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

NCT01976182 | Completed Phase 2

• 1 other identifier: 35RC12_8972 _LGL
• Study Type: interventional
• Target: 166
• Locations: 1 country
• Sites: 59

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. 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. 2.to evaluate the percentage of patients refractory to methotrexate or cyclophosphamide for which a second line treatment is efficacious
3. 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. 4.to evaluate the response rate according to the phenotypic subtype of LGL leukemia.

Conditions

Large Granular Lymphocytes Leukemia

Keywords

large granular lymphocytes leukemia; immunosuppressive drugs; methotrexate; cyclophosphamide; efficiency; phase II randomized controlled trial

Outcome Measures

Primary Outcomes (1)

• Complete response (CR)

  The main endpoint will be the hematological CR rate evaluated after 4 months of treatment (binary endpoint). Complete response (CR) is defined as a normalization of clinical examination (disappearance of splenomegaly) and a complete normalization of blood counts (i.e., hemoglobin \>12g/dL, platelets \>150x109/L, ANC \>1.5x109/L), lymphocytosis \<4x109/L and circulating LGL in the normal range (\<0.3x109/L). The number of LGL will be quantitated on blood smears.

  at Month 4

Secondary Outcomes (10)

• overall response rate (ORR)

  at Month 4, and at Month 8 and Month 12 in non-responders at Month 4

• Complete response (CR)

  at Month 8 and Month 12

• Hematological partial response (PR)

  at Month 4, Month 8 and Month 12

• Progressive disease

  at Month 4, Month 8 and Month 12

• Time-to-relapse

  from Month 4 to endpoint (in first-line treatment responders)

Study Arms (2)

METHOTREXATE

ACTIVE COMPARATOR

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.

Drug: Methotrexate

CYCLOPHOSPHAMIDE

ACTIVE COMPARATOR

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.

Drug: Cyclophosphamide

Interventions

Methotrexate 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.

METHOTREXATE

Cyclophosphamide DRUG

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

CYCLOPHOSPHAMIDE

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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

Sponsors & Collaborators

• Rennes University Hospital: lead

Study Sites (59)

CHU Sud

Amiens, 80054, France

Location

CHU Angers

Angers, 49033, France

Location

Intern medecine Service - CH Antibes-Juan-les-Pins

Antibes, France

Location

Hematology Service - CH Avignon

Avignon, 84902, France

Location

Hematology Service - CH de la cote basque

Bayonne, France

Location

hematology service - CH Beauvais

Beauvais, 60021, France

Location

Hematology Service - CH Jean Minjoz

Besançon, 25030, France

Location

Hematology Service - CH Beziers

Béziers, 34500, France

Location

Hematology Unit - HOpital Avicienne

Bobigny, 93009, France

Location

Hematology Service - CH Docteur Duchenne

Boulogne-sur-Mer, 62321, France

Location

Hematology Service - CH de Brest

Brest, 29609, France

Location

Institut d'Hématologie de Basse Normandie

Caen, 14000, France

Location

Hematology Service - CH François Baclesse

Caen, 14076, France

Location

hematology Service - CH Louis Pasteur

Chartres, 28018, France

Location

Centre Hospitalier de Cholet

Cholet, 49300, France

Location

Hopital Inter-Armées Percy

Clamart, 92141, France

Location

hematology Service - CHU Estaing

Clermont-Ferrand, 63003, France

Location

Hematology Service - Civils hospital

Colmar, 68024, France

Location

Hematology Service CHSF

Corbeil-Essonnes, 91110, France

Location

CHU Henri Mondor Lymphoid Hemopathy Unit

Créteil, 94000, France

Location

Hematology Unit CH Michalon

Grenoble, 38043, France

Location

Hematology Unit CHD Vendée

La Roche-sur-Yon, 85925, France

Location

Hematology Unit CH LE MANS

Le Mans, 72000, France

Location

CH Robert Boulin

Libourne, 33500, France

Location

Hematology Unit CHRU Lille

Lille, 59037, France

Location

Hematology Unit CHU Dupuytren

Limoges, 87042, France

Location

CH de Bretagne Sud

Lorient, 56322, France

Location

Hematology Unit CHU La Conception

Marseille, 13005, France

Location

Hematology Unit - Institut Paoli-Calmettes

Marseille, 13009, France

Location

Hematology Unit CH Meaux

Meaux, 77100, France

Location

Hematology Unit CH Notre Dame Bon Secours

Metz, 57000, France

Location

Hematogy Unit CHU ST ELOI

Montpellier, 34295, France

Location

Hematology Unit CH E.MULLER

Mulhouse, 68070, France

Location

Internal Medicine - CHU Hotel Dieu

Nantes, France

Location

Oncology Unit CH Antoine Lacassagne

Nice, France

Location

hematology Unit CHU Caremeau

Nîmes, 30029, France

Location

Hematology Unit - CHR Orleans

Orléans, 45067, France

Location

Hematology Service - Hopital La Pitié Salpetrière

Paris, 75013, France

Location

Hematology Unit - Hopital Hotel Dieu

Paris, 75181, France

Location

Hematology Unit - Hopital Saint Antoine

Paris, 75571, France

Location

AP-HP Hôpital Necker - Enfants Malades

Paris, 75743, France

Location

Hematology Unit - Hopital Saint Louis

Paris, France

Location

Hematology Unit Hopital Saint Jean

Perpignan, 66000, France

Location

Hematology Service- CH Haut Leveque

Pessac, 33604, France

Location

Hematology Unit CH LYON SUD

Pierre-Bénite, 69310, France

Location

Hematology Unit CHU La Miletrie

Poitiers, 86000, France

Location

Hematology Unit CH René DUBOS

Pontoise, 95000, France

Location

CH Annecy - Hematology Service

Pringy, 74374, France

Location

Hematology Unit- Hopital Robert Debré

Reims, 51092, France

Location

Hematology Service - CHU of Rennes

Rennes, 35000, France

Location

Hematology Unit - CH Becquerel

Rouen, 76038, France

Location

CH Yves Lefoll

Saint-Brieuc, 22027, France

Location

Oncology Unit - Institut de cancérologie de la Loire

Saint-Priest-en-Jarez, 60008, France

Location

CH Saint Quentin Oncohematology

Saint-Quentin, 21000, France

Location

Hematology Unit CHU Toulouse

Toulouse, 31000, France

Location

Hematology Unit CHU Bretonneau

Tours, 37044, France

Location

Hematology Unit Hopitaux de Brabois

Vandœuvre-lès-Nancy, 54511, France

Location

Intern Medecine Unit CHBA

Vannes, 56017, France

Location

Hôpital André Mignot Centre Hospitalier de Versailles

Versailles, 78157, France

Location

MeSH Terms

Interventions

Methotrexate; Cyclophosphamide

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2013
• First Posted: November 5, 2013
• Study Start: November 26, 2013
• Primary Completion: February 5, 2024
• Study Completion: October 7, 2024
• Last Updated: January 13, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (59)