T-cell large granular lymphocyte (T-
LGL) leukemia is clinically indolent, but is associated with severe
neutropenia in approximately 50% of cases. The pathogenesis of the
neutropenia is unclear. We report reversal of severe
neutropenia associated with
T-LGL leukemia in five patients treated with
cyclosporine (CSA). All five had persistent neutrophil counts below 0.5 x 10(9)/L, two had
agranulocytosis, and four had
recurrent infections. Increased populations of LGL were present in blood and marrow, with a T-LGL immunophenotype (CD3(+)CD8(+)CD16(+/-)CD56(+/-)CD57(+)) shown by multiparameter flow cytometry, and clonal
T-cell receptor (TCR) gene rearrangements in two of two pretreatment blood samples studied. CSA was initiated at doses of 1 to 1.5 mg/kg orally every 12 hours, with subsequent dose adjustments based on trough serum levels. Four patients attained normal neutrophil counts with CSA alone; one required addition of low-dose
granulocyte-macrophage colony-stimulating factor. Time to attainment of 1.5 x 10(9)/L neutrophils ranged from 21 to 75 days. Attempts to taper and withdraw CSA resulted in recurrent
neutropenia. Three patients have maintained normal neutrophil counts on continued CSA
therapy for 2, 8, and 8.5 years. Two patients died 1.7 and 4.6 years after initiation of CSA despite normal neutrophil counts-one of metastatic
melanoma and one of complications after aortofemoral bypass surgery. Despite resolution of
neutropenia, increased populations of T-LGL cells have persisted in all patients during CSA
therapy, as shown by morphology and flow cytometry and by the presence of clonal TCR gene rearrangements in four patients' posttreatment blood samples. We conclude that CSA is an effective
therapy for
neutropenia associated with
T-LGL leukemia, and that resolution of
neutropenia despite persistence of abnormal cells implies that CSA may inhibit T-LGL secretion of yet unidentified mediators of
neutropenia.