preheader BJH 1

CC-486 significantly lowers red blood cell transfusion dependence in patients with lower-risk myelodysplastic syndromes

Patients with lower-risk myelodysplastic syndromes (MDS) with unfavourable disease features, such as red blood cell transfusion dependent anaemia and thrombocytopenia, have limited treatment options. As such, for these patients there is an unmet need for disease-modifying treatments. The results of the phase III QUAZAR LR-MDS trial, evaluating the oral hypomethylating agent CC-486 in this setting, address this need by demonstrating an improved red blood cell transfusion independence, with durable haemoglobin and platelet improvements. Adverse events were more frequent with CC-486 than with placebo, but they could be managed with appropriate patient monitoring, supportive care measures and/or dose modifications or interruptions.


MDS is characterised by bone marrow dysplasia and peripheral cytopenias of variable severity. Treatment options are limited for lower-risk MDS (LR-MDS) patients with low blast counts but high-risk disease features. CC-486 is an oral hypomethylating agent with a pharmacokinetic and pharmacodynamic profile that differs from that of injectable azacitidine. Its extended oral dosing (for 14 or 21 days / cycle) can prolong the therapeutic activity across an entire 28-day treatment cycle. In early open-label studies, CC-486 demonstrated clinical activity in MDS, acute myeloid leukaemia and chronic myelomonocytic leukaemia.

The phase III placebo-controlled QUAZAR LR-MDS trial assessed CC-486 in lower-risk MDS patients with red blood cell transfusion dependency (RBC-TD) and thrombocytopenia at study entry. Eligible patients had to be 18 years or older, have International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS and they had to have an average RBC transfusion requirement of at least 2 units/28 days for 56 days, and 2 platelet counts ≤ 75 × 109/L taken ≥21 days apart. Patients were randomised (1:1) to CC-486 (300 mg, once daily) plus best supportive care (BSC) or placebo plus BSC for 21 days in 28-day treatment cycles. Baseline patient and disease characteristics were similar between treatment arms. The median age of the patients in the study was 74 years with a median haemoglobin level of 8.1 g/dL, a median platelet count of 25×109/L, a median absolute neutrophil count of 1.3×109/L, and a median RBC transfusion requirement of 6.7 units/ 56 days.


Compared to placebo, significantly more patients in the CC-486 arm achieved RBC-TI for ≥56 days (30.8%, vs. 11.1% with placebo; odds ratio [95%CI]: 3.6 [1.7-7.4], p=0.0002). The median number of treatment cycles was five for patients in the CC-486 arm and six for patients in the placebo arm. The RBC TI was maintained for at least 84 days for 28% of the patients in the CC-486 arm, as compared to only 5.6% of the patients in the placebo arm (odds ratio [95%CI]: 6.6 [2.6-16.7], p<0.0001). The median RBC-TI duration was prolonged from 5.0 months in the placebo arm to 11.1 months in patients treated with CC-486, although this difference was not statistically significant (p=0.42). While the erythroid haematologic improvement rates were comparable between both arms (p=0.12), significantly more CC-486 patients had a ≥1.5 g/dL haemoglobin increase from baseline (23.4% vs. 4.6%, p<0.0001). In the CC-486 and placebo arms, 42.1% and 30.6%, respectively, had RBC transfusion reductions of ≥4 units from baseline, sustained for a median of 10.0 and 2.3 months (p=0.12). The platelet haematologic improvement rate was significantly higher in the CC-486 arm as compared to the placebo arm (p=0.0003). Platelet-TI (≥56 days) rates were similar between arms (16.7% vs. 14.3%), but median platelet-TI duration was longer with CC-486 (12.1 vs. 4.4 months with placebo). In the CC-486 arm, mean haemoglobin increased by ~2 g/dL from baseline by cycle six, and platelet count increased by 38×109/L by cycle three. Both improvements were sustained during treatment while haemoglobin and platelet count changes were negligible with placebo.

The study sample size was underpowered for interim OS analysis, which showed no difference between CC-486 and placebo (median OS of 17.3 vs. 16.2 months, HR [95%CI]: 0.99 [0.70-1.40], p=0.9607). The overall death rate was similar between the two treatment arms but there was an imbalance in early deaths from day 1 to 56 (n=16 in the CC-486-arm and n=6 in the placebo arm). This difference was mostly related to infections. Of note, these early deaths in the CC-486 arm had a median baseline absolute neutrophil count of 0.57×109/L and a platelet count of 15.5×109/L. Eight patients in the CC-486 arm and 18 patients in the placebo arm progressed to AML. The most common adverse events (AEs) in both treatment arms were grade 1-2 gastrointestinal events. In the CC-486 and placebo arms, respectively, 90% and 73% of patients had a grade 3-4 AE, of which neutropenia, thrombocytopenia and febrile neutropenia were the most common. In total, 30% of patients in the CC-486 arm and 28% of patients in the placebo arm discontinued treatment due to any AE. Treatment-related AEs were more common with CC-486 and occurred mostly during early treatment cycles.


Intermediate-1 or low risk-MDS patients often suffer from RBC-TD and thrombocytopenia, and currently have limited disease-modifying treatment options to their disposal. The presented trial, evaluating CC-486 in this setting, met its primary endpoint of RBC transfusion independence and induced durable bilineage haemoglobin and platelets improvements. Adverse events were more frequent with CC-486. Patients with severe neutropenia pre-treatment are at higher risk for hematologic toxicity during early CC-486 treatment and could potentially benefit from a modified dosing regimen.


Garcia-Manero G, Santini V, Almeida A, et al. A phase III placebo-controlled trial of CC-486 in patients with red blood cell transfusion-dependent (RBC-TD) anemia and thrombocytopenia due to IPSS lower-risk myelodysplastic syndromes (LR-MDS). Presented at EHA 2020; Abstract S180.

Speaker G. Garcia-Manero


G. Garcia-Manero, MD, University of Texas MD Anderson Cancer Center, Houston, United States


See: Keyslides


Back to Top