Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory syndrome that is classified into primary and acquired forms. Primary-HLH has genetic components related to defects in cytotoxic T and NK cells. The acquired form of HLH is classified based on the underlying triggers of immune dysregulation through malignancy, infections, and/or autoimmune processes. The standard of care is established with etoposide and dexamethasone, but there are currently no guidelines for refractory HLH or cases with confounding presentations with infection or malignancy. We describe cases of malignancy-associated HLH (m-HLH) in pediatric patients to discuss the intricacies in the initial diagnostic considerations, the balance of therapeutic regimens and their toxicities, and the novel use of emapalumab and ruxolitinib in refractory patients.

We discuss a 16-year-old female with NK/T-cell lymphoma of the nasopharynx who presented in septic shock with pancytopenia and DIC. Diagnostic considerations included progressive lymphoma, bacteremia, and EBV viremia as possible explanations for her shock physiology. HLH was a consideration on admission given her presentation, but she did not meet criteria until HD#7 with ferritin of 740ng/mL (ref 10-291ng/mL), soluble IL-2 receptor (CD25) of 10,600pg/mL (ref <1033pg/mL), sCD163 of 5,636ng/mL (ref 387-1,785ng/mL) and an abnormal NK cell function. Standard treatment with etoposide and dexamethasone showed minimal effect, as did the introduction of rituximab. Gemcitabine and oxaliplatin were started as treatment for her lymphoma as the driver of her HLH, but she developed acute decompensation with hemodynamic instability and multi-organ system failure. Her systemic inflammation worsened as evidenced by a rise in her ferritin to 15,462ng/mL and sIL-2 receptor to 28,700pg/mL. Her CXCL9, a downstream chemokine and marker of IFN-gamma activity shown to be elevated in HLH, had a dramatic increase to 106,918 pg/mL (ref <121pg/mL). A decision to hold treatment for her lymphoma was made to reduce toxicities and better manage her HLH. Compassionate use of emapalumab, an IFN-gamma inhibitor indicated in primary HLH, led to dampening of her systemic inflammatory processes with resolution of fevers and signs of recovery of her hepatobiliary, renal, and gastrointestinal systems.

We also describe a 17-year-old male who presented with T-ALL and bacteremia who developed HLH during induction-chemotherapy with complications from bacterial sepsis and fulminant fungemia. He represented a diagnostic conundrum throughout his induction chemotherapy with persistent fevers despite appropriate treatment and improvement of his bacteremia and fungemia. It was not until HD#50 that he met criteria for HLH with the addition of a ferritin level of 6,073ng/mL. He had limited response to treatment and had multi-system toxicities from the therapies for his HLH, ALL, and fungemia that necessitated frequent adjustments to his treatment plans. The treatment for his HLH was not standard given the toxicities. Etoposide was never in consideration given concerns for myelosuppression and dexamethasone was not given at full doses due to intolerance but was given over a prolonged duration of months. His course included a waxing and waning response to a combination of steroids and IVIG with recurrent admissions for presumed HLH flares. A trial of ruxolitinib, a JAK inhibitor, demonstrated response with stabilization of his hyperinflammatory state. Although not curative, as evidenced by his persistent hyperferritinemia, the use of ruxolitinib has allowed him to better tolerate his chemotherapy and improve his overall quality of life with a decrease in frequency of flares and hospitalizations.

These cases highlight the intricacies of the management of m-HLH in pediatric patients with the spectrum of disease severity and complex diagnostic evaluations one must consider at presentation. Due to the toxicity of treatment options for often concurrent processes of malignancy, infection, and HLH, novel therapeutics such as emapalumab and ruxolitinib are required and should be evaluated in larger studies. Furthermore, guidelines for the management of pediatric m-HLH are required with inclusion of adjustments to standard therapy based on toxicity, inciting factors, concurrent processes, and the incorporation of novel therapeutics to achieve improved outcomes.

Disclosures

No relevant conflicts of interest to declare.

OffLabel Disclosure:

Ruxolitinib and emapalumab for refractory acquired HLH in Pediatric patients.

Author notes

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Asterisk with author names denotes non-ASH members.