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.

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.

Inclusion Criteria:

1. The gender of the patient is not limited, and the age is ≥18 years old;

2. Must meet diagnostic criteria of T-LGLL or CLPD-NK according to WHO 2016 version;

3. 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.

4. With LGLL treatment indications, it mainly includes (meets at least one of the following conditions):

   1. ANC <0.5 × 10^9 / L
   2. HGB <100g / L or need red blood cell infusion to maintain
   3. PLT <50 × 10^9 / L
   4. Combining autoimmune diseases that require treatment
   5. symptomatic splenomegaly
   6. Severe B symptoms
   7. Pulmonary hypertension.

5. ECOG performance status score is 0-2;

6. The patient's expected survival time is ≥ 6 months.

Exclusion Criteria:

1. Unable to understand or follow the research procedure;
2. Co-occurrent malignant tumors that has to be treated or course the symptom;
3. 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;
4. ALAT / ASAT or alkaline phosphatase> 3 times the normal value;
5. Creatinine clearance <60ml / min;
6. Serological evidence of active infection of HIV, hepatitis C or hepatitis B;
7. Ineffective contraception;
8. Positive pregnancy test;
9. Pregnant women.