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

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ClinicalTrials.gov Identifier: NCT01547143
Recruitment Status : Terminated (The PI resigned the institute, and the rest investigators at the institute decided to terminate the study.)
First Posted : March 7, 2012
Last Update Posted : January 10, 2018
Sponsor:
Information provided by (Responsible Party):
Dae-Young Kim, Asan Medical Center

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 Not Applicable

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 Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
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 : March 2012
Actual Primary Completion Date : May 2016
Actual Study Completion Date : May 2016


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.

  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.

Other Names:
  • Etoposide
  • Cyclosporine: Cipol
  • Dexamethasone
  • IV gammaglobulin




Primary Outcome Measures :
  1. overall survival rate [ Time Frame: 1-year ]

Secondary Outcome Measures :
  1. Complete response rate [ Time Frame: 28 days ]
  2. Complete response rate [ Time Frame: 56 days ]
  3. Complete response rate [ Time Frame: 3 months ]
  4. Partial response rate [ Time Frame: 28 days ]
  5. Partial response rate [ Time Frame: 56 days ]
  6. Partial response rate [ Time Frame: 3 months ]
  7. reactivation-free survival rate [ Time Frame: 3 months ]
  8. reactivation-free survival rate [ Time Frame: 6 months ]
  9. overall survival rate [ Time Frame: 3 months ]
  10. overall survival rate [ Time Frame: 6 months ]
  11. overall survival rate [ Time Frame: 1 year ]
  12. treatment-related mortality rate [ Time Frame: 1 year ]


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01547143


Locations
Korea, Republic of
Asan Medical center, University of Ulsan College of Medicine
Seoul, Korea, Republic of
Sponsors and Collaborators
Asan Medical Center
Investigators
Principal Investigator: Dae-Young Kim, MD Asan Medical Center

Publications:

Responsible Party: Dae-Young Kim, Assistant Professor, Asan Medical Center
ClinicalTrials.gov Identifier: NCT01547143     History of Changes
Other Study ID Numbers: AMC-H-72
First Posted: March 7, 2012    Key Record Dates
Last Update Posted: January 10, 2018
Last Verified: January 2018

Keywords provided by Dae-Young Kim, Asan Medical Center:
Secondary hemophagocytic lymphohistiocytosis of adults

Additional relevant MeSH terms:
Lymphohistiocytosis, Hemophagocytic
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases
Dexamethasone acetate
Dexamethasone
Etoposide phosphate
Etoposide
BB 1101
Cyclosporins
Cyclosporine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Immunosuppressive Agents
Immunologic Factors