Preferential cytogenetic response to continuous intravenous low-dose decitabine (DAC) administration in myelodysplastic syndrome with monosomy 7

To the editor:

We read with great interest the recent publication by Kantarjian and colleagues addressing the value of different outpatient low-dose decitabine (DAC) schedules in higher-risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia.¹  By the Bayesian design of that study, the number of patients randomized to 2 of the arms that were considered inferior (based on a somewhat lower hematologic response rate) was quite limited. Cytogenetic responses were also reported, however, not according to the 3 different schedules. Thus, it is unclear whether patients treated with the 5-day, 20-mg/m², intravenous 1-hour infusional schedule (considered by the authors to yield superior results) also showed a superior cytogenetic response rate compared with the 2 other schedules.

Their overall cytogenetic response rate of 33% (responses in different cytogenetic subgroups are not given) is well in line with previous results of several multicenter European trials of low-dose DAC (total dose of 120 to 225 mg/m² per course administered mostly as intravenous 4-hour infusional schedule over 72 hours every 6 weeks).²  In these studies we observed a cytogenetic response rate of 31% in the 61 patients with informative cytogenetic abnormalities.²  Interestingly, response rates differed among the cytogenetic subgroups: in patients with good-risk abnormalities according to the International Prognostic Scoring System, a 60% response rate was seen; with intermediate abnormalities, 20% responses; and patients with high-risk cytogenetics (ie, any chromosome 7 aberrations and/or complex abnormalities) had a 38% cytogenetic response rate.

Because for the other azanucleoside that is very active in MDS (ie, Vidaza [5-azacytidine]; Pharmion, Boulder, CO) particular efficacy has been suggested in MDS with sole chromosome 7 abnormalities,³  we have now expanded our previous analyses to address this possible “class effect” of azanucleosides. Reanalyzing our data according to the presence or absence of chromosome 7 abnormalities among these 61 patients, we arrived at the following results: in the 6 patients with isolated chromosome 7 abnormality, 4 achieved complete (n = 3) or major (n = 1) cytogenetic responses (67% total response rate). Median number of courses until best cytogenetic response was 2 (range, 2 to 3), and median time to (cytogenetic) relapse was 13.5 months (range, 9 to 15 months). Median cytogenetic response duration in the 15 patients with other cytogenetic abnormalities was 8 months (range, 3 to 12 months), and this difference was statistically significant by Student t test. Among the 20 patients with complex aberrations, 11 karyotypes contained a chromosome 7 abnormality (also mostly monosomy 7). Four of 11 patients with complex karyotype including aberrations of chromosome 7 showed cytogenetic responses (Figure 1; Table 1) compared with 2 responders of 9 patients with complex karyotype not containing a chromosome 7 abnormality. This high response rate in patients with chromosome 7 abnormalities is in stark contrast to the notoriously low response rate of MDS patients receiving conventional low-dose therapy with AraC.⁴ 

In summary, the optimal dose and schedule of DAC for a nonintensive, outpatient treatment of high-risk MDS patients may not yet be defined. The Bayesian design has not been uniformly accepted as the optimal methodology to identify treatment superiority.⁵  Systematic evaluation of cytogenetic responses in different cytogenetic subgroups of MDS and acute myeloid leukemia will continue to be a very valuable and robust surrogate parameter to compare efficiency of azanucleoside schedules⁶  and other novel agents⁷  used to treat MDS.