In two phase II trials, the protein synthesis inhibitor omacetaxine offered long-term efficacy in some patients with chronic-phase and accelerated-phase CML.
The protein synthesis inhibitor omacetaxine (Synribo) can offer long-term efficacy in some patients with chronic-phase and accelerated-phase chronic myeloid leukemia (CML), according to final results of two pooled phase II studies. The drug is indicated for patients who have developed resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs).
“Omacetaxine induces apoptosis by reducing levels of multiple short-lived oncoproteins, including BCR-ABL1, Mcl-1, cMyc, and cyclin D1,” wrote researchers led by Jorge Cortes, MD, of the University of Texas MD Anderson Cancer Center in Houston. “Because direct BCR-ABL1 binding is not required for omacetaxine activity, it is unaffected by mutations in the BCR-ABL1 gene that confer resistance to TKIs.”
The drug was approved by the US Food and Drug Administration in October 2012 based on pooled results from the CML-202 and CML-203 trials. The new paper provides a final analysis of that pooled study, with 24 months of follow-up. Results were published online ahead of print in Cancer.
The trial included 81 chronic-phase patients and 41 accelerated-phase patients, all of whom had resistance and/or intolerance to imatinib and at least one other TKI. That full cohort was included in the safety analysis, while 76 chronic-phase and 35 accelerated-phase patients were evaluable for efficacy.
Eighteen percent of the chronic-phase patients achieved a major cytogenetic response; the responses had a median duration of 12.5 months, and 3 of 14 responders maintained the response for at least 1 year. The median overall survival in chronic-phase patients was 40.3 months.
Among the accelerated-phase patients, 14% achieved or maintained a major hematologic response, which lasted a median of 4.7 months. There were no major cytogenetic responses, and overall survival was 14.3 months in these patients.
The median overall survival was better among patients in both groups who receive more than 3 cycles of omacetaxine treatment. In chronic-phase patients, median overall survival among those patients was 49.3 months; in accelerated-phase patients, it was 24.6 months.
Toxicity did pose a problem in some patients, with 10% of chronic-phase and 5% of accelerated-phase patients discontinuing the drug due to adverse events. Serious adverse events occurred in 57% of the chronic-phase patient cohort, and in 56% of the accelerated-phase cohort. Most commonly, these events were myelosuppression and related events such as pyrexia and infections. Two chronic-phase and four accelerated-phase patients died while on treatment with the study drug, but none of them were considered related to omacetaxine.
Though these toxicities could be serious, the researchers concluded that the efficacy of the drug remains clear, as in earlier analyses. “The results of extended follow-up analyses are consistent with earlier results and suggest that long-term administration of omacetaxine is feasible and safe with dose adjustments to manage toxicities,” they concluded.