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

NCT ID: NCT01547143

Last Updated: 2018-07-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: NA
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-03-31
• Study Completion Date: 2016-05-31

Brief Summary

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.

Detailed Description

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.

Conditions

Hemophagocytic Lymphohistiocytosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

IST and/or alloHCT

Patients who are newly diagnosed as HLH by HLH-2004 criteria, excluding those with HLH owing to malignancy or rheumatic disorder.

Group Type: EXPERIMENTAL

IST and/or alloHCT

Intervention Type: DRUG

1) Patients will be categorized by their initial serum ferritin level.

1. Mild ( ferritin<3,000 μg/L): close observation

2. Moderate (ferritin: 3,000-10,000 μg/L):

1. Initiation : cyclosporine 3mg/kg p.o.bid + dexamethasone 10mg/m2/d po. or i.v. (D1-3)

2. continuation: cyclosporine 3mg/kg p.o. bid (D4-56) + dexamethasone 10mg/m2/d (D4-14), then tapering.

3. Severe (ferritin>10,000 μg/L):

1. initiation : etoposide 100mg/m2/d i.v. + cyclosporine 2mg/kg i.v. q 12hours + dexamethasone 20mg/m2/d i.v. (D1-3)

2. continuation : etoposide 100mg/m2/day weekly (D15-49) + cyclosporine 2mg/kg i.v. q 12 hours? ? po. (D4-56) + dexamethasone 10mg/m2/d (D4-14), 5mg/m2/d (D15-28), 2.5mg/m2/d (D29-42), 1.25mg/m2/d (D43-56), then tapering off.

2) AlloHCT for refractory or reactivated cases.

Interventions

IST and/or alloHCT

1) Patients will be categorized by their initial serum ferritin level.

1. Mild ( ferritin<3,000 μg/L): close observation

2. Moderate (ferritin: 3,000-10,000 μg/L):

1. Initiation : cyclosporine 3mg/kg p.o.bid + dexamethasone 10mg/m2/d po. or i.v. (D1-3)

2. continuation: cyclosporine 3mg/kg p.o. bid (D4-56) + dexamethasone 10mg/m2/d (D4-14), then tapering.

3. Severe (ferritin>10,000 μg/L):

1. initiation : etoposide 100mg/m2/d i.v. + cyclosporine 2mg/kg i.v. q 12hours + dexamethasone 20mg/m2/d i.v. (D1-3)

2. continuation : etoposide 100mg/m2/day weekly (D15-49) + cyclosporine 2mg/kg i.v. q 12 hours? ? po. (D4-56) + dexamethasone 10mg/m2/d (D4-14), 5mg/m2/d (D15-28), 2.5mg/m2/d (D29-42), 1.25mg/m2/d (D43-56), then tapering off.

2) AlloHCT for refractory or reactivated cases.

Intervention Type: DRUG

Other Intervention Names

Etoposide; Cyclosporine: Cipol; Dexamethasone; IV gammaglobulin

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Asan Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Dae-Young Kim

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Dae-Young Kim, MD

Role: PRINCIPAL_INVESTIGATOR

Asan Medical Center

Locations

Asan Medical center, University of Ulsan College of Medicine

Seoul, , South Korea

Countries

South Korea

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Other Identifiers

AMC-H-72

Identifier Type: -

Identifier Source: org_study_id