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

NCT ID: NCT01976182

Last Updated: 2025-01-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 166 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-26
• Study Completion Date: 2024-10-07

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.

Conditions

Large Granular Lymphocytes Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

METHOTREXATE

In step 1, 55 patients will receive methotrexate 10mg / m² orally once a week, (at split doses of 5 mg/m2 in the morning and 5 mg/m2 at night), that is to say 2 tablets of 2.5 mg at each take

In step 2, responders at Month 4 (CR or PR) will be treated during 8 additional months with methotrexate at the same dosage.

Non responders at Month 4 will be randomized and treated either by:

• Cyclophosphamide delivered at 100 mg orally once daily, that is to say 2 tablets of 50 mg at each take between Month 5 and Month 8, decreased to 50 mg orally once daily beyond Month 8 for responders at Month 8;
• Ciclosporine A delivered at 3 mg/kg per day (at split doses of 1.5 mg/kg in the morning and 1.5 mg/kg at night) orally administered.

Group Type: ACTIVE_COMPARATOR

Methotrexate

Intervention Type: DRUG

methotrexate 10mg / m² orally once a week, (at split doses of 5 mg/m2 in the morning and 5 mg/m2 at night), that is to say 2 tablets of 2.5 mg at each take, during 4 months.

CYCLOPHOSPHAMIDE

In step 1, 55 patients will receive cyclophosphamide 100 mg orally once daily, that is to say 2 tablets of 50 mg at each take.

In step 2, responders at Month 4 (CR or PR) will be treated during 8 additional months with cyclophosphamide (at 50 mg orally once daily);

Non responders at Month 4 will be randomized and treated either by:

• Methotrexate administered at 10 mg/m2 orally once a week (at split doses of 5 mg/m2 in the morning and 5 mg/m2 at night), that is to say 2 tablets of 2.5 mg at each take;
• Ciclosporine A delivered at 3 mg/kg per day (at split doses of 1.5 mg/kg in the morning and 1.5 mg/kg at night) orally administered.

Group Type: ACTIVE_COMPARATOR

Cyclophosphamide

Intervention Type: DRUG

cyclophosphamide 100 mg orally once daily, that is to say 2 tablets of 50 mg at each take, during 4 months.

Interventions

Methotrexate

methotrexate 10mg / m² orally once a week, (at split doses of 5 mg/m2 in the morning and 5 mg/m2 at night), that is to say 2 tablets of 2.5 mg at each take, during 4 months.

Intervention Type: DRUG

Cyclophosphamide

cyclophosphamide 100 mg orally once daily, that is to say 2 tablets of 50 mg at each take, during 4 months.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Common criteria of LGL leukemia: the diagnosis is based on a chronic LGL peripheral blood expansion (>0.5x109/L), usually lasting more than 6 months
• Specific criteria for T-LGL leukemia or NK-LGL lymphocytosis or chronic NK-LGL leukemia:

• Specific criteria for T-LGL leukemia:
• Expression of LGL surface markers compatible with an activated T-cell (commonly alpha-beta+/CD3+/CD8+/CD57+ and/or CD16+) phenotype or gamma-delta+ T cells;
• Clonal rearrangement of TCRγ gene using PCR or specific and clonal Vβ expression using FCM.

• Specific criteria for NK-LGL lymphocytosis or chronic NK LGL leukemia:
• Expression of LGL surface markers compatible with a NK cell (commonly CD3-/CD8+/CD16+ and/or CD16+/CD56+) phenotype;
• CD56+ or CD16+ NK cells greater than 0.75x109/L;
• The term of chronic NK-LGL lymphocytosis is used for patients with chronic illness (NB: patients with massive tissue LGL infiltration of the spleen, liver and bone marrow and presenting aggressive clinical behavior are considered as having aggressive NK-LGL leukemia and should not be included).
• Age above 18 years
• ECOG performance status of 0-2
• Life expectancy of at least 1 year
• Lack of previous treatment (except with G-CSF or transfusions)
• At least one indication of treatment:

• Isolated severe neutropenia (ANC <0.5x109/L) or neutropenia (ANC <1.5x109/L) with two or more infections requiring antibiotics;
• Anemia (whatever the underlying mechanism: pure red cell aplasia or marrow infiltration) requiring transfusions greater than 2 units for two months prior to inclusion, or symptomatic anemia (hemoglobin <10g/dl) with impairment of the quality of life;
• Associated complications such as systemic diseases or auto-immune diseases (i.e. recurrent uveitis, cutaneous vasculitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, rheumatoid arthritis resistant to steroids and/or immunomodulator agents (colchicin, disulone, hydrochloroquine)) and justifying a treatment with methotrexate or cyclophosphamide
• Written informed consent

Exclusion Criteria

• Inability to understand or to follow study procedures
• Prior or concurrent malignancy within the past 5 years except inactive nonmelanomatous skin cancer or carcinoma in situ of the cervix
• Other serious medical illnesses, such as hepatic, renal, cardiac, pulmonary, neurologic, or metabolic disease that would preclude the patient's ability to tolerate methotrexate, cyclophosphamide, or ciclosporine A
• Reactive LGL lymphocytosis (i.e. after viral infection)
• ALAT/ASAT or alkalin phosphatases >3 times normal values
• Creatinine clairance <50 ml/min
• Serologic evidence of HIV, hepatitis C or hepatitis B infection
• Non effective contraception
• Positive pregnancy test
• Nursing woman

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rennes University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

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

Béziers, , France

Hematology Unit - HOpital Avicienne

Bobigny, , France

Hematology Service - CH Docteur Duchenne

Boulogne-sur-Mer, , France

Hematology Service - CH de Brest

Brest, , France

Institut d'Hématologie de Basse Normandie

Caen, , 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

Créteil, , 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

Nîmes, , France

Hematology Unit - CHR Orleans

Orléans, , 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-Bénite, , 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

CH Yves Lefoll

Saint-Brieuc, , France

Oncology Unit - Institut de cancérologie de la Loire

Saint-Priest-en-Jarez, , France

CH Saint Quentin Oncohematology

Saint-Quentin, , France

Hematology Unit CHU Toulouse

Toulouse, , France

Hematology Unit CHU Bretonneau

Tours, , France

Hematology Unit Hopitaux de Brabois

Vandœuvre-lès-Nancy, , France

Intern Medecine Unit CHBA

Vannes, , France

Hôpital André Mignot Centre Hospitalier de Versailles

Versailles, , France

Countries

France

Other Identifiers

35RC12_8972 _LGL

Identifier Type: -

Identifier Source: org_study_id