High CIP2A may guide TKI choice for chronic phase CML

By Lynda Williams, Senior medwireNews Reporter

Treatment with a second-generation (2G) tyrosine kinase inhibitor (TKI) prevents progression to blast crisis (BC) in chronic myeloid leukaemia (CML) patients with high levels of cancerous inhibitor of PP2A (CIP2A), research suggests.

Patients with a high CIP2A level at diagnosis have previously been shown to have a 100% actuarial risk of progressing to BC despite treatment with the first-generation TKI imatinib, explain Richard Clark, from the University of Liverpool in the UK, and co-authors in Leukemia.

To investigate the impact of 2G TKI therapy on the risk of BC, the team followed up 74 patients with chronic phase CML for a median of 50 months.

Twenty-one of the patients were considered at high risk of disease progression based on a high baseline CIP2A status, defined as a mean fluorescence index of 7.3 or above.

None of the nine high-risk patients given the 2G TKIs dasatinib or nilotinib experienced BC – and at 2 years this group had 100% progression-free and overall survival.

By contrast, progression-free and overall survival rate at 2 years in the high-risk patients treated with imatinib were 17% and 41%, respectively, with a median time to progression of 12.5 months.

The complete cytogenetic response (CCR) rate was 86% and 56% at 18 months for low and high CIP2A patients treated with a 2G TKI, respectively, and 85% for low CIP2A patients treated with imatinib. But just one high-risk patient treated with imatinib achieved CCR and this patient later progressed.

Furthermore, an early molecular response indicative of clinical outcome, defined as a BCR–ABL1/ABL1 ratio of less than 10% at 3 months, was achieved by 55% and 9% of low- and high-risk patients, respectively, treated with imatinib versus 90% and 44% of those given a 2G TKI.

Laboratory analysis confirmed that dasatinib and nilotinib significantly suppressed CIP2A and levels of c-Myc – elevated at BC transformation – significantly beyond that achieved by imatinib, the researchers report.

In addition, 2G TKI treatment of cells suppressed both the transcription factor E2F1, found in patients with high CIP2A, and RNA levels of CIP2A, whereas imatinib did not.

Finally, overexpression of CIP2A was shown to increase the rate of proliferation of neural progenitor cells while inhibition of CIP2A reduced the growth rate. While both the 2G TKIs and imatinib inhibited proliferation of control cells, only dasatinib and nilotinib were able to reduce proliferation of cells overexpressing CIP2A.

“[O]ur study highlights the importance of CIP2A/c-Myc/E2F1 pathway in CML”, write Richard Clark, from the University of Liverpool in the UK, and co-authors.

They emphasise: “Overall, these data suggest that if a patient has a high CIP2A level at diagnosis then they should not be treated with imatinib due to the high risk of disease progression; these patients should be offered either dasatinib or nilotinib upfront.”

Highlighting the need for routine CIP2A testing at diagnosis, they recommend further research to determine the true incidence of high CIP2A in CML and its relationship with other factors associated with TKI response and CML prognosis.

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