Clinical trial NCT04453345: TPM Regimen (Thalidomide, Prednisone and Methotrexate) in LGLL
Official title: The Efficacy of Thalidomide Plus Prednisone and Methotrexate for the Symptomatic Large Granular Lymphocytic Leukemia - a Prospective Multicenter Clinical Trial From China
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: T-LGL Leukemia
Clpd-Nk
Keywords: Large granular lymphocyte leukemia
thalidomide
methotrexate
Lead sponsor: Institute of Hematology & Blood Diseases Hospital, China
Sponsor class: OTHER
Collaborators: name: The First Affiliated Hospital of Nanchang University
name: First Affiliated Hospital of Guangxi Medical University
name: Henan Cancer Hospital
name: The First Hospital of Jilin University
name: Central South University
name: Tianjin First Central Hospital
First posted: 2020-07-01
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: TPM treatment plan: thalidomide 50-100mg qn + prednisone 0.5-1mg / kg qod +methotrexate 10mg / m2 / week.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Complete response (CR) rate of TPM regimen
timeFrame: From date of TPM treatment until the date of complete response, assessed up to 100 months
Secondary outcomes:
measure: Overall response (PR)
timeFrame: From date of TPM treatment until the date of at least partial response, assessed up to 100 months
measure: Progression-free survival (PFS)
timeFrame: 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
measure: Duration of response (DoR)
timeFrame: 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
measure: overall survival
timeFrame: From date of TPM treatment until the date of death from any cause, assessed up to 180 months
Other outcomes:
Locations:
city: Nanning
country: China
facility: The First Affiliated Hospital of Guangxi Medical University
state: Guangxi
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Tongji hopital, Huazhong University of Science and Technology
state: Hubei
city: Changsha
country: China
facility: The Second Xiangya Hospital of Central South University
state: Hunan
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University
state: Jiangxi
city: Ch'ang-ch'un
country: China
facility: The First Affiliated Hospital of Jilin University
state: Jilin
city: Xi'an
country: China
facility: Xijing Hospital, Air Force Military Medical University
state: Shanxi
city: Tianjin
country: China
facility: Institute of Hematology & Blood Diseases Hospital
state: Tianjin
city: Tianjin
country: China
facility: Tianjin First Central Hospital
state: Tianjin
Study officials:
affiliation: Blood Disease Hospital, CAMS and Peking Union Medical College
name: Lugui Qiu
role: STUDY_DIRECTOR
References:
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citation: Moignet A, Lamy T. Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Am Soc Clin Oncol Educ Book. 2018 May 23;38:616-625. doi: 10.1200/EDBK_200689.
citation: Zambello R, Teramo A, Gattazzo C, Semenzato G. Are T-LGL Leukemia and NK-Chronic Lymphoproliferative Disorder really two distinct diseases? Transl Med UniSa. 2014 Feb 4;8:4-11. eCollection 2014 Jan.
citation: Cheon H, Dziewulska KH, Moosic KB, Olson KC, Gru AA, Feith DJ, Loughran TP Jr. Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Curr Hematol Malig Rep. 2020 Apr;15(2):103-112. doi: 10.1007/s11899-020-00565-6.
citation: Lamy T, Moignet A, Loughran TP Jr. LGL leukemia: from pathogenesis to treatment. Blood. 2017 Mar 2;129(9):1082-1094. doi: 10.1182/blood-2016-08-692590. Epub 2017 Jan 23.