February marks the anniversary of the U.S. FDA’s approval of Synribo (omacetaxine) for the treatment of chronic myelogenous leukemia, and longer-term results have just been published.
Unlike the other CML medications, Synribo is not a TKI (tyrosine kinase inhibitor). It’s a semi-synthetic extract from a species of pine tree (the Cowtail pine), which causes leukemic stem cells to self-destruct (Chen and colleagues. Leukemia 2009;23:1446-1454). The chief advantage of the drug is that it has activity against the T315I mutation, which confers resistance to TKIs (Nicolini and colleagues. Clin Lymphoma Myeloma Leuk 2010;10:394-399). However, because of its side effect profile, which includes potentially fatal bleeding complications, Synribo is reserved for people who have not had a good response to two or more TKIs. Another difference from the oral TKI medications is that Synribo is administered by injection: twice-daily for 14 days in the first month, then one week of injections per month thereafter.
Synribo was studied in a phase II trial (Study 202) of 62 people with CML and the T315I mutation (Cortes and colleagues. Blood 2012;120:2573-2580). Overall, blood counts were normalized in 77% of people taking the drug (a complete hematologic response, or CHR), and 16% achieved a complete cytogenetic response (CCyR). A separate study (Study 203) in 46 people with resistance or intolerance to Gleevec and another TKI reported that 22% achieved a major cytogenetic response (MCyR) and 4% achieved CCyR (Cortes and colleagues. Am J Hematol 2013;88:350-354). The major side effect was low blood cell counts, most notably low platelet counts, which responded well to a lower dose. Other side effects included diarrhea, nausea, fatigue, fever and headache.
Results after two years of treatment with Synribo are now available (Cortes and colleagues. Cancer 2015; epublished January 13, 2015). Data were obtained from Study 202 and another unpublished phase II trial (Nanda and colleagues. Haematologica 2011;96:422-423). The study included people with chronic-phase (CP) or accelerated-phase (AP) CML who had not responded to Gleevec and at least one other TKI. Overall, 18% of people with CP-CML achieved MCyR. People with AP-CML did not achieve this benchmark. The median overall survival in these very ill people was 40 months for the CP-CML group and 14 months for the AP-CML group. Overall survival rates were better among those who took the drug for at least three months (49 and 25 months for CP-CML and AP-CML, respectively).
These results show that Synribo can achieve some degree of response and improve survival in people with highly resistant CML who haven’t responded to a number of prior therapies.