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.