Abstract
Simple SummaryTyrosine kinase inhibitor treatment has greatly improved the prognosis for many chronic myeloid leukaemia patients; however, disease progression is usually fatal for patients and remains a significant clinical challenge today. Using the UK SPIRIT 2 (STI571 Prospective International RandomIsed Trial 2) clinical trial, we have validated cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) as a diagnostic biomarker to identify patients at risk of disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be a useful diagnostic tool in planning treatment strategies.Background: It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). Overexpression of cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) protein is an adverse prognostic indicator in many cancers. Methods: We examined CIP2A protein levels in diagnostic samples from the SPIRIT2 trial in 172 unselected patients, of whom 90 received imatinib and 82 dasatinib as first-line treatment. Results: High CIP2A levels correlated with inferior progression-free survival (p = 0.04) and with worse freedom from progression (p = 0.03), and these effects were confined to dasatinib recipients. High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs. 7.5%; p = 0.0002), in both imatinib (45% vs. 11%; p = 0.02) and dasatinib recipients (36% vs. 4%; p = 0.007). Imatinib recipients with low CIP2A levels had a greater risk of treatment failure (p = 0.0008). CIP2A levels were independent of Sokal, Hasford, EUTOS (EUropean Treatment and Outcome Study), or EUTOS long-term survival scores (ELTS) or the presence of major route cytogenetic abnormalities. No association was seen between CIP2A levels and time to molecular response or the levels of the CIP2A-related proteins PP2A, SET, SET binding protein 1 (SETBP1), or AKT. Conclusions: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies.
Highlights
Tyrosine kinase inhibitors (TKIs) have transformed the clinical landscape for patients with chronic-phase chronic myeloid leukaemia (CML), with life expectancy essentially normal for about 90% of patients
A centralised molecular assessment of the BCR-ABL1/ABL1 ratio was carried out using International Standardisation (IS) at the Molecular Pathology Laboratory at the Imperial College Healthcare NHS Trust (ICHNT), London
The present data indicate that high CIP2A is associated with a higher chance of treatment failure for both imatinib and dasatinib recipients
Summary
Tyrosine kinase inhibitors (TKIs) have transformed the clinical landscape for patients with chronic-phase chronic myeloid leukaemia (CML), with life expectancy essentially normal for about 90% of patients. The EUTOS long-term survival score (ELTS) has been developed to look at the risk of disease progression to the advanced phase, but again even patients in the high-risk ELTS group had an 8-year incidence of death from CML of only 11% [11]. It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs 7.5%; p = 0.0002), in both imatinib (45% vs 11%; p = 0.02) and dasatinib recipients (36% vs 4%; p = 0.007). Conclusions: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies
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