Azacitidine for Treatment of Therapy Related Myelodysplastic Syndrome

Therapy related MDS (t-MDS) is a rising challenge, it accounts for about 10%-15% of MDS cases. Outcome of t-MDS is generally poor. Azacitidine is currently standard of care for higher risk MDS based on AZA-001 randomized clinical trial demonstrating survival advantage. Efficacy of azacitidine in t-MDS is not well studied. We investigated the outcome of t-MDS patients treated with azacitidine at the Moffitt Cancer Center (MCC).

This was a retrospective review of t-MDS cases treated at Moffitt Cancer Center (MCC) with azacitidine. Patients were identified through MCC MDS database and individual charts were reviewed. The primary objective was overall survival (OS) from time of azacitidine starting date. Patients were included if at least received one cycle of azacitidine. Disease status was defined by both the French American British (FAB) and the World Health Organization (WHO) classification systems, and risk was scored by the International Prognostic Scoring System (IPSS), and MD Anderson Scoring System (MDAS). Response to azacitidine was defined per the International Working Group (IWG 2006) criteria. All analyses were conducted using SPSS version 15.0. (SPSS Inc, Chicago, IL). Descriptive statistics were used for baseline characteristics and responses. Kaplan-Meier estimates were used to calculate overall survival (OS).

Between July 2004 and April 2010, 76 patients with t-MDS/AML were treated with azacitidine. The median duration of follow up was 58 months. The median age was 64.5 years (36–84). Majority of patients were Caucasians race 87% (n=66) and 55% (n=42) were male gender. The underlying malignancy was hematological malignancy in 38 patients (50%), solid tumor in 34 patients (45%), and 4 patients (5%) had both. Prior treatment for primary malignancy included chemotherapy in 44 patients (58%), chemoradiation in 23 patients (30%), and 9 patients (12%) received radiation therapy only. Fourteen patients received prior autologous SCT.

According to WHO classification 2.6% (2) were Refractory anemia (RA), 3.9% (3) Refractory anemia with ring sideroblasts (RARS), 30.3% (23) refractory anemia with multilineage cytopenia (RCMD), 28.9% (22) refractory anemia with excess blasts I (RAEB-I), 25% (19) refractory anemia with excess blasts II (RAEB-II), 1.3% (1) CMML, 6.6% (5) AML, and 1.3 % (1) unknown. The IPSS risk was low in 1.3% (1), intermediate-1 (int-1) 19.7% (15), int-2 57.9% (44), high risk 17.1% (13) and unknown 3.9% (3). Based on MDAS the risk groups were 1.3% (1) low, 7.9% (6) int-1, 26.3% (20) int-2, 63.2% (48) high risk, and 1.3% (1) unknown. The cytogenetic risk groups were in 13.2% (10) good, 10.5% (8) intermediate, 72.4% (55) poor, and 1.3% (1) unknown.

The median number of azacitidine cycles was 4 (Range 1–18). The response rates (IWG 2006 criteria) were 11.8% (9) CR, 2.6% (2) marrow CR, 10.5% (8) PR, 18.4% (14) HI, 14.5% (11) Stable disease (SD), 21.1 % (16) progressive disease (PD), and 17.1% (13) unknown. The overall response rate (CR+mCR+PR+HI) was 43.4 % (33). Among all patients 34.2% (26) had HI-E, 23.7% (18) had HI-N, and 32.9% (25) HI-P.

The median OS was 14.9 months (95%CI 12.2–17.7) from start of azacitidine treatment. Twenty patients underwent allogeneic stem cell transplant (allo SCT). The median OS survival for patients who underwent allo SCT was 22.2 months compared to 13.6 months for those who did not. (p-value 0.015, log rank test). The median OS for patients who achieved SD or better best response with azacitidine therapy was 17.2 months compared to 8.3 months for patients with PD (p-value 0.014).

Azacitidine is active in t-MDS; response rates are comparable to de novo MDS patients. Overall survival for t-MDS treated with azacitidine is slightly inferior to de novo MDS treated on AZA-001 study in general but similar to those with poor karyotype on the same study.

Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. List:Celgene: Consultancy.