Eradication of Residual Disease by Preemptive Immunointervention After Allogeneic Hematopoietic Stem Cells Transplantation in Chronic Lymphocytic Leukemia

Usually Chronic lymphocytic leukemia (CLL) is a disease of the elderly patients. However, the diagnosis in young patients become more frequently with poor prognosis. The identification of new prognostic factors permits early determination of the high risk population and provide them the therapeutic intensification. Allogeneic transplantation of hematopoietic stem cells transplantation (AHSCT) allows to long-term remission and in some cases complete and definitive eradication of the disease. After chemotherapy or antibodies, the Minimal Residual Disease (MRD) negativity is associated with better disease-free survival. MRD negativity occurs in some patients with the appearance of GVHD, stopping the immunosuppression or after donor lymphocyte injection (DLI). The negativity of MRD in the first year post-transplant is correlated with better progression-free survival or overall survival (Dreger 2010, Farina 2009, Caballero 2005, Algrin, 2011). So, MRD negativity may be an objective after AHSCT. The aim of this prospective study is to evaluate a standardized preemptive immunointervention of post-allograft immunosuppressive therapy modulation and DLI administration according to MRD level. The objective is to obtain MRD negativity at 12 months after AHSCT.

Patients will receive AHSCT with Fludarabine-Busulfan based conditioning :

* Fludarabine : 30 mg/m2/day - from Day-6 to Day-2
* Busulfan IV : 3.2 mg/kg/day - on Day-5 and Day-4
* ATG (Anti-thymocyte Globulin) : 2.5 mg/kg/day on Day-2 and Day-1

Preemptive immunointervention post AHSCT consists in reduce immunosuppressive treatment more or less associated with DLI according to :

* the presence or absence of severe Graft versus host disease (GVHD) (acute grade 2 and / or chronic)
* the presence or absence of a response on criteria of response IWCLL
* Getting or not a blood MRD negative (\<-10 \^ -4) evaluated by flow cytometry

Eligibility Criteria:
Inclusion Criteria:

* Patients with CLL (Matutes score 4 or 5) stages A, B, C with evolution criteria according IWCLL 2008 or lymphocytic lymphoma with severity criteria (EBMT criteria) which indicated allograft (deletion 17p) and requiring treatment
* Age: 18-70 years
* At least one of the following criteria of poor prognosis (EBMT recommendations - Dreger 2007)

  1. No response or relapse within 12 months of treatment with purine analogues (including "fludarabine refractory" i.e patients in response \<PR and / or relapse within 6 months after at least 2 courses of Fludurabine)
  2. relapse within 24 months after combination therapy including purine analogs or autograft, with indication of new start of treatment
  3. Mutation/deletion 17p13 (p53) with indication for treatment
* Partial response (PR) or complete response (CR) at the last treatment (IWCLL 2008)
* Residual mass \<5 cm (clinical and CT scan)
* Identical intrafamilial donor HLA (or with a mismatch) or in the absence of family donor, an unrelated donor 10/10 for HLA A, B, C, DR, DQ and is committed to giving DLI (see consent form donor)
* Sorror score comorbidity: ≤ 2
* Written informed consent
* Member or beneficiary of a social security system

Exclusion Criteria:

* Richter Syndrome
* Usual contraindications for realisation of allogeneic transplantation including
* Uncontrolled bacterial, viral or fungal infection
* Pregnancy or lactating women
* Cardiac contraindication : Cardiac ejection fraction \<50%
* Pulmonary contraindication : DLCO \<50%
* Renal contraindication : Creatininine clearance \<30 ml / min
* Hepatic contraindication : AST and / or ALT and / or total bilirubine\> 2 N except Gilbert disease or localisation specific LLC
* HIV positivity
* Cancer evolution or de novo occurred in the previous 5 years except basal cell cancer skin or carcinoma in situ of the cervix of uterus
* Affection psychiatric disease