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.*

ANC, absolute neutrophil count; ECOG-PS, Eastern Cooperative Oncology Group performance status; IPSS, International Prognostic Scoring System; IPSS-R, Revised IPSS; MDS, myelodysplastic syndromes; MDS-U, MDS-unclassified; RA, refractory anemia; RAEB, RA with excess blasts; RARS, RA with ringed sideroblasts; RBC, red blood cell; RCMD, refractory cytopenia with multilineage dysplasia; RT, refractory thrombocytopenia. *Adapted from Garcia-Manero et al.1 †Patients were considered platelet transfusion-dependent at baseline if they had received ≥2 platelet transfusions within the 56 days before random assignment and had no consecutive 28-day period during which no platelet transfusions were administered. ‡The average of RBC transfusion units per 28 days was derived using transfusion records for the 84 days or 56 days before random assignment.
Characteristic	CC-486 (n = 107)	Placebo (n = 109)
Median age, years, (range)               Age ≥ 65 years, %	74.0 (30−89) 85.0	73.0 (44−88) 87.2
Sex, %               Male	73.8	72.5
WHO 2008 MDS classification, % RCMD RAEB-1 RA RARS MDS-U RT	74.8 15.9 3.7 2.8 1.9 0.9	67.0 26.6 2.8 1.8 1.8 0.0
IPSS-R risk, % Very low (≤ 1.5) Low (> 1.5−3) Intermediate (> 3−4.5) High (> 4.5−6) Very high (> 6) Missing	0.0 22.4 47.7 25.2 0.9 3.7	0.0 19.3 44.0 30.3 0.0 6.4
ECOG-PS score, % 0−1 2	85.0 15.0	86.2 13.8
IPSS cytogenic risk, % Good Intermediate Missing	81.3 15.9 2.8	82.6 12.8 4.6
Gene mutations, % ASXL1 TET2 RUNX1 U2AF1 SRSF2 DNMT3A	28.4 20.6 9.8 17.6 13.7 9.8	38.2 22.5 22.5 14.7 15.7 14.7
Platelet transfusion-dependent†, %	28.0	32.1
Months since MDS diagnosis, median (range)	18.9 (0.9−153)	16.1 (0.4−381)
RBC transfusion requirement per 28 day‡, units, median (range) > 4 units, %	3.3 (1.3−10.0) 33.6	3.3 (1.3−9.5) 31.2
Hemoglobin, g/dL, median (range)	8.3 (5.4−10.9)	8.1 (5.7−10.1)
Platelets, 109/L, median, (range) Platelet count < 20 × 109/L, %	24 (566) 41.1	25 (573) 44.0
ANC, 109/L, median (range)	1.36 (0.07−25.2)	1.28 (0.06−20.5)
Absolute lymphocyte count, % < 0.5 × 109/L ≥ 0.5 × 109/L	18.7 81.3	10.1 89.0
Bone marrow blasts, median (range) < 5% blasts, % ≥ 5% blasts, %	3.0 (0.0−9.0) 83.2 15.9	3.5 (0.0−9.0) 71.6 28.4

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.*

CI, confidence interval; HI-E, hematologic improvement in erythroid; HI-P, hematologic improvement in platelet; RBC, red blood cell; RBC-TI, red blood cell transfusion independence. *Data from Garcia-Manero et al.1
Efficacy	CC-486 (n = 107)	Placebo (n = 109)	Odds ratio	95% CI; p value
RBC-TI ≥ 56 consecutive days, %	30.8	11.1	3.6	1.7–7.4; 0.0002
RBC-TI ≥ 84 consecutive days, %	28.0	5.6	6.6	2.6–16.7; < 0.0001
HI-E response, %	43.0	31.5	1.6	0.9–2.9; 0.12
HI-P response, %	24.3	6.5	4.6	1.9–11.2; 0.0003
≥1.5 g/dL increase in hemoglobin from baseline, %	23.4	4.6	6.3	2.3–17.1; < 0.0001
RBC transfusion reductions of ≥ 4 units/56 days, %	42.1	30.6	1.7	0.9–2.9; 0.12

 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.*

TEAEs, treatment-emergent adverse events. *Data from Garcia-Manero et al.1
TEAE	CC-486 (n = 107), %	Placebo (n = 109), %
≥ 1 Grade 3−4 TEAEs	89.7	73.4
Neutropenia	46.7	11.9
Thrombocytopenia	29.0	15.6
Febrile neutropenia	28.0	10.1
Anemia	18.7	16.5
Pneumonia	12.1	9.2

 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.