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

  • STATUS
    Recruiting
  • End date
    Nov 26, 2022
  • participants needed
    166
  • sponsor
    Rennes University Hospital
Updated on 5 September 2021

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.

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.

Details
Condition Large Granular Lymphocytes Leukemia
Treatment cyclophosphamide, methotrexate
Clinical Study IdentifierNCT01976182
SponsorRennes University Hospital
Last Modified on5 September 2021

Eligibility

Yes No Not Sure

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 TCR gene using PCR or specific and clonal V 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
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