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Two Cases of Refractory Large Granular Lymphocytic Leukemia Treated by Porcine Anti-human Thymocyte Immunoglobulin.

Byline: Qiang. Zeng, Hong. Wang, Hong. Chang

To the Editor: Large granular lymphocytic leukemia (LGLL) is a rare chronic clonal lymphoproliferative disease characterized by a persistent increase in large granular lymphocytes, which are large lymphocytes with a low nucleus to cytoplasm ratio and an abundant cytoplasm with azurophilic granules. [sup][1] Here we report two cases diagnosed as refractory LGLL treated with porcine antihuman thymocyte immunoglobulin (ATG) in West China Hospital.

A 44-year-old woman was admitted to the outpatient department with complaint of recurrent fatigue. The initial laboratory tests showed: Hemoglobin (Hb), 6.8 g/dl, reticulocytes (RET), 7.1 x 10 [sup]9 /L. Bone marrow smears showed mature lymphocytes of 29.5%, granulocytic cells 68%, erythroid cells 4% and myeloid/erythroid (M/E) ratio 27.2:1. Flow cytometry (FCM) showed CD3 [sup]+ , CD8 [sup]+ , CD57 [sup][+ or -] , CD56[sup]− , and restricted expression of T-cell receptor (TCR)-aa3. She was diagnosed as LGLL. The patient then received the treatment of cyclosporin A (CsA), steroid, methotrexate (MTX) and cyclophosphamide, all of which were failed. However, after porcine ATG therapy, her Hb count increased to normal value [Figure 1]a. Then, FCM of marrow suggested that just a few clonal T-cell might be presented. 7 months later, FCM of her peripheral blood showed nucleated cells with 38% lymphocytes, 68% of which were clonal cytotoxic T-cell. She was identified to relapse.{Figure 1}

A 46-year-old woman was admitted to our department due to dizziness and fatigue. Her initial laboratory tests showed: Hb 5.5 g/dl, RET 28 x 10 [sup]9 /L; bone marrow smear showed mature lymphocytes of 21%, granulocytic cells 71%; erythroid cells 7% and M/E ratio 10.1:1. FCM showed nucleated cells of 82% lymphocytes with an immunophenotype of CD2 [sup]+ , CD3 [sup]+ , CD7 [sup]+ , CD8 [sup]+ , CD57 [sup]+ , CD11c [sup]+ , CD4[sup]− , CD5[sup]− , CD16[sup]− , CD56[sup]− , and restricted expression of TCR-aa 7.1, suggesting large granular lymphoproliferative disorder. CsA and steroid failed initially. After porcine ATG, her Hb count elevated obviously [Figure 1]b. Then, bone marrow smear showed mature lymphocytes of 22.5%, granulocytic cells 53.5%, erythroid cells 23% and M/E ratio 2.33:1. FCM indicated CD8 [sup]+ cells of 67%, CD4 [sup]+ cells 27% and TCR-aa[sup]− . The patient continued to take CsA and her Hb count was maintained at 11 g/dl currently.

In 1977, LGLL was first described by McKenna; in 1985, the term LGLL was first used to describe this disorder involving clonal invasion of the blood, marrow and spleen; in 1999, the World Health Organization classification included T- and NK-cell LGLL in the mature peripheral T-cell neoplasm subgroup. [sup][2] The disease mainly affects middle-aged people, with a median age of 60 years, without gender predilection. [sup][3] It is asymptomatic or symptomatic with neutropenia, anemia, thrombocytopenia, recurrent infections and autoimmune conditions. The FCM is often characterized by expression of CD3 [sup]+ , CD8 [sup]+ , and TCR-a gene rearrangements. [sup][3]

The first-line therapy of LGLL includes CsA, steroid, MTX and cyclophosphamide. But some patients who do not respond well to these drugs are refractory. For these patients, Lamy and Loughran suggested that purine analogs, such as Fludarabine or Campath, could be used or that investigational drugs should be considered. [sup][4] Although ATG can bind to T-cell and relieve inhibition of red linage, few refractory patients received the treatment. We searched OVID databases and found that patients with refractory LGLL were treated with horse ATG in 1980s; no patients have been treated by porcine ATG before. Our two refractory patients received porcine ATG therapy and achieved remission. One of them even achieved molecular remission. However, one patient relapsed afterwards, so long-term follow-up is also necessary to monitor the recurrence.

References

1. Kwong YL, Wong KF. Association of pure red cell aplasia with T large granular lymphocyte leukaemia. J Clin Pathol 1998;51:672-5.

2. Steinway SN, LeBlanc F, Loughran TP Jr. The pathogenesis and treatment of large granular lymphocyte leukemia. Blood Rev 2014;28:87-94.

3. Sokol L, Loughran TP Jr. Large granular lymphocyte leukemia. Oncologist 2006;11:263-73.

4. Lamy T, Loughran TP Jr. How I treat LGL leukemia. Blood 2011;117:2764-74.
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Title Annotation:Correspondence
Author:Zeng, Qiang; Wang, Hong; Chang, Hong
Publication:Chinese Medical Journal
Article Type:Letter to the editor
Geographic Code:9CHIN
Date:May 1, 2015
Words:707
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