Outcomes of Patients With MDS After Secondary Failure of Hypomethylating Drugs

Mojtaba Akhtari, MD

Hypomethylating drugs azacitidine and decitabine have shown significant clinical activity with hematologic and cytogenetic responses in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML); and they are now the standard of care for patients with MDS and CMML.

The results of the CALGB-9221 multicenter phase III trial comparing azacitidine (75 mg/m² subcutaneously for 7 days every 28 days) to supportive care showed statistically significant improvements in response rate, survival, delay in leukemic transformation, and quality of life for azacitidine-treated patients. The median time to death or transformation to acute myelogenous leukemia (AML) was 21 months in azacitidine-treated patients vs 12 months in the supportive care arm (P = .007). Azacitidine improved survival in all FAB subtypes of MDS.[1]

This was followed by a AZA-001 phase III trial comparing azacitidine (75 mg/m² per day for 7 days every 28 days) to conventional care (best supportive care, low-dose cytarabine, and intensive chemotherapy) in high-risk MDS patients; this trial showed a statistically significant overall survival difference, with a median survival of 24.5 months for the azacitidine-treated patients and 15 months for the conventional care arm (P = .0001).[2] The data from a phase III trial comparing decitabine (15 mg/m² every 8 hours for 9 doses intravenously given in an inpatient setting) to supportive care in higher-risk MDS patients showed a response rate of 30% vs 12% in the supportive care arm; in addition, decitabine-treated patients had a trend toward a longer median time to leukemic progression or death compared with patients who received supportive care.[3]

Those significant results have resulted in widespread use of azacitidine and decitabine; however, there is an important issue of outcomes of MDS patients after secondary failure of hypomethylating drugs since these agents cannot cure MDS, and many patients could progress, and lose their response within 24 months after starting hypomethylating therapy.[2]

In a report from the MD Anderson group, who used decitabine for 14 previously treated patients with azacitidine, 3 patients had complete remission, and 1 patient showed hematologic improvement.[4] However, a more recent report from the same group analyzed outcomes of 67 MDS patients and 20 CMML patients after secondary failure of decitabine, and showed that median survival after secondary failure was 4.3 months, and the 1-year survival probability was 28%.[5]

Another recent report from Le Groupe Francophone des Mylodysplasies, which was published in the Journal of Oncology last August, reviewed outcomes of 435 high-risk MDS patients after secondary failure of azacitidine, and the median survival was found to be only 5.6 months, and the 2-year survival probability was 15%.[6] According to their report none of the patients who received decitabine after azacitidine secondary failure experienced a response and the median overall survival was 11.8 months. There were 37 patients in the cohort, who underwent allogeneic hematopoietic stem cell transplantation, and their median overall survival was 19 months.

These two reports show that the prognosis of MDS patients after secondary failure of hypomethylating drugs is poor, and switching from one failing hypomethylating drug to another cannot induce clinically significant responses.

References:

1. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429-2440. Pubmed

2. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol. 2009;10:223-232. Pubmed

3. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794-1803. Pubmed

4. Borthakur G, Ahdab SE, Ravandi F, et al. Activity of decitabine in patients with myelodysplastic syndrome previously treated with azacitidine. Leuk Lymphoma. 2008;49:690-695. Pubmed

5. Jabbour E, Garcia-Manero G, Batty N, et al. Outcomes of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010;116:3830-3834. Pubmed

6. Prbet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;24:3322-3327. Pubmed