Ponatinib ‘superior’ to sequential second-generation TKI treatment in CML

By Shreeya Nanda, Senior medwireNews Reporter

Patients with chronic myelogenous leukaemia (CML) resistant or intolerant to at least one second-generation tyrosine kinase inhibitor (TKI) have a higher probability of achieving a response to the third-generation TKI ponatinib than to a further second-generation TKI, research indicates.

“Our review of studies of the efficacy of third-line TKI treatment indicates that sequential use of [second-generation] TKIs is of limited value for most patients with CML who have experienced failure of prior [second-generation] TKIs”, say Manpreet Sidhu (ICON Health Economics, Morristown, New Jersey, USA) and colleagues.

The analysis included 134 patients who were treated with ponatinib and 452 who received a second-generation TKI, either bosutinib, dasatinib or nilotinib, as third-line treatment from 12 treatment arms of 11 studies.

When studies using the same regimen or choice of regimens were pooled, receipt of ponatinib was associated with a 60% probability of achieving a complete cytogenetic response compared with a 22% to 26% probability with a further second-generation TKI.

The likelihood that ponatinib treatment would result in higher complete and major cytogenetic response rates than all other included agents was 99% and 97%, respectively.

When participants were stratified by their T315I mutation status, there was a 52% probability that ponatinib would induce a response in patients lacking the mutation (n=99). Moreover, the likelihood of ponatinib providing a higher complete and major cytogenetic response rate in this patient population than that provided by all included second-generation TKIs in a mixed population was 98% and 90%, respectively.

These findings suggest that “ponatinib’s superior probability of response is not driven solely by its status as the only agent effective against T315I”, write the authors in Leukemia Research.

Sidhu et al are careful to point out the limitations of their analysis, specifically that the included studies were considerably heterogeneous in terms of not only their design, but also the definition and reporting of endpoints.

The researchers did not evaluate safety data, but "[i]n the light of emerging concerns over the safety of ponatinib and other TKIs in the long-term treatment of CML, more careful assessment of the risk–benefit for individual patients will be required when making treatment decisions", they observe.

"However, efficacy is likely to remain the paramount consideration in patients with treatment-resistant disease, especially for those who do not have the option of allogeneic stem cell transplant."

They conclude: "The overall risk–benefit assessment for treatments available for [resistant or intolerant] patients must heavily weight the ability of the treatment to control the patient’s underlying leukemia by rapidly achieving clinically meaningful responses that are as deep and durable as possible and ultimately prolong survival."

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