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Large Granular Lymphocytes LeukemiaPhase 2LGLNCT01976182

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

A Phase 2 study testing Methotrexate and Cyclophosphamide in people with Large Granular Lymphocytes Leukemia, run by Rennes University Hospital at 59 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Large Granular Lymphocytes Leukemia
What is being tested?
Methotrexate and Cyclophosphamide
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
166 participants
Where
59 sitesFrance
Study dates
26 Nov 2013to 7 Oct 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
Show all 18Show fewer
  • 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

Who cannot join

  • 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
Show all 10Show fewer
  • Serologic evidence of HIV, hepatitis C or hepatitis B infection
  • Non effective contraception
  • Positive pregnancy test
  • Nursing woman

Trial locations and contacts

59 sites in 1 country.

59 sites in 1 country

France59 sites

  • CHU Sud

    Amiens, 80054

  • CHU Angers

    Angers, 49033

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

    Antibes

  • Hematology Service - CH Avignon

    Avignon, 84902

  • Hematology Service - CH de la cote basque

    Bayonne

  • hematology service - CH Beauvais

    Beauvais, 60021

  • Hematology Service - CH Jean Minjoz

    Besançon, 25030

  • Hematology Service - CH Beziers

    Béziers, 34500

  • Hematology Unit - HOpital Avicienne

    Bobigny, 93009

  • Hematology Service - CH Docteur Duchenne

    Boulogne-sur-Mer, 62321

  • Hematology Service - CH de Brest

    Brest, 29609

  • Institut d'Hématologie de Basse Normandie

    Caen, 14000

  • Hematology Service - CH François Baclesse

    Caen, 14076

  • hematology Service - CH Louis Pasteur

    Chartres, 28018

  • Centre Hospitalier de Cholet

    Cholet, 49300

  • Hopital Inter-Armées Percy

    Clamart, 92141

  • hematology Service - CHU Estaing

    Clermont-Ferrand, 63003

  • Hematology Service - Civils hospital

    Colmar, 68024

  • Hematology Service CHSF

    Corbeil-Essonnes, 91110

  • CHU Henri Mondor Lymphoid Hemopathy Unit

    Créteil, 94000

  • Hematology Unit CH Michalon

    Grenoble, 38043

  • Hematology Unit CHD Vendée

    La Roche-sur-Yon, 85925

  • Hematology Unit CH LE MANS

    Le Mans, 72000

  • CH Robert Boulin

    Libourne, 33500

  • Hematology Unit CHRU Lille

    Lille, 59037

  • Hematology Unit CHU Dupuytren

    Limoges, 87042

  • CH de Bretagne Sud

    Lorient, 56322

  • Hematology Unit CHU La Conception

    Marseille, 13005

  • Hematology Unit - Institut Paoli-Calmettes

    Marseille, 13009

  • Hematology Unit CH Meaux

    Meaux, 77100

  • Hematology Unit CH Notre Dame Bon Secours

    Metz, 57000

  • Hematogy Unit CHU ST ELOI

    Montpellier, 34295

  • Hematology Unit CH E.MULLER

    Mulhouse, 68070

  • Internal Medicine - CHU Hotel Dieu

    Nantes

  • Oncology Unit CH Antoine Lacassagne

    Nice

  • hematology Unit CHU Caremeau

    Nîmes, 30029

  • Hematology Unit - CHR Orleans

    Orléans, 45067

  • Hematology Service - Hopital La Pitié Salpetrière

    Paris, 75013

  • Hematology Unit - Hopital Hotel Dieu

    Paris, 75181

  • Hematology Unit - Hopital Saint Antoine

    Paris, 75571

  • AP-HP Hôpital Necker - Enfants Malades

    Paris, 75743

  • Hematology Unit - Hopital Saint Louis

    Paris

  • Hematology Unit Hopital Saint Jean

    Perpignan, 66000

  • Hematology Service- CH Haut Leveque

    Pessac, 33604

  • Hematology Unit CH LYON SUD

    Pierre-Bénite, 69310

  • Hematology Unit CHU La Miletrie

    Poitiers, 86000

  • Hematology Unit CH René DUBOS

    Pontoise, 95000

  • CH Annecy - Hematology Service

    Pringy, 74374

  • Hematology Unit- Hopital Robert Debré

    Reims, 51092

  • Hematology Service - CHU of Rennes

    Rennes, 35000

  • Hematology Unit - CH Becquerel

    Rouen, 76038

  • CH Yves Lefoll

    Saint-Brieuc, 22027

  • Oncology Unit - Institut de cancérologie de la Loire

    Saint-Priest-en-Jarez, 60008

  • CH Saint Quentin Oncohematology

    Saint-Quentin, 21000

  • Hematology Unit CHU Toulouse

    Toulouse, 31000

  • Hematology Unit CHU Bretonneau

    Tours, 37044

  • Hematology Unit Hopitaux de Brabois

    Vandœuvre-lès-Nancy, 54511

  • Intern Medecine Unit CHBA

    Vannes, 56017

  • Hôpital André Mignot Centre Hospitalier de Versailles

    Versailles, 78157

Other trials in France

About this study

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

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.

Read more

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.
Read the 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.
Keywords
large granular lymphocytes leukemia, immunosuppressive drugs, methotrexate, cyclophosphamide, efficiency, phase II randomized controlled trial

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MethotrexateDrug

    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.

  • CyclophosphamideDrug

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

Study groups in NCT01976182
Study groupRoleWhat they receive
METHOTREXATEActive comparatorIn 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.
Receives: Drug: Methotrexate
CYCLOPHOSPHAMIDEActive comparatorIn 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.
Receives: Drug: Cyclophosphamide

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: at Month 4

Secondary outcomes (10)

  1. overall response rate (ORR)

    Hematological overall response rate (ORR) defined as the sum of complete responses and partial responses over the total number of patients.

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

  2. Complete response (CR)

    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.

    Measured: at Month 8 and Month 12

  3. Hematological partial response (PR)

    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).

    Measured: at Month 4, Month 8 and Month 12

  4. Progressive disease

    Progressive disease defined as worsening of cytopenia or organomegaly or incidence of infections.

    Measured: at Month 4, Month 8 and Month 12

  5. Time-to-relapse

    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.

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

  6. Time-to-relapse

    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.

    Measured: from Month 8 to endpoint (in second-line treatment responders)

  7. Molecular remission

    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)

    Measured: at Month 4 and Month 12 for hematological complete responders

  8. Adverse events rate

    Adverse events rate

    Measured: Month 2, Month 4, Month 6, Month 8, Month 10, Month 12

  9. Compliance

    Compliance

    Measured: Month 2, Month 4, Month 6, Month 8, Month 10, Month 12

  10. relationship between the response to treatment and the phenotypic subtype

    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.

    Measured: Day 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Nov 2013 (estimated)
  2. Study start26 Nov 2013
  3. Primary completion5 Feb 2024
  4. Study completion7 Oct 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
166 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01976182
Sponsor's protocol ID
35RC12_8972 _LGL
Acronym
LGL
Status last verified
Jan 2025
First submitted
22 Oct 2013
Last updated
13 Jan 2025
Results posted
No
Data monitoring committee
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Methotrexate and Cyclophosphamide in people with Large Granular Lymphocytes Leukemia, run by Rennes University Hospital at 59 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 59 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Complete response (CR) (time frame: at Month 4). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01976182.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2025.

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