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

Sponsor

University Hospital, Clermont-Ferrand (Other)

Overall Status

Unknown status

CT.gov ID

NCT01849939

Collaborator

Pierre Fabre Laboratories (Industry)

Enrollment

Location

Arm

Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia Lymphocytic Lymphoma	Drug: Fludarabin (post-allograft immunosuppressive therapy modulation and DLI Mononuclear cells from allogenic blood)	Phase 2

Detailed Description

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

43 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Reduced Intensity Conditioning Allogeneic Transplantation for CLL With Preemptive MDR Management (ICLL 03 RICAC-PMM)

Study Start Date :

Sep 1, 2012

Anticipated Primary Completion Date :

Sep 1, 2017

Anticipated Study Completion Date :

Sep 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fludarabin	Drug: Fludarabin (post-allograft immunosuppressive therapy modulation and DLI Mononuclear cells from allogenic blood)

Arm

Intervention/Treatment

Experimental: Fludarabin

Drug: Fludarabin (post-allograft immunosuppressive therapy modulation and DLI Mononuclear cells from allogenic blood)

Outcome Measures

Primary Outcome Measures

MRD(Minimal Residual Disease) negativity level [12 months after AHSCT(Allogenic Transplantation of Hematopoietic Stem Cells Transplantation)]

Secondary Outcome Measures

Incidence of relapses progression [at 12 months]
Incidence of toxic deaths [at 12 months]
Incidence of GVHD (acute and chronic) [at 12 months]
Survival (progression free survival, overall survival, survival without treatment) [at 12 months]
Post-transplant chimerism (total blood and lymphoid T lymphocyte populations) [baseline; 1, 2, 3, 6 and 12 months]
Incidence of infectious complications and severity [at 12 months]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

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)
relapse within 24 months after combination therapy including purine analogs or autograft, with indication of new start of treatment
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