Year: 2019
Type: article
Abstract: The rationale for treating PV patients with an MDM2 inhibitor was strong.Although the overall response rate was impressive, the median duration of response was disappointing at only 16.8 months.Why was the therapy not more durable, and how can it be improved upon?It may be that the patients did not have sufficient elevation of MDM2 to have an optimal response to treatment.Additionally, although idasanutlin may cause cell-cycle arrest, there may be quiescent cells that linger and proliferate leading to new mutations after the drug has been stopped.Additional P53 regulators may block the response to MDM2 antagonists, such as MDM4 or NPM-1 or resistance may be caused by additional mutations acquired during idasanutlin treatment that cause resistance to the drug.In this study, patients who were unresponsive to single-agent therapy could receive combination therapy with interferon-a2a.In the 4 patients treated with combination therapy, there was a 50% response rate.Idasanutlin may therefore need to be used in combination with other drugs to prevent resistance and increase effectiveness, and prolong duration of response.9 Although interferon-a2a is a logical partner for idasanutlin, there are other possible combinations.Nonetheless, the problem with combination therapies in PV is the additive toxicities of using 2 drugs.The difficulty of treating this particular population and the low tolerance for even grade 1 to 2 toxicities will make combination therapy a challenge.Conflict-of-interest disclosure: E.K.R.
Source: Blood
Author: Ulf Klein
Institution: University of Leeds
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2968547744