A Phase 2 interventional study of Methotrexate and Cyclophosphamide in Large Granular Lymphocytes Leukemia, sponsored by Rennes University Hospital. Completed at 59 sites in France. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-01-13.
Sponsored by Rennes University Hospital · Phase 2, Interventional, and Treatment
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 :
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 :
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Specific criteria for T-LGL leukemia or NK-LGL lymphocytosis or chronic NK-LGL leukemia:
Clonal rearrangement of TCRγ gene using PCR or specific and clonal Vβ expression using FCM.
At least one indication of treatment:
Exclusion Criteria:
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
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
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.
cyclophosphamide 100 mg orally once daily, that is to say 2 tablets of 50 mg at each take, during 4 months.
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.
Time frame: at Month 4
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.
Time frame: at Month 4, and at Month 8 and Month 12 in non-responders at Month 4
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.
Time frame: at Month 8 and Month 12
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).
Time frame: at Month 4, Month 8 and Month 12
Progressive disease
Progressive disease defined as worsening of cytopenia or organomegaly or incidence of infections.
Time frame: at Month 4, Month 8 and Month 12
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.
Time frame: from Month 4 to endpoint (in first-line treatment responders)
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.
Time frame: from Month 8 to endpoint (in second-line treatment responders)
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)
Time frame: at Month 4 and Month 12 for hematological complete responders
Adverse events rate
Adverse events rate
Time frame: Month 2, Month 4, Month 6, Month 8, Month 10, Month 12
Compliance
Compliance
Time frame: Month 2, Month 4, Month 6, Month 8, Month 10, Month 12
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.
Time frame: Day 1
Plan to share: No
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Rennes University Hospital