Treatment dilemmas in asymptomatic children with primary hemophagocytic lymphohistiocytosis

Giovanna Lucchini, Rebecca Marsh, Kimberly Gilmour, Austen Worth, Zohreh Nademi, Anupama Rao, Claire Booth, Persis Amrolia, Juliana Silva, Robert Chiesa, Robert Wynn, Kai Lehmberg, Itziar Astigarraga, Tayfun Güngör, Jan Stary, Despina Moshous, Marianne Ifversen, Daniel Zinn, Michael Jordan, Ashish Kumar, Takahiro Yasumi, Paul Veys and Kanchan Rao

Key Points

  • Preemptive allogeneic stem cell transplantation improves prognosis of asymptomatic children genetically predisposed to primary HLH.

Publisher's Note: There is a Blood Commentary on this article in this issue.


Asymptomatic carriers (ACs) of pathogenic biallelic mutations in causative genes for primary hemophagocytic lymphohistiocytosis (HLH) are at high risk of developing life-threatening HLH, which requires allogeneic hematopoietic stem cell transplantation (HSCT) to be cured. There are no guidelines on the management of these asymptomatic patients. We analyzed the outcomes of pairs of index cases (ICs) and subsequently diagnosed asymptomatic family members carrying the same genetic defect. We collected data from 22 HSCT centers worldwide. Sixty-four children were evaluable. ICs presented with HLH at a median age of 16 months. Seven of 32 ICs died during first-line therapy, and 2 are alive after chemotherapy only. In all, 23/32 underwent HSCT, and 16 of them are alive. At a median follow-up of 36 months from diagnosis, 18/32 ICs are alive. Median age of ACs at diagnosis was 5 months. Ten of 32 ACs activated HLH while being observed, and all underwent HSCT: 6/10 are alive and in complete remission (CR). 22/32 ACs remained asymptomatic, and 6/22 have received no treatment and are in CR at a median follow-up of 39 months. Sixteen of 22 underwent preemptive HSCT: 15/16 are alive and in CR. Eight-year probability of overall survival (pOS) in ACs who did not have activated HLH was significantly higher than that in ICs (95% vs 45%; P = .02), and pOS in ACs receiving HSCT before disease activation was significantly higher than in ACs receiving HSCT after HLH activation (93% vs 64%; P = .03). Preemptive HSCT in ACs proved to be safe and should be considered.

  • Submitted January 30, 2018.
  • Accepted July 23, 2018.
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