Clinical trial NCT02389231: Evaluating the Interest of Interleukine-2 for Patients With Active Warm Hemolytic Anemia Resistant to Conventional Treatment
Official title: " Anemil Trial ": Phase I/II Clinical Trial Evaluating the Interest of Interleukine-2 for Patients With Active Warm Hemolytic Anemia Resistant to Conventional Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Autoimmune Hemolytic Anemia
Keywords: interleukine 2
warm autoimmune hemolytic anemia
CD8 regulatory T cells
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
First posted: 2015-03-17
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The investigators have demonstrated that the mean percentage of circulating CD8+ regulatory T (CD8 Tregs) cells is significantly higher in patients with warm hemolytic anemia (wAHAI) in remission than in controls and is correlated to hemoglobin levels. In vitro, low dose of interleukine-2 (IL2) induce the expansion of CD8 Tregs. The objective is to demonstrate that, over a 9 week treatment period; low doses of IL2 can induce the expansion of CD8Tregs in patients with active wAHAI.

Detailed description: wAIHA is a B-cell-mediated autoimmune disease in which red blood cells are targeted by autoantibodies, which leads to marked decrease in their lifespan. The investigators demonstrated two years ago in a multivariate retrospective study that the CD3+CD8+ HLA-DR+ T-cell population was associated to a better outcome. The investigators observed that the proportion of circulating CD3+CD8+CD25highFoxp3+ T cells was significantly higher in patients with wAIHA in remission than in controls and correlated to hemoglobin levels. Extensive phenotyping and functional analysis revealed that those cells were bona fide Tregs acting in an IL10-dependent manner. Finally, culture of PBMC from normal donors or active wAIHAI patients with low dose of IL2 promoted the expansion of functional CD3+CD8+CD25+Foxp3+. Those observations constituted the rationale to propose low dose of IL2 to treat patients with active wAIHA with the objective of demonstrating that this treatment is able to induce the expansion of CD8Tregs, over a 9 week treatment period.

Four courses of IL2 (aldesleukin \[Proleukin, Novartis\]) will be administered subcutaneously for 5 days. The first course will be limited to a dose of 1.5 million IU per day and followed by a 9 day wash-out. The other courses of 3 million IU per day will be initiated after a 16 day wash-out.

Patients will be evaluated on day 1 and day 5 of each treatment course, before the first and last administration of interleukin-2 and will also be evaluated at 6 months.

Eligibility criteria: Inclusion Criteria:

* Adults (18 years old)
* wAHAI defined by the presence of hemolysis and positive coombs test (IgG +/-C3)
* Absence of infection or other hematologic disease
* wAHAI not responding to conventional steroids despite a dose over 10 mg
* No treatment with rituximab for a minimum of 6 months
* Signed informed consent form

Exclusion Criteria:

* Less than 18 years old
* Cold AHAI
* IL2 allergy
* Chemiotherapy or immunosuppressive treatment
* Treatment with rituximab for less than 6 months
* Neoplasia or hematologic malignancy
* Aplastic anemia
* Neutropenia ≤ 1000 mm3
* Infection
* Hepatitis B or C
* wAHAI associated with systemic lupus erythematosus depending on ACR criteria
* Cardiac insufficiency
* Hypertension
* Pulmonary insufficiency
* Liver cirrhosis
* Thrombopenia below 50000/mm3
* Drug addiction, alcohol abuse
* Psychiatric disorder
* Absence of signed informed consent

Primary outcomes:
measure: Percentage of LTCD8+CD25highFoxp3+ .
timeFrame: 9 weeks after inclusion
Secondary outcomes:
measure: Incidence of complications with the treatment.
timeFrame: 6 months after inclusion
measure: Hemolysis as measured by hemoglobin, haptoglobin, reticulocytes and LDH levels
timeFrame: 5 days, 20 days, 40 days, 61 days, 63 days and 6 months after inclusion
measure: Evaluation of lymphocyte sub-populations
timeFrame: 5 days, 20 days, 40 days, 61 days, 63 days and 6 months after inclusion
measure: Evaluation of lymphocyte activation.
timeFrame: 5 days, 20 days, 40 days, 61 days, 63 days and 6 months after inclusion
measure: Dose of steroid treatment
timeFrame: 5 days, 20 days, 40 days, 61 days, 63 days and 6 months after inclusion
Other outcomes:
Locations:
city: Pessac
country: France
facility: CHU de Bordeaux Hôpital Haut Lévêque
state: Aquitaine
Study officials:
affiliation: University Hospital, Bordeaux
name: Estibaliz LAZARO, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Bordeaux
name: Rodolphe THIEBAUT, Prof
role: STUDY_CHAIR
References: