Clinical Trial: 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
Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional
Official Title: Prospective, Sequential Multiple Assignment, Multicentric, Phase II Randomized Controlled Trial on Two Parallel Groups Comparing the Efficacy of Two Immunosuppressive Drugs (Methotrexate, Cyclophospha
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 ex
Detailed Summary:
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 releas
Sponsor: Rennes University Hospital
Current Primary Outcome: Complete response (CR) [ Time Frame: 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.
Original Primary Outcome: Same as current
Current Secondary Outcome:
- overall response rate (ORR) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: at Month 4, Month 8 and Month 12 ]Progressive disease defined as worsening of cytopenia or organomegaly or incidence of infections.
- Time-to-relapse [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Month 2, Month 4, Month 6, Month 8, Month 10, Month 12 ]Adverse events rate
- Compliance [ Time Frame: Month 2, Month 4, Month 6, Month 8, Month 10, Month 12 ]Compliance
- relationship between the response to treatment and the phenotypic subtype [ Time Frame: 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.
Original Secondary Outcome: Same as current
Information By: Rennes University Hospital
Dates:
Date Received: October 22, 2013
Date Started: September 2013
Date Completion: March 2018
Last Updated: April 11, 2016
Last Verified: April 2016
- overall response rate (ORR) [ Time Frame: at Month 4, and at Month 8 and Month 12 in non-responders at Month 4 ]
