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Treatment of Familiar Lymphohistiocytosis (C-HLH)

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ClinicalTrials.gov Identifier: NCT02472054
Recruitment Status : Recruiting
First Posted : June 15, 2015
Last Update Posted : December 21, 2017
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:
The purpose of this project is to study the number of surviving patients until hematopoietic stem cell transplantation (HSCT) after first line treatment of hemophagocytic lymphohistiocytosis (HLH) by Alemtuzumab

Condition or disease Intervention/treatment Phase
Hemophagocytic Lymphohistiocytosis (HLH) Drug: Alemtuzumab Drug: Methyl Prednisolone (MP) Drug: Cyclosporin A (CSA) Phase 1 Phase 2

Detailed Description:

The hemophagocytic lymphohistiocytosis (HLH) or lymphohistiocytic activation syndrome is an inflammatory condition caused by a uncontrolled proliferation of activated lymphocytes and macrophages secreting an excess of inflammatory cytokines. Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disorder of the immune system, which is invariably fatal when untreated. Treatment requires the achievement of remission of HLH prior to allogeneic hematopoietic stem cell transplantation, the only curative therapy to date.

Despite significant progress in the treatment, mortality remains high and an important number of patients will die before being eligible for HSCT.

A better understanding of the pathophysiology of FHL has opened new avenues for immunotherapy. Based on previous observations concerning the utilization of Anti-thymoglobulins (ATG) for the treatment of patients with FHL, the protocol propose a new therapeutic strategy using Alemtuzumab in association with steroids as first line treatment in FHL. This proposition is based on the hypothesis that Alemtuzumab, capable of killing T lymphocytes efficiently in vivo, should be better tolerated than ATG. In fact, in contrast to the mechanism of action of ATG, Alemtuzumab does not activate T lymphocytes.

A better tolerance and efficacy of Alemtuzumab is expected in the treatment of the hemophagocytic lymphohistiocytic syndrome. This may have a positive impact not only on survival until HSCT, but also on overall survival and quality of life with regard to long-term neurological sequelae.

This is a multicenter, open, phase I/II, non-comparative, non randomized study. Patients are recruited by the investigators during hospitalization for a first episode of lymphohistiocytic activation syndrome requiring specific treatment.

Several visits (including the final visit) are scheduled within the trial over a period of approximately 10 months for all patients, from the signature of the consent up to 6 months after hematopoietic stem cell transplantation.

The recruitment period will be 30 months; the total period of the study is 40 months. The treatment consists in an intravenous administration of CAMPATH®.

For the research purpose, investigators will collect specific samples for:

  • biobank (Cytokine dosage) at the inclusion visit and the day prior to the conditioning;
  • pharmacokinetics of CAMPATH® : at every cure of CAMPATH® and every week. Also diagnostic lumbar puncture at the inclusion visit, day 14 is required to document the response to treatment and to determine the result of the therapeutic care.

The efficacy of the treatment will be measured to Day14, Day21 and Day28. All adverse events must be reported in the e-Case Report Form (e-CRF)


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: First Line Treatment of Familiar Lymphohistiocytosis by Alemtuzumab (CAMPATH®)
Actual Study Start Date : June 29, 2015
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : April 2020


Arm Intervention/treatment
Experimental: hemophagocytic lymphohistiocytosis (HLH)

Alemtuzumab (CAMPATH®)

  1. Initial Treatment (D1 to D3) D1: 0.5 mg / kg / day Alemtuzumab combined with 2 mg /kg/d of IV Methylprednisolone (MP) or PO Prednisolone, and IVC or PO cyclosporine (CSA) (target rate from 150 to 200 ng / ml in the absence of renal failure) D2 and D3: 1 mg / kg / day Alemtuzumab combined with 2 mg / kg / d of IV MP or PO Prednisolone and IVC or PO CSA (target rate 150-200 ng / ml)

    The maximum dose of Alemtuzumab is limited to 30 mg per day (1 vial).

  2. Maintenance treatment (D4 to D14)

    • MP/Prednisolone progressive tapering starting at D4 (2 mg / kg / day) to reach the dose 0.5 mg / kg / day at D14
    • CSA IVC or PO at a target rate of 150-200 ng / ml
Drug: Alemtuzumab
Other Name: CAMPATH®

Drug: Methyl Prednisolone (MP)
Drug: Cyclosporin A (CSA)



Primary Outcome Measures :
  1. Number of surviving patients until HSCT [ Time Frame: Day 1 until transplantation, up to 4 months ]

Secondary Outcome Measures :
  1. Number of complete remissions following treatment [ Time Frame: Day 14, Day 21, Day 28 ]
    To assess the efficacy of the Alemtuzumab

  2. Time of delay between the first administration of Alemtuzumab and complete remission [ Time Frame: Day 14, Day 21, Day 28 ]
    To assess the efficacy of the Alemtuzumab

  3. Dosage of Alemtuzumab [ Time Frame: Day1-3, Day7, Day15-16, Day22-23, Day28 ]
    Pharmacokinetic

  4. Number of side effects [ Time Frame: Day 1 until transplantation, up to 4 months ]
    To assess the tolerance of the Alemtuzumab



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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria :

  • Patient < 18 years
  • Patient with diagnosis of hemophagocytic lymphohistiocytic syndrome confirmed by at least one of the following two criteria :

    • Genetic diagnosis FHL or other genetic disease predisposing to HLH like Chediak-Higashi syndrome, Griscelli syndrome type II and X-linked lymphoproliferative syndrome type I and II (XLP-1 and XLP-2) or positive family history of HLH
    • Presence of at least 5 of the following 8 criteria (diagnostic criteria as defined by the "Histiocyte Society" ) :
    • Fever
    • Splenomegaly
    • Cytopenia (affecting at least two cell lineages : Hemoglobin <9.0 g / dl, Platelets <100.000/μl, Absolute neutrophil count (ANC) <1.000/µl)
    • Hypertriglyceridemia and / or hypofibrinogenemia (Fasting triglycerides ≥ 3 mmol / l, Fibrinogen ≤ 1.5 g / l)
    • Haemophagocytosis found in a histological specimen (without evidence of a malignant process and rheumatic disease)
    • Decreased or absent NK function (<10% of the laboratory standard)
    • Ferritin ≥ 500μg / l
    • Soluble CD25 ≥ 2.400U/ml or presence of activated T cells in the immune phenotyping
  • Patient without prior specific treatment of lymphohistiocytic activation syndrome or under treatment with corticosteroids and / or ciclosporin.
  • Patient beneficiary of a health insurance scheme
  • Holder (s) of parental authority who signed the informed consent
  • Man or woman in reproductive age willing to take reliable contraceptive measures during the treatment and 6 months after the end of the treatment

Specific situation of patients with neurological involvement :

Most patients with neurological involvement caused by a HLH will meet the inclusion criteria. However some patients may present an isolated neurological involvement as the first manifestation of familiar lymphohistiocytosis as described in the literature. These patients do not always present all the inclusion criteria. However their clinical condition may justify their inclusion prior to the confirmation of a genetic diagnosis and/or the detection of all required diagnostic inclusion criteria.

In the absence of the required 5 out of 8 diagnostic criteria, the eventual inclusion of patients with predominant neurological involvement will be evaluated by a scientific committee to judge their inclusion or not in the study. The remaining inclusion and exclusion criteria must be fulfilled. A written report will be established.

Exclusion Criteria :

  • Age ≥ 18 years
  • Patients previously treated with Anti-Thymoglobulin (SAL), etoposide (VP16) or Alemtuzumab.
  • Confirmed or suspected diagnosis of a malignant or rheumatic disease
  • Contraindication (s) to the administration of Alemtuzumab :

    • Hypersensitivity to murine proteins or to any of the excipients (sodium chloride, dibasic sodium phosphate, potassium chloride, potassium dihydrogen phosphate, polysorbate 80, disodium edetate dihydrate, and water for injection)
    • General evolving infection except infections that are the triggering factor of the HLH .
    • HIV
    • Progressing malignant tumors
    • Pregnancy

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): NCT02472054


Contacts
Contact: Despina MOSHOUS, MD, PhD +33 (0) 1 44 49 48 23 despina.moshous@inserm.fr
Contact: Valérie JOLAINE, Master +33 (0) 1 42 19 28 79 valerie.jolaine@nck.aphp.fr

Locations
France
Hôpital Necker-Enfants Malades Recruiting
Paris, France, 75015
Contact: Despina MOSHOUS, MD, PhD    +33 (0) 1 44 49 48 23    despina.moshous@inserm.fr   
Contact: Valérie JOLAINE, Master    +33 (0) 1 42 19 28 79    valerie.jolaine@nck.aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Study Director: Alain FISCHER, MD, PhD Assistance Publique - Hôpitaux de Paris

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02472054     History of Changes
Other Study ID Numbers: P120109
2014-005585-30 ( EudraCT Number )
First Posted: June 15, 2015    Key Record Dates
Last Update Posted: December 21, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:
hemophagocytic lymphohistiocytosis (HLH)
Alemtuzumab (CAMPATH®)

Additional relevant MeSH terms:
Lymphohistiocytosis, Hemophagocytic
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases
Cyclosporins
Cyclosporine
Prednisolone acetate
Methylprednisolone acetate
Prednisolone
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone hemisuccinate
Prednisolone phosphate
Alemtuzumab
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents