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J. Stomper et al.
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Figure 3. Elevated HbF after course 2 of decitabine treatment is associated with improved survival in patients with myelodysplastic syndrome. Kaplan-Meier sur- vival estimates were determined according to whether HbF after course 2 of decitabine treatment was in the normal range (i.e. 0-1.0% of total hemoglobin) or ele- vated (i.e. >1.0%). (A) Overall survival of 15 patients with myelodysplastic syndrome (MDS), two in the group with elevated HbF censored at 100 months (still alive in remission following allografting). (B) Progression-free survival of 15 MDS patients, one in the group with elevated HbF censored (still alive in remission following allografting). (C) Acute myeloid leukemia (AML)-free survival of 15 MDS patients, one in the group with elevated HbF censored (still alive in remission following allo- grafting). (D) Overall survival of 17 AML patients, one in the group with elevated HbF censored (still alive in remission following allografting).
Looking in more detail at the subgroup of 18 patients who received more than four courses of treatment, it was noted that six attained not only a multilineage hematolog- ic response but also bone marrow blast clearance. Interestingly, in all of them HbF levels were, or became, elevated at the time of remission. In four of these patients, the complete remission status could be confirmed by cyto- genetics: chromosomal abnormalities present at baseline were no longer detectable at that point (cytogenetic remis- sion; in several of these patients, suppression of the abnor- mal clone was confirmed by fluorescence in situ hybridiza- tion).
Taken together, these analyses strongly suggested that HbF induction observed after four courses of treatment occurred preferentially in the emerging non-clonal ery- throid cells, in which epigenetically silenced beta-globin- like genes were reactivated by treatment with the HMA.
For seven MDS/AML patients, HbF measurements were obtained both after the end of decitabine course 2 and at the time of hematologic relapse. Relative to an elevated HbF level after course 2 (median 1.9%; range, 1.5-4.6%), a decrease was observed in all seven patients at the time of relapse (median 1.1%; range, 0.2-1.9%). In two of these
patients (both of whom had a complex karyotype), the decline in HbF level preceded the hematologic relapse, implicating it as a potential early predictor of relapse in a subgroup of patients. Notably, the initial increase after course 2 compared to pre-treatment HbF levels (available for 6 patients: median 1.2%; range, 0.3-3.9%) became reversed at relapse in five of the six patients (Figure 4B).
Decitabine triggers an erythroid but not a megakaryocytic maturation program in bi-potential myeloid leukemia cells
To model the effects of decitabine in vitro, two myeloblastic cell lines (K562, HEL) with bi-lineage differ- entiation potential were treated with decitabine at non- toxic concentrations. Striking morphological changes included polyploidy and cytoplasmic maturation indica- tive of partial erythroid differentiation (Figure 5A), con- firmed by benzidine staining in K562 cells: decitabine- and hemin- but not PMA-treated cells became hemoglobin- positive (Figure 5B). K562 cells treated with PMA devel- oped morphological changes indicative of megakaryocytic differentiation and induction of surface CD41/61 whereas lack of CD41 detection by FACS analysis after decitabine
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haematologica | 2019; 104(1)