Skip to main content
  • Correspondence
  • Open access
  • Published:

The role of etoposide in the treatment of adult patients with hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal inflammatory clinical condition, in which an exaggerated immune response is ineffectively regulated. Although etoposide-containing regimens are generally recommended for children with HLH, the exact role of etoposide in the adult setting remains unclear. We performed a systematic review of the literature on the use of etoposide in adults with HLH. All articles written in English on the use of etoposide in adults with HLH available from seven databases and published on or before July 2021 were analyzed. Thirteen studies were found to be relevant to the search results. Ten of these studies report a statistical analysis on the effect of etoposide, of which five found etoposide-containing regimens superior to non-etoposide-containing regimens. Seven studies provided sufficient data to be included in the meta-analysis. For these data, the estimated logit relative risk of etoposide on survival was 1.06 (95% confidence interval: 0.92–1.21, standard error: 2.06). The pooled data of the meta-analysis did thus not support a beneficial effect of etoposide. It should be taken into account that the presented results are highly susceptible to bias and that the effect of etoposide differs between HLH-triggers. Although the meta-analysis does not support the effect of etoposide, we do not recommend abandoning etoposide as treatment modality. The limitations of the meta-analysis, together with several individual articles confirming the benefit of etoposide, justify etoposide for select cases in adults with HLH such as refractory or severe disease with (threatening) multiorgan failure.

To the editor,

HLH is a severe and life-threatening immunological dysregulation either caused by genetic mutation (familial HLH; FHL) or secondary to various triggers (secondary HLH; sHLH). The estimated incidence of FHL is 1 to 1.5 per million children per year [1].

Although etoposide-containing regimens are generally recommended for children with HLH, the exact role of etoposide in the adult patient remains unclear. The treatment strategy in adult patients with sHLH, as recommended by the interdisciplinary working group on adult HLH of the Histiocyte Society, does include etoposide in its treatment strategy [2]. Following this recommendation, etoposide could be considered for sHLH with all underlying triggers, although its use in auto-immune and immunotherapy associated HLH is more restricted [2]. However, evidence to support the use of etoposide in adult sHLH patients is scarce. Therefore we performed a systematic literature review and meta-analysis on the clinical use and effectiveness of etoposide in adult HLH patients. A detailed description of the methods including the search strategy is available in the Additional file 1.

The seven studies that are included in the meta-analysis (Table 1) show an estimated logit relative risk (RRL) of 1.06 (standard error: 2.06; 95% CI: 0.92–1.21) (Fig. 1). The survival probability of the etoposide-treated patients did thus not differ significantly from the survival probability of the non-etoposide-treated patients. As detailed in the Additional file 1, the homogeneity was not rejected. Five individual studies show an analysis that is significantly in favor of etoposide [3,4,5,6,7] whereas five other papers report no additional benefit of etoposide [8,9,10,11,12] (Table 1). Similar to a study by Imashuku et al. [13] Song et al. [6] also analyzed patients receiving etoposide within 4 weeks after diagnosis and compared this group with a group of patients receiving etoposide 4 weeks after diagnosis or who did not receive etoposide. No significant difference was observed in survival between the two groups (p = 0.163).

Table 1 Articles reporting the effect of etoposide in adults with hemophagocytic lymphohistiocytosis
Fig. 1
figure 1

The estimated relative risks of seven studies, which provided data on an etoposide-treated group and a non-etoposide-treated group. The black vertical line represents the logit relative risk estimator. CI confidence interval

The presented results should be interpreted with caution. All studies concern retrospective cohort studies and used different statistical methods. In our meta-analysis we used the risk ratio for addressing the outcome. Due to a lack of provided data by the articles, we could not use a more suitable time-to-event measure such as a hazard ratio. Moreover, there is a high risk of bias in all studies (Table 1). In particular, confounding by indication should be noted since patients receiving etoposide generally concern more severe cases and consequently have a prior survival probability which is lower. As the confounding by indication is in favor of non-etoposide-treated patients, a stronger benefit of etoposide than the calculated effect size could be assumed.

The seven studies included in the meta-analysis were homogeneous based on the findings of the χ2 homogeneity test (Additional file 1). However, within individual groups (i.e. etoposide and non-etoposide-treated), a high degree of heterogeneity is assumed to be present. For example, the studies included patients with diverse etiological HLH triggers, all having a different a priori survival rate [14]. Etoposide may have a different effect among patients with these different etiological triggers. Moreover, several confounders are assumed to effect outcome and should ideally be taken into account. Therefore, it is highly favorable to perform an alternative/additional analysis taking (baseline) confounders into account. In this regard, it would be of particular interest to sub-analyze groups by HLH trigger, since our data suggests that etoposide might be especially beneficial in EBV and lymphoma associated HLH (Table 1) [4, 6, 7]. Owing to the lack of data, we were unable to perform such analysis. However, assuming an equal degree of heterogeneity among the groups (i.e. etoposide and non-etoposide-treated), the data will be averaged out and will thus bring forward a pooled data set that might be compared, although with caution. Given the available data, we believe that this approach is the best available method to address the research question but we also emphasize its limitation.

It is important to note that the studies included in the meta-analysis primarily concern studies that do not present data that support the effect of etoposide (one out of seven studies showing benefit, Table 1). On the contrary, the studies that are not included in the meta-analysis primarily concern studies that do show a benefit of etoposide (four out of seven studies showing benefit, Table 1). Only taking the meta-analysis into account might thus underestimate the effect of etoposide.

The data presented by the meta-analysis should not lead to abandoning etoposide as a treatment modality. The limitations of the meta-analysis that generally lead to an underestimation of the effect size of etoposide, together with several individual articles confirming the benefit of etoposide, justify etoposide for individualized cases of adult HLH. These data support the recent management recommendations by the interdisciplinary working group on adult HLH of the histiocyte society [2]. According to this guideline, it is proposed to initiate a monitored step-up approach starting with corticosteroids and IVIG, especially in patients with mild or moderate disease. Etoposide can be considered for individualized treatment of cases of refractory or severe disease with (threatening) multiorgan failure.

Conclusive studies on etoposide as a treatment modality in adults are not available. To make definitive conclusions on etoposide and its timely administration, a collaboration between HLH treatment centers is needed to initiate a prospective randomized controlled trial. Currently, no definite evidence is available to guide which HLH patients may benefit from etoposide. Thus, etoposide should be administered after careful consideration.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

References

  1. Meeths M, Horne A, Sabel M, Bryceson YT, Henter JI. Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden. Pediatr Blood Cancer. 2015;62(2):346–52.

    Article  Google Scholar 

  2. La Rosée P, Horne A, Hines M, von Bahr Greenwood T, Machowicz R, Berliner N, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465–77.

    Article  Google Scholar 

  3. Arca M, Fardet L, Galicier L, Riviere S, Marzac C, Aumont C, et al. Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide. Br J Haematol. 2015;168(1):63–8.

    Article  Google Scholar 

  4. Bigenwald C, Fardet L, Coppo P, Meignin V, Lazure T, Fabiani B, et al. A comprehensive analysis of lymphoma-associated haemophagocytic syndrome in a large french multicentre cohort detects some clues to improve prognosis. Br J Haematol. 2018;183(1):68–75.

    Article  CAS  Google Scholar 

  5. Bubik RJ, Barth DM, Hook C, Wolf RC, Muth JM, Mara K, et al. Clinical outcomes of adults with hemophagocytic lymphohistiocytosis treated with the HLH-04 protocol: a retrospective analysis. Leuk Lymphoma. 2020;61(7):1592–600.

    Article  CAS  Google Scholar 

  6. Song Y, Wang Y, Wang Z. Requirement for etoposide in the initial treatment of Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis. Br J Haematol. 2019;186(5):717–23.

    Article  CAS  Google Scholar 

  7. Li B, Guo J, Li T, Gu J, Zeng C, Xiao M, et al. Clinical characteristics of hemophagocytic lymphohistiocytosis associated with non-hodgkin B-cell lymphoma: a multicenter retrospective study. Clin Lymphoma Myeloma Leuk. 2021;21(2):e198–205.

    Article  Google Scholar 

  8. Diack ND, Kane BS, Fall S, Sall A, Daher AK, Niasse M, et al. Adult hemophagocytic lymphohistiocytosis in sub-saharan area: a retrospective study of 26 cases. Cureus. 2020;12(3):e7258.

    Google Scholar 

  9. Barba T, Maucort-Boulch D, Iwaz J, Bohe J, Ninet J, Hot A, et al. Hemophagocytic lymphohistiocytosis in intensive care unit: a 71-case strobe-compliant retrospective study. Med (Baltim). 2015;94(51):e2318.

    Article  Google Scholar 

  10. Buyse S, Teixeira L, Galicier L, Mariotte E, Lemiale V, Seguin A, et al. Critical care management of patients with hemophagocytic lymphohistiocytosis. Intensive Care Med. 2010;36(10):1695–702.

    Article  Google Scholar 

  11. Schram AM, Comstock P, Campo M, Gorovets D, Mullally A, Bodio K, et al. Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. Br J Haematol. 2016;172(3):412–9.

    Article  CAS  Google Scholar 

  12. Naymagon L, Tremblay D, Mascarenhas J. The efficacy of etoposide-based therapy in adult secondary hemophagocytic lymphohistiocytosis. Acta Haematol. 2021;144(5):560–8.

    Article  CAS  Google Scholar 

  13. Imashuku S, Kuriyama K, Sakai R, Nakao Y, Masuda S, Yasuda N, et al. Treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in young adults: a report from the HLH study center. Med Pediatr Oncol. 2003;41(2):103–9.

    Article  Google Scholar 

  14. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16.

    Article  Google Scholar 

  15. Song Y, Wang Z, Hao Z, Li L, Lu J, Kang H, et al. Requirement for etoposide in the treatment of pregnancy related hemophagocytic lymphohistiocytosis: a multicenter retrospective study. Orphanet J Rare Dis. 2019;14(1):50.

    Article  Google Scholar 

  16. Knaak C, Schuster FS, Spies C, Vorderwulbecke G, Nyvlt P, Schenk T, et al. Hemophagocytic lymphohistiocytosis in critically ill patients. Shock. 2020;53(6):701–9.

    Article  Google Scholar 

  17. Ahn JS, Rew SY, Shin MG, Kim HR, Yang DH, Cho D, et al. Clinical significance of clonality and Epstein-Barr virus infection in adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol. 2010;85(9):719–22.

    Article  Google Scholar 

Download references

Acknowledgements

We thank W.M. Bramer from the Erasmus MC Medical Library for developing and updating the search strategies. Additionally, we would like to thank M. Udo from the Erasmus MC Medical Library for updating the search results.

Funding

No funding was received for this manuscript.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to the study conception and design. Literature search an preparations were done by TZ. Literature selection and data extraction was done by TZ and JL. Data analysis was performed by AL and TZ. The first draft of the manuscript was written by TZ and AL. All authors commented on the previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jan A. M. van Laar.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflicts of interest related to this paper, including no competing financial interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1. Fig. S1.

Flow diagram showing the study section process. Additional sections.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zondag, T.C.E., Lika, A. & van Laar, J.A.M. The role of etoposide in the treatment of adult patients with hemophagocytic lymphohistiocytosis. Exp Hematol Oncol 12, 2 (2023). https://doi.org/10.1186/s40164-022-00362-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s40164-022-00362-2

Keywords