TPM Regimen (Thalidomide, Prednisone and Methotrexate) in LGLL

Study Overview
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Brief Summary
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Large granular lymphocytic leukemia (LGLL) is a lymphoproliferative disease, with LGL infiltration in peripheral blood and bone marrow, hepatosplenomegaly, and cytopenia. Both T-LGLL and CLPD-NK are indolent disease and share similar biology and clinical course, and treated under the same strategy. So the investigators put them together as LGLL. The investigators used TPM regimen (thalidomide + prednison + methotrexate ) to treat LGLL since 2013, and 18/20 patients (90%) obtained clinical response, including 80% complete response. Adverse events (AE) of grade 3 and above are rare and safe. Therefore, the investigators designed this multicenter clinical trial to validate the efficacy of the TPM regimen in symptomatic T-LGLL and CLPD-NK.

Detailed Description
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Because LGLL has continuously activated cytotoxic T lymphocytes, immunosuppressive therapy is the standard first-line therapy for T-LGLL and CLPD-NK. Previous studies showed that the overall response rate (ORR) of first-line oral immunosuppressants ranged from 21% to 85% (median: 50%). Both methotrexate and cyclosporine A are LGLL first-line treatment options, but the CR rate of methotrexate is only 21%, while the CR rate of CsA is less than 5%. There is insufficient evidence for the treatment of LGLL with prednisone and other glucocorticoids, but it can reduce RA-related inflammation and increase granulocyte levels. The TPM regimen was designed by the investigators. A pilot prospect observation showed that 18/20 (90%) patients obtained response, including 80% CR. This study is a prospective multiple center clinical trail to evaluate the efficacy of TPM regimen in the treatment of symptomatic LGLL. Eligible patients choose the initial treatment plan: thalidomide 50-100mg qn+ prednisone 0.5-1mg / kg qod +methotrexate 10mg / m2 / week. Four months is one course. Maximum three courses will be given if there is a response and thalidomide maintenance will be for another year.

Official Title
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The Efficacy of Thalidomide Plus Prednisone and Methotrexate for the Symptomatic Large Granular Lymphocytic Leukemia - a Prospective Multicenter Clinical Trial From China

Conditions
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T-LGL Leukemia, Clpd-Nk

Intervention / Treatment
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* Drug: thalidomide + prednisone + methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The gender of the patient is not limited, and the age is ≥18 years old; Must meet diagnostic criteria of T-LGLL or CLPD-NK according to WHO 2016 version; The patient is treatment naive or received single methotrexate less than 4 weeks and without response. If relapsed or refractory patients, the patients must be naive for both thalidomide and methotrexate. With LGLL treatment indications, it mainly includes (meets at least one of the following conditions): ANC <0.5 × 10^9 / L HGB <100g / L or need red blood cell infusion to maintain PLT <50 × 10^9 / L Combining autoimmune diseases that require treatment symptomatic splenomegaly Severe B symptoms Pulmonary hypertension. ECOG performance status score is 0-2; The patient's expected survival time is ≥ 6 months. Exclusion Criteria: Unable to understand or follow the research procedure; Co-occurrent malignant tumors that has to be treated or course the symptom; Other serious diseases, such as liver, kidney, heart, lung, nerve or metabolic diseases, may impede the ability of patients to tolerate methotrexate, cyclophosphamide or cyclosporin A; ALAT / ASAT or alkaline phosphatase> 3 times the normal value; Creatinine clearance <60ml / min; Serological evidence of active infection of HIV, hepatitis C or hepatitis B; Ineffective contraception; Positive pregnancy test; Pregnant women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: TPM treatment plan: thalidomide 50-100mg qn + prednisone 0.5-1mg / kg qod +methotrexate 10mg / m2 / week.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TPM regimen<br>thalidomide 50-100mg daily at bedtime + prednisone 0.5mg/kg qod to 1mg/kg qd + methotrexate 10mg/m2 per week. 4 months one cycle, up to 3 cycles. After get partial remission, thalidomide maintenance will continue up to 2 years. | Drug: thalidomide + prednisone + methotrexate<br>* thalidomide 50-100mg daily at bedtime + prednisone 0.5mg/kg qod to 1mg/kg qd + methotrexate 10mg/m2 per week. 4 months one cycle, up to 3 cycles. After get partial remission, thalidomide maintenance will continue up to 2 years.<br>* Other names: TPM regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate of TPM regimen | Hb> 120g / L，platelet> 100×109 / L，ANC > 1.5×109 / L），ALC< 4×109 / L，peripheral LGL in normal（< 0.5×109 / L） | From date of TPM treatment until the date of complete response, assessed up to 100 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response (PR) | improvement in blood counts (ANC > 0.5 × 10^9/L; HGB increased by >1 g/dL; PLT > 50 × 10^9/L), and the absence of required transfusions. | From date of TPM treatment until the date of at least partial response, assessed up to 100 months | 
| Progression-free survival (PFS) | the length of time during and after the treatment of LGLL | From date of TPM treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| Duration of response (DoR) | the time from response to progression/death (P/D) | From date of getting response until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| overall survival | the length of the patients survival time | From date of TPM treatment until the date of death from any cause, assessed up to 180 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Large granular lymphocyte leukemia, thalidomide, methotrexate