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 ().
Diagnostic Criteria for HLH and Other Pertinent Testing
Treatment with high-dose corticosteroids resulted in rapid organ function improvement and resolution of fevers. Ferritin decreased but did not normalize (see ). 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.
Figure 1 Treatment course and disease response. Panel A: WBC count (1,000/μL). Panel B: Serum ferritin (ng/mL), log scale. Stars indicate recurrence of fever. Panel C: Prednisone dose (mg/day) or equivalent. Arrows indicate each course of daclizumab (1 (more ...)
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.