Prognostic markers associated with tyrosine kinase inhibitor treatment response and maintenance of treatment free remission in chronic myeloid leukaemia

Abstract

Treatment outcomes in Chronic Phase Chronic Myeloid Leukaemia (CP-CML) have dramatically improved with the introduction of highly active tyrosine kinase inhibitors (TKIs). However, treatment responses are highly heterogeneous. The aim of this thesis is to identify prognostic markers that may help individualise treatment and optimise outcome by stratifying patients into risk groups. Selective treatment intensification is important - more potent treatment may be associated with increased toxicity, and universal adoption of the most potent treatment does not optimally balance risk versus benefit, nor is such a strategy cost effective. This thesis will summarise factors with prognostic significance in CP-CML. Such predictive factors include the metric called the “halving time”, which measures the velocity of BCR-ABL1 decline with initial TKI treatment. This correlates well with future treatment response and risk of disease progression. Conversely, the treatment resistance can be measured by the speed at which the BCR-ABL1 rises, in a similar metric called the “doubling time”. A patient’s Killer Immunoglobulin-like Receptor (KIR) genotype is also correlated with survival as well as molecular outcomes. Whilst the biological basis for this interaction is poorly understand, it is believed to be underpinned by the innate immune system’s role in tumour surveillance and suppression. In the setting of disease resistance mediated by BCR-ABL1 kinase domain mutations, demonstrating an increased number of low level mutants via the use of ultra sensitive mutation detection techniques may help prognosticate patients with a history of the T315I mutation. Early molecular response (EMR, BCR-ABL1 ≤10% at 3 months after starting treatment) is currently acknowledged as one of the strongest prognostic markers, and salvage strategies targeting patients failing to achieve time dependent molecular targets may be an optimal point of intervention. The TIDEL-II study examined such a strategy, firstly by imatinib dose escalation, followed by switching to nilotinib, in patients who fail to achieve time dependent molecular responses. This study also examined the effectiveness of increasing imatinib dose in patients with serum trough levels <1000 ng/mL, a threshold thought to be necessary to achieve cytogenetic response. Although survival and overall molecular response in TIDEL-II is excellent, this strategy was found to be of only marginal benefit in those who failed to achieve EMR. The subsequent study, Pinnacle, aims to study the combination of pegylated interferon and nilotinib in a similar context. Enrolment in this study is ongoing. The same prognostic marker (EMR) may identify patients unlikely to achieve deep molecular responses (DMR), a milestone associated with excellent long term event free survival. It is also commonly stipulated as a pre-requisite to participation in treatment cessation studies. Consistent performance of BCR-ABL1 qRT-PCR assays of a sufficient quality to determine this may be a challenge for some laboratories. To avoid false negatives which may lead to inappropriate reassurance and cessation attempts, we have developed an improved protocol that reliably achieves detection sensitivity required to classify patients in DMR. This assay may also be used as a basis for further enhancing BCR-ABL1 qRT-PCR sensitivity, aimed at identifying patients with an ultra-low level of residual disease. Such patients are hypothesised to have negligible risk of molecular recurrence upon treatment cessation, versus patients who have residual disease just below the current limit of detection. Such ultra-sensitive BCR-ABL1 qRT-PCR may, in this manner, contribute to further elucidation of the prognostic markers of successful treatment cessation. The thesis will conclude with prospects in prognostic markers in CML research and clinical management.