Introducion: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive immune activation. HLH following immune checkpoint inhibitor (ICI) exposure (ICI-HLH) is increasingly reported but not well characterized or studied. Given the pro-inflammatory mechanism of ICIs, ICI-HLH may present with more rapid clinical deterioration than traditional HLH, potentially limiting the benefit of standard HLH therapies if not initiated early.

Methods: Using TriNetX database, we identified adult patients with neoplasm and a diagnosis of HLH within 1 year of ICI exposure (ICI-HLH, n=128) and compared them to patients with neoplasm and HLH without ICI exposure (non-ICI HLH, n=7,724). ICI exposure was defined via medication records for PD-1, PD-L1, or CTLA-4 inhibitors. After 1:1 propensity score matching (n=118 per group), we evaluated treatment patterns and survival outcomes at 7, 14, and 30 days.

Results: ICI-HLH was strongly clustered early in the ICI treatment course: 49% occurred within 1 month, 74% within 2 months, and 90% within 6 months. This suggests that when HLH occurs with ICI therapy, it often emerges during early cycles of immunotherapy. Despite similar baseline characteristics after matching, treatment patterns were different between the cohorts: steroid use was significantly lower in ICI-HLH (26% vs. 58%), which may reflect both clinical hesitation to use immunosuppressants early in ICI therapy and the rapid decline observed in these patients.

At 7 days, ICI-HLH patients receiving etoposide, tocilizumab, or anakinra had significantly worse survival (HR 5.26, 95% CI 1.50–18.46, p=0.004), indicating that escalation therapies often began too late to affect outcomes. Among steroid-treated patients, mortality was markedly higher in the ICI group (OR 16.11, 95% CI 1.90–136.68, p=0.002), with a median survival of 1 day, further supporting the notion that treatment timing was a critical limiting factor. Although overall 7-day survival was not significantly different (HR 1.96, p=0.101), this likely reflects limited statistical power and the extremely early mortality in the ICI group.

At 14 days, outcomes remained worse for ICI-HLH patients treated with second-line therapies (HR 3.13, 95% CI 1.31–7.49, p=0.007) and steroids (HR 2.82, 95% CI 1.19–6.72, p=0.012). Tocilizumab in particular was associated with worse outcomes (HR 4.67, 95% CI 1.01–21.59, p=0.030), possibly reflecting selection bias toward its use in rapidly deteriorating patients or limited efficacy in ICI-driven cytokine release. Dexamethasone alone was not significantly different (HR 0.50, 95% CI 0.17–1.46), and trended toward improved survival in ICI-HLH, further supporting the benefit of early intervention.

At 30 days, overall survival was significantly worse in the ICI-HLH group (HR 2.59, 95% CI 1.14–5.87, p=0.018). Among those treated with etoposide, tocilizumab, or anakinra, outcomes were again poorer (HR 4.20, 95% CI 1.80–9.79, p<0.001). Odds of mortality remained higher among steroid-treated ICI-HLH patients (OR 14.74, 95% CI 1.74–124.83), reinforcing that time to treatment is a primary determinant of outcome, not necessarily treatment ineffectiveness.

In time-to-treatment sensitivity analyses excluding deaths within the first 3 days, survival differences between groups narrowed significantly. For example, among steroid-treated patients who survived past day 3, survival probability by day 12 trended higher in ICI-HLH, and the risk difference was 0.70 (95% CI 0.54–0.85, p<0.001). These findings support the hypothesis that early initiation of immunosuppressive therapy may improve survival in ICI-HLH, but a narrow therapeutic window limits the opportunity to intervene. We conducted a subgroup analysis comparing dual ICI therapy to single-agent ICI in patients who developed HLH; however, due to the small sample size, the analysis was underpowered to detect meaningful differences in outcomes.

Conclusions: ICI-HLH represents a distinct and rapidly progressive form of HLH. While standard therapies—including corticosteroids and cytokine-targeting agents—appear effective when administered early, many patients deteriorate before treatment can be delivered. These findings underscore the need for earlier recognition and faster intervention in patients receiving ICIs. Further studies are warranted to better characterize ICI-HLH and elucidate its underlying mechanisms.

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2025
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