Pilot Study of Etoposide-based Therapy and Hematopoietic Cell Transplantation for Hemophagocytic Lymphohistiocytosis

Pilot Study of First-line Immunosuppressive Therapy Combined With Etoposide and Allogeneic Hematopoietic Cell Transplantation in Refractory/Reactivated Cases for Hemophagocytic Lymphohistiocytosis (HLH) in Adult Patients

The investigators would like to propose a pilot study evaluating the efficacy of etoposide combined with immunosuppressive agents for adult secondary hemophagocytic lymphohistiocytosis (HLH), in order to prove out whether the modification of previous HLH-94 or HLH-2004 protocol for childhood patients can improve the outcome and decrease the toxicities. The results of this pilot study will be a base of a more-improved phase-2 protocol.

The treatment of HLH in adult patients has not been determined yet. Actually, we adopted the treatment protocol HLH2004, which was developed for pediatric HLH patients. The HLH2004 protocol, which is a potent and successful treatment for HLH, has shown some limitations in the treatment of adult HLH. First, the dose of etoposide is somewhat high for adult patients to tolerate. Second, the high incidence of opportunistic infection such as fungal, bacterial, and viral has threatened the patients. Third, more aggressive and intensive approach to adopt allogeneic hematopoietic cell transplantation will be needed earlier in adult patients. Based on these rationales, we developed a modified protocol based on HLH2004 to pit the treatment of adult HLH patients.

Inclusion Criteria:

• Patients whose clinical findings satisfy 5 or more criteria out of the following 8 ones

  1. Fever ≥ 38.5 ℃ for ≥ 7 days
  2. Splenomegaly ≥ 3 FB below left subcostal margin
  3. Cytopenias affecting ≥ 2 of 3 lineages in PB Hb < 9 g/L Platelet < 100 x 109 /L ANC < 1.0 x 109 /L
  4. Hypertriglyceridemia and/or hypofibrinogenemia (fasting triglycerides ≥ 265 mg/dL, fibrinogen ≤ 1.5 g/L)
  5. Hemophagocytosis in BM or spleen or LN
  6. Low or absent NK-cell activity ( according to local laboratory reference)
  7. Serum-ferritin ≥ 500 mcg/L
  8. Soluble CD25(sIL-2 receptor) ≥ 2,400 U/ml

• 18 years of age and over.

• All patients (or his/her family when the patient cannot sign the consent form because of his/her general conditions) give written informed consent according to guidelines at institution's committee on human research.

Exclusion Criteria:

• HLH from malignancy (such as lymphoma, myeloma, leukemia, and other solid tumor)
• HLH from rheumatic disorder (such as SLE, AOSD, antiphospholipid antibody syndrome)
• Patients with psychiatric disorder or mental deficiency severe as to make compliance with the treatment unlike, and making informed consent impossible
• Nursing women, pregnant women, women of childbearing potential who do not want adequate contraception
• Male patient who reject the methods of avoiding pregnancy via methods such as abstinence, barrier method (condom etc).
• Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years following therapy with curative intent (except curatively treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia)