Table 3 Studies describing the use of etoposide-based therapy in secondary HLH. We were able to identify only 5 small retrospective studies which included any mention of a comparison between patients who received etoposide-based therapy, and those who did not. Those, as well as one additional study describing use of the HLH- 2004 protocol in adult secondary HLH (Bubik et al.) are summarized above. Note all above studies were uncontrolled and may have been skewed by use of etoposide in the most ill or refractory patients 

Parikh et al. [40]

In a retrospective cohort of 62 adults with secondary HLH assessed for relevant prognostic factors, the OS among those who received etoposide-based therapy (n = 21) was similar to those who did not (n = 41) [40]. The underlying cause of HLH was malignancy in 32 patients (52%), infection in 21 (34%), autoimmune disease in 5 (8%), and idiopathic in 4 (6%)

Arca et al. [38]

In a study investigating predictors of early death (within 30 days of diagnosis) among 162 adult patients with secondary HLH, the 81 patients who received etoposide-based therapy did not demonstrate significantly improved 30-day survival relative to the 81 who did not [38]. Although the use of etoposide was not associated with better survival in univariate analysis (p = 0.079), in multivariate analysis, the absence of etoposide use was associated with a worse prognosis (p = 0.04). Hematological malignancies (n = 75, 46%), infections (n = 40, 25%), and multicentric Castleman disease (n = 17, 10%) were the most common identified triggers

Schram et al. [41]

In a cohort of 68 adult HLH patients OS was not significantly different between the etoposide (n = 32) and no-etoposide (n = 36) groups [41]. Underlying disorders included malignancy in 33 patients (49%), infection in 22 (33%), autoimmune disease in 19 (28%) and idiopathic HLH in 15 (22%)

Apodaca et al. [39]

A study investigating prognostic factors and outcomes among a 64 patient adult HLH cohort (16 of whom received etoposide based therapy) found that etoposide did not have an impact on OS [39]. Causes of HLH included malignancy in 33 patients (52%), infection in 17 (27%), autoimmune in 3 (5%), familial in 1 (2%), idiopathic in 10 (16%)

Bubik et al. [42]

A retrospective study of 31 adult HLH patients treated according to the HLH- 2004 protocol demonstrated a median OS of 3.2 months, and 1-year overall survival of 35% [42]. HLH etiology included malignancy (n = 9, 29%), autoimmune (n = 8, 26%), infection (n = 8, 26%), and idiopathic (n = 6, 19%)

Naymagon et al. [7]

In a retrospective study of 90 adult secondary HLH patients comparing outcomes among those who received etoposide-based therapy (n = 42) to those who did not (n = 48), use of etoposide was not associated with an improvement in survival [7]. Causes of HLH included infection in 63 patients (70%), malignancy in 44 (49%), rheumatologic disease in 13 (14%). Thirty patients (33%) had multiple concurrent causes