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Blood, 1 August 2007, Vol. 110, No. 3, pp. 1080-1082.
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CORRESPONDENCE
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
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Figure 1. Repeated 4-hour infusions of low-dose decitabine induce hematologic and cytogenetic remissions in older, high-risk MDS patients with complex karyotype including monosomy 7. (A) A 76-year-old woman (patient 4003 of phase 2 study PCH 95-11; see also Lübbert et al2) diagnosed with MDS RAEB-t (French-American-British [FAB] classification)/AML (World Health Association [WHO] classification) and complex karyotype (8 different structural and numerical abnormalities including monosomy 7) achieved a complete cytogenetic normalization after 3 courses, and a complete hematologic remission after 4 courses of low-dose DAC (nine 4-hour infusions of 15 mg/m2 decitabine, 3 times per day, on 3 consecutive days). Note early, isolated platelet response after course 1 (filled arrow). The patient relapsed 6 months after the fifth course of DAC, and a repeated treatment (one course only) was not successful. The patient required 93 days in the hospital from the start of therapy, thus 79% of surviving days were spent at home. (B) A 75-year-old woman (patient 4007 of phase 2 study PCH 95-11) diagnosed with MDS RAEB-t (FAB)/AML (WHO) with complex karyotype (t chromosomal aberrations including monosomy 7) received 4 courses of DAC (same dosing and schedule as the patient in panel A). This patient achieved a complete hematologic and cytogenetic remission after 2 courses. Note early, isolated platelet response also after course 1 (filled arrow). Two months after discontinuation of DAC, the patient suffered a relapse presenting as full-blown acute myeloid leukemia, and she succumbed to refractory disease shortly thereafter. In total, 82% of surviving days from start of therapy were spent at home.
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Table 1. Characteristics of 2 patients with complex karyotype including monosomy 7 achieving a cytogenetic and hematologic complete remission
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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.
Authorship
Conflict-of-interest disclosure: The authors declare no competing financial interests.
This work was supported in part by Wilhelm-Sander-Siftung, grant 1999.032.2. The authors wish to thank Dr Christian Robbel for help with karyotypic analyses, and Drs Detlef Haase and Christian Steidl, Göttingen, Germany, for helpful discussions.
Correspondence: M. Lübbert, Department of Medicine, Division of Hematology/Oncology, University of Freiburg Medical Center, Freiburg, Germany; e-mail: luebbert{at}mm11.ukl.uni-freiburg.de.
Björn Rüter,
Pierre Wijermans,
Rainer Claus,
Regina Kunzmann, and
Michael Lübbert
References
- Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007; 109:52–57.[Abstract/Free Full Text]
- Lübbert M, Wijermans P, Kunzmann R, et al. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Br J Haematol 2001; 114:349–357.[CrossRef][Medline]
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- Raj KK, John AM, Ho A, et al. Early and sustained response to azacytidine in high-risk MDS patients with monosomy 7 correlates with increased apoptosis and not CDKN2B demethylation [abstract]. Blood 2005; 106:suppl 1, 2530a.[CrossRef]
- Hellström-Lindberg E, Robert KH, Gahrton G, et al. A predictive model for the clinical response to low dose ara-C: a study of 102 patients with myelodysplastic syndromes or acute leukaemia. Br J Haematol 1992; 81:503–511.[Medline]
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- Heitjan DF. Bayesian interim analysis of phase II cancer clinical trials. Stat Med 1997; 16:1791–802.[CrossRef][Medline]
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- Issa JP. Optimizing therapy with methylation inhibitors in myelodysplastic syndromes: dose, duration, and patient selection. Nat Clin Pract Oncol 2005; 2:suppl 1, S24–S29.[CrossRef][Medline]
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- List A, Dewald G, Bennett J, Giagounidis A, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355:1456–65.[Abstract/Free Full Text]
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