Hemophagocytic lymphohistiocytosis (HLH) is a rare non-neoplastic, frequently fatal disease of childhood. It has been divided into two categories, familial and secondary, but the distinction between the forms is not easily made2. J.I. Henter, G. Elinder and A. Ost, FHL Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol 18 (1991), p. 29. View Record in Scopus | Cited By in Scopus (389). Clinical features including high fever, hepatosplenomegaly, and several neurological manifestations associated with pancytopenia, hypertriglyceridemia, hypofibrinogenemia, elevated liver enzymes, and hyperferritinemia are seen mainly in small children. HLH is considered a defect in immunomodulation, characterized by a benign, generalized lymphocytic and histiocytic proliferation associated with hypercytokinemia. The use of etoposide, steroids, and intrathecal methotrexate has led to remission in some patients; nevertheless, most patients still relapse and ultimately die from the disease. HLA-matched bone marrow transplantation (BMT) can bring about long-term remission. In the majority of patients, the transplant conditioning regimen consisted of busulfan, cyclophosphamide, and etoposide, which was well tolerated but accompanied by relevant toxicity, mainly severe oral mucositis. We report the beneficial effect of BMT in one patient, using a less toxic conditioning regimen.

A 2-month-old male, the third child of unrelated parents, was admitted with a history of 7 days of fever, abdominal distention, and jaundice. The physical examination showed an enlarged liver and spleen, 6 and 4 cm below the costal margin, respectively. Hemoglobin concentration was 78 g/L, total neutrophils 0.75 × 10⁹/ L, and the platelet count, 91 × 10⁹/L. Increases in direct bilirubin (82 ?mol/L), lactic dehydrogenase (660 IU), triglycerides (3.3 mmol/L), and decreased fibrinogen of 1.16 g/L were reported. The search for syphilis, toxoplasma, rubella, herpes, cytomegalovirus, and Epstein Barr virus was negative. The cerebrospinal fluid showed 15 mononuclear cells and hemophagocytosis was detected in the bone marrow, establishing the diagnosis of hemophagocytic lymphohistiocytosis.

The patient was given etoposide (150 mg/m²/day) for 3 consecutive days and dexamethasone (0.3 mg/kg/day) on 7 consecutive days, in addition to intrathecal methotrexate. Four weeks later, the patient was in complete remission, the physical examination was normal, and all of the altered laboratory studies had returned to normal limits. Cyclosporine at 5 mg/kg/day was initiated.

Three months later, allogenic BMT was performed. The donor was the patient’s healthy 8-year-old, HLA-identically-matched sister. The conditioning regimen included busulfan (4 mg/kg/days ?8, ?7, ?6, and ?5), etoposide (300 mg/m²/day on days ?3 and ?2), and cyclophosphamide (50 mg/kg/day on days ?4, ?3, and ?2). The number of nucleated cells infused was 4 × 10⁸/kg body weight of the recipient. Prophylactics for graft-vs.-host disease included methotrexate (10 mg/m² on days +3, +5, and +11), and cyclosporine 2 mg/kg twice per day i.v. Intravenous gamma globulin (65 mg/kg every 3 weeks until day +100) was used. An absolute neutrophil count of 500/uL was noted on day +12, the last day of platelet transfusion was day +14, and the patient was discharged on day +16.

Manifestations of GVHD in skin and liver were noticed on day +80 and required oral prednisone for its control. At present (day +400), the patient is asymptomatic, his physical examination is normal, and slightly increased GGT and alkaline phosphatase are the only laboratory abnormalities.

In the treatment of HLH, long-term remissions have been obtained with the use of systemic and intrathecal chemotherapy. However, most children treated with etoposide and steroids eventually relapse and die of the disease. Therefore, the use of allogeneic BMT appears to be a logical approach to the treatment of HLH regardless of whether excessive macrophage activation is intrinsic or secondary to T-cell activation. A recent report from the International HLH Registry cited an estimated 5-year survival rate of 68% after matched sibling transplantation, compared with 10.1% for patients treated solely with chemotherapy (p = 0.0001).

In the majority of patients, the transplant conditioning regimen has consisted of oral busulfan at 4 mg/kg/day (total dose 16 mg/kg), intravenous cyclophosphamide at 50 mg/kg/day (total dose 200 mg/kg), and intravenous etoposide at 500 mg/m²/day (total dose 1,500 mg/m²). This regimen has been well tolerated, but relevant toxicity, mainly severe oral mucositis has been reported without excessive incidence of transplant-related mortality. Some patients have also received intravenous ATG and aracytine. In some cases, toxicity was reduced by decreasing the etoposide dose from 1,500–900 mg/m² (300 mg/m²/day). The case reported here, the transplant conditioning regimen consisted of the same dose of oral busulfan, but reduced doses of cyclophosphamide (150 mg/kg) and etoposide (600 mg/m²). This regimen was adequate for the eradication of the disease and allowed persistent engraftment without significant toxicity. High doses of busulfan associated with cyclophosphamide have strong myeloablative and immunosuppressive effects. The inclusion of etoposide provides a third drug known to be effective in the treatment of HLH.

It is not always necessary to administer very high and potentially toxic doses of chemotherapy to eradicate the disease. In adults with leukemia, the use of cyclophosphamide at a dose of 120 mg/kg instead of 200 mg/kg did not compromise the antileukemic activity of the original regimen and markedly reduced the complication rate. Recently, the use of non-myeloablative stem cell transplantation has been successfully attempted as an alternative to conventional BMT with lethal cytoreduction for the treatment of malignant and non-malignant hematological diseases. The results in our patient suggest that a less toxic regimen permits a rapid engraftment of the donor stem cells without compromising the effectiveness of the chemotherapy. Fewer myeloablative or non-ablative regimens may also help bypass frequent late complications that result from the combined effects of high doses of chemotherapy in addition to prior conventional treatments. In the low-age group, allogeneic minus myeloablative BMT may reduce the incidence of growth retardation and infertility due to the unique sensitivity to chemoradiotherapy of the growth centers of the bones, gonads, and testicles. The use of non-myeloablative BMT should be attempted in HLH to reduce the morbidity and mortality related to this modality of treatment.