Efficacy of azacitidine combined with pevonedistat in high-risk MDS/CMML and low-blast AML patients

The PANTHER trial is a randomized phase 3 clinical trial
worldwide.
Study inclusion criteria: age 18 years and older; Morphologically confirmed high-risk MDS, nonproliferative CMML (white blood cell count < 13,000/uL), or bone marrow blasts account for 20% to 30% of AML<b11>.
Study exclusion criteria: eligible for intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation; Previous treatment
with chemotherapy or other antineoplastic drugs including decitabine and azacitidine.

Included patients were randomized 1:1 to be assigned to pevonedistat plus azacitidine (combination) and single-agent azacitidine (monotherapy).

The combined group received 20 mg/m2 of pevonedistat intravenously on days 1, 3 and 5 and intravenously or subcutaneously with azacitidine 75 mg/^m2
on days 1-5, 8 and 9.
The monotherapy group received only azacitidine
in a 28-day treatment cycle.
The primary endpoint was EFS
.
The key secondary endpoint was overall survival (OS).

Other secondary endpoints included time to AML in patients with high-risk MDS/CMML; remission rate and duration of remission; Proportion and duration of patients independent of red blood cell and platelet transfusion; Security
.

Baseline characteristics of the patient

A total of 454 patients and 324 patients with high-risk MDS were included in the study (161 patients in the combined group; 163 patients in the monotherapy group), 103 patients with AML with 20%-30% blast cells (50 patients in the combined group; 53 patients in the monotherapy group) and 27 patients with high-risk CMML (16 in the combined group; 11 cases in the single-drug group).

Demographic and disease baseline characteristics were balanced
between groups.
Among patients with high-risk MDS, the median age in the combined group was 73 years and the monotherapy group was 74 years, with 58% and 63%
of men, respectively.
Among patients with high-risk MDS with mutation information (n=270), the distribution of adverse prognostic factors and high-frequency mutant genes was also balanced between the combination group (n=135) and the monotherapy group (n=135), with the most common mutated genes being ASXL1 (41% vs.
39%), RUNX1 (26% vs.
33%), SRFS2 (27% vs.
21%), STAG2 (19% vs.
21%), TET2 (30% vs26%), and TP53 (29% vs26%）
。 In patients with AML with blasts accounting for 20% to 30%, the incidence of secondary disease (36% vs.
51%), high risk of ELN risk stratification (60% vs.
70%), and ECOG PS score of 2 (14% vs.
25%) were lower
in the combination group compared with the monotherapy group.
The specific baseline characteristics are shown in Table 1
.

Table 1 Baseline characteristics of 454 patients included

Effectiveness analysis and safety analysis

In the intention-to-treat (ITT) population, median follow-up was 26.
2 months in the combined group and 25.
7 months in the monotherapy group, and median EFS in the combination group was 17.
7 months and 15.
7 months in the monotherapy group (HR, 0.
968; 95% CI, 0.
757-1.
238; P = 0.
557); In the combination and monotherapy groups, 97 and 94 patients died, and 38 and 32 patients underwent AML transformation, respectively; median OS was 20.
3 months in the combined group and 16.
8 months in the monotherapy group (HR, 0.
881; 95% CI, 0.
697-1.
115; P = 0.
181).

In the cohort of patients with high-risk MDS, median EFS was 19.
2 months in the combination group and 15.
6 months in the monotherapy group (HR, 0.
887; 95% CI, 0.
659-1.
193; P = 0.
431); In the combination and monotherapy groups, 55 and 57 patients died, and 37 and 31 patients underwent AML transformation
, respectively.
Compared with the ITT population, median OS was longer in the combination group at 21.
6 months and 17.
5 months in the monotherapy group (HR, 0.
785; 95% CI, 0.
593-1.
039; P = 0.
092)
in patients with high-risk MDS.
The KM curves of EFS and OS in patients with high-risk MDS are shown in Figure 1
.
In patients with AML with 20% to 30% of bone marrow blasts, median OS was 14.
5 and 14.
7 months, respectively, in the combination and monotherapy groups, with no significant difference (HR, 1.
107; 95% CI, 0.
694 to 1.
765; P = 0.
664).

There was also no significant difference
in EFS and OS between the combination and monotherapy groups in the cohort of high-risk CMML patients.
When the number of treatment cycles was included in the analysis, the median OS in the combination and monotherapy groups was 23.
8 months and 20.
6 months, respectively, in the cohort of high-risk MDS patients with > three treatment cycles (HR, 0.
714; 95% CI, 0.
515-0.
990; P = 0.
021); In the cohort of high-risk MDS patients with > 6 treatment cycles, median OS was 27.
1 and 22.
5 months in the combination and monotherapy groups, respectively (HR, 0.
626; 95% CI, 0.
427-0.
917; P=0.
008).

For the safety analysis results, no new safety events were found in the study, and the dose of azacitidine was maintained at a certain level
.
In the overall patient cohort, the most common grade 3 and above adverse events in combination and monotherapy groups were anaemia (33% and 34%), neutropenia (31% and 33%), and thrombocytopenia (30% and 30%)
.

Fig.
1 KM curves of EFS and OS in patients with high-risk MDS