R-CHOP and Alemtuzumab in Patients With Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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Since there is no standard rescue therapy for refractory CLL or relapsed to the purine analogous, our target is to carry out a rescue therapy combining several chemotherapy agents (CHOP) adding the synergistic effect of Rituximab in order to act against tumour-like CLL forms, with assessable size lymph nodes. Afterwards, based in other studies, we shall study the role of Alemtuzumab as drug for consolidation or improvement of responses obtained with the initial therapy (CHOP-R), acting by cleaning from peripheral blood and bone marrow the CLL lymphocytes that may have had remain as residual after chemotherapy induction therapy. More precisely, the addition of Alemtuzumab as maintenance treatment would increase the complete responses with negative residual disease number and may prolong the duration of the response. For this, it is necessary to have not only an adequate and rigorous clinical follow-up but also biological, i.e. being able to analyze minimal residual disease by molecular biology techniques. This is the reason of writing this phase II clinical trial protocol.

Detailed Description
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OBJECTIVES The objectives of this clinical trial are the following: Main objective of the study: Overall response rate obtained after R-CHOP regime followed by Alemtuzumab consolidation as second line therapy Secondary objectives Determine the molecular complete response rate after R-CHOP regimen Determine the efficacy of Alemtuzumab in response improvement after R-CHOP regimen: conversion of PR to CR and of MRD+ to MRD-. Applicability (toxicity profile) of Alemtuzumab consolidation therapy. As additional objectives will be considered: Prognostic value of several biological variables (ZAP-70 and cytogenetics) having influence on the response Response duration Progression free survival Overall survival

Official Title
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Rescue Treatment With Rituximab-CHOP Therapy and Alemtuzumab (R-CHOP-A) in Refractory or Recidivant Patients With Chronic Lymphocytic Leukemia After Purine-analogous Treatment

Conditions
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Chronic Lymphocytic Leukaemia, Patients Resistant to a Purine Analogous, Patients Relapsed With Purines Therapy

Intervention / Treatment
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* Drug: Rituximab-CHOP-Alemtuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient's written informed consent before initiation of any specific procedure related with the study. Age ≥ 18 years and ≤ 70 years (ECOG) ≤ 2 Patients suffering from chronic lymphocyte leukaemia according to the established diagnostic criteria (Addendum A). Active CLL defined by the presence of one or more of the following criteria: Related symptoms: weight loss >10% in the 6 previous months, or fever >38ºC for 2 weeks with no evidence of infections, or extreme fatigue, or night sweats with no evidence of infection. 5.2.Enlarged lymph nodes or giant node clusters (>10 cm in diameter) or progressive growth lymph nodes. 5.3.Giant splenomegaly (> 6 cm under ribs border) or progressive splenomegaly. 5.4.Progressive lymphocytosis (>50% increase in a period of 2 months) or lymphocyte duplication time (expected) < 6 months 5.5.Proof of progressive bone marrow failure evidenced by development or worsening of anaemia and/or thrombopenia. Patients previously treated in first line with purine analogous and showing: Treatment failure (stable disease or progression) Relapse within three years of therapy. Agreement to use a high efficacy contraception method throughout all study period. Exclusion Criteria: Age > 70 years Patients having received more than one therapy line Patients that had not received previously purine analogous therapy. CLL patients in transformation to more aggressive cytologic or pathologic forms (Pro-lymphocytic leukaemia large cell lymphoma, Hodgkin's lymphoma) Hypersensitivity shown as anaphylactic reaction to any of the DRUGS used in the trial. Patients with severe heart, lung, neurological, psychiatric or metabolic diseases not due to CLL Patients under systemic and continued steroid therapy. Impairment of renal function (Creatinine > 2 times the upper limit of normal) non-attributable to CLL. Patients suffering anaemia or thrombocytopenia of autoimmune origin as well as those with a positive Coombs test Impairment of liver function (Bilirubin, ASAT/ALAT or Gamma-GT > 2 times upper limit of normal) non attributable to CLL Patients with active severe infectious disease Patients suffering another malignancy (with the exception of focalized skin carcinoma) Patients with positive serum tests for HBsAg or CHV Patients with history of HIV or other severe immune depression conditions. Pregnant or breast feeding women Patients unable to attend the controls under outpatient regimen Patients previously treated with alemtuzumab

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Four Rituximab - CHOP courses will be given The courses will be given every 21 days Drug Dose Day Rituximab (Mabthera) 500mg/m2 1(*) (**) Cyclophosphamide 750mg/m2 1 Adriamycin 50mg/m2 1 Vincristine 1,4 mg/m2 1 Prednisone 60mg/m2 1 to 5 (**) 1st course, 375 mg/m2 (*) If lymphocyte count is > 30 X 10 9/l, dose will be split up in two, which will be given in days 0 and 1 | Drug: Rituximab-CHOP-Alemtuzumab<br>* Four Rituximab - CHOP courses will be given The courses will be given every 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate obtained after R-CHOP regimen followed by consolidation therapy with Alemtuzumab, as second line therapy. Haematological and non haematological toxicity will be graded in accordance with the WHO system |  | 57 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rituximab-CHOP, Alemtuzumab, Chronic lymphocytic leukaemia