Retrospective Treatment Analysis of a Series of 104 Patients with Adult Onset Hemophagocytic Lymphohistiocytosis in a Single Institution of China
Authors: Shuai Xiao , Xu Juan , Zhong Xushu , Li Yan , Tang Wenjiao , Zhu Huanling , Niu Ting , Wu Yu , Jia Yongqian , Cui Xu , Pan Ling , Chang Hong , Gong Yuping , Xiang Bing , Huang Jie , Li Jianjun , He Chuan , Chen Xinchuan , Xie Liping , Ma Hongbing , Ji Jie , Dai Yang , Liu Zhigang , Liu Ting 
Published: October 2019

Abstract
Objective.
Hemophagocytic lymphohistiocytosis (HLH), also known as Hemophagocytic Syndrome (HPS), is an increasingly recognized clinical syndrome that is characterized by extreme immune activation. HLH was first described as an inherited immune disorder in pediatrics, but it may also arise in adults as the result of persistent antigen stimulation due to infections, autoimmune disorders or malignancies. Early recognition of HLH and appropriate treatment are critically important. For the pediatric patients, the Histiocyte Society Study Group for HLH has developed the HLH-94 and HLH-2004 treatment protocols, but there is no such guideline or consensus for adult HLH. Although there were increasing amount of clinical studies in adult HLH, the majority of them just described the etiologies and clinical profiles, and failed to analyze the treatment effects on outcomes. Therefore, there is an urgent need for more clinical data focusing on treatment in adult HLH patients, in order to clarify optimal therapeutic regimens. Our study retrospectively analyzed the causes, treatment strategies, and relevant outcomes in 104 adult HLH patients in our institution, and with the goal of identifying more appropriate therapeutic strategies for adult HLH patients.
Methods.
After the approval of our protocol by local institutional Ethics Committee, the medical records of 104 consecutive patients with adult onset HLH in West China Hospital from June 2008 to February 2016 were reviewed. The diagnosis was re-confirmed according to HLH-04 criteria, and demographic data, clinical profiles, treatments and outcomes were collected and analyzed. The latest follow-up visit occurred on 1st July 2016. The different therapeutic effects on prognosis were discussed based on the endpoints which were defined as short-term (30 days) and long-term (last follow-up date) survival rates. Statistical analysis was performed on SAS 9.4 software, and was involved in Log-rank test in univariate analysis and Cox proportional hazard regression model in multivariate analysis. All p values were two-sided and p<0.05 were considered statistically significant.
Results.
All of 104 consecutive patients with adult HLH were enrolled in this study. The male/female ratio was 1.6:1 with the median age of 35 (range 16-77). In etiological classification, 75 cases were lymphoma-associated HLH, 13 cases were infection-associated HLH, 2 cases were with autoimmune disorders, and for the remaining 14 cases, the underlying diseases could not be identified. In treatment analysis, corticosteroids were used in 91 cases (87.5%), the median initiation time was 0 day (range 0-26 days) after HLH diagnosis, the median four-week accumulating dosage was 236.57mg dexamethasone. Etoposide was employed in 55 cases (52.9%), the median initiation time was 3.5 days (range 0-62 days), the median four-week accumulating dosage was 590.00mg. Cyclosporine A (CSA) was used in 42 cases (40.4%), the median initiation time was 2 days (range 0-51 days), the median four-week accumulating dosage was 7100.00mg. The median survival time for all patients was 46 days (1-2529 days). On the 30th day after admission, 27 patients (26.0%) had died, and 77 patients (74.0%) had survived. At the last follow-up visit, 74 patients (71.2%) had died, 17 patients (16.2%) were still alive, and 13 patients had been lost to follow-up. Statistical analysis indicated that patients in etoposide-treated group was associated with superior short-term survival rate, compared with non-etoposide-treated group (p=0.0471), but there was no difference in long-term survival rate between the two groups. CSA-treated group was associated with inferior long-term survival rate (p=0.0214), compared with non-CSA-treated group. In patients with lymphoma-associated HLH, those who received antineoplastic chemotherapy had a higher long-term survival rate than those who did not receive it (HAZARD=0.07, p<0.0001).
Conclusion.
The major underlying diseases of adult onset HLH are malignant lymphomas. Etoposide might only improve the short-term survival, but fail to change the long-term survival. Immunosuppressor CSA seems to be associated with negative effects on long-term survival rate. For patients with lymphoma-associated HLH, antineoplastic chemotherapy might improve the long-term outcome. More clinical prospective studies should be initiated for adult acquired HLH.

Disclosures
No relevant conflicts of interest to declare.