Because patients with higher-risk myelodysplastic syndromes (MDS), higher-risk chronic myelomonocytic leukemia (CMML) or low-blast acute myeloid leukemia (AML) tend to be older and have comorbidities, they are often not eligible for high-intensity chemotherapy or allogeneic stem cell transplantation.
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The drug typically used to treat these patients is azacitidine, a hypomethylating agent that reduces abnormal blood cell production and growth. But azacitidine monotherapy has a low success rate, with a 35% chance of improved blood counts or remission, and a median overall survival of 12 to 18 months.
Now, promising results from a study of a novel combination therapy could offer new hope to these patients.
The international, multicenter phase II clinical trial compared the standard azacitidine treatment with a combination of azacitidine and pevonedistat, a selective inhibitor of the NEDD8-activating enzyme.
“The thought is that, if you attack MDS or leukemia cells from different directions with drugs that have different mechanisms of action, you have a better chance of eradicating them,” says medical oncologist Mikkael Sekeres, MD, MS, the study’s North American lead investigator. Dr. Sekeres is Cleveland Clinic Cancer Center’s Vice Chair for Clinical Research and Director of the Leukemia Program.
Results were presented at the 2020 annual meeting of the American Society of Clinical Oncology, which was held virtually due to the COVID-19 pandemic.
Comparable safety profiles
Some 120 patients with higher-risk MDS, higher-risk CMML and low-blast AML were randomized to receive either azacitidine alone or azacitidine plus pevonedistat. Previous attempts to combine azacitidine with other drugs resulted in an increase in adverse events, explains Dr. Sekeres, and researchers thought that might be the case with this combination as well.
“What we actually found was that the adverse events were pretty similar between patients who got the azacitidine alone or the azacitidine combined with the pevonedistat,” he says.
Of the two groups, 45% of patients on the combination therapy experienced a drug-related adverse event of grade 3 or higher, compared to 47% of the group that received azacitidine alone. And 52% of the combination therapy group experienced an adverse event requiring dose modification, compared to 56% of the group that received only azacitidine.
The most common adverse events of grade 3 or higher were neutropenia, febrile neutropenia, decreased neutrophil count, anemia, thrombocytopenia and pneumonia.
“The combination was well tolerated. That phrase is used often, but I think you can say it with a clear conscience here because there weren’t any increased adverse events in patients who got the combination,” Dr. Sekeres says.
The study also found that event-free survival was longer in patients who received the combination therapy. An event was defined as progression to AML or death in patients with higher-risk MDS or CMML, or death in low-blast AML. Patients who received pevonedistat and azacitidine had a median event-free survival of 21 months compared with 16.6 months for azacitidine alone.
While the study did not initially use overall survival as a primary endpoint, there were encouraging trends in that area as well, with 21.8 months overall survival for patients with combination therapy vs. 19 months for azacitidine alone.
“All the signals of activity go in the same direction, which is always encouraging with a drug,” Dr. Sekeres says.
Efficacy results were strongest in the higher-risk MDS group, with a significant improvement in event-free survival among the cohort receiving the combination therapy compared with azacitidine alone (20.2 months vs. 14.8 months), and in overall survival (23.9 months vs. 19.1 months).
Patients with low-blast AML at the start of the study had an overall survival advantage of 23.6 months with the combination therapy compared to 16 months with azacitidine alone.
“The combination led to an improvement in event-free survival for the entire population, Dr. Sekeres says. “That was particularly meaningful and significant in those who had higher-risk myelodysplastic syndrome, and there was a trend toward an improvement in overall survival for those who had frank leukemia at the beginning of this study.”
The study found that combination therapy did not provide an efficacy advantage for patients with higher-risk CMML, which Dr. Sekeres notes is a rare diagnosis.
“We think that it tends to work on conditions that are more prolific — where you have more cells actively growing — and that seems to be more common with the patients who had MDS and low-blast-count leukemia,” he says.
Conclusions and next steps
In summary, the researchers observed encouraging clinical efficacy with the combination therapy in patients with higher-risk MDS and low-blast AML.
In higher-risk MDS, it led to longer event-free survival, longer response duration and a doubled complete response rate compared with azacitidine alone. In low-blast AML, the combination therapy was associated with a longer overall survival trend than in azacitidine alone.
Pevonedistat plus azacitidine had a comparable safety profile to azacitidine alone, did not increase myelosuppression, and the azacitidine dose intensity was maintained.
A randomized phase III study of the combination therapy in the same patient groups is now underway to further evaluate its efficacy.
Dr. Sekeres says the results are encouraging, not only because the combination therapy did not appear to lead to an increase in adverse events, but also because it was associated with better survival rates.
“What we’re hoping is that combination therapy will become a new standard in the MDS patients, and in the patients who have leukemia,” he says.