Case report
A 79-year-old man with coronary artery disease, chronic kidney disease
(CKD) stage III and non-melanocytic skin cancer presented to his primary
care physician in June 2019 with shortness of breath and decreased
exercise tolerance. Initial work-up revealed macrocytic anemia
(hemoglobin [Hb] 9.4 g/L; MCV 105 fL), absolute neutrophil count of
1.6x109/L, and normal platelet count
(180x109/L). Abnormal large granular lymphocytes (LGL)
were noted on blood smear and represented 80% of total circulating
lymphocytes (absolute lymphocyte count 1.5x109/L). A
bone marrow (BM) evaluation showed moderate erythroid hyperplasia,
normal granulopoiesis and megakaryopoiesis, no dysplastic changes or
chromosomal abnormalities, and infiltration by abnormal cytotoxic
T-cells confirmed by flow cytometry (Fig.1A ). Molecular studies
revealed a canonical STAT3 Y640F mutation
(variant allelic frequency 11.5%) and a clonal T-cell rearrangement,
confirming the diagnosis of T-LGL.1,2The anemia was progressive, resulting in red cell transfusion-dependence
and prompting initiation of therapy with MTX 15 mg weekly. During 6
weeks of MTX therapy, fatigue worsened and red cell transfusion needs
increased, leading to MTX discontinuation and the initiation of
2nd-line therapy with prednisone 60 mg daily for 3
weeks with subsequent tapering, for a total duration of 8 weeks. Again,
no response was observed, prompting initiation of
3rd-line therapy with CsA 2 mg/kg per day in divided
doses along with short-course of prednisone (40 mg daily orally tapered
over 14 days). Over 4 months of CsA therapy, there was no decrease in
red cell transfusion needs, and kidney toxicity required CsA
dose-reduction. At this point, BM evaluation was repeated: morphological
observations were similar to initial presentation - expanded
erythropoiesis and T-LGL cell infiltration. Two cytogenetic
abnormalities, not observed at initial presentation, were detected (-Y
in 3/20, and +8 in 4/20 metaphases). Clonal hematopoiesis with -Y is not
uncommon in older individuals, and trisomy 8 has been reported in
association with T-LGL10,11,
but since there were no dysplastic changes the diagnosis remained
unchanged. CsA therapy was discontinued because of nephrotoxicity and
lack of response and 4th-line therapy with tacrolimus
(4 mg per day in divided doses) was initiated. As patient’s
erythropoietin level was inappropriately low in the context of anemia
(90 mU/mL), epoetin alpha (60,000 units biweekly) was incorporated into
therapy (as per indication of anemia caused by CKD). Red cell
transfusion needs did not decrease after 12 weeks of this treatment,
prompting the addition of MTX 10 mg weekly. After 12 weeks of
tacrolimus, MTX and epoetin combination, the patient was still
transfusion-dependent, therefore, the tacrolimus and MTX were
discontinued and the HDAC-inhibitor vorinostat (400 mg per osdaily), approved for the treatment of other peripheral T-cell
malignancies, was initiated as 5th-line therapy. Over
a 3 month period, this treatment was complicated by anorexia, diarrhea
and worsening of fatigue, and did not register any improvement. The
HDAC-inhibitor was thus discontinued and the patient was initiated on
6th-line therapy with a non-cytotoxic, DNMT1-targeting
regimen of subcutaneous decitabine 0.2 mg/kg once a week. Red cell
transfusion-independence was achieved around 7 weeks after initiation of
this therapy, accompanied by subjective improvements in the patient’s
symptoms and sense of well-being with no side-effects (Fig.1B ).