Hemophagocytic lymphohistiocytosis (HLH) is a severe or even fatal inflammatory status caused by a hereditary or acquired immunoregulatory abnormality, non-malignant proliferation of lymphocytes and tissue cells, and secretion of a large number of inflammatory cytokines[1, 2, 16]. Acquired HLH is often associated with and caused by infections, malignant tumors, and autoimmune diseases. Malignancy HLH is one of the most common secondary HLH, especially in adult patients. M-HLH may occur in up to 1% of patients with hematologic malignancies, and the lymphoma associated HLH (LAHS) is the most common type in M-HLH[17]. M-HLH is considered to suffer the worst outcome among the secondary HLH[3, 18]. The mortality of MAS (macrophage activation syndrome) secondary to sJIA (systemic juvenile idiopathic arthritis) is only 8%, while the mortality rate of M-HLH is even > 80%[3]. The median survival time of M-HLH is only 2 months[4, 5, 18]. However, the standard treatment strategy is still controversial. First, HLH-94/04 regimen is based on the study of patients < 16 years old, but actually, most of LAHS patients are adults[19]. Only 2 patients with LAHS in this study were < 16 years old. Previous reports have also confirmed that the prognosis of adult HLH is worse than that of children[20]. HLH-94 is not suitable enough for LAHS. Second, the priority of HLH-directed treatment and lymphoma-directed treatment is still controversial[4, 5, 21], even though in some clinical observation, many patients died of HLH within 2–4 weeks in spite of continued treatment of the underlying malignancy[5]. Third, due to the severe cytopenia caused by HLH, cytotoxic therapy’s usage, such as etoposide, is limited for the concern of myelosuppression. The above three reasons lead to LAHS's urgent need for relevant clinical study to play a certain therapeutic guiding significance. Etoposide is one of the core drugs in the HLH-94/04 standard protocol, and its importance in the treatment of HLH has been confirmed, such as the improvement of prognosis in the initial treatment of EBV-HLH[7, 8, 20]. But its significance in LAHS treatment has not yet been discussed. In the “How I treat” article in adult HLH, Alison S. and Nancy B. reported one case of LAHS patient who was effectively treated with etoposide combined with CHOP regimen[9]. Camille Bigenwald et al. re-evaluated 162 patients with secondary HLH reported by Rivière S in 2014 in France[10]. Reanalysis of 71 patients with LAHS data revealed that etoposide was an independent prognostic factor in the treatment of HLH. In the 2017 adult M-HLH expert consensus review, it is recommended to prioritize treatment for cytokine storms and T cell proliferation, such as etoposide, for patients with HLH who have experienced severe organ damages[5]. In this study, it was evident that the early response rate, short-term survival, and overall survival of the treatment group containing etoposide were superior to those of lymphoma directed chemotherapy without etoposide. Even though we cannot draw a conclusion about the priority between HLH or lymphoma directed treatment, it can be concluded that no matter which method is chosen, the inclusion of etoposide in initial therapy, accounts for a definitely better prognosis.
The mechanism of etoposide in HLH is that it reduces the production of excessive proinflammatory factors by selectively ablating over-activated T cells and inhibiting mononuclear-macrophage activation[22]. This effect is different from immunosuppressive effects of corticosteroids and the immunomodulatory effects of IVIG or cyclosporin, which makes it indispensable in some kind of HLH treatment strategy. In some previous studies, the median survival time of M-HLH is only 8 weeks[4, 18]. In the study of Camille B et al, by observing the outcome of B-NHL and T-NHL-related HLH, they have an opinion that the long-term lymphoma prognosis may be comparable to a similar lymphoma not associated with HLH, once the initial and crucial early period is overcome[10]. And, thus, the long-term prognosis improvement of lymphoma associated with HLH may be accomplished through the optimization of management during the initial HLH diagnostic period. In our study, it was observed that nearly half of all deaths occurred within 2 months after diagnosis, and the median survival of the without-etoposide group was only 7.8 weeks. In addition to the early response rate, the improvement of 2-month survival rate was also significant in etoposide-contained group, and we have reason to believe that the improvement in short-term survival is also why the etoposide group contributes to a better long-term survival. The poor prognosis of LAHS has be considered relating to its pathogenesis, that the lymphoma may drive secondary HLH by its ability to secrete inflammatory cytokines, or to present antigens that can activate a cytotoxic T cell response. The underlining malignancy plays a crucial role in the development of HLH. Etoposide is a chemotherapy medication used for the treatment of a number of cancers, including lymphoma. It forms a ternary complex with DNA and the topoisomerase II enzyme (that aids DNA unwinding), preventing re-ligation of the DNA strands. Thus, etoposide causes DNA strands to break[23]. Although etoposide is not currently a commonly used first-line regimen in lymphoma, it has been reported that it can improve EFS and PFS in some patients with T-cell lymphoma under 60 years old[11, 24], also used in some B-cell lymphoma[25], indicating that the usage of etoposide in LAHS, not only effects on controlling HLH, but also may affect a little on the underlining lymphoma. In addition, although the relapse rate in the containing etoposide group was lower than that in the etoposide-free group, the difference was not statistically significant and may be related to the limited number of data. The persistence of etoposide’s effect, treatment course and dosage still need further clinical data.
For the intervention time of etoposide, considering the high early mortality observed in this study, and that the prognosis of LAHS patients who achieved early remission was significantly better than those failed to achieve, and that the inclusion of etoposide is a significant improvement in early remission rate, therefore, it is appropriate to include etoposide in the initial treatment. And as the lymphoma directed treatment requirement for subsequent therapy, early effective control of inflammatory conditions provides good conditions for subsequent therapy and even allo-HSCT. However, the sever cytopenia caused by HLH may bring some concern for the usage of etoposide. One of the main reasons why less than 50% of LAHS patients received HLH directed treatment, is the concern of myelosuppression deterioration after cytotoxic therapy. But in fact, etoposide’s efficiency occurs within 24–48 h and in HLH, far outweighs the risk of transient worsening of the cytopenia[6, 20]. Previous reports are also considered to be in the treatment of HLH, and in some circumstances, etoposide prevented the development of cytopenia and marrow hypocellularity[26]. This study evaluated the level of myelosuppression and there was no significant difference between the two groups, but the etoposide dose in this study was indeed adjusted according to adult intolerance and taking into account the cytopenia. It seems that as long as appropriate doses, concerns about myelosuppression are not sufficient to constitute a good reason for not using etoposide. On the other side, there are truly 4 deaths of complications in the etoposide group. Therefore, after the reduction of etoposide, whether its anti-tumor and anti-HLH effects are affected, and whether the risk of serious infection and bleeding complications increases, further research is needed.
It is interesting that in the multivariate prognosis analysis, it was found that in patients with positive EBV, whether etoposide was included in the initial treatment had little effect on the prognosis, but in patients who did not suffer EBV infection, the initial treatment included etoposide could clearly improve the prognosis. In previous reports, whether it is T / NK-cell or B-cell lymphoma, the presence of EBV infection is a clear poor prognostic factor. The meta-analysis in 2018 of 356 patients suggested that, the pretreatment positive EBV was significantly correlated with the overall survival of extra-nodal NK/T-cell lymphoma (pooled HR = 3.78, p = 0.004)[27]. EBV-positive diffuse large B-cell lymphoma also contribute a poor prognosis[28]. Also, as we all know, the type of lymphoma secondary to HLH is closely related to the prognosis. In the study of Sano H et al., the rate of early death was higher in patients with T/NK-cell LAHS than in those with B-cell LAHS (62.5 vs. 10.5%)[29]. However, in this study, for patients without positive EBV, the type of lymphoma was not significantly correlated with prognosis. This result suggests that the worse prognosis of T/NK-cell LAHS may be related with that EBV infection is more common in T/NK cell lymphoma. EBV itself can cause HLH, and whether it is EBV-HLH or EBV (+) NK/T-LAHS[3, 30], combined with positive EBV is an independent prognostic factor, as also observed in our study (Fig. 3). Therefore, a possible conjecture is that when lymphoma is secondary to HLH and combined with positive EBV, EBV influences the prognosis from both aspects of lymphoma and HLH. In this EBV + LAHS, the inclusion of etoposide in the initial treatment is not sufficient to improve the outcome. But for EBV- LAHS, initial treatment with etoposide is clearly helpful for prognosis and is certainly recommended.