Treatment of Familiar Lymphohistiocytosis

Phase 1

Completed

• Conditions: Hemophagocytic Lymphohistiocytosis (HLH)
• Interventions: Drug: Alemtuzumab; Drug: Methyl Prednisolone (MP); Drug: Cyclosporin A (CSA)

• Registration Number: NCT02472054
• Lead Sponsor: 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

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)

Study Timeline

• Study First Submitted: 2015-06-08
• Study First Submitted QC: 2015-06-10
• Study First Posted: 2015-06-15
• Study Start: 2015-06-29
• Primary Completion: 2019-09-12
• Study Completion: 2020-05-20
• Status Verified: 2021-04
• Last Update Submitted: 2021-04-13
• Last Update Posted: 2021-04-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 29

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
hemophagocytic lymphohistiocytosis (HLH)	Cyclosporin A (CSA)	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
hemophagocytic lymphohistiocytosis (HLH)	Methyl Prednisolone (MP)	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
hemophagocytic lymphohistiocytosis (HLH)	Alemtuzumab	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

Primary Outcome Measures

Name	Time	Method
Number of surviving patients until HSCT	Day 1 until transplantation, up to 4 months

Secondary Outcome Measures

Name	Time	Method
Number of complete remissions following treatment	Day 14, Day 21, Day 28	To assess the efficacy of the Alemtuzumab
Time of delay between the first administration of Alemtuzumab and complete remission	Day 14, Day 21, Day 28	To assess the efficacy of the Alemtuzumab
Dosage of Alemtuzumab	Day1-3, Day7, Day15-16, Day22-23, Day28	Pharmacokinetic
Number of side effects	Day 1 until transplantation, up to 4 months	To assess the tolerance of the Alemtuzumab

Trial Locations

Locations (1)

Hôpital Necker-Enfants Malades; 🇫🇷 Paris, France