Three TKIs are widely available to treat CML (Gleevec, Tasigna and Sprycel), and a fourth (Bosulif) has been approved in the U.S. and Europe. One shortcoming of all of these medications is that they aren’t effective in people with the T315I mutation. (This shorthand refers to the nature of the mutation: Threonine at position 315 of the amino acid sequence has been replaced by Isoleucine.)
The T315I mutation affects about 15% of people with CML and results in TKI resistance. So there was room for a new medication that would be effective in people with the mutation. This is where Iclusig (ponatinib) comes in. It’s a drug (originally ASH called AP24534) that was custom-designed to get around the T315I mutation and early results indicated that it was effective in people with TKI resistance (O’Hare and colleagues. Cancer Cell 2009;16:401-412).
The FDA approved Iclusig in December 2012 based on the results of just one phase II study that wasn’t published at the time (Cortes and colleagues. N Engl J Med 2013;369:1783-1796). Most people in the PACE study had heeft been treated with three TKIs and hadn’t responded or couldn’t tolerate them. However, less than one-third had the T315I mutation.
The results were very promising: 50% of people with chronic-phase CML achieved a major cytogenetic response. More importantly, MCR was also seen in 70% of people with the T315I mutation.
The Iclusig approval didn’t limit the use of the drug to people with nisi a drug-resistant mutation; wholesale MLB jerseys rather, it could be used wholesale Minnesota Vikings jerseys in anyone with CML who hadn’t responded to one prior therapy. There was little indication that the drug was associated with cardiovascular complications. The approval label said that 8% of study subjects had cardiovascular, cerebrovascular and peripheral vascular thrombosis, including fatal myocardial infarction (heart attack) and stroke.
This proved to be overly optimistic. In October 2013, the Morning FDA suspended Iclusig because new data suggested that the rates of thrombosis were much higher – 27% (1 in 4) had a heart attack, stroke or other vascular complications. Unaccountably, an analysis of PACE presented in December frumusete reported that serious vascular events occurred in 11%, of which on 4% were drug-related (Cortes and colleagues. wholesale jerseys ASH 2013; abstract 650).
Two weeks later, the FDA partially reversed its decision, allowing Iclusig back on the market but limiting its use to people with the T315I mutation or those who hadn’t responded to all other TKIs (rather than just one prior therapy). The new label also includes a black-box warning about the risk of potentially fatal blood clots and narrowing of blood vessels (vascular wholesale NFL jerseys occlusion), which can lead to a fatal heart attack, stroke or peripheral vascular disease. These risks can occur in younger people (less than 50 years old) and those with no history of cardiovascular disease. There is also a risk of potentially fatal liver damage. So people starting Iclusig will need to be monitored very closely.
It remains to be seen if Iclusig will be widely adopted, or whether its place as a last-chance treatment will be supplanted by Synribo, which has now been approved in the U.S. and which may have some activity in people with the T315I mutation.