%, including 33.3% complete response, 36.7% partial response, and 10.0% stable disease. Thirty-one patients underwent a total of 81 scans by PET. A total of 17 patients underwent at least one follow-up FDG-PET scan, median of 4 (2-6). The SUVmax / SUVliver changed during treatment (Figure 1). At the last follow-up, nine (52.9%) of these patients had experienced a partial metabolic response. The median reduction in SUVmax / SUVliverfrom baseline to last PET/CT scan was 61.4% (range, 8.8%-86.6%). Thirteen (76.5%) patients experienced continuous clinical improvement during follow-up. Eight of 13 (61.5%) patients recorded at least one SUVmax / SUVliverincrease during follow-up: the median increase in this ratio was 32.0% (range, 2.6%-45.4%), which decreased in subsequent scans without changing the treatment (Figure 2). The estimated 3-year progression-free survival (PFS) and overall survival (OS) were 64.1% and 84.5%, respectively. The univariate analyses of survival showed that a significantly higher PFS was attained in patients without CNS involvement compared to those with CNS involvement (not reached vs 24 m, p=0.018).Patientswithout CNS involvement also had a significantly higher OS than those with CNS involvement (p=0.023). BRAF status was not an independent prognostic factor for PFS or OS.
Conclusion: High-dose IFN-α treatment is a cost-effective option, especially for patients without CNS involvement. Single target lesion SUV elevation according to FDG-PET do not accurately demonstrate disease progression, but serial FDG-PET imaging effectively discriminate treatment response.

Disclosures
No relevant conflicts of interest to declare.