Evaluating the Interest of Interleukine-2 for Patients With Active Warm Hemolytic Anemia Resistant to Conventional Treatment

Study Overview
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Brief Summary
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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
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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.

Official Title
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 Anemil Trial : Phase I/II Clinical Trial Evaluating the Interest of Interleukine-2 for Patients With Active Warm Hemolytic Anemia Resistant to Conventional Treatment

Conditions
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Autoimmune Hemolytic Anemia

Intervention / Treatment
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* Drug: Interleukine-2


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low doses of Interleukine-2<br>Low doses of Interleukine-2 over a 9 week treatment period | Drug: Interleukine-2<br>* Four courses of IL2 ( [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.<br>* Other names: aldesleukine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of LTCD8+CD25highFoxp3+ . | Increase of the percentage of LTCD8+CD25highFoxp3+ at the end of the IL2 treatment. | 9 weeks after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of complications with the treatment. | Safety of the treatment during the trial and 6 months after the inclusion | 6 months after inclusion | 
| Hemolysis as measured by hemoglobin, haptoglobin, reticulocytes and LDH levels | Impact of IL2 on hemolysis defined by hemoglobin, haptoglobin, reticulocytes, LDH levels | 5 days, 20 days, 40 days, 61 days, 63 days and 6 months after inclusion | 
| Evaluation of lymphocyte sub-populations | Impact of IL2 on lymphocyte sub-populations (NK cells, B lymphocyte, CD4T lymphocyte, CD8T lymphocytes, CD4Tregs levels) at each time point of evaluation. | 5 days, 20 days, 40 days, 61 days, 63 days and 6 months after inclusion | 
| Evaluation of lymphocyte activation. | Impact of IL2 on lymphocyte activation defined by DR expression at each time point of evaluation. | 5 days, 20 days, 40 days, 61 days, 63 days and 6 months after inclusion | 
| Dose of steroid treatment | Impact of IL2 on steroid treatment (dose) during the trial and 6 months after the inclusion | 5 days, 20 days, 40 days, 61 days, 63 days and 6 months after inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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interleukine 2, warm autoimmune hemolytic anemia, CD8 regulatory T cells