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Brief Title: Prospective, Multicentric, Phase II Randomized Controlled Trial on Two Parallel Groups Comparing the Efficacy of Two Immunosuppressive Drugs (Methotrexate, Cyclophosphamide) in Large Granular Lymphocytes Leukemia
Official Title: Prospective, Sequential Multiple Assignment, Multicentric, Phase II Randomized Controlled Trial on Two Parallel Groups Comparing the Efficacy of Two Immunosuppressive Drugs (Methotrexate, Cyclophosphamide) in Large Granular Lymphocytes Leukemia
Study ID: NCT01976182
Brief Summary: LGL leukemia represents a rare subtype of chronic T or NK lymphoproliferative disorders. It is an indolent disease, the main hematological or autoimmune complications lead to a treatment in more than 60% of patients. Investigators set up at the University Hospital of Rennes, a database of more than 300 patients with LGL leukemia from major French services that support this disease, and published in 2010 the largest series of patients in the world (n = 229). However, the limited heterogeneity and retrospective data collected, as all previously released, makes it difficult the proposal of consensual treatment options. If first and second line treatments are based on the use of immunosuppression with methotrexate, cyclophosphamide, or cyclosporin A, no molecule has proven superiority over others. Methotrexate and cyclophosphamide are mainly used in the first line. Invetigators just have in the literature data on about 100 patients treated with either of these drugs. Combining the results of our series with those in the literature, invetigators estimate the respective overall response rate (RG) and complete response rate (CR) in 55% and 30% for methotrexate, and 60% and 50% for cyclophosphamide. Thus, there are four objective in this study : 1. to compare the respective efficacies of methotrexate and cyclophosphamide when administered as first-line therapies in patients suffering from T/NK LGL leukemia with severe neutropenia or neutropenia associated with infections, and/or anemia requiring transfusions, and/or auto-immune associated disease 2. to evaluate the percentage of patients refractory to methotrexate or cyclophosphamide for which a second line treatment is efficacious 3. to explore, in case of non-response to the first-line therapy, the efficacy of ciclosporine A, the comparison being performed with the treatment which was not administered in the first-line therapy 4. to evaluate the response rate according to the phenotypic subtype of LGL leukemia.
Detailed Description: Large Granular Lymphocyte (LGL) leukemia is a clonal disorder involving tissue invasion of marrow, spleen and liver. Clinical presentation is dominated by recurrent infections associated with neutropenia, anemia, splenomegaly, and auto-immune diseases, particularly rheumatoid arthritis. Both T cell and NK cell subtypes of LGL leukemia are indolent disease and considered as a chronic illness and lead to a treatment in more than 60% of patients. LGL leukemia displays a chronic clinical course. Recommendations regarding therapy are similar for both subtypes. Indications for treatment include 1) severe neutropenia (ANC \<500 mm3); 2) neutropenia (ANC \<1500mm3) with symptomatic recurrent infections; 3) symptomatic or transfusion-dependent anemia and 4) associated autoimmune conditions requiring therapy, most often rheumatoid arthritis. There is no standard treatment for patients with LGL leukemia. The numerous case reports published do not provide a consensus for a particular treatment. All the six largest series published in the literature so far (collecting data on more than 40 patients) are retrospective. Immunosuppressive therapy remains the foundation of treatment including single three agents i.e. methotrexate, oral cyclophosphamide and ciclosporin A. However prospective trials involving large numbers of patients have not been performed and no molecule has proven superiority over others. Invetigators set up at the University Hospital of Rennes, a database of more than 300 patients with LGL leukemia from major French services that support this disease, and published in 2010 the largest series of patients in the world (n = 229). However, the limited heterogeneity and retrospective data collected, as all previously released, makes it difficult the proposal of consensual treatment options. Combining the results of our series with those of the literature, invetigators estimate that overall response rate and complete response rate are 55% and 30% with methotrexate, 60% and 50% with cyclophosphamide, and 55% and less than 20% with ciclosporine A, respectively. Thus, there are four objective in this study : 1. to compare the respective efficacies of methotrexate and cyclophosphamide when administered as first-line therapies in patients suffering from T/NK LGL leukemia with severe neutropenia or neutropenia associated with infections, and/or anemia requiring transfusions, and/or auto-immune associated disease 2. to evaluate the percentage of patients refractory to methotrexate or cyclophosphamide for which a second line treatment is efficacious 3. to explore, in case of non-response to the first-line therapy, the efficacy of ciclosporine A, the comparison being performed with the treatment which was not administered in the first-line therapy 4. to evaluate the response rate according to the phenotypic subtype of LGL leukemia.
Minimum Age: 18 Years
Eligible Ages: ADULT, OLDER_ADULT
Sex: ALL
Healthy Volunteers: No
CHU Sud, Amiens, , France
CHU Angers, Angers, , France
Intern medecine Service - CH Antibes-Juan-les-Pins, Antibes, , France
Hematology Service - CH Avignon, Avignon, , France
Hematology Service - CH de la cote basque, Bayonne, , France
hematology service - CH Beauvais, Beauvais, , France
Hematology Service - CH Jean Minjoz, Besançon, , France
Hematology Service - CH Beziers, Beziers, , France
Hematology Unit - HOpital Avicienne, Bobigny, , France
Hematology Service - CH Docteur Duchenne, Boulogne sur Mer, , France
Hematology Service - CH de Brest, Brest, , France
Hematology Service - CH François Baclesse, Caen, , France
hematology Service - CH Louis Pasteur, Chartres, , France
Centre Hospitalier de Cholet, Cholet, , France
Hopital Inter-Armées Percy, Clamart, , France
hematology Service - CHU Estaing, Clermont-Ferrand, , France
Hematology Service - Civils hospital, Colmar, , France
Hematology Service CHSF, Corbeil Essonnes, , France
CHU Henri Mondor Lymphoid Hemopathy Unit, Creteil, , France
Hematology Unit CH Michalon, Grenoble, , France
Hematology Unit CHD Vendée, La Roche sur Yon, , France
Hematology Unit CH LE MANS, Le Mans, , France
CH Robert Boulin, Libourne, , France
Hematology Unit CHRU Lille, Lille, , France
Hematology Unit CHU Dupuytren, Limoges, , France
CH de Bretagne Sud, Lorient, , France
Hematology Unit CHU La Conception, Marseille, , France
Hematology Unit - Institut Paoli-Calmettes, Marseille, , France
Hematology Unit CH Meaux, Meaux, , France
Hematology Unit CH Notre Dame Bon Secours, Metz, , France
Hematogy Unit CHU ST ELOI, Montpellier, , France
Hematology Unit CH E.MULLER, Mulhouse, , France
Internal Medicine - CHU Hotel Dieu, Nantes, , France
Oncology Unit CH Antoine Lacassagne, Nice, , France
hematology Unit CHU Caremeau, Nimes, , France
Hematology Unit - CHR Orleans, Orleans, , France
Hematology Service - Hopital La Pitié Salpetrière, Paris, , France
Hematology Unit - Hopital Hotel Dieu, Paris, , France
Hematology Unit - Hopital Saint Antoine, Paris, , France
AP-HP Hôpital Necker - Enfants Malades, Paris, , France
Hematology Unit - Hopital Saint Louis, Paris, , France
Hematology Unit Hopital Saint Jean, Perpignan, , France
Hematology Service- CH Haut Leveque, Pessac, , France
Hematology Unit CH LYON SUD, Pierre Benite, , France
Hematology Unit CHU La Miletrie, Poitiers, , France
Hematology Unit CH René DUBOS, Pontoise, , France
CH Annecy - Hematology Service, Pringy, , France
Hematology Unit- Hopital Robert Debré, Reims, , France
Hematology Service - CHU of Rennes, Rennes, , France
Hematology Unit - CH Becquerel, Rouen, , France
Oncology Unit - Institut de cancérologie de la Loire, Saint Priest en Jarez, , France
CH Saint Quentin Oncohematology, Saint Quentin, , France
CH Yves Lefoll, Saint-Brieuc, , France
Hematology Unit CHU Toulouse, Toulouse, , France
Hematology Unit CHU Bretonneau, Tours, , France
Hematology Unit Hopitaux de Brabois, Vandoeuvre les Nancy, , France
Intern Medecine Unit CHBA, Vannes, , France
Hôpital André Mignot Centre Hospitalier de Versailles, Versailles, , France