Can low-risk MDS benefit from oral azacitidine?

Professor Guillermo Garcia-Manero and others recently reported the results of a randomized, placebo-controlled, phase III clinical study that evaluated placebo vs CC-486 (oral azacitidine) in patients with red blood cell transfusion dependence ( RBC-TD) anemia and thrombocytopenia, and the efficacy and safety of low-risk myelodysplastic syndrome (LR-MDS) patients determined by the International Prognostic Scoring System (IPSS).

Research background and purpose MDS is a type of malignant clonal disease of hematopoietic stem cells.
Its main characteristics are ineffective hematopoiesis, refractory cytopenia, and high risk of transforming to acute myeloid leukemia (AML).

MDS is divided into four risk groups based on IPSS.
Low-risk and medium-risk-1 risk groups are considered LR-MDS, while medium-risk-2 and high-risk groups are considered high-risk MDS.

The treatment options for patients with LR-MDS are limited.
At present, different treatment measures are mainly taken for anemia (5q-/without 5q-) and thrombocytopenia; whether it can benefit from oral azacitidine is currently unclear.

CC-486 is an oral azacitidine tablet that has been approved by the US FDA for the continuous treatment of adult AML patients who are not suitable for transplantation after the first remission of induction chemotherapy.

The study is a randomized, placebo-controlled phase III clinical trial comparing CC-486 and placebo in patients with LR-MDS with RBC-TD anemia and thrombocytopenia as defined by IPSS.

Research Methods The study recruited 216 patients from 101 centers in 20 countries/regions between April 2013 and February 2018.

Patients were randomly assigned (1:1) to receive CC-486 300 mg (N=107) or placebo (N=109) treatment, and each cycle was 28 days for a total of 21 days to receive treatment.

The primary endpoint of the study was the incidence of red blood cell transfusion independence (RBC-TI) in patients for ≥56 consecutive days.

The primary endpoint was assessed after all patients completed 12 months of treatment or stopped study medication.

From the first dose to 28 days after the last dose, all patients were evaluated for treatment emergency adverse events (TEAE).

The results of the study showed that the baseline characteristics of patients in the CC-486 group and the placebo group were evenly distributed.
Among them, patients with a bone marrow blast ratio >5% were higher in the placebo group.
The median age of the patients was 74 years.
Most patients ( 70.
8%) refractory cytopenia with multi-lineage dysplasia.

The most common genetic mutations are ASXL1 (33.
2%) and TET2 (21.
5%).

Compared with the placebo group, the CC-486 group had a significantly higher incidence of RBC-TI for ≥56 days (30.
8% vs 11.
1%, P=0.
0002).

The median time to reach RBC-TI for patients in the CC-486 group and placebo group were 2.
4 months and 2 months, respectively, and the estimated median duration of RBC-TI was 11.
1 months and 5.
0 months, respectively (P=0.
42 ).

Multivariate analysis showed that the use of CC-486 treatment was an independent factor in improving patients' RBC-TI (P=0.
0002).

42.
1% and 30.
6% of patients in the CC-486 group and placebo group reduced the infusion of ≥4 RBC units, and the median duration of reduced RBC infusion was 10.
0 months and 2.
3 months, respectively.

Further analysis showed that compared with patients in the placebo group, the proportion of patients with hemoglobin increased by ≥1.
5g/dL from baseline was higher in the CC-486 group (23.
4% vs.
4.
6%).

Similarly, compared with patients in the placebo group, the rate of platelet improvement in the CC-486 group was higher (24.
3% vs 6.
5%).

The results of the mid-term survival analysis at a median follow-up of 13.
3 months showed that the estimated median overall survival (OS) of patients in the CC-486 group and placebo group were 17.
3 months and 16.
2 months, respectively (P=0.
96). The overall mortality rate between the two groups was similar, but the proportion of deaths in the first 56 days was higher in patients in the CC-486 group, mainly due to infection.

The most common adverse event (AE) in all patients was a low-grade gastrointestinal AE.

Among them, 90% and 73% of patients in the CC-486 group and the placebo group had grade 3-4 TEAEs.

Among them, the incidence of grade 3-4 neutropenia, thrombocytopenia, febrile neutropenia and infection was higher in the CC-486 group.

In addition, 32 patients (29.
9%) in the CC-486 group and 31 patients (28.
4%) in the placebo group permanently discontinued the study drug due to TEAE.

The most common TEAEs for discontinuation of CC-486 were nausea (3.
7%), febrile neutropenia (2.
8%), and sepsis (2.
8%).

Research conclusions The research shows that CC-486 significantly improves the continuous RBC-TI rate of LR-MDS patients ≥56 days, and enables patients to obtain lasting erythroid and platelet improvement.

However, the proportion of early deaths in the CC-486 group was higher, most of which were related to infection.

The results of the study suggest that more research results are needed to answer whether CC-486 can benefit patients with LR-MDS.

References: Guillermo Garcia-Manero, Valeria Santini, Antonio Almeida, et al.
Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.
J Clin Oncol.
2021 Mar 25 ;JCO2002619.
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