Discussion
Although a potential role for MTX to treat STAT3 -mutated cases, which in general appear to have worse survival outcomes than wild-type counterparts, has been proposed12,13, there is no consensus as to the optimal treatment algorithm for T-LGL, whether STAT3 -mutated or otherwise.1 A non-cytotoxic molecular-targeted therapy would be ideal, since the therapy aims at improving low blood counts, a goal that can be undermined by cytotoxicity, especially in elderly patients who have functional hematopoiesis reserves already diminished by age and disease processes. As a molecular target, DNMT1 has been (i) clinically validated for treating other T-cell malignancies; (ii) pre-clinically validated for the treatment of T-LGL14; and (iii) we had previously developed and described a dose, route-of-administration and schedule of decitabine to deplete DNMT1 without cytotoxicity to BM.6-9 The non-cytotoxic, DNMT1-targeting mechanism-of-action of this regimen has been documented previously in patients with myeloid malignancies and β-hemoglobinopathies.6-9Taken altogether, these data prompted our first use of this decitabine regimen to treat an elderly patient with T-LGL refractory to multiple lines of therapy and red cell transfusion-dependence. The subjective and objective clinical response and safety profile, and the clinical responses to DNMT1-targeting reported also for other T-cell malignancies, suggest that non-cytotoxic DNMT1-targeting should be further evaluated to treat T-LGL.