There have been few therapeutic options for treating thrombocytopenia in MDS patients. Now, early phase data suggest that CC-486 (oral azacytidine, an investigational drug sponsored by Celgene) is a relatively safe and effective treatment for thrombocytopenic patients with MDS.
Thrombocytopenia is among the strongest predictors of decreased survival for patients with myelodysplastic syndromes (MDS), whatever their prognostic risk group, because it heightens the risk of transformation to acute myeloid leukemia.1 Approximately 40% of all patients with MDS, and up to 80% of patients with higher-risk MDS, experience thrombocytopenia (platelet count <100 x 109/L).
There have been few therapeutic options for treating thrombocytopenia in MDS patients. Now, early phase data suggest that CC-486 (oral azacytidine, an investigational drug sponsored by Celgene) is a relatively safe and effective treatment for thrombocytopenic patients with MDS, according to research published in Leukemia Research.2 Guillermo Garcia-Manero, MD, and colleagues compared clinical outcomes of treatment with CC-486 in patients with MDS with pretreatment thrombocytopenia (≤75 x 109/L platelets) with patients with MDS who have platelet counts >75 x 109/L. Their exploratory post-hoc analyses include patients who received CC-486 in an open-label phase 1 study (MDS-004; ClinicalTrials.gov NCT00528983) or an open-label phase 1/2 study (CL005; NCT01519011).
Patients received CC-486 at a 300 mg once daily for 14 or 21 days of repeated 28-day cycles. There were a total of 81 patients with MDS (median age, 72) in the Low Platelets (n = 45) and High Platelets (n = 36) cohorts. Pretreatment median platelet counts were 34 × 109/L and 198 × 109/L, respectively. Grade 3-4 bleeding events occurred in 2 patients in the Low Platelets cohort and 1 patient in the High Platelets cohort. The rate of grade 3-4 neutropenia reported for all patients in the analysis was 24% lower than rates typically reported for parenteral azacytidine or decitabine. Events resolved without sequelae.
Treatment-related mortality was reported for 7 patients, 5 of whom had pretreatment platelet values <25 × 109/L. Overall response rates were 38% and 46% in the Low Platelets and High Platelets groups, respectively. Five thrombocytopenic patients attained complete remission (CR) and 9 attained platelet hematologic improvement. In both cohorts, platelet counts dropped during the first CC-486 treatment cycle, and then increased thereafter.
Extended CC-486 dosing was generally well tolerated and induced hematologic responses in these patients regardless of pretreatment thrombocytopenia. Patients in the High Platelets group had a higher rate of response than patients in the Low Platelets group, which the investigators said may reflect a greater likelihood of additional adverse disease features when thrombocytopenia is present.
“Nevertheless, all  patients in this analysis who attained CR were in the Low Platelet cohort,  patients in this group achieved hematologic improvement in the platelet lineage, and  patient who was platelet transfusion-dependent at baseline achieved transfusion independence during CC-486 treatment,” the researchers wrote. “These early ‘proof-of-concept’ data suggest CC-486 is relatively safe and effective in thrombocytopenic patients with MDS.”
Three patients in the Low Platelets group continued to receive CC-486 treatment for ≥2 years, which the researchers said attests to its tolerability. “Oral dosing and a reduced need for clinic visits may have facilitated long-term use,” they noted.
These findings require confirmation in larger patient populations, and the investigators expect greater clarity after results are analyzed from the ongoing placebo-controlled phase 3 study evaluating CC-486 in patients with lower-risk MDS with red blood cell transfusion dependence and platelet counts ≤75 × 109/L.
The studies were funded by Celgene Corporation. Several investigators disclosed they are employees of Celgene and have equity ownership in the company; one consults for Celgene; and another has received support from the Leukemia & Lymphoma Society.