Dual-Center Experience of Using Etoposide for Secondary Hemophagocytic Lymphohistiocytosis from Infectious Etiologies

Introduction:

Hemophagocytic lymphohistiocytosis (HLH) is a rare but devastating immune hyperactivity syndrome that results in a cytokine storm from cytotoxic CD8+ T-cell and macrophage activation. HLH is categorized into two groups: primary HLH (pHLH) from genetic mutations typically found in children and secondary HLH (sHLH) from acquired triggers typically found in adults. Secondary HLH is increasingly seen as a heterogeneous group with multitude of etiologies, treatment response, and prognosis. The question of whether the treatment and prognostic data that comes from children with pHLH can be applied to adults with sHLH is not yet fully answered. Prior retrospective data showed the benefit of using etoposide and steroids as per the HLH-94 protocol to treat HLH triggered by malignancy or EBV infection, while autoimmune-associated HLH responds better to steroid therapy without etoposide. These findings are reflected in the clinical practice recommendations published by La Rosee and colleagues (2019). Data for etoposide use in sHLH triggered by infection other than EBV remains equivocal. Here, we describe a dual center experience of treating HLH secondary to infection.

Method:

Following the IRB approval at the two study centers, list of patients who received ICD-10 code of D76.1 for HLH during hospitalization from 1/1/2007 to 1/1/2023 were obtained using the internal search program within the electronic medical records. We included patients who met 5 of 8 HLH-2004 diagnostic criteria and had a concurrent infection. Patients with age less than 18 at diagnosis, active cancer (defined as progression or chemotherapy within 1 year), or active autoimmune disorder (defined as a flare requiring steroids within 1 year) were excluded. In our medical records review, we gathered demographics, baseline characteristics, treatment modality, response, and survival up to 3 years. Subjects were divided into two groups: etoposide and the non-etoposide. Fisher's exact tests were performed to examine differences in categorical variables while student T-tests were used for continuous variables. The survival comparison was completed at set points of 8 weeks, 6 months, 1 year, and 2 years using Fisher's exact test.

Results:

Twenty-two patients with infection-induced sHLH were identified for the study. All patients received trigger-specific antimicrobial treatment and steroids. Out of the 22 patients, 11 received etoposide while 11 did not. Within the etoposide group, 2 received tacrolimus, 1 received anakina, 1 received alemtuzumab, and 1 received IVIG as additional HLH therapy. In the no etoposide group, 1 received IVIG and 1 received cyclosporine as additional therapy. The median age and Charlson Comorbidity Index were 55 and 2, respectively in both groups. No statistically significant differences were observed between the groups in measurements of hemoglobin, platelet, white blood cells, fibrinogen, triglyceride, ferritin, or soluble IL-2 receptor activity. No differences were observed in proportions of female gender or presence of fever, splenomegaly, hemophagocytosis in marrow, hemodynamic instability at diagnosis, or intubated status at diagnosis. All patients in the etoposide had viremia as suspected trigger while 43% of the no etoposide group had viremia as a trigger. The rest of the no etoposide group had fungemia. Survival at 8 weeks, 6 months, 1 year, and 2 year for the etoposide group was 91%, 73%, 73% and 50%, respectively. It was 82%, 73%, 64%, and 55% for the no etoposide group. Three patients were lost to follow up in the etoposide group after 6 months. Associated p-values were 1, 1, 0.635, and 1.

Conclusions:

The study was limited due to small sample size, higher proportion of patients with fungal infection in the no etoposide group, and loss of patient follow up in the etoposide group. Despite these challenges, no difference in survival outcome was observed between the two groups. Further testing is appropriate to challenge the utility of etoposide-based regimen for adults with HLH secondary to non-EBV infection.

No relevant conflicts of interest to declare.