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Azacitidine
Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.
The results showed no additional benefit with the combination, when compared to azacitidine alone.
However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.
“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.
“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”
Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.
Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.
To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.
The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.
Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).
In both arms, azacitidine was given at 75 mg/m2 on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.
Results
The combination did not significantly improve response rates or survival times.
The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).
The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).
The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).
Impact of mutations
In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).
In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.
The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.
The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.
And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.
The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.
The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.
