Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia

Abstract

Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in approximately 50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.

Towards a Personalized Treatment of Patients with Chronic Myeloid Leukemia

“…Despite this impressive accomplishment, a number of challenges remain, such as more accurate CML prognostication, safer dosing options of TKIs, multi-resistance to therapy, expanded eligibility to and better outcome of TKI discontinuation. As somatic mutations outside the BCR-ABL gene may be present in CML, investigation of a patient's genetic and epigenetic landscape with the use of modern sequencing technologies in order to improve existing CML risk prediction models not only at the time of diagnosis but also in case of resistance or progression and help choosing or developing treatments that are most likely to be successful is worth exploring [57]. Advances in the past 20 years with TKIs being the cornerstone of treatment have helped transform CML from a fatal malignancy to a chronic condition, and safety should be placed at the forefront of management together with efficacy.…”

Clinical Pharmacists in Chronic Care

“…The incidence of ALL is about 3.3 cases per 100,000 children [420]. Outcomes for patients with CML have substantially improved due to advances in drug development and rational treatment intervention strategies [421]. Allowed costs for leukemia patients averaged almost $157,000 in the year after diagnosis, with costs for AML almost tripling that amount, according to a new report from the Leukemia & Lymphoma Society (LLS) [422].…”

Alternative Treatments for Cancer Prevention and Cure [Part 1]

“…The incidence of ALL is about 3.3 cases per 100,000 children [200]. Outcomes for patients with CML have substantially improved due to advances in drug development and rational treatment intervention strategies [201]. Allowed costs for leukemia patients averaged almost $157,000 in the year after diagnosis, with costs for AML almost tripling that amount, according to a new report from the Leukemia & Lymphoma Society (LLS) [202] (Table 2), (Figure 4).…”