Comparison between clinical features and prognosis of malignancy- and non-malignancy–associated pediatric hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is characterized by aberrant activation and proliferation of polyclonal CD8⁺ T lymphocytes and macrophages that infiltrate multiple organs and overproduce inflammatory cytokines [1]. HLH has been characterized as primary HLH or secondary HLH (SHLH). Primary HLH is often associated with inherited gene defects.

SHLH generally occurs later in life than primary HLH. SHLH is an acquired phenomenon that develops in response to severe infections, autoimmune or rheumatologic disorders, drugs, and in association with concurrent malignancies [2]. Malignancy-associated HLH is most commonly seen in acute leukemia in children. HLH can occur as initial HLH or concomitantly with malignant disease. The mechanism of malignancy-associated hemophagocytosis is not well understood, and may be associated with cytokine secretion (including interferon-γ and interleukin-6), persistent antigen stimulation by malignant cells, chemotherapy-induced immunosuppression, hematopoietic stem cell transplantation (HSCT), or infection [3].

The difference between malignancy- and non-malignancy–associated (i.e., causes other than tumor) HLH remains unclear. We retrospectively reviewed patients with malignancy- and non-malignancy–associated HLH at our institution and compared the clinical characteristics, treatment response, overall survival time, and prognostic factors of the two groups. In this study, we also share our limited experiences with allogeneic HSCT in malignancy-associated HLH. We aimed to distinguish between malignancy-associated and non-malignancy–associated HLH, compare their clinical features and prognostic significance, and analyze the difference between the two conditions.

We performed a retrospective analysis of 22 children with malignancy-associated HLH and 69 children with non-malignancy–associated HLH at a single institution. The pathogenesis of SHLH remains unclear. Delavigne et al. [6] proposed extended 18-point diagnostic criteria that are more easily and rapidly available in smaller institutions and primary care settings than the HLH-2004 variables. Non-malignancy–associated HLH is common in acute self-limited infectious mononucleosis (IM), rheumatic or autoimmune diseases, immunodeficiency diseases, and CAEV.

EBV is the most frequent antigen activator of SHLH [7]. The pathological changes in IM and CAEV differ. In contrast to B cell infection in IM, CAEV features the proliferation and infection of polyclonal, predominantly non-CD8⁺ (CD4⁺CD8⁻ and CD4⁺CD8⁺) T cells, and CD16⁺ natural killer (NK) lymphocytes [8]. In CAEV, mortality generally results from the subsequent development of HLH and/or T/NK lymphoproliferative neoplasm [9]. The prognosis is poor once CAEV develops into HLH [9]. Chronic granulomatous disease is an inherited disorder of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which may be associated with HLH [10, 11]. HLH is characterized by impaired function of T cell–mediated inflammation, which is partly regulated by NADPH oxidase. This pathophysiological cooperation may account for the increased severity.

EBV-related HLH is an acquired, infection-related HLH that typically represents a fulminant presentation of acute EBV infection of CD8⁺ T cells, and has a mortality rate of 30–50% [8]. In the present study, 30.4% of the children with non-malignancy–associated HLH were EBV-positive; eight patients (36.4%) with malignancy-associated HLH were positive for EBV infection. Ahn et al. [12] suggested that patients with high EBV DNA viral load have poor prognosis. In the present cohort, a 12-year-old girl with γδ T cell lymphoma relapsed and developed hemophagocytic syndrome after receiving chemotherapy for 6 weeks; she died of severe EBV infection. Strenger et al. [13] found that malignancy-induced HLH concurrent with EBV infection might be a possible trigger in immunocompromised patients.

In children, HLH may be associated with SLE, a systemic autoimmune disorder involving multiple visceral organs. In HLH due to SLE, corticosteroids and immunosuppressive agents, including cyclosporine, cyclophosphamide, intravenous immunoglobulin, and etoposide, have been used with variable success [14].

In the present study, patients with non-malignancy–associated HLH had significantly higher HGB (p = 0.004), ALT (p = 0.002), and AST (p = 0.001) levels than the patients with malignancy-associated HLH. The cause of low HGB in malignancy-associated HLH may be associated with the inhibition of hematopoiesis by malignance and chemotherapy. However, the cause of high ALT and AST levels in non-malignancy-associated HLH is unclear. Damage to liver function is characterized by severe inflammation and immune-mediated organ damage. Inflammatory cell proliferation and infiltration into organs and tissues and uncontrolled hypercytokinemia in non-malignancy–associated HLH may be more obvious than that in malignancy-associated HLH [15].

The difference in survival time was not statistically significant between the two groups (p = 0.055). However, previous studies have confirmed that patients with malignancy have worse survival than those without malignancy [16‐18]. Celkan et al. [19] reported 54% overall survival in 13 children and adolescents with malignancy-associated HLH. The 13 children included five patients with leukemia; eight patients with rhabdomyosarcoma, neuroblastoma, or lymphoma; and one patient with Langerhans cell histiocytosis. Another study reported that the 2-year survival rate of 25 children with malignancy-associated HLH was 40.9%, and survival was 56% following the acute phase of HLH; a 5-year survival rate of 36% has also been reported [20]. We did not detect significant differences in outcome between malignancy-associated HLH and non-malignancy–associated HLH. Our results show that the low survival rate in the latter group might be due to CAEV, immunodeficiency diseases, and autoimmune diseases, as the prognosis of the abovementioned underlying diseases was poor.

The factors that affect survival are not well known, and there are currently no standard outcome predictors for SHLH. Recent data have shown that ferritin reduction is a prognostic variable for mortality in children with HLH [21]. Following univariate analysis, Park et al. [22] found that serum Fib ≥166 mg/dL at the initial visit was significantly associated with survival time. Low histiocyte proportion in the bone marrow and early initiation of treatment are generally correlated with favorable outcome. However, we did not find any relationship between the decline in serum ferritin, Fib level, and survival. Univariate analysis demonstrated that DIC score > 5 at diagnosis (p = 0.001) and albumin < 25 g/L (p = 0.000), HGB < 60 g/L (p = 0.001), and PLT < 30 × 10⁹/L (p = 0.042) were negative prognostic factors for patients with malignancy-associated HLH. The multivariate analysis showed that HGB < 60 g/L (p = 0.027), albumin < 25 g/L (p = 0.017), and bone marrow hemophagocytosis (p = 0.034) were negative prognostic factors for both groups. A previous comprehensive study involving 52 Turkish children with HLH suggested that high DIC score (≥5) and age < 2 years at diagnosis are important risk factors that can increase the mortality risk by twofold [23]. We also found that high DIC score (≥5) and low albumin, HGB, and PLT levels predict poor progress.

Most cases of non-malignancy–associated HLH should be treated aggressively with standard HLH protocols. In particular, the prognosis for such cases has improved dramatically with chemotherapy and immune-modifying agents such as corticosteroids, intravenous immunoglobulins, cyclosporin A, and etoposide.

The treatment of malignancy-associated HLH has not been prospectively studied. In the present study, the malignancy-associated cohort received malignancy-directed treatments, HLH-directed treatments, or a combined approach to overcome HLH. However, we could not determine which approach was superior. In a murine model of familial HLH type 2, mice that received etoposide, cyclophosphamide, or methotrexate survived [24]. Regimens involving the three agents can possibly treat malignancy-associated HLH. Moreover, clinical experience is greatest for etoposide [25]. In malignancy-associated HLH, 13 patients (59.1%) received etoposide as initial therapy for HLH, and six children are alive; the survival rate was 46.2%. Therefore, we found that etoposide is effective.

Stem cell transplantation might be considered consolidation in malignancy-associated HLH. The complete remission rate of malignancy-associated HLH was 90%. Therefore, stem cell transplantation is an effective therapy.

We analyzed a single center’s experience with malignancy-associated HLH and non-malignancy–associated HLH in children. The etiology of malignancy-associated SHLH is unclear. New research has demonstrated that an underlying polygenic inheritance defect should be suspected in acquired HLH [4]. Prospective studies with a randomized controlled design and involving large cohorts of children are warranted to evaluate the exact incidence, clinical features, and appropriate treatment protocols of this association. Mutation analysis, effective diagnostic criteria, and new targeted treatments for HLH for improving the survival rate of patients with malignancy-associated HLH are necessary.