Efficacy and safety of CC-486 (oral azacitidine) in patients with lower risk myelodysplastic syndromes

The most common feature of myelodysplastic syndromes (MDS) is anemia, with thrombocytopenia having a particularly poor prognostic implication for patients with low-risk MDS (LR-MDS), subsequently decreasing overall survival (OS). LR-MDS patients have conventionally been managed with transfusions, erythropoiesis stimulating agents, and hematopoietic growth factors. However, a subgroup of LR-MDS patients with red blood cell transfusion-dependency (RBC-TD) anemia, and thrombocytopenia require therapeutic agents that address both these deficiencies. There is anecdotal evidence that injectable hypomethylating agents (HMAs) may address anemia and thrombocytopenia in MDS patients.

In a randomized controlled trial, published in the Journal of Clinical Oncology, Garcia-Manero et al. evaluated CC-486 (oral azacitidine) in LR-MDS patients, and the key findings are summarized below.¹

Study design

Phase III, randomized, placebo-controlled multicenter trial (NCT01566695). The patients were aged ≥18 years with LR-MDS, had an Eastern Cooperative Oncology Group (ECOG) performance status score ≤2, and having RBC-TD anemia and thrombocytopenia.

Patients (n = 216) were randomly assigned either to 300 mg of CC-486 (n = 107) or placebo (n = 109), administered once daily for 21 days per 28-day treatment cycle.

• Primary endpoint was rate of RBC transfusion independence (TI) lasting ≥56 consecutive days at 12 months.
• Secondary endpoint included OS, time to and duration of RBC-TI, rate and duration of ≥84 days of RBC-TI and platelet TI, hematologic improvement in the erythroid (HI-E) and platelet (HI-P) lineages, morphologic response among patients with >5% blasts at baseline, and AML progression.

Results

Baseline characteristics

The median age was 74 years, median platelet count was 25 × 10⁹/L, and absolute platelet count was 1.3 × 10⁹/L. Baseline characteristics were well balanced between the two groups except that a higher proportion of patients in the placebo arm had >5% blasts (28.4% versus 15.9%) (Table 1).

Table 1. Baseline characteristics.*

Efficacy

• Patients in the CC-486 arm achieved significantly higher RBC-TI ≥ 56 consecutive days compared with placebo (30.8% vs 11.1%) (Table 2). Similarly, the CC-486 arm achieved a higher RBC-TI ≥84 days compared with the placebo arm (28% vs 5.6%).
• The median time to RBC-TI was 2.4 vs 2 months in CC-486 and placebo arm respectively. The median RBC-TI duration was much higher in the CC-486 arm (11.1 vs 5 months) compared with the placebo arm.
• RBC transfusion reductions were sustained longer for a median of 10 months in the CC-486 arm compared with 2.3 months in the placebo arm.
• HI-P response was higher in the CC-486 arm (24.3% vs 6.5%) compared with placebo.
• Platelet-TI was attained in 16.7% of patients in the CC-486 arm compared with 14.3% in the placebo arm. It was also sustained longer in the CC-486 arm for a median of 12.1 months (95% CI, 8.3−not estimable [NE]) compared with 4.4 months (95% CI, 2.3−NE) in the placebo arm.

Table 2. Efficacy.*

 Overall survival

• Overall, there were 140 deaths; 39 (CC-486, n = 25; placebo, n = 14) during treatment, and 101 (CC-486, n = 44; placebo, n = 57) during posttreatment follow-up.
• There was no difference in OS between CC-486 and placebo (median, 17.3 vs 16.2 months, hazards ratio, 0.99 (95% CI, 0.70–1.40; p = 0.96).
• Rate of AML progression was nearly half in the CC-486 arm (7.5% vs 16.7%; HR, 0.40; 95% CI, 0.16–0.97; p = 0.04) compared with placebo.

Safety

• The most common adverse events (AEs) in both arms were lower grade gastrointestinal (GI) events (100% in CC-486, and 99.1% in placebo).
• Grade 3−4 hematologic TEAEs and infections were more frequent in the CC-486 arm compared with placebo (Table 3).
• 29% of patients in the CC-486 arm required ≥ 1 dose reduction due to TEAEs. Patients who permanently discontinued the study due to TEAEs were similar across both groups (29.9% in the CC-486 group and 28.4% in the placebo group).
• Early deaths were imbalanced between groups, with 16 in the CC-486 and six in the placebo, occurring during the first 56 days.

Table 3. Grade 3−4 TEAEs.*

 Conclusions

The findings from this study demonstrate that CC-486 can provide clinically significant reductions in the RBC transfusion burden and improve thrombocytopenia in patients with LR-MDS. Although a higher rate of early deaths occurred in patients in the CC-486 arm, most of these were related to infections in patients with significant pretreatment neutropenia. Further studies are needed to evaluate CC-486 in different subgroups of patients with MDS.