Cyclosporine Plus Methotrexate or Alemtuzumab

Study Overview
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Brief Summary
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The primary aim of the study was to compare the efficacy of the procedure in terms of event-free survival between patients receiving cyclosporine (CsA) plus either alemtuzumab (CAMPATH-1H ) or methotrexate (MTX) after matched related donor allo-reduced intensity conditioning. Secondary aims were: 1. To compare the incidence of infections and transplant-related mortality between the two arms; 2. to compare the incidence of acute and chronic GVHD 3. to evaluate hematologic and immunologic reconstitution and evolution of chimerism and residual disease. Patients were randomly assigned to received cyclosporine plus alemtuzumab or cyclosporine plus MTX and were stratified according to diagnosis: Chronic lymphocytic leukemia or Low grade- non-Hodgkin's lymphoma. All patients received the same reduced-intensity conditioning (RIC) scheme based on fludarabine 150mg/m2 (30 mg/m2/day everyday from -8 to -4) plus melphalan 140mg/m2 (70 mg/m2/day everyday from -3 to -2). Regarding the GVHD prophylaxis, patients in group 1 (n=17) received CsA 1 mg/kg intravenously starting on day -7 and 2/mg/Kg from day -1 plus alemtuzumab administered at a dose of 20 mg IV on -8 to -4 whereas in group 2 (n=23) pts received CsA at same doses as group 1 plus MTX given at a dose of 15 mg/m2 intravenously on days 1 and 10 mg/m2 on days 3, 6 and 11, followed by folinic acid rescue (15 mg in +1 and 10 mg in +3, +6 and +11 intravenously every 6 hours for 4 doses starting 24 hours after each dose of MTX). Acute and chronic GVHD were similarly graded by established criteria [20, 21]. In patients receiving alemtuzumab, CsA was suspended by day +130. They also received donor lymphocyte infusion (DLI) at a dose of 1 x 107 cluster of differentiation 3 / kg on day +180 in case of active disease, persistence of minimal residual disease detected by flow cytometry or mixed chimerism and no GVHD. In case mixed chimerism, donor lymphocyte infusion was performed if patient hematopoiesis progressively increased. In patients receiving CsA + MTX, CsA was suspended by day +180. These patients received DLI only in situations specified above. The statistical analysis has been designed to identify a 20% difference in terms of disease-free survival (based on the increased incidence of relapse in patients receiving T-cell depletion).

Official Title
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Randomized Trial of Cyclosporine + CAMPATH-1H (ALEMTUZUMAB) vs. Cyclosporine + METHOTREXATE in Patients Diagnosed With Mature B-cell Neoplasms - Chronic Lymphocytic Leukemia and Low-grade Lymphomas - Receiving Allogeneic Hematopoietic Stem Cell Transplantation With Nonmyeloablative Conditioning Regimen

Conditions
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Unrecognized Condition: Mature B or T-cell Neoplasm

Intervention / Treatment
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* Drug: Cyclosporine + METHOTREXATE
* Drug: Cyclosporine + CAMPATH-1H


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Having an identical Human Leukocyte Antigens (HLA) or a mismatched family donor. Age between 45 and 65 years (outside this age range at the discretion of each center). Indications: Follicular lymphoma with one of the following characteristics: Poor prognosis follicular NHL (3 or more factors by Federico et al: erythrocyte sedimentation rate (ESR)> 30, male,> 60 years, high LDH> 2 extranodal areas, pathologic stage (PS) >2 or The International Prognostic Index (IPI) 3 or high lactate dehydrogenase (LDH) or micro Beta 2) failing to achieve CR with regimens including fludarabine and anti CD20 (cluster of differentiation antigen 20 ). 2nd CR (complete response) or PR (partial response) not candidates for autologous transplantation; persistent disease or relapse after autologous transplantation. Other low-grade lymphomas: relapsed after autologous transplantation. autologous transplant candidates which can not be performed because of the inability to collect a sufficient number of cells, steam cells disease persistence, etc.. Chronic lymphocytic leukemia with one of the following characteristics: B symptoms: weight loss >10% in the last 6 months, fever >38ºC (degrees centigrade) for 14 days without infection, night sweats without infection lymphadenopathy >10 cm or progressive, progressive splenomegaly Anemia and/or thrombocytopenia secondary to bone marrow infiltration Diffuse lymphocytic infiltration of the bone marrow Progressive lymphocytosis (>50% in 2 months) or a lymphocyte doubling time <12 months Any of the above criteria is an inclusion criteria in the protocol in patients who have received at least one line of treatment including fludarabine Patients with poor prognostic cytogenetic abnormalities: 17p-, 11q-with VDJ unmutated Patients must also meet the following general requirements: Performance status <3 (Zubrod score, Eastern Cooperative Oncology Group (ECOG) performance status or WHO (World Health Organization) ) forced expiratory volume at one second (FEV1) > 39%, lung diffusing capacity for carbon monoxide (DLCO) and forced vital capacity (FVC) > 39% of the theoretical values Total bilirubin and transaminases <3 x the normal maximum value, unless attributable to base haemopathy Creatinine <2 x normal maximum and clearance> 40 mL / min unless attributable to his base haemopathy No evidence of symptomatic disease, cirrhosis or active hepatitis Negative serology for HIV Written informed consent Exclusion criteria: Impaired hepatic or renal function superior to that described above Presence of serious diseases that prevent chemotherapy treatments Presence of psychiatric comorbidity HIV infection Other prior neoplasm Do not have signed informed consent Pregnant or at risk of pregnancy by inadequate contraceptive measures. Patients diagnosed with chronic lymphocytic leukemia (CLL) transformation to more aggressive cytologic or histologic forms (prolymphocytic leukemia, large cell lymphoma, Hodgkin's disease) and those affected with autoimmune hemolytic anemia

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 65 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cyclosporine + METHOTREXATE<br>MTX days +1, +3, +6 and +11 followed by folinic acid rescue. All patients will receive CSA from day -7. | Drug: Cyclosporine + METHOTREXATE<br>* MTX days +1, +3, +6 and +11 followed by rescue with folinic Ac. All patients receive CSA from day -7.<br>|
| Experimental: Cyclosporine + CAMPATH-1H<br>CAMPATH-1H at a dose of 20 mg / day at 8-hour intravenous infusion on days -8 to -4. All patients will receive CSA from day -7. | Drug: Cyclosporine + CAMPATH-1H<br>* CAMPATH-1H at a dose of 20 mg / day at 8-hour intravenous infusion on days -8 to -4. All patients will receive CSA from day -7.<br>* Other names: Alemtuzumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of transplantation in terms of event-free survival | To compare the efficacy of transplantation in terms of event-free survival between patients receiving CAMPATH-1H or methotrexate in allogeneic related donor with nonmyeloablative conditioning. | From +270 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of infections and transplant-related mortality | Compare the incidence of infections and transplant-related mortality between the two arms | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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conditioning treatment, alemtuzumab, allogeneic hematopoietic stem cell transplantation, chronic lymphoproliferative disorders