Chemotherapy-sparing treatment of haemophagocytic lymphohistiocytosis with intravenous immunoglobulins and corticosteroids

Background

Haemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterised by pancytopenia and elevated circulating ferritin. It exists in two forms: familial HLH (FHL) and adult HLH. FHL is a hereditary disorder that presents most often in children and is characterised by mutations hindering lymphocyte cytotoxic function.1 2 Adult HLH is more heterogeneous and typically associated with underlying immune activation, such as occurs with infections (frequently viral), malignancies or autoimmune/rheumatological disorders.

The diagnosis of adult HLH can be difficult. The Histiocyte Society Study Group’s HLH-2004 guidelines require five of eight criteria to be met for the diagnosis of non-familial HLH (listed in box 1).3 In 2014, an additional weighted score for estimating the risk of HLH—known as the HScore (available at http://saintantoine.aphp.fr/score/)—was published by Fardet et al.4 Yet, in limited retrospective validation studies, the sensitivity (~90%) and specificity (~70% to 90%) of the HScore have been moderate, and identifying adult patients that need therapy for HLH remains challenging.5

Without treatment, HLH can become quickly fatal. FHL treatment is per the HLH-2004 protocol, which specifies up to 24 weeks of etoposide, dexamethasone and cyclosporine.4 Patients with neurological symptoms also receive intrathecal methotrexate and prednisolone. Treatment of adult HLH is less clear, and typically the HLH-2004 protocol is extrapolated to the adult population. HLH presents as a spectrum of disease severity, and in milder cases the harms of myelosuppressive chemotherapy with etoposide may outweigh the benefit. Here, we present a case of an adult with HLH who developed significant pancytopenia but was otherwise not critically ill and who responded to treatment with a chemotherapy-sparing approach consisting of intravenous immunoglobulins (IVIG) and corticosteroids alone.

Case presentation

A 59-year-old man with HIV and AIDS was seen in the emergency department because of newly identified pancytopenia and hyperferritinaemia. The patient appeared well. He was oriented and conversant, and a complete review of systems was negative aside from chronic weight loss. He was afebrile. Physical examination showed a thin chronically ill-appearing man without hepatomegaly or splenomegaly. His neurological examination was normal.

Four months prior to presentation, the patient was diagnosed with HIV/AIDS when he presented with severe pneumocystis carinii pneumonia (PCP) that was treated with trimethoprim-sulfamethoxazole (TMP-SMX). He was started on highly active antiretroviral therapy (HAART) with tenofovir/emtricitabine and dolutegravir. Three months prior to presentation, the patient had another hospitalisation for pulmonary infection with PCP and cytomegalovirus (CMV) viraemia. He was treated with TMP-SMX, a 2-week prednisone taper beginning at 20 mg/day, and valganciclovir. He continued prophylactic TMP-SMX and fluconazole both taken three times a week, and prophylactic valganciclovir taken daily. Due to renal impairment, his HAART regimen was changed to abacavir, lamivudine and dolutegravir.

Two months prior to presentation, the patient developed recurrent anaemia requiring transfusions of packed red blood cells (table 1). One day prior to presentation, at an appointment with his haematologist, laboratory testing revealed persistent anaemia (haemoglobin 90 g/L), new-onset thrombocytopaenia (49×10⁹/L) and neutropaenia (absolute neutrophil count of 1.1×10⁹/L), as well as hyperferritinaemia (11 885 ug/L) and elevated LDH (7.0 µkat/L). These findings raised concern for HLH, and the patient’s haematologist recommended discontinuing his antimicrobials and referred the patient to our institution.

Investigations

Laboratory studies on the day of presentation in the emergency department are shown in table 1. Peripheral blood smear revealed normocytic red blood cells (RBCs), 0 to 2 schistocytes per high power field, neutrophils with normal granulation, normal lymphocytes and unremarkable platelets. No monocytes with phagocytosed RBCs were seen. Vitamin B12 and folate levels were normal. A bone marrow biopsy revealed trilineage haematopoiesis with haemophagocytosis observed in the aspirate specimen and supported by immunohistochemistry for the histiocyte (macrophage) marker CD163 in the core biopsy specimen (figure 1). Molecular testing with Heme SNAPSHOT-NGS-V4 assay revealed no genetic mutations including no mutations typical of myelodysplasia.6 His karyotype was normal.

A diagnostic evaluation found no specific cause for HLH. An immunological work-up revealed a CD4+ count of 37/µL and low IgG (34.1 µmol/L), IgA (0.8 µmol/L) and IgM (8 µmol/L) levels. A rheumatological screen revealed antinuclear antibodies that were undetectable after 1:40 dilution, double-stranded DNA antibodies undetectable after 1:10 dilution, normal cyclic citrullinated peptide antibody level <8 U/mL and normal rheumatoid factor antibody level of 11 IU/mL. An infectious work-up was negative for antibodies against hepatitis B virus, hepatitis C virus and parvovirus B19. No quantifiable DNA was detected for adenovirus, bartonella, CMV or Epstein-Barr virus. There was no antigen detected for Histoplasma. The HIV-1 viral load was 153 copies/mL. CT scans of the patient’s chest revealed multifocal ground-glass opacities suggestive of resolving bronchopneumonia. CT scans of the abdomen and pelvis did not reveal focal lesions concerning for malignancy.

Differential diagnosis

We considered the patient to have a milder form of HLH meeting five of seven testable criteria defined in Box 1 (natural killer cell functional testing was not available to us): these were (1) peripheral cytopenia, (2) hypertriglyceridaemia, (3) hyperferritinaemia, (4) haemophagocytosis and (5) elevated soluble interleukin-2 receptor. His HScore was 200, conferring a 88% probability of HLH.4 The differential diagnosis for pancytopenia and elevated inflammatory markers includes an active infection, but negative test results for infectious causes narrowed our diagnosis to HLH.

The question that follows a diagnosis of HLH in an adult patient is what the cause of HLH might be. Adult HLH is typically secondary to immune activation from an antecedent cause for which the differential diagnosis includes infection, malignancy or autoimmune disorders. In this case, the cause of the patient’s low-grade HLH is not definitively known given the patient had negative immunological, rheumatological and infectious investigations, and a CT scan of his chest, abdomen and pelvis did not reveal lesions concerning for malignancy. Based on the patient’s history of presenting illness, it is possible that his severe respiratory infections with PCP and CMV 3 months prior to presentation triggered immune dysregulation leading to HLH. HLH may have initially manifested as anaemia 2 months prior to presentation because of high-dose steroids given for PCP treatment at that time before progressing to pancytopenia with elevated inflammatory markers.

Treatment

Given concern regarding the toxicity of the HLH-2004 regimen that consists of etoposide and cyclosporine, and given the patient was not critically ill as described above, we elected to treat the patient with IVIG 0.5 g/kg daily x 4 days and prednisone 1 mg/kg/day which are commonly used immunosuppressive doses at our hospital.

Outcome and follow-up

The patient’s haematological indices improved within 1 week (table 1). IVIG was stopped after 4 days and prednisone was continued as an outpatient. The patient was seen in follow-up on day 24 of prednisone treatment with further improvement in his laboratory indices (table 1).