Clinical trial NCT01976182: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Large Granular Lymphocytes Leukemia
Keywords: large granular lymphocytes leukemia
immunosuppressive drugs
methotrexate
cyclophosphamide
efficiency
phase II randomized controlled trial
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2013-11-05
Enrollment: 166
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Complete response (CR)
timeFrame: at Month 4
Secondary outcomes:
measure: overall response rate (ORR)
timeFrame: at Month 4, and at Month 8 and Month 12 in non-responders at Month 4
measure: Complete response (CR)
timeFrame: at Month 8 and Month 12
measure: Hematological partial response (PR)
timeFrame: at Month 4, Month 8 and Month 12
measure: Progressive disease
timeFrame: at Month 4, Month 8 and Month 12
measure: Time-to-relapse
timeFrame: from Month 4 to endpoint (in first-line treatment responders)
measure: Time-to-relapse
timeFrame: from Month 8 to endpoint (in second-line treatment responders)
measure: Molecular remission
timeFrame: at Month 4 and Month 12 for hematological complete responders
measure: Adverse events rate
timeFrame: Month 2, Month 4, Month 6, Month 8, Month 10, Month 12
measure: Compliance
timeFrame: Month 2, Month 4, Month 6, Month 8, Month 10, Month 12
measure: relationship between the response to treatment and the phenotypic subtype
timeFrame: Day 1
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Sud
city: Angers
country: France
facility: CHU Angers
city: Antibes
country: France
facility: Intern medecine Service - CH Antibes-Juan-les-Pins
city: Avignon
country: France
facility: Hematology Service - CH Avignon
city: Bayonne
country: France
facility: Hematology Service - CH de la cote basque
city: Beauvais
country: France
facility: hematology service - CH Beauvais
city: Besançon
country: France
facility: Hematology Service - CH Jean Minjoz
city: Beziers
country: France
facility: Hematology Service - CH Beziers
city: Bobigny
country: France
facility: Hematology Unit - HOpital Avicienne
city: Boulogne sur Mer
country: France
facility: Hematology Service - CH Docteur Duchenne
city: Brest
country: France
facility: Hematology Service - CH de Brest
city: Caen
country: France
facility: Institut d'Hématologie de Basse Normandie
city: Caen
country: France
facility: Hematology Service - CH François Baclesse
city: Chartres
country: France
facility: hematology Service - CH Louis Pasteur
city: Cholet
country: France
facility: Centre Hospitalier de Cholet
city: Clamart
country: France
facility: Hopital Inter-Armées Percy
city: Clermont-Ferrand
country: France
facility: hematology Service - CHU Estaing
city: Colmar
country: France
facility: Hematology Service - Civils hospital
city: Corbeil Essonnes
country: France
facility: Hematology Service CHSF
city: Creteil
country: France
facility: CHU Henri Mondor Lymphoid Hemopathy Unit
city: Grenoble
country: France
facility: Hematology Unit CH Michalon
city: La Roche sur Yon
country: France
facility: Hematology Unit CHD Vendée
city: Le Mans
country: France
facility: Hematology Unit CH LE MANS
city: Libourne
country: France
facility: CH Robert Boulin
city: Lille
country: France
facility: Hematology Unit CHRU Lille
city: Limoges
country: France
facility: Hematology Unit CHU Dupuytren
city: Lorient
country: France
facility: CH de Bretagne Sud
city: Marseille
country: France
facility: Hematology Unit CHU La Conception
city: Marseille
country: France
facility: Hematology Unit - Institut Paoli-Calmettes
city: Meaux
country: France
facility: Hematology Unit CH Meaux
city: Metz
country: France
facility: Hematology Unit CH Notre Dame Bon Secours
city: Montpellier
country: France
facility: Hematogy Unit CHU ST ELOI
city: Mulhouse
country: France
facility: Hematology Unit CH E.MULLER
city: Nantes
country: France
facility: Internal Medicine - CHU Hotel Dieu
city: Nice
country: France
facility: Oncology Unit CH Antoine Lacassagne
city: Nimes
country: France
facility: hematology Unit CHU Caremeau
city: Orleans
country: France
facility: Hematology Unit - CHR Orleans
city: Paris
country: France
facility: Hematology Service - Hopital La Pitié Salpetrière
city: Paris
country: France
facility: Hematology Unit - Hopital Hotel Dieu
city: Paris
country: France
facility: Hematology Unit - Hopital Saint Antoine
city: Paris
country: France
facility: AP-HP Hôpital Necker - Enfants Malades
city: Paris
country: France
facility: Hematology Unit - Hopital Saint Louis
city: Perpignan
country: France
facility: Hematology Unit Hopital Saint Jean
city: Pessac
country: France
facility: Hematology Service- CH Haut Leveque
city: Pierre Benite
country: France
facility: Hematology Unit CH LYON SUD
city: Poitiers
country: France
facility: Hematology Unit CHU La Miletrie
city: Pontoise
country: France
facility: Hematology Unit CH René DUBOS
city: Pringy
country: France
facility: CH Annecy - Hematology Service
city: Reims
country: France
facility: Hematology Unit- Hopital Robert Debré
city: Rennes
country: France
facility: Hematology Service - CHU of Rennes
city: Rouen
country: France
facility: Hematology Unit - CH Becquerel
city: Saint Priest en Jarez
country: France
facility: Oncology Unit - Institut de cancérologie de la Loire
city: Saint Quentin
country: France
facility: CH Saint Quentin Oncohematology
city: Saint-Brieuc
country: France
facility: CH Yves Lefoll
city: Toulouse
country: France
facility: Hematology Unit CHU Toulouse
city: Tours
country: France
facility: Hematology Unit CHU Bretonneau
city: Vandoeuvre les Nancy
country: France
facility: Hematology Unit Hopitaux de Brabois
city: Vannes
country: France
facility: Intern Medecine Unit CHBA
city: Versailles
country: France
facility: Hôpital André Mignot Centre Hospitalier de Versailles
Study officials:
References: