LGL: 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

Sponsor

Rennes University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT01976182

Collaborator

(none)

166

Enrollment

Locations

Arms

108

Anticipated Duration (Months)

2.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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 :

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

Condition or Disease	Intervention/Treatment	Phase
Large Granular Lymphocytes Leukemia	Drug: Methotrexate Drug: Cyclophosphamide	Phase 2

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 :

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

166 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 26, 2013

Anticipated Primary Completion Date :

Nov 26, 2022

Anticipated Study Completion Date :

Nov 26, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: 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.
Active Comparator: 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.	Drug: Cyclophosphamide cyclophosphamide 100 mg orally once daily, that is to say 2 tablets of 50 mg at each take, during 4 months.

Arm

Intervention/Treatment

Active Comparator: 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.

Drug: 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.

Active Comparator: 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.

Drug: Cyclophosphamide

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

Outcome Measures

Primary Outcome Measures

Complete response (CR) [at Month 4]
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.

Secondary Outcome Measures

overall response rate (ORR) [at Month 4, and at Month 8 and Month 12 in non-responders at Month 4]
Hematological overall response rate (ORR) defined as the sum of complete responses and partial responses over the total number of patients.
Complete response (CR) [at Month 8 and Month 12]
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.
Hematological partial response (PR) [at Month 4, Month 8 and Month 12]
Hematological partial response (PR) defined as an improvement in blood counts which do not meet criteria for complete remission (e.g., ANC increasing more than 50% and reaching more than 0.5 but less than 1.5x109/L with non-recurrence of infections, or hemoglobin level increasing more than 2 g/dL from baseline and transfusion requirements stopping without normalization of the hemoglobin level defined as hemoglobin >12g/dL).
Progressive disease [at Month 4, Month 8 and Month 12]
Progressive disease defined as worsening of cytopenia or organomegaly or incidence of infections.
Time-to-relapse [from Month 4 to endpoint (in first-line treatment responders)]
Time-to-relapse (censored variable). Relapse is defined as re-occurrence of either neutropenia or anemia (ANC <1x109/L and/or hemoglobin <10g/dL) or clonal LGL >0.5x109/L in complete responders, or as a return to baseline values of either ANC or hemoglobin in partial responders, at two monthly consecutive blood tests.
Time-to-relapse [from Month 8 to endpoint (in second-line treatment responders)]
Time-to-relapse (censored variable). Relapse is defined as re-occurrence of either neutropenia or anemia (ANC <1x109/L and/or hemoglobin <10g/dL) or clonal LGL >0.5x109/L in complete responders, or as a return to baseline values of either ANC or hemoglobin in partial responders, at two monthly consecutive blood tests.
Molecular remission [at Month 4 and Month 12 for hematological complete responders]
Molecular remission defined as the disappearance of the clonal pattern of TCR gamma multiplex rearrangement and Phenotypic remission is defined as : For the T subtype: disappearance of the excess of CD3+/CD8+ cells (or disappearance of the LGL clone according to the specific subtype observed at inclusion); For the NK subtype: disappearance of the excess of CD3-/CD56+ cells (or disappearance of the LGL clone according to the specific subtype observed at inclusion)
Adverse events rate [Month 2, Month 4, Month 6, Month 8, Month 10, Month 12]
Adverse events rate
Compliance [Month 2, Month 4, Month 6, Month 8, Month 10, Month 12]
Compliance
relationship between the response to treatment and the phenotypic subtype [Day 1]
Identification of a relationship between the response to treatment and the phenotypic subtype characterized by the panel of monoclonal antibodies defined in the ancillary study subsection.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHU Sud	Amiens	France	80054
2	CHU Angers	Angers	France	49033
3	Intern medecine Service - CH Antibes-Juan-les-Pins	Antibes	France
4	Hematology Service - CH Avignon	Avignon	France	84902
5	Hematology Service - CH de la cote basque	Bayonne	France
6	hematology service - CH Beauvais	Beauvais	France	60021
7	Hematology Service - CH Jean Minjoz	Besançon	France	25030
8	Hematology Service - CH Beziers	Beziers	France	34500
9	Hematology Unit - HOpital Avicienne	Bobigny	France	93009
10	Hematology Service - CH Docteur Duchenne	Boulogne sur Mer	France	62321
11	Hematology Service - CH de Brest	Brest	France	29609
12	Hematology Service - CH François Baclesse	Caen	France	14076
13	hematology Service - CH Louis Pasteur	Chartres	France	28018
14	Centre Hospitalier de Cholet	Cholet	France	49300
15	Hopital Inter-Armées Percy	Clamart	France	92141
16	hematology Service - CHU Estaing	Clermont-Ferrand	France	63003
17	Hematology Service - Civils hospital	Colmar	France	68024
18	Hematology Service CHSF	Corbeil Essonnes	France	91110
19	CHU Henri Mondor Lymphoid Hemopathy Unit	Creteil	France	94000
20	CHU Dijon Hematology Unit	Dijon	France	21000
21	Hematology Unit CH Michalon	Grenoble	France	38043
22	Hematology Unit CHD Vendée	La Roche sur Yon	France	85925
23	Hematology Unit CH LE MANS	Le Mans	France	72000
24	CH Robert Boulin	Libourne	France	33500
25	Hematology Unit CHRU Lille	Lille	France	59037
26	Hematology Unit CHU Dupuytren	Limoges	France	87042
27	CH de Bretagne Sud	Lorient	France	56322
28	Hematology Unit CHU La Conception	Marseille	France	13005
29	Hematology Unit - Institut Paoli-Calmettes	Marseille	France	13009
30	Hematology Unit CH Meaux	Meaux	France	77100
31	Hematology Unit CH Notre Dame Bon Secours	Metz	France	57000
32	Hematogy Unit CHU ST ELOI	Montpellier	France	34295
33	Hematology Unit CH E.MULLER	Mulhouse	France	68070
34	Internal Medicine - CHU Hotel Dieu	Nantes	France
35	Oncology Unit CH Antoine Lacassagne	Nice	France
36	hematology Unit CHU Caremeau	Nimes	France	30029
37	Hematology Unit - CHR Orleans	Orleans	France	45067
38	Hematology Service - Hopital La Pitié Salpetrière	Paris	France	75013
39	Hematology Unit - Hopital Hotel Dieu	Paris	France	75181
40	Hematology Unit - Hopital Saint Antoine	Paris	France	75571
41	AP-HP Hôpital Necker - Enfants Malades	Paris	France	75743
42	Hematology Unit - Hopital Saint Louis	Paris	France
43	Hematology Unit Hopital Saint Jean	Perpignan	France	66000
44	Hematology Service- CH Haut Leveque	Pessac	France	33604
45	Hematology Unit CH LYON SUD	Pierre Benite	France	69310
46	Hematology Unit CHU La Miletrie	Poitiers	France	86000
47	Hematology Unit CH René DUBOS	Pontoise	France	95000
48	CH Annecy - Hematology Service	Pringy	France	74374
49	Hematology Unit- Hopital Robert Debré	Reims	France	51092
50	Hematology Service - CHU of Rennes	Rennes	France	35000
51	Hematology Unit - CH Becquerel	Rouen	France	76038
52	Oncology Unit - Institut de cancérologie de la Loire	Saint Priest en Jarez	France	60008
53	CH Saint Quentin Oncohematology	Saint Quentin	France	21000
54	CH Yves Lefoll	Saint-Brieuc	France	22027
55	Hematology Unit CHU Toulouse	Toulouse	France	31000
56	Hematology Unit CHU Bretonneau	Tours	France	37044
57	Hematology Unit Hopitaux de Brabois	Vandoeuvre les Nancy	France	54511
58	Intern Medecine Unit CHBA	Vannes	France	56017
59	Hôpital André Mignot Centre Hospitalier de Versailles	Versailles	France	78157