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Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe inflammatory disorder marked by abnormal cytotoxic T and natural killer cell activity, resulting in impaired clearance of pathogen, excessive cytokine production, and continued immune system activation. Soluble IL-2 receptor (sIL-2R or sCD25) is typically elevated in HLH and can serve as a marker of disease activity, although its role in the pathophysiology of the disease is unclear. Here we present a case of an adult patient with steroid-dependent HLH who was treated successfully with daclizumab, a monoclonal anti-CD25 antibody, allowing successful withdrawal of steroid therapy without an increase in symptoms.
Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory syndrome consisting of fever, pancytopenia, hyperferritinemia, multiorgan dysfunction, and the pathologic finding of hemophagocytosis. Classically, primary HLH is defined as an inherited genetic disorder manifesting in the first few years of life, while secondary HLH, which presents in older children and adults, occurs in the context of infection, autoimmune disease, or malignancy. With increasing understanding of the pathophysiology of the disease, the distinction between primary and secondary HLH is less clear, as both may be associated with defective T/natural killer (NK) cell cytotoxicity as well as a dysregulated cytokine-based immune response to specific triggers .
An elevated serum level of soluble IL-2-receptor (sIL-2R, or sCD25) is common in patients with HLH, is a criterion for its diagnosis , and correlates with a poor prognosis [3,4]. CD25 is also expressed on the surface of activated T cells, and is the target of daclizumab (Zenapax, Roche), a chimeric monoclonal antibody used for prevention of allograft rejection, treatment of graft-versus-host disease, and treatment of autoimmune disorders . Because of the anti-T-cell properties of daclizumab, its favorable toxicity profile, and the dramatic elevation of sCD25 seen in patients with HLH, we hypothesized that daclizumab might be useful as a therapy for this disease. Here we report a case of an adult patient with steroid-dependent HLH whose disease responded dramatically following therapy with daclizumab, allowing complete discontinuation of steroids, at diagnosis and again at relapse 1 year later. A second relapse was accompanied by evidence of anaplastic T-cell lymphoma, which was treated successfully with chemotherapy.
A 51-year-old male with no significant medical history presented with fever, pancytopenia, and splenomegaly. He quickly developed renal failure, elevated liver function tests, disseminated intravascular coagulation, and altered mental status. Serum ferritin was 160,000 ng/mL, and bone marrow biopsy revealed a diffuse histiocytic infiltrate, with evidence of hemophagocytosis. T-cell receptor polymerase chain reaction (TCR PCR) performed on the bone marrow aspirate demonstrated the presence of a T-cell clone, but no malignancy was evident by morphology or flow cytometry. CT imaging showed no adenopathy, and an extensive infectious workup was negative, including EBV (Table I).
Treatment with high-dose corticosteroids resulted in rapid organ function improvement and resolution of fevers. Ferritin decreased but did not normalize (see Fig. 1). As the corticosteroid dose was tapered, fever, pancytopenia and hyperferritinemia recurred. A bone marrow biopsy again showed hemophagocytosis. Cytogenetic analysis of phytohemagglutinin-stimulated bone marrow revealed 8/21 cells with complex karyotype (del(5)(p15.1), add(9)(p24), t(13:14)(q34;q22)). Steroids and cyclosporine were restarted with some clinical benefit; however, because of hyperkalemia and renal insufficiency, the cyclosporine was discontinued, and fever and myalgias returned. A 12-week course of daclizumab was initiated (1 mg/kg IV every 2 weeks for six doses), along with a brief steroid taper. The patient’s fever resolved and his ferritin became normal for the first time since diagnosis.
The patient remained well without signs or symptoms of HLH for over 1 year, until fever, myalgias, hyperferritinemia, and other signs of HLH recurred. Bone marrow biopsy again revealed hemophagocytosis, and flow cytometry demonstrated a small population of aberrant CD4+ CD7− CD26− CD56− CD57(small subset)+ T-cells (3%) possibly consistent with a lymphoproliferative disorder; these cells were CD25−. TCR PCR again demonstrated a clone, though with a different-sized PCR product, and cytogenetics was indicative of further clonal evolution with the addition of del(2)(q35).
Immunologic and genetic testing was performed. Soluble CD25 level was 7,175 pg/mL (normal range 186–2,678). NK cell functional assays showed normal to high NK cell function. The proportion of cytotoxic cells expressing perforin and granzyme B were normal, and the mean channel fluorescence values for perforin and granzyme B within NK cells were high. Genetic testing for MUNC13-4 showed no evidence of mutation, and SAP (SLAM-associated protein) expression was also normal.
Given the low toxicity of daclizumab and nondefinitive flow cytometry findings, a second course of daclizumab was administered, again with a brief steroid course. The patient improved symptomatically, and his ferritin decreased. He remained well for another 7 months, until the time of his second recurrence of HLH, 3 years after initial diagnosis. Bone marrow biopsy revealed a diffuse lymphohistiocytic infiltrate and a small population (5%) of morphologically malignant cells, which by immunohistochemistry were CD30+ PAX5− TIA1(subset)+ Alk1−, consistent with involvement by anaplastic large T-cell lymphoma. CT imaging showed new bilateral subcentimeter pulmonary nodules and increasing splenomegaly with a 1.3-cm hypodense splenic lesion. The patient received treatment with six cycles of dose-dense CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone every 14 days) and responded well, with resolution of his splenomegaly, cytogenetic abnormalities, and elevated ferritin. With 7 months of follow-up after chemotherapy, he remains free of symptoms with a normal serum ferritin level.
To our knowledge, this is the first reported case of the use of the anti-CD25 antibody daclizumab in an adult patient with HLH, with a clear relationship between its administration and response of disease. While corticosteroids were able to control disease symptoms, there was rapid relapse with each tapering of steroid dose. Administration of daclizumab allowed the discontinuation of steroids and led to prolonged control of the HLH without interval therapy, as well as normalization of serum ferritin. Retreatment with daclizumab at relapse of HLH was similarly successful.
Cytokine-based therapy for HLH, either alone or in combination with standard therapy, is of growing interest. Infliximab, an anti-TNF-α monoclonal antibody, has been used successfully in a pediatric case of chemotherapy-associated HLH . For HLH associated with rheumatologic disorders and macrophage activation syndrome, both anti-IL-1 receptor and anti-TNF-α therapies have been used, the latter with mixed results [7–10].
Use of daclizumab for HLH has been reported twice: in combination with cyclosporine and etoposide for pediatric idiopathic HLH , and in combination with dexamethasone and etoposide for pediatric infection-associated HLH after allogeneic bone marrow transplant for leukemia . In both of these reports, the combination of daclizumab with other cytotoxic and immunosuppressive agents makes it difficult to determine which agents were responsible for the observed clinical improvement. In our case, daclizumab was not administered with any cytotoxic agents and allowed rapid discontinuation of steroids.
This patient’s initial clinical presentation with HLH is typical for adult patients, in that he was critically ill and had seemingly idiopathic multiorgan system failure. However, most adult cases of HLH are found to be secondary to malignancy or other autoimmune or infectious trigger; in our case, there was no definitive evidence of malignancy until years after initial presentation. For this reason, it is unclear to what degree our findings are generalizable to other patients with HLH. This is particularly true for children, in whom genetic and primary idiopathic HLH are more common.
We cannot exclude the possibility that, rather than modulating the immune reaction of the HLH, daclizumab provided clinical benefit by treating an underlying CD25+ T-cell malignancy that had not yet declared itself at the time of the initial presentation. However, the long duration of time between initial diagnosis of HLH and the clear development of lymphoma is atypical for lymphoma-associated HLH , and suggests that the initial HLH may have had an alternative and unidentified environmental or viral trigger.
We conclude that daclizumab may be useful in the treatment of steroid-dependent HLH. Further study of daclizumab in patients with HLH is necessary, although the absence of large numbers of patients with HLH makes studies of novel agents difficult. In the context of an individual patient with HLH who has either failed or is ineligible for standard therapy, our experience suggests that a trial of daclizumab may be warranted.
We thank Jacob J.H. Bleesing, MD, PhD (Cincinnati Children’s Hospital) for the immunologic testing including perforin and granzyme B studies, SAP expression, and MUNC13-4 genetic testing. Dr. Vogl is supported by a Special Fellow in Clinical Research Award from the Leukemia and Lymphoma Society and a Fellow Scholar Award from the American Society of Hematology.
Conflict of Interest: Nothing to report.