HELA2012: Pilot Study of Etoposide-based Therapy and Hematopoietic Cell Transplantation for Hemophagocytic Lymphohistiocytosis

Sponsor

Asan Medical Center (Other)

Overall Status

Terminated

CT.gov ID

NCT01547143

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hemophagocytic Lymphohistiocytosis	Drug: IST and/or alloHCT	N/A

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Mar 1, 2012

Actual Primary Completion Date :

May 1, 2016

Actual Study Completion Date :

May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: IST and/or alloHCT 1) Patients will be categorized by their initial serum ferritin level. Mild ( ferritin<3,000 μg/L): close observation Moderate (ferritin: 3,000-10,000 μg/L): Initiation : cyclosporine 3mg/kg p.o.bid + dexamethasone 10mg/m2/d po. or i.v. (D1-3) continuation: cyclosporine 3mg/kg p.o. bid (D4-56) + dexamethasone 10mg/m2/d (D4-14), then tapering. Severe (ferritin>10,000 μg/L): initiation : etoposide 100mg/m2/d i.v. + cyclosporine 2mg/kg i.v. q 12hours + dexamethasone 20mg/m2/d i.v. (D1-3) 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. Other Names: Etoposide Cyclosporine: Cipol Dexamethasone IV gammaglobulin

Arm

Intervention/Treatment

Experimental: 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.

Drug: IST and/or alloHCT

1) Patients will be categorized by their initial serum ferritin level. Mild ( ferritin<3,000 μg/L): close observation Moderate (ferritin: 3,000-10,000 μg/L): Initiation : cyclosporine 3mg/kg p.o.bid + dexamethasone 10mg/m2/d po. or i.v. (D1-3) continuation: cyclosporine 3mg/kg p.o. bid (D4-56) + dexamethasone 10mg/m2/d (D4-14), then tapering. Severe (ferritin>10,000 μg/L): initiation : etoposide 100mg/m2/d i.v. + cyclosporine 2mg/kg i.v. q 12hours + dexamethasone 20mg/m2/d i.v. (D1-3) 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.

Other Names:

Etoposide

Cyclosporine: Cipol

Dexamethasone

IV gammaglobulin

Outcome Measures

Primary Outcome Measures

overall survival rate [1-year]

Secondary Outcome Measures

Complete response rate [28 days]
Complete response rate [56 days]
Complete response rate [3 months]
Partial response rate [28 days]
Partial response rate [56 days]
Partial response rate [3 months]
reactivation-free survival rate [3 months]
reactivation-free survival rate [6 months]
overall survival rate [3 months]
overall survival rate [6 months]
overall survival rate [1 year]
treatment-related mortality rate [1 year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

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