Hybrid Immunotherapy for Hemophagocytic LymphoHistiocytosis

Cincinnati Children's Hospital Medical Center

Status and phase: Completed; Phase 2

Conditions: Hemophagocytic Lymphohistiocytosis

Treatments: Drug: hydrocortisone; Drug: Etoposide; Drug: Dexamethasone; Drug: Methotrexate; Drug: ATG, rabbit

Study type: Interventional

Funder types: Other

Identifiers

NCT01104025

HIT-HLH

Details and patient eligibility

About

Despite good progress during the last decade, hemophagocytic lymphohistiocytosis (HLH) remains difficult to treat. Two different treatment regimens have been used successfully. The first one, a treatment regimen based on two drugs called etoposide and dexamethasone, has been used worldwide. The second regimen, based on two drugs called Anti-thymocyte globulin (ATG) and prednisone, has been used mostly at one hospital in Paris, for over 15 years. With either regimen, about three quarters of treated children survive the most difficult time, the first two months after diagnosis. These two different regimens appear to work somewhat differently, and we suspect that combining them may give better results than either regimen alone. We are conducting this clinical trial to test the combination of ATG, dexamethasone, and etoposide for the treatment of HLH.

The purpose of this research study is to find out what effects (good and bad) this drug combination has on you and your HLH.

Full description

Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder first recognized almost 70 years ago.(1) Genetic and animal studies have indicated that the familial form of HLH is clearly due to a deficiency of cytotoxic killing. Patients with HLH present with a potentially fatal syndrome of 'hyperimmunity.' These patients have severe inflammation, associated with cytopenias and variably severe bone marrow, liver, or CNS damage. Tissue damage and mortality appear to be due to hypercytokinemia related to persistent immune hyperactivation. An animal model of HLH and correlative human studies all suggest that excessive and abnormal activation of T cells drives the pathophysiology of this disorder, and that suppressing this excessive activation is critical for successful therapy of HLH. It is believed a combination of the two proven induction regimens for hemophagocytic lymphohistiocytosis (HLH) (anti-thymocyte globulin (ATG)- and etoposide-based) will result in response rates and overall survival rates at eight weeks which are comparable or better than the current standard of care (induction therapy per the HLH-94 protocol).

Enrollment: 31 patients

Sex: All

Ages: Under 18 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• diagnosis of hemophagocytic lymphohistiocytosis
• Patients <18 years of age
• The patient must have active disease at the time of enrollment
• Patient's legal guardians must sign an Institutional Review Board approved consent form indicating their awareness of the investigational nature and the risks of this study.
• Eligible subjects must be enrolled with the protocol coordinating center

Exclusion criteria

• Recent treatment, within 3 months, with another therapeutic regimen for HLH
• Known active malignancy
• Known rheumatologic diagnosis which may be the underlying cause of HLH
• Pregnancy (as determined by serum or urine test) or active breast feeding
• Failure to provide signed informed consent

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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31 participants in 1 patient group

Induction Therapy

Experimental group

Description:

ATG, rabbit: intravenous, 5 mg/kg/dose, 5 consecutive days Dexamethasone: intravenous, 20mg/m2/day x7days, 10mg/m2/day x7days, 5mg/m2/day x14days, 2.5mg/m2/day x14days, 1.25mg/m2/day x14days Etoposide: intravenous, 150 mg/m2 weekly, starting 7 days after first dose of Thymoglobulin Methotrexate and hydrocortisone: intrathecal to patients with central nervous system involvement, age\< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, \>3 yrs: 12/15 mg, on day 7, 14, 21 and 42

Treatment:

Drug: ATG, rabbit

Drug: Methotrexate

Drug: Etoposide

Drug: Dexamethasone

Drug: hydrocortisone