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Treatment of Familiar Lymphohistiocytosis (C-HLH)

Primary Purpose

Hemophagocytic Lymphohistiocytosis (HLH)

Status

Completed

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

Alemtuzumab

Methyl Prednisolone (MP)

Cyclosporin A (CSA)

About this trial

This is an interventional treatment trial for Hemophagocytic Lymphohistiocytosis (HLH) focused on measuring hemophagocytic lymphohistiocytosis (HLH), Alemtuzumab (CAMPATH®)

Eligibility Criteria

undefined - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Hôpital Necker-Enfants Malades

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

hemophagocytic lymphohistiocytosis (HLH)

Arm Description

Alemtuzumab (CAMPATH®) 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). 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

Outcomes

Primary Outcome Measures

Number of surviving patients until HSCT

Secondary Outcome Measures

Number of complete remissions following treatment

To assess the efficacy of the Alemtuzumab

Time of delay between the first administration of Alemtuzumab and complete remission

To assess the efficacy of the Alemtuzumab

Dosage of Alemtuzumab

Pharmacokinetic

Number of side effects

To assess the tolerance of the Alemtuzumab

Full Information

NCT ID

NCT02472054

First Posted

June 8, 2015

Last Updated

April 13, 2021

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT02472054

Brief Title

Treatment of Familiar Lymphohistiocytosis

Acronym

C-HLH

Official Title

First Line Treatment of Familiar Lymphohistiocytosis by Alemtuzumab (CAMPATH®)

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

June 29, 2015 (Actual)

Primary Completion Date

September 12, 2019 (Actual)

Study Completion Date

May 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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

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 48 months; the total period of the study is 58 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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hemophagocytic Lymphohistiocytosis (HLH)

Keywords

hemophagocytic lymphohistiocytosis (HLH), Alemtuzumab (CAMPATH®)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

29 (Actual)

8. Arms, Groups, and Interventions

Arm Title

hemophagocytic lymphohistiocytosis (HLH)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Alemtuzumab

Other Intervention Name(s)

CAMPATH®

Intervention Type

Drug

Intervention Name(s)

Methyl Prednisolone (MP)

Intervention Type

Drug

Intervention Name(s)

Cyclosporin A (CSA)

Primary Outcome Measure Information:

Title

Number of surviving patients until HSCT

Time Frame

Day 1 until transplantation, up to 4 months

Secondary Outcome Measure Information:

Title

Number of complete remissions following treatment

Description

To assess the efficacy of the Alemtuzumab

Time Frame

Day 14, Day 21, Day 28

Title

Time of delay between the first administration of Alemtuzumab and complete remission

Description

To assess the efficacy of the Alemtuzumab

Time Frame

Day 14, Day 21, Day 28

Title

Dosage of Alemtuzumab

Description

Pharmacokinetic

Time Frame

Day1-3, Day7, Day15-16, Day22-23, Day28

Title

Number of side effects

Description

To assess the tolerance of the Alemtuzumab

Time Frame

Day 1 until transplantation, up to 4 months

10. Eligibility

Sex

All

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alain FISCHER, MD, PhD

Organizational Affiliation

Assistance Publique - Hôpitaux de Paris

Official's Role

Study Director

Facility Information:

Facility Name

Hôpital Necker-Enfants Malades

City

Paris

ZIP/Postal Code

75015

Country

France

12. IPD Sharing Statement

Plan to Share IPD

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Treatment of Familiar Lymphohistiocytosis

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