Phase II Study of 5-Azacitidine and Vorinostat In Patients (pts) with Newly Diagnosed Myelodysplastic Syndrome (MDS) or Acute Myelogenous Leukemia (AML) Not Eligible for Clinical Trials Because Poor Performance or Presence of Other comorbidities

Standard eligibility criteria for most clinical trials in MDS and AML include acceptable performance status, renal and hepatic functions and lack of other comorbidities including other concomitant malignancies or HIV infection. Our experience is that without therapy survival in this group of pts is very poor (less than 60 days). To be able to treat this pt population in a systematic fashion, we developed a phase II trial using 5-azacitidine and vorinostat. The combination of these two agents is known to be safe and to have significant activity in MDS and AML.

Eligible pts included those with previously untreated MDS (INT-1 or above) or AML and any of these: creatinine or bilirubin greater than 2 mg/dL, ECOG performance status (PS) more than 2 or not eligible for any other protocol. Pts with HIV disease or concomitant malignancies were also eligible. Pts with CBF abnormalities were excluded. Therapy was 5-azacitidine 75 mg/m² IV daily × 5 every 3 to 6 weeks and vorinostat 200 mg orally three times a day on days 1 to 5 with 5-azacitidine. The clinical trial was designed to stop if expectations for survival at 60 days and/or achievement of complete remission (CR) rates were not achieved based on priors derived from historical experience at MD Anderson. The study is to stop if the # pts alive at > 60 days is < 0/3, 2/6, 3/9, 5/12, 6/15, 8/18, 10/21,11/24, or 13/27 evaluable or if the number of pts with no CR is > 6/6, 11/12, 16/18,21/24, 26/30. A maximum of 30 pts can be treated if none of the stopping rules are met. Operating characteristics targeted a 20% improvement in response and survival. As pharmacodynamic endpoints, global and gene specific hypomethylation, induction of histone acetylation, autophagy and ROS signaling are being evaluated.

At the present time, 18 pts have been treated. The characteristics are as follows: median age 71 years (range 56–83), median WBC 3 K/uL (range 0.6–123), median % bone marrow blasts 9% (range 1–62), complex cytogenetics in 13 pts (72%), Flt-3 or Ras mutated 3 (16%), median creatinine 1 mg/dL (range 0.6 to 2.1), median bilirubin 0.6 mg/dL (range 0 to 4.2). Using WHO criteria, 12 pts (66%) had MDS and the rest AML. Eligibility criteria included: presence of another malignancy 9 pts (50%), (metastatic (met) sarcoma, met breast ca (2 pts), met ovarian ca, refractory active CLL and NHL, prostate ca and Waldenstrom's), liver cirrhosis 1 pt (5.5%), liver failure 1 pt (5.5%), cardiac dysfunction 2 pt (11%), severe COPD 1 pt (5.5%) and poor PS (ECOG 4) in 4 pt (20%). An additional 2 pts (11%) had PS 4 in the setting of other comorbidities. Treatment has been well tolerated with only 1 pt (5%) developing severe (nausea, vomiting) non-heme related toxicity. Only 1 (5%) pt died during induction therapy. The first pt was enrolled on 9/09 and the last 7/10. The median number of cycles administered is 2+ (1+ to 9+). Currently, 11 pts are evaluable for survival at 60 days and 8 (72%) have survived longer than that (median survival of the 18 pts 6.5+ weeks: range 1+ to 40+). Three of 9 (33%) pts currently off study died due to progression of primary malignancy.

17 of 18 pts are evaluable for response: 3 (17%) achieved CR and 4 (23%) complete marrow CRs (blasts less than 5%) for an overall response of 7 pts (41%). Of interest, stable disease in a pt with metastic sarcoma and 1 with breast cancer has been observed. PD analysis are ongoing.

The study is ongoing but current evaluation of pts not yet evaluable for survival (less than 60 days since initiation of therapy) indicate that is likely the study will pass both survival and response stopping rules. The combination of 5-azacitidine and vorinostat is safe and active in this poor prognosis population resulting in levels of activity and safety similar to those observed in populations eligible for clinical trials. These results support treatment of these pt population and questions current eligibility for phase I/II trials.

No relevant conflicts of interest to declare.