How I treat hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, occurring as either a familial disorder or a sporadic condition, in association with a variety of triggers. This immune dysregulatory disorder is prominently associated with cytopenias and a unique combination of clinical signs and symptoms of extreme inflammation. Prompt initiation of immunochemotherapy is essential for survival, but timely diagnosis may be challenging because of the rarity of HLH, its variable presentation, and the time required to perform diagnostic testing. Therapy is complicated by dynamic clinical course, high risk of treatment-related morbidity, and disease recurrence. Here, we review the clinical manifestations and patterns of HLH and describe our approach to the diagnosis and therapy for this elusive and potentially lethal condition.

Figure 1

Mechanics of cytotoxic function revealed by HLH-associated gene mutations. HLH-associated genetic abnormalities (in the indicated genes) may affect granule-dependent lymphocyte cytotoxicity by impairing trafficking, docking, priming for exocytosis, or membrane fusion of cytolytic granules. The function of this pathway may also be severely impaired by loss of functional perforin, the key delivery molecule for proapoptotic granzymes. Diverse mutations in this pathway all give rise to similar clinical phenotypes (albeit of variable severity). Lyst (the gene affected in Chediak-Higashi syndrome) is not portrayed because its function is not entirely clear, although it appears to play an important role in the maintenance of normally sized (and functional) cytolytic granules.

Figure 2

Immunologic and genetic workup of HLH. Rapid immunologic testing (which may be performed in 1-3 days) may support a diagnosis of HLH and provide etiologic data, whereas gene sequencing (typically requiring 3-8 weeks) may define the underlying genetic cause. Measurement of NK cytotoxic function and sCD25 may also support the diagnosis of HLH but is not included in the diagram because abnormalities in these assays do not suggest specific genetic lesions. Of note, whereas an abnormal test suggests an underlying gene abnormality, a normal immunologic test does not preclude genetic testing. Genetic testing should be pursued until biallelic (or hemizygous) mutations are found or until all 5 genes (or 7, in the case of males) are assayed. LYST gene sequencing is not currently commercially available.

Figure 3

HLH diagnostic and induction surveillance strategy. A complete diagnostic evaluation, thorough search for underlying triggers (including infection or malignancy), and assessment of relevant immune studies are indicated in patients suspected to have HLH. In addition, ongoing reevaluation of inflammatory markers is essential to gauge the response to therapy. ● represents recommended studies; and ○, recommended studies with sufficient clinical suspicion. Arrows indicate recommendations for initial daily labs with decreasing frequency to one study per week as values normalize. Italicized studies are those that may facilitate diagnosis but are not directly part of current diagnostic criteria. CT or abdominal ultrasound may also facilitate diagnosis by documenting splenomegaly. sCD25 and sCD163 are useful markers of inflammation that may be more reliable measures of HLH disease activity than ferritin in some patients. CD107 mobilization may corroborate NK functional studies and quickly indicate a relevant degranulation defect. Careful monitoring of infection status is appropriate when persistent viral (or other infection) is found. Initial viral PCRs should assess EBV, CMV, adenovirus, and other relevant viruses. CSF studies are important to determine CNS involvement of HLH, although MRI may be substituted initially in coagulopathic patients. Pan-CT may be helpful in cases where there is concern for abscess or underlying malignancy. EKG/echocardiogram establish baseline organ function and screen for coronary artery vasculopathy in patients with overlapping symptoms of Kawasaki disease. We also recommend initiating HLA testing at the time of diagnosis to avoid delays in identifying donors for HCT.

Figure 4

Hemophagocytosis on bone marrow aspirate and biopsy. (A) Two examples of hemophagocytic macrophages identified on bone marrow aspiration (Wright-Giemsa stain). (B) CD163 staining of bone marrow biopsy section highlights hemophagocytosis (counterstained with hematoxylin). Images were taken on a Nikon Elipse microscope (panel A: 100×/10; panel B: 20×/10) without oil, with a Spot digital camera. Images are unmanipulated. Courtesy of Dr Jun Mo.

Figure 5

Induction therapy for HLH. Based on the HLH-94 study, this approach should be considered standard of care for all patients not enrolled in clinical trials, based on published evidence of efficacy. Etoposide is dosed as 150 mg/m² per dose. Alternatively, for patients weighing < 10 kg, consideration may be given to dosing etoposide as 5 mg/kg per dose. Dexamethasone (Dex.) is dosed as indicated and may be given orally or intravenously, although the latter is preferred at therapy initiation. Intrathecal methotrexate and hydrocortisone (IT MTX/HC) should be given to patients with evidence of CNS involvement, as early as LP may be safely performed (which may vary from the diagram) and dosed as follows: age < 1 year, 6/8 mg (MTX/HC); 1-2 years, 8/10 mg; 2-3 years, 10/12 mg; > 3 years, 12/15 mg. Weekly intrathecal therapy is generally continued until at least 1 week after resolution of CNS involvement (both clinical and CSF indices).

Figure 6

Treatment strategy for HLH. An algorithm for HLH treatment strategies in various clinical contexts.