Methotrexate therapy of T-cell large granular lymphocytic leukemia impact of STAT3 mutation

Abstract

T-cell large granular lymphocytic leukemia (T-LGLL) is a rare haematologic neoplasm. Consequntly, there are no large prospective studies of therapy and no uniform therapy recommendations. We analyzed data from 36 subjects receiving methotrexate alone (N = 27) or with prednisone (N = 9) as initial therapy. 31 subjects responded (86%, 95% confidence interval [CI], 73, 95%) with 8 complete responses and 23 partial responses. Median time-to-response was 3 months (range, 1–5 months). Median response duration was 20 months (range, 2–55 months). β2-microoglobulin (β2-MG) and erythrocyte sedimentation rate (ESR) decreased significantly post-therapy (P < 0.0001). Pure red cell aplasia (PRCA) was present in 18 subjects (50%) of our subjects and responded well to methotrexate. 26 subjects (72%) were tested for STAT3 mutation. 9 with a mutation had a median treatment-free survival of 5 months (range, 0.5–13 months), significantly briefer than that of 17 subjects without a STAT3 mutation (19 months, range, 3–97 months; P = 0.012; log-rank test). Methotrexate with or without prednisone is an effective initial therapy of persons with T-LGLL with wild-type STAT3.

<p>Pathophysiologic Mechanisms And Management Of Large Granular Lymphocytic Leukemia Associated Pure Red Cell Aplasia</p>

“…PRCA with STAT3 mutation was recognized in 13 T-LGLL patients 31. In our research, 7 patients with LGLL-associated PRCA (25%) were found to have STAT3 mutations 10. Balasubramanian et al recently reported the results of targeted sequencing for PRCA patients with and without T-LGLL 18.…”

“…In 2 reports from Japan, 15 patients (42.9%) in one report met the criteria of PRCA among 35 T-LGLL patients and the incidence in the other was 11.0% (14/127) 9,14. In China, we reported PRCA was present in 18 (50%) of 36 T-LGLL patients and Zhao X et al reported 19 (67.9%) of 28 T-LGLL patients 10,15. Kwong YL et al also reported PRCA was more frequent in Asians than western LGLL patients (52/110, 47% versus 6/143, 4%) 16…”

“…The absence of STAT3 mutations may be due to the ethnic background of the patients. T-LGLL is known to be frequently accompanied by RA or neutropenia in western countries, whereas PRCA is frequently associated with T-LGLL in East Asian populations 10,12,16…”

Large granular lymphocytosis after transplantation

“…In the non-transplant setting, the indications for T-LGLL treatment are severe neutropenia with recurrent infections, severe refractory anaemia, and severe thrombocytopenia [ 50 ]; cyclophosphamide, cyclosporine, and methotrexate have been used as first-line treatment agents [ 51 , 52 ], and alemtuzumab and antithymocyte globulin have been proposed for refractory disease [ 53 , 54 ]. There are no formal trials guiding the specific management options for LGL lymphocytosis after transplantation.…”

T-cell large granular lymphocytic leukemia associated with renal cell carcinoma

“…For asymptomatic T-LGLL patients with an indolent course, a wait-and-see approach can be considered. [ 9 ] After discharge, the patient was stable and remained asymptomatic without any treatment.…”