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

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

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.

Study Overview

• Status: Unknown
• Conditions: Chronic Lymphocytic Leukemia; Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Fludarabin (post-allograft immunosuppressive therapy modulation and DLI Mononuclear cells from allogenic blood)

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 Type: Interventional
• Enrollment (Anticipated): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Clermont-Ferrand, France, 63003
    • Recruiting
    • Chu Clermont-Ferrand

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
MRD(Minimal Residual Disease) negativity level	12 months after AHSCT(Allogenic Transplantation of Hematopoietic Stem Cells Transplantation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	at 12 months

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand
• Collaborators: Pierre Fabre Laboratories
• Investigators: Principal Investigator: Olivier Tournilhac, University Hospital, Clermont-Ferrand

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Anticipated): September 1, 2017
• Study Completion (Anticipated): September 1, 2017

Study Registration Dates

• First Submitted: March 12, 2013
• First Submitted That Met QC Criteria: May 8, 2013
• First Posted (Estimate): May 9, 2013

Study Record Updates

• Last Update Posted (Estimate): May 9, 2013
• Last Update Submitted That Met QC Criteria: May 8, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Chronic Lymphocytic Leukemia; Allogeneic transplantation of hematopoietic stem cells transplantation; Donor Lymphocyte Injection; Preemptive immunointervention
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Immunologic Factors; Immunosuppressive Agents
• Other Study ID Numbers: CHU-0150; 2011-A00906-35

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No